daily and cumulative dose radiation · research reviews, challenging clinical cases, ... •...

CONTEMPORARY

RadiationOncology

Daily and Cumulative Dose Recalculation and in Vivo Verifi- cation for Helical TomoTherapy: Multicenter Verification

Gustavo Olivera, PhD, Xiaohu Mo, MS, Don Parnell, CMD, Stephanie Key, CMD, Constantine Mantz, MD, Eduardo Fernandez, MD, PhD, Daniel Dosoretz, MD, Arie Dosoretz, MD, Larry Krestin, MD, Alvaro Martinez, MD, Steven Finkelstein, MD, and Daniel Galmarini, MS

A Phase III Randomized Trial of MRI-Mapped,Dose-Escalated Salvage Radiotherapy Post-Prostatectomy: The MAPS TrialAmber Orman, MD, Alan Pollack, MD, PhD, Kelin Wang, PhD, Radka Stoyanova, PhD, Elizabeth Bossart, PhD, Deukwoo Kwon, PhD, Matthew Abramowitz, MD

Adjuvant Radiotherapy in Low-Risk Breast Cancer Patients: Review and Clinical Implications Chirag Shah, MD, Vivek Verma, MD, Michelle Frances Barrord, BS, Frank Vicini, MD

Liposomal Encapsulation of Radiotherapeutics Holds Promise in Treating GlioblastomaAndrew Brenner, MD, PhD

Radiotherapy’s Immunologic Properties Offer Paradigm- Changing PotentialSteven Eric Finkelstein, MD

Volume 1Number 1

6.15

CONTEMPORARY

RadiationOncology

Bringing the Oncology Community Together

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Come hear the latest information on emerging therapies and evolving clinical practices in the management of breast cancer to maintain state-of-the-art care in your practice.The 14th Annual International Congress on the Future of Breast Cancer® is a 3-day international meeting that serves as an update on advances in the treatment of patients with breast cancer. International experts will discuss the practical implications of emerging data and evolving management regimens that are changing the future of breast cancer therapy and the clinical questions and challenges facing community oncologists in their daily practice.

Join us to stay up-to-date on state-of-the-art therapies for the management of breast cancer, including:•Prospectsforimmunotherapyforbreastcancer•PALB2/RAD51C:Identifyingandmanagingnewhereditaryrisk•PromisingemergingtherapiesforER+metastaticbreastcancer•Novelhypothesesintargetingmetastaticbreastcancer•Emergingstrategiesformetastatictriple-negativebreastcancer•Practicalcase-baseddiscussions•Andmuchmore

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C O N T E N T S

CONTEMPORARY

Radiation OncologyEDITOR-IN-CHIEF

Steven E. Finkelstein, MD21st Century Oncology

Scottsdale, AZ

CALL FOR PAPERSWe invite submissions to Contemporary Radiation Oncology, a peer-reviewed clinical journal designed to help community oncologists translate the latest advances in oncology into everyday clinical practice. The editors are primarily interested in brief research reviews, challenging clinical cases, and informed commentaries that examine specific treatment algorithms and diagnostic techniques. Articles must describe how novel treatments and diagnostics fit into clinical practice, and address their day-to-day impact on clinical decision making in the community setting.

All submissions will undergo peer review. To learn how you can submit an article to Contemporary Oncology for consideration, e-mail Anthony Berberabe at [email protected].

ARTICLES

TOMOTHERAPY6 Daily and Cumulative Dose Recalculation and

in Vivo Verification for Helical TomoTherapy: Multicenter Validation


�� In�vivo�dosimetry�and�verification�(IVV)�in�conjunction�with�adaptive�dose�recalculation�(ADR)�is�a�synergistic�set�of�processes�that�provides�insight�into�actual�treatment.�Our�in-tent�was�to�test�an�automatic,�multi-center�procedure�for�IVV�and�ADR�for�all�patients�and�all fractions treated on 14 helical TomoTherapy units across the United States. Additionally, our�secondary�goal�was�to�create�a�system�with�metrics�to�flag�for�possible�issues,�establish�trending, and determine possible clinical impact; establishment of this system could both provide�internal�recommendations�for�daily�IGRT�and�clinical�improvements�using�IV�and�ADR�findings.�Moreover,�our�final�goal�was�to�evaluate�deviations�of�the�cumulative�dose�at�the end of the treatment using QUANTEC recommendations for organs at risk..

MAPS

13 A Phase III Randomized Trial of MRI-Mapped, Dose- Escalated Salvage Radiotherapy Post-Prostatectomy: The MAPS Trial

Amber Orman, MD; Alan Pollack, MD, PhD; Kelin Wang, PhD; Radka Stoyanova, PhD; Elizabeth Bossart, PhD; Deukwoo Kwon, PhD; Matthew Abramowitz, MD

�MAPS�is� the�first� �phase�III�randomized�trial�of�MRI-mapped,�dose-escalated�salvage�radiotherapy. In this planned feasibility analysis, we ensure dosimetric adequacy of the protocol�as�it�relates�to�acute�toxicity.�In�all�plans,�≥95%�of�the�planning�target�volume�and�GTV�received�the�prescribed�dose.�Dosimetric�constraints�were�achieved�for�all�organs�at�risk�except�B-CTV.�The�highest�toxicity�recorded�was�grade�2�gastrointestinal�toxicity:�1�episode�per�arm.�Dose�escalation�is�achievable�with�expected�variations�in�cases�with�small bladders. There was no observed increase in acute toxicity.

BREAST CANCER20 Adjuvant Radiotherapy in Low-Risk Breast Cancer

Patients: Review and Clinical Implications Chirag Shah, MD, Vivek Verma, MD, Michelle Frances Barrord, BS, Frank Vicini, MD

�� Breast�conserving�therapy�(BCT)�offers�women�the�ability�to�preserve�their�breast�without�sacrificing�local�control�or�survival.�A�key�component�of�BCT�from�its�inception�to�today�has�been�the�delivery�of�adjuvant�radiotherapy�following�breast-conserving�surgery�(BCS).�However, there remains a growing interest in determining if there exists a subset of wom-en with low-risk features for whom adjuvant radiotherapy may be omitted following BCS. To date, the data are consistent in demonstrating that adjuvant radiotherapy reduces the rate of local recurrences in all risk groups of patients. In lower-risk groups, modern trials have�failed�to�demonstrate�a�survival�advantage�from�the�local�control�benefit�derived�from�radiotherapy. Currently, studies are being performed to identify low-risk patients based on tumor genetics, nomograms, and other techniques. In the interim, clinicians now have alternative techniques including hypofractionated whole breast irradiation as well as ac-celerated�partial�breast�irradiation�which�allows�for�a�reduction�in�treatment�duration�(and�possibly�treatment�volume)�while�still�maintaining�local�control.

CONTEMPORARY�RADIATION�ONCOLOGY • VOL.�1,�NO.�1�•�06.15 1

Cover image: Radiotherapy, conceptual image. Computer artwork representing the use of ionizing radiation to kill cancerous cells (center). © Richard Kail / Science Source






This activity is supported by educational grants from AstraZeneca, Celgene Corporation, Genomic Health, Inc., Lilly, Nektar Therapeutics, and Novartis Pharmaceuticals Corporation.

For further information concerning Lilly grant funding visit www.lillygrantoffice.com


REGISTRATION FEESMAY 18-JULY 15,



Fellows* $349 $449 $199


Industry** $699 $799 $499


JULY 16 - 18, 2015Hyatt Regency Huntington Beach Huntington Beach, CA

Course Director

Joyce A. O’Shaughnessy, MDCo-Director, Breast Cancer Research Baylor Charles A. Sammons Cancer Center Texas Oncology The US Oncology Network Dallas, TX

Come hear the latest information on emerging therapies and evolving clinical practices in the management of breast cancer to maintain state-of-the-art care in your practice.The 14th Annual International Congress on the Future of Breast Cancer® is a 3-day international meeting that serves as an update on advances in the treatment of patients with breast cancer. International experts will discuss the practical implications of emerging data and evolving management regimens that are changing the future of breast cancer therapy and the clinical questions and challenges facing community oncologists in their daily practice.

Join us to stay up-to-date on state-of-the-art therapies for the management of breast cancer, including:•Prospectsforimmunotherapyforbreastcancer•PALB2/RAD51C:Identifyingandmanagingnewhereditaryrisk•PromisingemergingtherapiesforER+metastaticbreastcancer•Novelhypothesesintargetingmetastaticbreastcancer•Emergingstrategiesformetastatictriple-negativebreastcancer•Practicalcase-baseddiscussions•Andmuchmore

Register now and save $75 off the price of registration. Use code BC15ONC*Discount available for physicians only


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NEW THIS YEAR! Updated Case-Based Format Featuring “Real World” Scenarios

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2 CONTEMPORARY�RADIATION�ONCOLOGY • VOL.�1,�NO.�1�•�06.15

The content contained in this publication is for general information purposes only. The reader is encouraged to confirm the information presented with other sources. Contemporary Radiation Oncology makes no representations or warranties of any kind about the completeness, accuracy, timeliness, reliability, or suitability of any of the information, including content or advertisements, contained in this publication, and expressly disclaims liability for any errors or omissions that may be presented in this publication. Contemporary Radiation Oncology reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. Contemporary Radiation Oncology further disclaims any and all liability for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any material or information presented in this publication. The views expressed in this publica-tion are those of the authors and do not necessarily reflect the opinion or policy of Contemporary Radiation Oncology.

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C H A I R M A N ’ S N O T E

Declaring�Our�Objectives� in This Inaugural Issue

As we embark on this inaugural issue of Contemporary Radiation Oncology, it occurs to me that the launch of every new journal is always made with the best in-tentions. But a journal cannot be all things to all of its readers. It can only be success-ful if it stays focused on its objectives.

So what better time to declare those ob-jectives�than�in�the�first�issue?

Contemporary Radiation Oncology�will:•� Share the latest advances in the science

of�personalized�radiation�oncology.�•� Evaluate the treatment of acute and

long-term complications of radiation therapy for head and neck, gastroin-testinal, genitourinary, cervical, and breast malignancies.

•� Explain state of the art treatment management for head and neck, gas-trointestinal, genitourinary, cervical, and breast malignancies.

•� Include clinical/practice updates about clinical controversies.

•� Describe�new�advances�in�technology�that�may�influence�future�treatment.

To be sure, attaining the objectives listed�above�will�be�difficult�in�each�issue,�but with dedication, these goals can be reached. I, for one, am excited about how the journal evolves to meet the needs of our readership.To�kick�off�this�inaugural�issue,�we�pres-

ent 3 original manuscripts.In� “A� Phase� III� Randomized� Trial� of�

MRI-Mapped,�Dose�Escalated�Salvage�Ra-diotherapy�Post-Prostatectomy:�The�MAPs�Trial,” Orman et al report on the feasibility and acute toxicity of 14 patients enrolled in a�trial�randomizing�subjects�to�either�stan-dard�68�Gy�radiotherapy�or�the�same�plus�a�simultaneous�integrated�boost�of�76.5�Gy�at�2.25�Gy/fx.�If�the�authors�show�improved�biochemical� relapse-free� survival� (bRFS),�then dose-escalation could become a new standard of care.

In the second article, Shah et al note that in women with low-risk breast can-cer, there is a subset for whom adjuvant radiotherapy� (RT)� may� not� be� appropri-ate. Current trials have failed to demon-strate a survival advantage from the local control� benefit� derived� from� RT.� Trials�are ongoing to identify these low-risk pa-tients, but in the interim clinicians have alternative techniques including hypofractionated whole breast irradiation as well as accelerated partial breast irradia-tion, which allows for a reduction in treat-ment�duration�(and�possibly�treatment�vol-ume)�while�still�maintaining�local�control.

In the third manuscript, Olivera et al test an automatic, multicenter procedure for� in�vivo�dosimetry�and�verification� (IV)�and� adaptive� dose� recalculation� (ADR)�for all patients and all fractions treated on 14 helical TomoTherapy units across the United� States.� Their� manuscript,� “Daily�and�Cumulative�Dose�Recalculation�and�in�Vivo�Verification�for�Helical�TomoTherapy:�Multicenter� Validation,”� describes� a� met-ric-driven�system�that�flags�potential�issues,�establishes trends, and determines possible clinical impact. This system could provide both internal recommendations for daily image-guided radiation therapy and clinical improvements�using�IV�and�ADR�findings.�Moreover,� the� authors’� final� goal� was� to�evaluate deviations of the cumulative dose at the end of the treatment using Quantita-tive�Analysis�of�Normal�Tissue�Effects�in�the�Clinic� (QUANTEC)� recommendations� for�organs at risk.

If you would like Contemporary Radia-tion Oncology to consider your manuscript for publication, send a copy of the manu-script with cover letter via e-mail to the man-aging�editor,�Tony�Berberabe�([email protected]).Here’s�to�a�well-informed�future.

–Mike HennessyChairman

E D I T O R I A L B O A R D

Steven E. Finkelstein, MDEditor-in-Chief21st Century OncologyScottsdale, AZ

Felix Feng, MDAssociate EditorUniversity�of�Michigan� Ann�Arbor,�MI

Matthew C. Abramowitz, MDSylvester Comprehensive Cancer CenterMiami,�FL

Matthew Biagioli, MDMoffitt�Cancer�CenterTampa,�FL

Christopher Crane, MDThe�University�of�Texas�MD�Anderson�Cancer CenterHouston, TX

Roy Decker, MD, PhDSmilow�Cancer�Hospital�at�YaleNew Haven, CT

Jason A. Efstathiou, MD, DPhilMassachusetts�General�HospitalHarvard�Medical�SchoolBoston,�MA

Megan Daly, MDUniversity�of�California,�Davis� Comprehensive Cancer CenterSacramento, CA

Mary Feng, MDUniversity�of�Michigan�Health�SystemAnn�Arbor,�MI

Eduardo Fernandez, MD21st Century OncologyFt.�Lauderdale,�FL

Gregg Franklin, MDNew�Mexico�Cancer�CenterAlbuquerque,�NM

Laura M. Freedman, MDSylvester Comprehensive Cancer CenterMiami,�FL

Daniel Hamstra, MD, PhDThe�University�of�Michigan�Hospital�� and Health SystemsAnn�Arbor,�MI

Joseph Herman, MD, MScJohns Hopkins Sidney Kimmel Comprehensive Cancer CenterBaltimore,�MD

Sarah E. Hoffe, MDMoffitt�Cancer�CenterTampa,�FL

Salma Jabbour, MDRutgers Cancer Institute of New JerseyNew Brunswick, NJ

Reshma Jagsi, MD, DPhilUniversity�of�Michigan� Ann�Arbor,�MI

Sameer Keole, MDMayo�ClinicScottsdale, AZ

Mitchell Kamrava, MDUCLA�Health�SystemLos�Angeles,�CA

Constantine Mantz, MD21st Century OncologyFt.�Myers,�FL

Timur Mitin, MD, PhDOregon Health & Science UniversityPortland,�OR

Drew Moghanaki, MDVirginia�Commonwealth�UniversityRichmond,�VA

Chirag Shah, MDNortheast�Ohio�Medical�UniversityAkron, OH

Kevin Stephans, MDCleveland ClinicCleveland, OH

Stephanie Terezakis, MDJohns Hopkins University Radiation OncologyBaltimore,�MD

Jonathan Tward, MDUniversity of Utah Health CareSalt�Lake�City,�UT

Terence Williams, MD, PhDThe Ohio State UniversityColumbus, OH

Frederic Zenhausern, PhD, MBAUniversity�of�ArizonaPhoenix,�AZ

DEPARTMENTS FROM THE EDITOR

4 Cutting Through the Clutter for a Contemporary, Straightforward Experience

STRATEGIC ALLIANCE PARTNERSHIP

26 Liposomal Encapsulation of Radiotherapeutics Holds Promise in Treating Glioblastoma

28 Radiotherapy’s Immunologic Properties Offer Paradigm-Changing Potential

C O N T E N T S (CONTINUED) The largest cancer-focused consumer magazine is now part of the fastest growing oncology network.


OBTN_Ads.indd 2 6/3/15 9:57 AM

4 CONTEMPORARY�RADIATION�ONCOLOGY • VOL.�1,�NO.�1�•�06.15

F R O M T H E E D I T O R

It is my pleasure to present to you the inaugural is-sue of Contemporary Radiation Oncology. Radiation therapy is an ever-changing field and keeping current is of paramount importance to clinicians caring for pa-tients with cancer. One of the major challenges faced by radiation oncologists is the arduous process of mul-titasking and time management that comes with deliv-ering patient care and conducting clinical research tri-als. The sheer volume of clinical studies, case reports, and review articles available in print journals and on-line creates a daunting mountain to face. Indeed, it is my hope that this journal can cut through that clutter and provide readers a contemporary, straightforward experience, with useful strategies and thought-pro-voking data that can be used by the radiation oncolo-gist in practice today.Publishing�a�journal�is�no�small�undertaking�and�its�

success, much like the delivery of radiation therapy, re-quires the concerted efforts of many talented and ded-icated individuals. To get this journal off the ground, I have enlisted the talents of many radiation oncologists whose collective experience covers the various care delivery� settings:� academic� research� facilities,� cancer�treatment centers, and hospital and private practices. Drawing�on�this�diverse�experience,�Contemporary Ra-diation Oncology will publish original research, clinical investigations, review articles, editorial comments, and other scientific articles relating to radiation oncology. As editor-in-chief, I would like it to serve as a forum for collaboration and knowledge exchange in the manage-ment of cancer using radiation therapy.Joining�me�in�this�endeavor� is�Associate�Editor,�Fe-

lix�Feng,�MD,�of� the�University�of�Michigan.�Dr.�Feng�brings a wealth of knowledge to the journal from his experience with clinical trials in the single-institution

and cooperative group settings, basic and translational laboratory science, and physics research using cutting edge technologies.

Thus, the scope of this journal encompasses radia-tion treatment delivered via external beam radiation, proton therapy, gamma knife, intensity modulated and image guided radiation therapy, brachytherapy, and in-traoperative approaches.

We welcome and encourage the submission of origi-nal research or review manuscripts of high quality that provide new knowledge about patient care. Technologi-cal advances and developments are especially welcome. Manuscripts� on� topics� that� cover� radiation� oncology,�including palliative treatment, quality-of-life issues, chemotherapy, and surgery will also be considered.

Contemporary Radiation Oncology is written for radiation oncologists, medical oncologists, surgical on-cologists, oncology nurses, palliative care specialists, allied health professionals, and radiologists.

I am looking forward to bringing you topics that cov-er contemporary advances in the field of radiation on-cology so that we can provide the best patient care.

Sincerely,

Steven�Eric�Finkelstein,�MDChief�Science�Officer21st Century Oncology

Cutting Through the Clutter for a Contemporary, Straightforward Experience

Contemporary Radiation Oncology, a peer-reviewed journal designed to help community oncologists translate the latest advances in oncology into everyday clinical practice, is issuing an open Call for Papers. The journal’s core objective is to provide a clear, concise interpretation of the latest advances in oncology treatment and diagnostics and to facilitate real-world application of these techniques and findings in the community setting.

The editors are primarily interested in brief research reviews, challenging clinical cases, and informed commentary that examines emerging treatments and diagnostic techniques. Articles must describe how novel treatments and diagnostics fit into clinical practice, and address the day-to-day impact of the latest research findings on clinical decision making in the community setting.

A copy of the journal’s complete Instructions for Authors is available at www.onclive.com/publications/contemporary-oncology. Areas of particular interest and potential article topics include:

• Review of the pathway [eg, antibody drug conjugates: TDM-1]

• Immunotherapy for the practicing oncologist • Brief reviews [eg, targeted therapies in kidney

cancer: how to sequence drugs and manage side effects in clinical practice]

• Clinical diagnostics: how they fit into clinical practice

• Case series: How I treat—critical issues in the ambulatory clinic

• Survivorship and palliative care

All submissions will undergo peer review. Final decisions regarding ultimate acceptance and publication rest solely with the editors. Please direct editorial inquiries and manuscript submissions to Anthony Berberabe at [email protected] / (609) 716-7777.

Call for Papers

CONTEMPORARY

RadiationOncology

Daily and Cumulative Dose Recalculation and in Vivo Verifi- cation for Helical TomoTherapy: Multicenter Verification


A Phase III Randomized Trial of MRI-Mapped,Dose-Escalated Salvage Radiotherapy Post-Prostatectomy: The MAPS TrialAmber Orman, MD, Alan Pollack, MD, PhD, Kelin Wang, PhD, Radka Stoyanova, PhD, Elizabeth Bossart, PhD, Deukwoo Kwon, PhD, Matthew Abramowitz, MD

Adjuvant Radiotherapy in Low-Risk Breast Cancer Patients: Review and Clinical Implications Chirag Shah, MD, Vivek Verma, MD, Michelle Frances Barrord, BS, Frank Vicini, MD

Liposomal Encapsulation of Radiotherapeutics Holds Promise in Treating GlioblastomaAndrew Brenner, MD, PhD

Radiotherapy’s Immunologic Properties Offer Paradigm- Changing PotentialSteven Eric Finkelstein, MD

Volume 1, Number 1, 6.15

ISSN 1939-6163 (print)

ISSN 2334-0274 (online)

CONTEMPORARY

RadiationOncology


T O M O T H E R A P Y

Daily and Cumulative Dose Recalculation

and in Vivo Verification for Helical

TomoTherapy: Multicenter Validation

Gustavo Olivera PhD, Xiaohu Mo MS, Don Parnell CMD, Stephanie Key CMD,

Constantine Mantz MD, Eduardo Fernandez MD, PhD, Daniel Dosoretz MD, Arie

Dosoretz MD, Larry Kestin MD, Alvaro Martinez MD, Steven Eric Finkelstein MD, and

Daniel Galmarini MS

Background and Purpose:

In vivo dosimetry and verification (IVV) in conjunction with adaptive dose recalculation (ADR) is a

synergistic set of processes that provides insight into actual treatment. Our intent was to test an au-

tomatic, multicenter procedure for IVV and ADR for all patients and all fractions treated on 14 helical

TomoTherapy units across the United States. Additionally, our secondary goal was to create a system

with metrics to flag for possible issues, establish trending, and determine possible clinical impact.

Establishment of this system could both provide internal recommendations for daily IGRT and clinical

improvements using IV and ADR findings. Moreover, our final goal was to evaluate deviations of the

cumulative dose at the end of the treatment using Quantitative Analyses of Normal Tissue Effects in

the Clinic (QUANTEC) recommendations for organs at risk.

Materials and Methods:

A system for IVV and ADR that retrieves and processes machine and patient information during treat-

ment was created. The IVV portion includes (1) checking consistency values using machine encoders

and (2) using the imaging detector data and comparing a reference fraction with respect to daily

treatment deliveries using the Gamma metric. The ADR component computes daily and cumulative

doses; DVH data are compared plan data and the flagging system. Thus, a reviewer can (1) identify

machine, setup, and/or anatomical issues and (2) infer possible clinical impact.

Results and Conclusions:

Across multi-center clinics (n=14), 153,330 IVV and 66,294 ADR fractions were analyzed. The extent

of in vivo flags was independent of an individual clinic’s volume. The number of in vivo flags consid-

erably decreases as a function of the length of time that the system is used. This was accomplished

by tailoring IGRT procedures to specific anatomical sites and specific patients. With respect to dis-

ease site, 5% of all prostate treatments and more than 20% of head and neck treatments triggered

some IVV action level. ADR results demonstrated that cumulative doses at the end of treatment for

head and neck patients exceed QUANTEC limits for 9% of parotids glands and 2% larynxes. Following

treatment for breast cancer, approximately 10.5% of patients exceeded QUANTEC limits for lung and

3% for heart at the end of treatment. Thus, these data suggest ADR and IV are a synergistic set of

processes that allows flagging and quantifying potential clinical impact to analyze dosimetrical infor-

mation on patient registries.

Matthew Abramowitz, MD

Assistant Professor

Co-Chairperson Genitourinary Site Disease

Group, Director of Compliance

Department of Radiation Oncology

Sylvester Comprehensive Cancer Center

University of Miami

Why is this article contemporary?

Rapid advances in the technological de-

velopment of precise and conformal ra-

diation therapy and its incorporation

into the clinic have generally outpaced

our ability to test these technologies in a

clinical trial format. With improvements

in conformity utilizing intensity modu-

lation and set-up accuracy utilizing ste-

reotactic techniques and tumor motion

management, margins continue to shrink.

We hope this will translate into improved

patient outcomes by allowing higher tu-

mor doses and decreased morbidity by

improved avoidance of critical structures.

However, these advances create new

questions. Respiratory motion manage-

ment based upon modeling and fiducial

tracking assume minimal changes in the

patient’s respiratory cycle, both during a

single fraction and during a course of thera-

py. In addition, how changes in body shape

that are attributed to weight loss, bowel gas,

or slight differences in patient body posi-

tion that may occur inter-or intra-fraction

affect the delivered dose when using these

new modalities remains unclear.

This study is contemporary in how it

utilizes existing resources in a massive

data set to evaluate the implications of

these changes measured in delivered dose

to patients. With the growing integration

of adaptive dose recalculation, identifica-

tion and correction of these issues may

now be possible.

About the lead author:

Gustavo Olivera, PhD

21st Century Oncology ATD

Madison, WI 53719

The Reviewer’s Viewpoint

B R E A S T C A N C E R

Adjuvant Radiotherapy in Low-Risk Breast Cancer Patients: Review and Clinical ImplicationsChirag Shah, MD, Vivek Verma, MD, Michelle Frances Barrord, BS, Frank Vicini, MD

ABSTRACTBreast conserving therapy (BCT) offers women the ability to preserve their breast without

sacrificing local control or survival. Since its inception, a key component of BCT has been

the delivery of adjuvant radiotherapy following breast-conserving surgery (BCS). However,

a growing interest remains in determining if there exists a subset of women with low-risk

features for whom adjuvant radiotherapy may be omitted following BCS. To date, the data

are consistent in demonstrating that adjuvant radiotherapy reduces the rate of local re-

currences in all risk groups. In lower-risk groups, modern trials have failed to demonstrate

a survival advantage from the local control benefit derived from radiotherapy. Currently,

studies are being performed to identify low-risk patients based on tumor genetics, nomo-

grams, and other techniques. In the interim, clinicians now have alternative techniques

including hypofractionated whole breast irradiation as well as accelerated partial breast

irradiation which allows for a reduction in treatment duration (and possibly treatment

volume) while still maintaining local control.David E. Wazer, MD, FACRO, FACR, FASTRODepartment of Radiation OncologyTufts University School of MedicineAlpert Medical School of Brown University

Why is this article contemporary?Contemporary risk-adapted local therapy for early breast cancer is a complex and evolving paradigm. Shah et al do an excellent job in summariz-ing the multitude of evidence-based approaches related to risk stratifica-tion, treatment options, and results. By also placing these in the context of real-world case examples, clinicians can gain valuable insight into the ap-propriate application of these multi-faceted clinical trial data to manage the individual patient. This review highlights the enormous progress that has been achieved in recent years toward providing women with local therapy options that are safe, effec-tive, convenient, and cost efficient.

About the lead author:Chirag Shah, MDDepartment of Radiation OncologySumma Health System

IntroductionOver the past several decades, breast-con-serving therapy (BCT) has emerged as the standard of care in the management of early-stage breast cancer. With greater than twenty-five years of follow-up, mul-tiple randomized trials have demonstrat-ed equivalence in outcomes between mas-tectomy and BCT, with BCT being shown to improve the quality of life of breast cancer survivors compared with mas-tectomy.1-4 A key component in the BCT arms of the randomized trials was stan-dard fractionation whole-breast irradia-tion (WBI) delivered over 5 to 6 weeks. In the decades since the initial randomized trials, adjuvant radiation therapy (RT) has continued to be a key component of the BCT technique to optimize local con-trol. While RT has been shown to enhance local control following breast-conserving surgery (BCS), concerns exist, including acute/chronic toxicities associated with treatment, the duration of treatment,

and the potential for overtreatment.5,6 A key question being considered is the role of RT in patients who will not manifest large local control benefits with adjuvant RT compared with BCS with or without endocrine therapy. Multiple attempts have been made to omit RT following BCS, with mixed results. In spite of the lack of clarity, clinicians are facing pres-sure to tailor RT recommendations based on patient (age, performance status), pathologic (tumor size, margin status, grade, hormone receptor status, lymph node status), and systemic treatment (tamoxifen/aromatase inhibitor utiliza-tion) characteristics and to identify low-risk patients for whom RT may not be required. Therefore, the purpose of this clinical review is to evaluate the role of RT in low-risk patients (based on patient and pathologic features) following BCS and to provide common scenarios and recommendations based on current data and guidelines.



Daily and Cumulative Dose Recalculation and in Vivo Verification for Helical

TomoTherapy: Multicenter ValidationGustavo Olivera PhD, Xiaohu Mo MS, Don Parnell CMD, Stephanie Key CMD,

Constantine Mantz MD, Eduardo Fernandez MD, PhD, Daniel Dosoretz MD, Arie Dosoretz MD, Larry Kestin MD, Alvaro Martinez MD, Steven Eric Finkelstein MD, and

Daniel Galmarini MS

Background and Purpose: In vivo dosimetry and verification (IVV) in conjunction with adaptive dose recalculation (ADR) is a synergistic set of processes that provides insight into actual treatment. Our intent was to test an au-tomatic, multicenter procedure for IVV and ADR for all patients and all fractions treated on 14 helical TomoTherapy units across the United States. Additionally, our secondary goal was to create a system with metrics to flag for possible issues, establish trending, and determine possible clinical impact. Establishment of this system could both provide internal recommendations for daily IGRT and clinical improvements using IV and ADR findings. Moreover, our final goal was to evaluate deviations of the cumulative dose at the end of the treatment using Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) recommendations for organs at risk.

Materials and Methods: A system for IVV and ADR that retrieves and processes machine and patient information during treat-ment was created. The IVV portion includes (1) checking consistency values using machine encoders and (2) using the imaging detector data and comparing a reference fraction with respect to daily treatment deliveries using the Gamma metric. The ADR component computes daily and cumulative doses; DVH data are compared plan data and the flagging system. Thus, a reviewer can (1) identify machine, setup, and/or anatomical issues and (2) infer possible clinical impact.

Results and Conclusions: Across multi-center clinics (n=14), 153,330 IVV and 66,294 ADR fractions were analyzed. The extent of in vivo flags was independent of an individual clinic’s volume. The number of in vivo flags consid-erably decreases as a function of the length of time that the system is used. This was accomplished by tailoring IGRT procedures to specific anatomical sites and specific patients. With respect to dis-ease site, 5% of all prostate treatments and more than 20% of head and neck treatments triggered some IVV action level. ADR results demonstrated that cumulative doses at the end of treatment for head and neck patients exceed QUANTEC limits for 9% of parotids glands and 2% larynxes. Following treatment for breast cancer, approximately 10.5% of patients exceeded QUANTEC limits for lung and 3% for heart at the end of treatment. Thus, these data suggest ADR and IV are a synergistic set of processes that allows flagging and quantifying potential clinical impact to analyze dosimetrical infor-mation on patient registries.

Matthew Abramowitz, MD

Assistant ProfessorCo-Chairperson Genitourinary Site Disease Group, Director of Compliance Department of Radiation Oncology Sylvester Comprehensive Cancer Center University of Miami

Why is this article contemporary?Rapid advances in the technological de-velopment of precise and conformal ra-diation therapy and its incorporation into the clinic have generally outpaced our ability to test these technologies in a clinical trial format. With improvements in conformity utilizing intensity modu-lation and set-up accuracy utilizing ste-reotactic techniques and tumor motion management, margins continue to shrink. We hope this will translate into improved patient outcomes by allowing higher tu-mor doses and decreased morbidity by improved avoidance of critical structures.

However, these advances create new questions. Respiratory motion manage-ment based upon modeling and fiducial tracking assume minimal changes in the patient’s respiratory cycle, both during a single fraction and during a course of thera-py. In addition, how changes in body shape that are attributed to weight loss, bowel gas, or slight differences in patient body posi-tion that may occur inter-or intra-fraction affect the delivered dose when using these new modalities remains unclear.

This study is contemporary in how it utilizes existing resources in a massive data set to evaluate the implications of these changes measured in delivered dose to patients. With the growing integration of adaptive dose recalculation, identifica-tion and correction of these issues may now be possible.


Gustavo Olivera, PhD21st Century Oncology ATDMadison, WI 53719


CONTEMPORARY RADIATION ONCOLOGY • VOL. 1, NO. 1 • 06.15 7

Daily and Cumulative Dose Recalculation and in vivo Verification (IVV) for Helical TomoTherapy: Multicenter Validation Based on Greater Than 150,000 Daily Fractions Delivered

Introduction

Radiotherapy has evolved from three-dimensional con-formal radiotherapy (3D), to intensity modulated radio-therapy (IMRT)1,2 and many forms of image-guided radio-therapy (IGRT).1 Comprehensive quality assurance (QA) procedures are evolving as the technology evolves.3-8

In IMRT, the typical QA procedures involve the use of phantom measurements or the delivery of a plan to a por-tal imager.9 IMRT QA is typically performed before clinical treatment.

Verification of what hap-pens during the time that of actual treatment deliv-ery may provide significant insight to evaluate the ac-tual course of treatment. Possible issues that may go undetected with QA before treatment can be found us-ing IVV.10,11

Indeed, it is currently possible for the user not only to access the imaging detector information, but also gather machine sen-sors and monitor cham-bers, daily CTs from the data base or logs to create a more comprehensive IVV program. The Tomo-Therapy archive contains information such as couch encoders, monitor cham-bers, daily megavolt com-puted tomography (MVCT) and other sensors that pro-vide key information during treatment. This information may be paramount to dis-cern the cause of inaccura-cies between machine, setup or anatomical changes.

Herein, an approach has been employed to com-bine the in-vivo dosimetry with other types of in-vivo verification (IVV). We at-tempted to optimize issues related to robustness and specificity of in vivo dosim-

etry by using information from adaptive dose recalculation (ADR). Hence, the ADR is able to compute daily doses, cumu-lative doses, and dose-volume histograms (DVHs) using the daily CT and machine information.

Thus, we generated a patient verification process that uses both IV and ADR as synergistic tools to analyze 153,330 IV fractions and 66,294 ADR fractions (corre-sponding to 3,687 ADR patients).

Figure 1. Number of Fractions per Clinical Site

A.

B.

(a) Number of fractions analyzed per clinic during the first 10 months of using IVV, (b) for each clinic, the blue line rep-resents the average number of treatment deliveries per day (right axis); this is also an indicator of patient load per clinic (right axis). Yellow and red correspond to the percentage of yellow and red flags for each clinic (left axis).


8 CONTEMPORARY RADIATION ONCOLOGY • VOL. 1, NO. 1 • 06.15

Materials and Methods

Workflow and System DescriptionThe verification system presented has two major compo-nents: the IVV portion and the ADR. The IVV was deployed in advance of the ADR system. Approximately 87,000 frac-tions over 14 clinics were generated and processed having only the IVV system. The remaining fractions (~66,000), which corresponds to approximately 3,600 patients, were processed using IV and ADR.

Information was gathered from patient archives for both processes. The TomoTherapy machine digitally re-cords information, such as couch position, daily CT, and machine output from its imaging detectors and stores the information in the patient archive. The process be-gins by analyzing the patient archive information. The only human intervention to generate results consists of using the TomoTherapy patient data management sys-tem to archive treated patients two times per day. Our system automatically processes the data, generates daily and weekly reports, and sends an e-mail notification to designated personnel if a flag is out of tolerance. The re-ports are web based and can be accessed from any com-puter allowed. The flagging system is an important com-ponent to aid in the identification of possible issues and will be described later in the manuscript. Most of the

processing time consists of parsing the data and generat-ing movies used to analyze the data. The report could be generated in few minutes—per patient, per fraction—if there was a mechanism to retrieve the new information immediately after each fraction without the need to ar-chive the patient data.

The generation of IVV and ADR systems are transparent to clinic staff and add minimal time to daily patient treat-ment operations. IVV provides flags related to treatment consistency using exit detectors and machine encoders. ADR computes daily and cumulative doses and DVHs to analyze possible daily and cumulative clinical impact. A more detailed description of IVV and ADR can be found in the Supplemental Materials and Methods available on the online version of the manuscript.

ResultsGamma Flagging and Number of Patients per DayTo evaluate the impact of clinical load on differences be-tween planned vs delivered doses, we examined between clinical volume and gamma flagging. Figure 1a represents the number of fractions for each of the 14 participating clin-ics from the beginning of the implementation of the IVV program until the end of May of 2012 (10 months). In total, there were 42,866 fractions considered during this period of time that were used to answer the question of whether

Incident rate of flags for the first 10 months of use. A clear improvement is observed for Gamma (Gamma Red) and Similarity Metric (Sym Red) as a function of time in months of usage for the in vivo verification program.

Figure 2.



couch encoders setup offset information. A difference of this type corresponds to either a decision to not move the patient or that the therapist forgot to move the pa-tient after accepting the image registration. If something

clinics with more patients treated per day have more in-vivo dosimetry flags or not. As shown in figure 1b, in which each index (1 to 14) represents a clinic, there is hardly any correlation between patient load and the percentage of yellow and red flags (correlation coeffi-cient -0.14). In fact, the busiest clinic is the one with the lowest fraction of yellow and red flags. Therefore, dose differences between planned and delivered were not correlated with patient volume in each clinic.

Flagging Trend as Function of Time of UseThe reduction of the number of flags as a function of time was analyzed for the first 10 months that the IVV system was used. Figure 2 shows the reduction of red flags as a function of time after the clinics actively started the IVV program. The trend includes transla-tional (Trans Red) and rotational offsets (Rot Red), kV-MV similarity metric (Sim Red), machine output related (Outp Red, Var Red) and exit dosimetry gam-ma (Gamma Red). A decrease in gamma flagging of 7% was observed after 10 months.

IVV Segmented by Anatomical Site and Couch Setup VerificationSeveral studies have reported in vivo dosimetry studies for different anatomical sites.12-22 Figure 3a shows the number of cases for each anatomical site used on this study. The total number of fractions an-alyzed was 153,330. The largest number corresponds to prostate, head and neck, breast, pelvis and lung. Figure 3b is the fraction of gamma green, yellow, and red flags for each of the anatomical sites considered. Prostate and brain had the lowest yellow and red flags. For prostate, the level of red flags is under 5%, while red and yellow flags for prostate cases are on the order of 10%. Pelvis cases show similar behavior to prostate, but with a slightly higher occurrence of combined red and yellow gamma flags. Some pelvic cases involve very long fields with inguinal nodes and a large area of the femur treated at once. The gamma failures for these cases mostly relate to con-tralateral leg placement after the beam exits the tar-get. In cases within the regions of head and neck, bone and connective tissue, mediastinum, lymphat-ic, skin, abdomen, and breast and lung, the red flags are between 10% and 20% and the combined yellow and red flag components are between 40% to 50%. The anatomical site information was determined us-ing the ICD-9 and ICD-10 codes as reference.

In figure 3c a per-clinic tally is shown to analyze cas-es where the image registration indicated an offset and that differs in more than 3mm with respect to the actual

Brain

Figure 3

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Figure 3.

A. Distribution of Disease

B. Gamma vs Disease

C. Number of Couch Delta (>3mm) vs Clinic

(a) The case mix by anatomical site is presented in this figure. Corresponds to the number of fractions for each case type for a total of 153,330 fractions (b) Percentage of gamma values green, yellow, and red for each type of case bin. (c) Number of times per clinic that the offset saved during registration differs more than 3mm respect to the one register by the couch encoder.

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like that happened to the patient, the physician receives that information on the daily IGRT report, which is emailed and needs his/her approval. This verification is performed using the couch encoders to verify that the actual offset on the couch is the same as was accepted during patient registration process. A total of 85 were found in 14 clinics in 153,330 delivered fractions during a period of approximately 3 years. This corresponds to a rate of 0.0013% per clinic per year.

Plan Dose and Cumulative DoseIn figure 4 the results of the planned doses and the cu-mulative dose at the end of the treatment computed by the ADR for the organs at risk is analyzed. This corre-sponds to 66,294 fractions in 3,687 patients. In figures 4 a–h for each anatomical site the percentage of pa-tients that a particular organ at risk violate the QUAN-TEC criteria either during planning (blue column) or as cumulative dose at the end of the treatment (red col-umn) is displayed. No plan adaptation or modification had been performed in any of these cases during the course of treatment. Therefore, these data allow es-tablishing a reference for possible improvements that can be obtained either by adaptation or other improve-ments with respect to the current state of technology and treatment delivery.

In our head and neck results (figure 4a), approximate-ly 21% of the patients deviated from the QUANTEC cri-teria for the parotids on the original plan. We observed that in 9% of the patients the cumulative dose at the end of the treatment for the parotids deviate from the QUANTEC, comparable to what has been previously re-ported.23-25 The cumulative dose at the end of treatment to the larynx exceeded the tolerance for approximately 2% of the patients. For breast cases (figure 4b), the re-gions at risk that violated plan constraints were lung and heart for 10% and 3.8% of the patients, respectively. An-alyzing the cumulative dose at the end of treatment for breast cases, the regions at risk that violated cumulative dose constraints, were lung and heart for 10.5% and 3% of the patients, respectively.

DiscussionIn this study, we analyzed 153,330 IV and 66,293 ADR frac-tions across 14 multicenter clinics to determine the effect of various clinical factors on planned and delivered doses. In one of the largest analyses of its kind, we demonstrate that the degree of in vivo gamma flagging was independent of an individual clinic’s volume (Figure 1).

Indeed, the use of IV in our hands in conjunction with ADR appears to provide insight into actual treatment. In

this large data set, our automatic, multicenter procedure for IV and ADR for all patients and all fractions treated across the United States moves from the theoretical to the contemporary. Our work suggests that this system provides internal recommendations for daily IGRT and clinical improvements using IV and ADR findings. Thus, we successfully created a system with metrics to flag for possible issues, establish trending, and determine possi-ble clinical impact. We were also able to evaluate devia-tions of the cumulative dose at the end of the treatment using QUANTEC recommendations for organs at risk.

Interestingly, the extent of in vivo flags was indepen-dent of clinic volume. The number of in vivo flags decreas-es considerably as a function of the length of time that the system is used. We were able to tailor IGRT procedures to specific anatomical sites and specific patients based on the information provided by the system. Again, our findings suggest 5% of all prostate treatments and more than 20% of head and neck treatments triggered some IV action level. It appears for certain anatomical sites, long CTs may not reduce the number of IVV flags but in vivo dosimetry still indicates possible problem locations. ADR results demonstrated that cumulative doses at the end of treatment for head and neck patients exceed QUANTEC limits for 9% of parotid glands and 2% of larynxes. It is educational for treatment purposes that 10.5% of patients exceeded QUANTEC limits for lung and 3% for heart at the end of treatment.

Finally, these data help establish ADR and IV as a syner-gistic set of processes that allows flagging and quantifying potential clinical impact to analyze dosimetric information on patient registries. The implication for use in further prospective studies or integrating key focus retrospective studies on a grand scale cannot be overlooked.

ConclusionsThis study represents one of the largest multicenter ex-periences with the use of an IVV system coupled with an ADR system. In the spirit of “big data,” a total of 153,330 IVV fractions and 66,294 ADR fractions, corresponding to 3687 ADR patients, for a multicenter study were ana-lyzed and interpreted. Data generated by IVV provides a useful system of flags to be used in conjunction with an ADR program. Taken together, these tools can identify potential issues with treatment delivery that may other-wise go undetected.

ABOUT THE AUTHORS21st Century Oncology (GO, XM, DP, SK, CM, EF, DD, LK, AM, SEF, DG) and Yale Medical School (AD).



Figure 4.

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Head & Neck Prostate

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Percent of patients that the plan (blue columns) and cumulative dose at the end of the treatment (red columns) exceed QUANTEC criteria for different anatomical sites and organs at risk. (a) head and neck, (b) prostate, (c) breast, (d) lung, (e) abdomen, (f) brain, (g) pelvis, (h) other.

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Address correspondence to: Gustavo Olivera, 21st Century Oncology ATD; 555 D’onofrio Dr Suite 104 Madison WI 53719. Tel: 608 332 6274 Fax: 608 332 6274 E-mail: [email protected].

Conflicts of interest: None.

REFERENCES

1. Bortfeld T. Image-guided IMRT. Berlin, Germany: Springer; 2006.2. Webb S. Intensity-Modulated Radiation Therapy. Philadelphia, PA: Institute of

Physics Publishing; 2001.3. Murphy MJ, Balter J, Balter S, et al. The management of imaging dose during

image-guided radiotherapy: report of the AAPM Task Group 75. Med Phys. 2007;34:4041-4063.

4. Ezzell GA, Burmeister JW, Dogan N, et al. IMRT commissioning: multiple insti-tution planning and dosimetry comparisons, a report from AAPM Task Group 119. Med Phys. 2009;36:5359-5373.

5. Klein EE, Hanley J, Bayouth J, et al. Task Group 142 report: quality assurance of medical accelerators. Med Phys. 2009;36:4197-4212.

6. Langen KM, Papanikolaou N, Balog J, et al. QA for helical tomotherapy: report of the AAPM Task Group 148. Med Phys. 2010;37:4817-4853.

7. Gregoire V, Mackie TR. State of the art on dose prescription, reporting and recording in Intensity-Modulated Radiation Therapy (ICRU report No. 83). Can-cer Radiother. 2011;15:555-559.

8. Bissonnette JP, Balter PA, Dong L, et al. Quality assurance for image-guided radiation therapy utilizing CT-based technologies: a report of the AAPM TG-179. Med Phys. 2012;39:1946-1963.

9. Low DA, Moran JM, Dempsey JF, et al. Dosimetry tools and techniques for IMRT. Med Phys. 2011;38:1313-1338.

10. Fiorino C, Corletto D, Mangili P, et al. Quality assurance by systematic in vivo dosimetry: results on a large cohort of patients. Radiother Oncol. 2000;56:85-95.

11. Mans A, Wendling M, McDermott LN, et al. Catching errors with in vivo EPID dosimetry. Med Phys. 2010;37:2638-2644.

12. Meijer GJ, Minken AW, van Ingen KM, et al. Accurate in vivo dosimetry of a randomized trial of prostate cancer irradiation. Int J Radiat Oncol Biol Phys. 2001;49:1409-1418.

13. Fidanzio A, Greco F, Mameli A, et al. Breast in vivo dosimetry by EPID. J Appl Clin Med Physics. 2010;11:3275.

14. Higgins PD, Alaei P, Gerbi BJ, et al. In vivo diode dosimetry for routine quality assurance in IMRT. Med Phys. 2003;30:3118-3123.

15. Piermattei A, Stimato G, Gaudino D, et al. Dynamic conformal arc therapy: transmitted signal in vivo dosimetry. Med Phys. 2008;35:1830-1839.

16. Hardcastle N, Cutajar DL, Metcalfe PE, et al. In vivo real-time rectal wall do-simetry for prostate radiotherapy. Phys Med Biol. 2010;55:3859-3871.

17. Kroonwijk M, Pasma KL, Quint S, et al. In vivo dosimetry for prostate cancer patients using an electronic portal imaging device (EPID); demonstration of internal organ motion. Radiother Oncol. 1998;49:125-132.

18. Lanson JH, Essers M, Meijer GJ, et al. In vivo dosimetry during conformal ra-diotherapy: requirements for and findings of a routine procedure. Radiother Oncol. 1999;52:51-59.

19. Tournel K, Verellen D, Duchateau M, et al. An assessment of the use of skin flashes in helical tomotherapy using phantom and in-vivo dosimetry. Radiother Oncol. 2007;84:34-39.

20. Noel A, Aletti P, Bey P, et al. Detection of errors in individual patients in radio-therapy by systematic in vivo dosimetry. Radiother Oncol. 1995;34:144-151.

21. Cilla S, Macchia G, Digesu C, et al. Endocavitary in vivo dosimetry for IMRT treatments of gynecologic tumors. Med Dosim. 2011;36:455-462.

22. Grimaldi L, D’Onofrio G, Cilla S, et al. Breast in vivo dosimetry by a portal ionization chamber. Med Phys. 2007;34:1121-1127.

23. Geets X, Tomsej M, Lee JA, et al. Adaptive biological image-guided IMRT with anatomic and functional imaging in pharyngo-laryngeal tumors: impact on target volume delineation and dose distribution using helical tomotherapy. Radiother Oncol. 2007;85:105-115.

24. Gregoire V, Jeraj R, Lee JA, et al. Radiotherapy for head and neck tumours in 2012 and beyond: conformal, tailored, and adaptive? Lancet Oncol. 2012;13:e292-300.

25. F. Carruthers JAL, R. Lhommel, V. Grégoire. Adaptive treatment with Hi-Art Tomotherapy for locally advanced head and neck squamous cell carcinoma. Radiother Oncol. 2011;99 (suppl 1):S236.

M A P S

About the lead author:Amber Orman, MDDepartment of Radiation Oncology Miller School of MedicineUniversity of Miami

A Phase III Randomized Trial of MRI-Mapped, Dose-Escalated Salvage

Radiotherapy Post-Prostatectomy: The MAPS Trial

Amber Orman, MD; Alan Pollack, MD, PhD; Kelin Wang, PhD; Radka Stoyanova, PhD; Elizabeth Bossart, PhD; Deukwoo Kwon, PhD; Matthew Abramowitz, MD

ABSTRACT

ObjectiveMAPS is the first phase III randomized trial of MRI-mapped, dose-escalated salvage radio-therapy. In this planned feasibility analysis, we ensure dosimetric adequacy of the protocol as it relates to acute toxicity.

Materials and MethodsTwo intensity modulated radiotherapy plans were generated for each patient. In the stan-dard fraction radiotherapy arm, 68 Gy in 34 fractions was prescribed to ≥95% of the plan-ning target volume. In the simultaneous incorporated hypofractionated boost (SIHB) arm, an additional 2.25 Gy daily SIHB was prescribed to the gross tumor volume (GTV). The trial stipulates that ≤35% and ≤55% of the rectum should receive ≥65 Gy and ≥40 Gy, respec-tively, and ≤50% and ≤70% of the bladder minus the clinical target volume (B-CTV) should receive ≥65 Gy and ≥40 Gy, respectively. Acute toxicities were recorded per National Can-cer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.0).

ResultsIn all plans, ≥95% of the planning target volume and GTV received the prescribed dose. Do-simetric constraints were achieved for all organs at risk except B-CTV. The highest toxicity recorded was grade 2 gastrointestinal toxicity: 1 episode per arm.

ConclusionsDose escalation is achievable with expected variations in cases with small bladders. There was no observed increase in acute toxicity.

INTRODUCTIONRadical prostatectomy (RP) cures the majority of patients with localized pros-tate cancer. However, within 10 years of diagnosis as many as one-third will develop recurrent disease.1,2 In the set-ting of localized recurrence, salvage radiotherapy to the prostate bed is the standard treatment. However, long-term salvage rates remain suboptimal, possibly due to poor patient selection.3,4

Ideally, only those with disease isolated

to the prostate bed would receive treatment. Dynamic contrast-enhanced (DCE) MRI has been shown to reveal residual or recurrent disease with specificities of at least 80%, and sensitivities ranging from 67% to 97%.5 This is an improvement over transrectal ultra-sound and conventional imaging,6 provides objective evidence for treatment, and identi-fies a target for dose escalation.

Compared with definitive radiothera-py, salvage doses are lower due to the as-sumption of only microscopic disease and

Jonathan D. Tward, MD, PhD

Department of Radiation OncologyHuntsman Cancer HospitalUniversity of Utah

Why is this article contemporary?Conventionally fractionated dose esca-lation above 78 Gy for intact prostate cancer has been shown to improve fail-ure-free survival. Previously occult pros-tatic fossa recurrences can now occasion-ally be visualized using advanced imaging methods such as MRI. As the disease is no longer “microscopic,” it stands to reason that dose escalation to the recurrent tu-mor may improve failure-free survival in the salvage setting as well.

In the current study, the authors report on the feasibility and acute toxicity of the first 14 patients enrolled on a trial ran-domizing subjects to either standard 68 Gy radiotherapy to the fossa, or the same plus a simultaneous integrated boost of 76.5 Gy at 2.25 Gy/fx (EQD2= 82 Gy, al-pha/beta assumption 1.5).

In this initial report, the authors showed the dosimetric feasibility via DVH parameters of the approach and that there was clinically no discernible acute toxicity difference between the standard arm and the dose-escalated arm. The trial contin-ues to accrue and we await reports on late toxicity as well as impact on their prima-ry endpoint of biochemical failure-free survival. If the authors ultimately show improved bRFS and similar late toxicity, then dose escalation to visualized fossa le-sions should become a new care standard.


M A P S


toxicity limits associated with treating the bladder neck. However, dose escalation may show benefit,7,8 and radio-biological modeling predicts that PSA control rates will in-crease along with increasing doses.8,9 In terms of toxicity, salvage IMRT up to 76 Gy results in <1% grade 3 GI toxici-ty, and 3% grade 3 GU toxicity at 5 years.10

If there is a potential dose response above what is thought permissible in terms of toxicity, and we have an emerging ability to visualize foci of gross disease in the prostate bed, it follows that the addition of targeted dose escalation may improve outcomes compared with standard salvage radiotherapy alone. This is the focus of the MAPS trial— the first phase III randomized trial of MRI-mapped, dose- escalated salvage radiotherapy. The primary objective is to determine the effect of an SIHB to MRI-identified foci on initial complete biochemical response (initial PSA <0.1 ng/mL at 9 months). The trial has a planned accrual of 76 evaluable patients, which would provide 80% power to de-tect an absolute increase of 27% in the PSA response rate, using a one-sided Fisher’s exact test with 5% significance level. This feasibility analysis details dosimetry and acute toxicity, revealing dose escalation as safely achievable.

METHODS AND MATERIALSPatient PopulationBetween December 2010 and September 2013, 14 patients who had developed biochemical recurrence after defini-tive RP were enrolled in our institutional review board- approved MAPS trial. The trial stipulates that all patients are ≥3 months post RP with the following inclusion cri-teria: a PSA of ≥0.1 ng/mL and ≤3.0 ng/mL within 3 months of enrollment, an MRI detectable lesion in the prostate bed, no evidence of distant metastasis, a serum total testosterone within 40% of normal assay limits with-in 3 months prior to enrollment, a BUN and creatinine within 40% of normal assay limits within 3 months prior

Figure 2. Typical dose distributions for SFRT (left) and SIHB (right) plans.

SFRT indicates standard fraction salvage radiotherapy; SIHB, simultaneous integrated hypo-fractionated boost.

Figure 1. Typical DCE-MRI appearance of the non-contoured (above) and contoured GTV (below).

DCE-MRI indicates dynamic contrast-enhanced MRI; GTV, gross tumor volume.

to enrollment, no current active malignancy aside from nonmetastatic skin cancer or early chronic lymphocytic leukemia, Zubrod performance status <2, and age be-tween 35 and 85 years. Any prior androgen deprivation therapy must be completed >6 months previous to enroll-ment and be ≤7 months in duration. Patients meeting the criteria were randomized between the SFRT arm and the SIHB arm.

Acquisition and SimulationAll patients underwent computed tomography (CT)-based


A Phase III Randomized Trial of MRI-mapped, Dose Escalated Salvage Radiotherapy Postprostatectomy: The MAPS Trial. Feasibility and Acute Toxicity

virtual simulation in the supine position with 1.5-2-mm thick slices extending from the top of the sacrum to mid femur. Per institutional protocol, all patients were instructed to eat a diet designed to reduce bowel gas for at least 24 hours prior to simulation, use a rectal enema prior to arrival, and maintain a full bladder. Tattoos were placed at the anterior, right lateral, and left lateral isocenter skin points. Under the same condi-tions and often during the same encounter, T2, T1 non-con-trast, diffusion weighed images (DWIs), and DCE-MRI (3.0 T MRI) scans were obtained at 2.5-mm intervals. Approxi- mately 12 DCE-MRI scans were obtained, beginning precon-trast and continuing at approximately 30-second intervals postcontrast. The pelvis and prostate bed were imaged.

CT-MRI CoregistrationIn order to deliver the daily SIHB to the MRI-identified foci, the anatomical, diffusion, and dynamic MRI sequences were coregistered to the planning CT. Coregistration was performed within the Eclipse software using anatomical matching of the MRI and CT acquisitions in the areas of the prostate bed, penile bulb, and bladder and rectal interfaces in the region of the prostate bed. This resulted in the high quality and reproducible alignment between the two acqui-sitions necessary to ensure that the SIHB was delivered to the proper location.

Contouring and Volume DefinitionStructures were manually contoured on the CT simulation

scan using an adaptation of the recommendations of the Ra-diation Therapy Oncology Group.11 The clinical target volume (CTV) included the prostate bed, extending cranially from the seminal vesicle remnants and caudally to approximately 2.5 mm above the superior aspect of the penile bulb. Borders below the superior border of the pubic symphysis were the posterior aspect of the pubis anteriorly, the rectum posteri-orly, and the levator ani laterally. Borders above the pubic symphysis were approximately 1 cm of the posterior blad-der wall anteriorly, the mesorectal fascia posteriorly, and the sacrorectogenitopubic fascia laterally. Using CT-MRI coregistration, the MRI revealed that GTV (Figure 1) was contoured on the CT simulation scan by using the anatom-ical, diffusion, and dynamic MRI series. Suspicious lesions are most visible on the early and late DCE-MRI sequences (characterized by early contrast wash-in and late contrast wash-out). However, the T2 and DWI images were also used to confirm the lesion location. There was no expansion on the GTV, as the goal was to increase dose to the general area of the GTV. In addition, while the effect was greatest in the area of the GTV, the presence of a boost volume increased dose to the entire prostate bed. Therefore, adding a margin to the GTV would unnecessarily place critical organs at risk. A PTV around the CTV was defined to account for daily set-up errors, and consisted of a 7 mm expansion of the CTV in all directions. The bladder was contoured in its entirety. The rectum was contoured as a whole organ from the rectosig-moid flexion to the bottom of the ischial tuberosities. The

Figure 3. Typical dose volume histogram for SFRT and SIHB plans. All SIHB DVH curves are shifted slightly to the right. The GTV for the SIHB plan is also included.

SFRT indicates standard fraction salvage radiotherapy; SIHB, simultaneous integrated hypo-fractionated boost; DVH, dose-volume histogram, GTV, gross tumor volume.

M A P S


femoral heads were outlined from the top of the acetabulum to an area between the lesser and greater trochanters. For evaluation purposes, a bladder minus CTV volume was also created (B-CTV). All contours were reviewed by the princi-ple investigator or co-investigator.

Treatment Planning by IMRTTreatment plans were generated using commercial software (Eclipse, version 11.0, Varian, Palo Alto, California) with het-erogeneity correction. Two IMRT plans were generated for each patient data set: 1 for the SFRT arm and 1 for the SIHB arm (regardless of the arm under which the patient was actu-ally treated). The prescription dose was 68 Gy in 34 fractions to ≥95% of the PTV in all plans. In the SIHB arm, a 2.25-Gy daily SIHB was prescribed to the GTV, for an absolute dose of 76.5 Gy in 34 fractions (Fig-ure 2). The plans were quality controlled by utilizing the ArcCHECK QA device (Sun Nuclear Corporation, Melbourne, Florida) to compare the calculated and measured doses within the phantom using gamma analy-sis with 3% dose difference and 3-mm dis-tance-to-agreement criterion.

Treatment Delivery by IMATA Varian Trilogy (Varian, Palo Alto, Cal-ifornia) linear accelerator delivered vol-umetric-modulated arc therapy (VMAT) at either 6 MV or 18 MV energies. All pa-tients were treated once daily, 5 times a week. Image guided radiotherapy (IGRT) was accomplished with daily cone beam CT (CBCT), using prostate bed clips and bladder and rectal filling to perform dai-ly alignment. Patients were not treated unless aligned to any clips, with blad-der and rectal filling similar to the CT simulation. Patients were instructed to express gas/stool, and urine and drink additional fluids before a repeat CBCT, as needed.

Acute Toxicity ScoringAcute toxicity was defined as during and up to 3 months after treatment. Pros-tate-related symptoms were assessed be-fore treatment, weekly during treatment, and 6 weeks and 3 months after treatment completion using the NCI CTCAE v4.0. Only patients with data at all above time points were included.

Table 1. Dosimetric constraints.

Volume (%) Dose (Gy) Volume (%) Dose (Gy)

PTV (SFRT) ≥ 95 68

PTV (SIHB) ≥ 95 68

GTV ≥ 95 76.5

Rectum ≤35 65 ≤55 40

B-CTV ≤50 65 ≤70 40

SFRT indicates standard fraction salvage radiotherapy; PTV, planning target volume; SIHB, simultaneous integrated hypo-fractionated boost; GTV, gross tumor volume; B-CTV, bladder minus clinical target volume.

Table 2. Dosimetric results for SFRT and SIHB plans.

SFRTmean (range, SD)

SIHBmean (range, SD)

P valuea

V40 (R)% 34.6 (20-45.6, 7.7) 34.6 (19.7-45.7, 7.9) .987

V65 (R)% 14.1 (8.4-22, 3.6) 14.4 (8.2-22.9, 3.4) .832

Max (R)Gy 76.7 (71.6-80.4, 2.8) 78.5 (73.5-83.4, 2.9) .113

V40 (B-CTV)% 63.1 (32.1-97, 23.3) 64.3 (35.5-99, 22.6) .892

V65 (B-CTV)% 31.3 (14.5-49.8, 10.9) 33.8 (14.5-55.5, 13.2) .596

Max (B-CTV)Gy 77.8 (74.4-83.2, 2.8) 78.1 (75-82.5, 2.3) .707

V76.5 (GTV)% NA 96.7 (95.2-100, 1.7) NA

V68 (PTV)% 95.6 (94.9-97.9, 0.96) 96.1 (95-97.9, 0.90) .037b

a P value from Student’s T test.b P value from Kruskal-Wallis test due to non-normality. R indicates rectum; B-CTV, bladder minus clinical target volume; GTV, gross tumor volume; PTV, planning target volume; SFRT, standard fraction salvage radiotherapy; SIHB, simultaneous integrated hypofractionated boost; NA, not applicable.

Statistical AnalysisThe percentage of the volume of the PTV and GTV receiv-ing the prescribed dose was recorded for the SFRT and SIHB plans. Also recorded were the maximum doses to the OARs, as well as the percentage of volume of the rec-tum and B-CTV receiving ≥65 Gy and ≥40 Gy. The Shap-iro-Wilk normality test was used for the variables of inter-est. The Student’s T test was used for comparison between the SFRT and SIHB plans when the normality test was not significant. Otherwise, the Kruskal-Wallis test was used for comparing the two plans. A 2-tailed P value (<.05) was used to indicate statistical significance.



RESULTS

Fourteen patients have been enrolled on the trial to date, and data from 13 are available for acute toxicity analysis (7 randomized to SFRT and 6 to SIHB treatment). The median follow-up at this time is 15 months.

Treatment Volume Charac-teristicsThe mean CTV volume was 143.3 cc, with a range of 84.8-202.7 cc SD, 39.2 cc). The mean PTV vol-ume was 312.8 cc, with a range of 218.3-388.9 cc (SD, 57.4). The mean GTV volume was 2.34 cc, with a range of 0.31-10.4 cc (SD, 2.8 cc). The mean volume encompassed within the 76.5 Gy isodose line was 27.6 cc, with a range of 1.02-151.3 cc (SD, 39 cc).

Dose-Volume HistogramsDose-volume histograms (DVH) were generated for all plans (Fig-ure 3). In every case, at least 95% of the PTV received 68 Gy, and at least 95% of the GTV received 76.5 Gy, as specified in the con-straints (Table 1), with maximum doses to the GTV kept below 115% of the prescription dose. SIHB plans demonstrated an increased integral dose to the prostate bed PTV as shown in Figure 3. While this increase occurred throughout the PTV volume, it was greatest in the region of the GTV.

Dosimetric values for target volumes and OAR are present-ed in Table 2 for both SFRT and SIHB plans. We tested normality for each variable using the Sha-piro-Wilk test. V76.5 (GTV)% in SIHB and V68 (PTV)% in SFRT were statistically significant (both P <.001), ie, not normal. All other variables were as-sumed to be normal. Dosimetric constraints were achieved for all OARs except for bladder. Five plans had >70% of the bladder receiving ≥40 Gy in both the

SFRT and SIHB plans, and 1 plan had >50% of the blad-der receiving ≥65 Gy in the SIHB plan only. Review of the plans revealed this to be due to suboptimal bladder filling. In terms of dosimetric constraints for OARs, as well as PTV and GTV coverage, there was no difference between the SFRT and SIHB plans per patient or overall, except in

Table 3. Number of radiotherapy-related toxicities per arm.

SFRT SIHB

GRADE 1 2 ≥3 1 2 ≥3

URINARY

Hematuria 1 2

Urgency 4 3

Frequency 3 3

Incontinence 1

Dysuria 2

Retention 1

Cystitis 1 3

GASTROINTESTINAL

Diarrhea 1 1

Hemorrhoids 1

Proctitis 1

Anal Pain 1

SKINHyperpigmentation 1

Acute dermatitis 1

REPRODUCTIVE

Testicular pain 1

Libido decreased 1

Ejaculation disorder

1

OTHERFatigue 5 3

Myalgia 1

SFRT indicates standard fraction salvage radiotherapy; SIHB, simultaneous integrated hypofractionated boost.

M A P S


the case of V68 (PTV)% (Table 2).

Acute ToxicityThirteen patients (7 treated with SFRT and 6 with SHIB) are included in the toxicity analysis. Twelve of these patients experienced toxicities (1 patient in arm 2 did not). Table 3 details the number of oc-currences of all radiation related toxicities by treat-ment arm. Table 4 details the highest grade GU and GI toxicity per patient.

DISCUSSIONSalvage radiotherapy is the only curative treatment for patients with a localized recurrence post RP. Multiple retrospective studies have reported on the efficacy of standard dose salvage radiotherapy in achieving biochemical control, with actuarial 5-year biochemical recurrence free survival (bRFS) rates ranging from 10% to 66%.12-14 Advances in IMRT and IGRT have now made possible the delivery of definitive-range radiotherapy doses. Dose escalation in the salvage setting has been shown to improve biochemi-cal control in various retrospective studies.8,9,15 King et al compared 38 patients treated with 60 Gy with 84 patients treated with 70 Gy, demonstrating a significant improve-ment in 5-year bRFS from 25% to 58% with the higher dose. Another study reviewed 364 men who received sal-vage radiotherapy at 1 of 3 dose levels (low, <64.8 Gy; moderate, 64.8-66.6 Gy; high, >66.6 Gy) and found that doses greater than 66.6 Gy resulted in improved bRFS.15 A review of published reports by Ohri et al in 2012 exam-ined the role of salvage radiotherapy dose and timing on biochemical control and found that bRFS increased with salvage radiotherapy dose by 2.5% per Gy and decreased with pre-salvage radiotherapy PSA by 18.3% per ng/mL (P <.001). Radiobiological models predicted that an increase in the pre-salvage radiotherapy PSA from 0.4 to 1 ng/mL would increase the salvage radiotherapy dose required to achieve a 50% bRFS rate by 60 to 70 Gy.9 While random-ized trial data are not yet available, these studies demon-strate the potential for improved outcomes with dose esca-lated salvage radiotherapy.

The benefits of dose escalation to the prostate bed are limited by the possible increase in side effects. Three-di-mensional conformal radiotherapy (3D-CRT) first allowed for escalation to biologic equivalent doses of 68 Gy16 with-out an increase in toxicity compared with 64 Gy delivered by conventional radiotherapy (<5% late grade 3 GU tox-icity and <5% late grade 3 GI toxicity).17-19 However, esca-lation >68 Gy using 3D-CRT resulted in a 5-year risk of late grade 3 GU toxicity of 16%.16 The model by Ohri et al

Table 4. Highest grade GU and GI toxicity per patient according to NCI CTCAE v4.0.

Grade 0 1 2 3 4 5

SFRTGU 2 5

GI 4 2 1

SIHBGU 1 5

GI 5 1

SFRT = standard fraction salvage radiotherapy; SIHB, simultaneous integrated hypofractionated boost.

estimated that severe late toxicity rates may reach 10% at doses of approximately 70 Gy;9 however, toxicity data used for this model came from series employing 2-D or 3-D treatment techniques. In fact, it was recently reported that IMRT to a median dose of 76 Gy resulted in a 5-year risk of late grade 3 GU toxicity of 3%, and late grade 2 to 3 GI toxicity of 8%,10 which is comparable to toxicity reported with doses of 64 Gy using conventional radiotherapy.17-19 In our trial, with only acute toxicity available at this time, the highest reported toxicity included 1 episode of grade 2 gas-trointestinal toxicity in each arm. Finally, be aware that the CTCAE grading system used in our trial may report lower grade toxicity for similar side effects compared with other scoring scales, such as that used by the Radiation Therapy Oncology Group (RTOG).

With retrospective and radiobiologic modeling evidence for improved bRFS with dose escalation,8,9 reservations regarding potential increases in toxicity,9 and the ability to identify gross disease in the prostate bed using DCE-MRI,20-22 it follows that dose escalation to the gross disease alone has the potential to improve the therapeutic ratio of salvage radiotherapy.

In this study, we have demonstrated that even though areas of gross disease in the prostate bed are close to crit-ical structures, dose escalation to these areas results in good coverage of the PTV (range: 95%-97.9%) and GTV (range: 95%-100%) without exceeding conservative dosim-etric constraints specified for the rectum in all cases and the bladder in the majority of cases. This is occasionally unavoidable, as the bladder neck must be pulled into the CTV to account for the absence of the intraprostatic ure-thra, and some patients are unable to achieve or maintain



a full bladder (due to anatomic or physiologic limitations). In cases like this, bladder constraints were unachievable in both the SFRT and SIHB plans. Per the protocol, a primary variation will be noted if up to an additional 7.5% of the B-CTV volume exceeds the dose constraint. Beyond this constitutes a secondary protocol variation. At the least, a portion of the bladder is included in the PTV by necessity; these constitute protocol variations, not violations. There-fore, none of the plans would have resulted in a protocol violation. Regardless, the clinical acute toxicity was com-parably low in both arms.

In conclusion, treating MRI-identified prostate lesions to definitive doses using an SIHB is possible without sig-nificantly increased dose or acute toxicity to critical struc-tures. Long term follow-up of the randomized trial is re-quired for biochemical outcomes.

ABOUT THE AUTHORSDepartment of Radiation Oncology (AO, AP, KW, RS, EB, DK, MA), University of Miami, Miller School of Medicine, Miami, FL.

Address correspondence to: Matthew Abramowitz, MD, De-partment of Radiation Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Ave, Suite 1500, Miami, FL 33136, Phone: 305-243-4319. Fax: 305-243-4363. E-mail: [email protected]

Disclosures: Drs Pollack and Abramowitz participate in consult-ing for General Electric. Dr Abramowitz receives research honor- aria from Elekta. This work is supported by Grant 1BT-03 (Imaging Core: AP, RS) from the Bankhead Coley Cancer Research Program.

Conflicts of interest: None.

REFERENCES1. Amling CL, Blute ML, Bergstralh EJ, et al. Long-term hazard of progression

after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. J Urol. 2000;164(1):101-105.

2. Chun FK, Graefen M, Zacharias M, et al. Anatomic radical retropubic prostatectomy-long-term recurrence-free survival rates for localized prostate cancer. World J Urol. 2006;24(3):273-280.

3. Boorjian SA, Karnes RJ, Crispen PL, et al. Radiation therapy after radical pros-tatectomy: impact on metastasis and survival. J Urol. 2009;182(6):2708-2714.

4. Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival follow-ing salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299(23):2760-2769.

5. Rischke HC, Schafer AO, Nestle U, et al. Detection of local recurrent prostate cancer after radical prostatectomy in terms of salvage radiotherapy using dynamic contrast enhanced-MRI without endorectal coil. Radiat Oncol. 2012; 7:185.

6. Martino P, Scattoni V, Galosi AB, et al. Role of imaging and biopsy to assess local recurrence after definitive treatment for prostate carcinoma (surgery, radiotherapy, cryotherapy, HIFU). World J Urol. 2011;29(5):595-605.

7. Goenka A, Magsanoc JM, Pei X, et al. Long-term outcomes after high-dose postprostatectomy salvage radiation treatment. Int J Radiat Oncol Biol Phys. 2012;84(1):112-118.

8. King CR, Spiotto MT. Improved outcomes with higher doses for salvage radio-therapy after prostatectomy. Int J Radiat Oncol Biol Phys. 2008;71(1):23-27.

9. Ohri N, Dicker AP, Trabulsi EJ, et al. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? a systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer. 2012;48(6):837-844.

10. Ost P, Lumen N, Goessaert AS, et al. High-dose salvage intensity-modulated radiotherapy with or without androgen deprivation after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year results. Eur Urol. 2011;60(4):842-849.

11. Michalski JM, Lawton C, El Naqa I, Ritter M, O’Meara E, Seider MJ, et al. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010;76(2):361-368.

12. Chawla AK, Thakral HK, Zietman AL, et al. Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prog-nostic factors. Urology. 2002;59(5):726-731.

13. Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prosta-tectomy. J Clin Oncol. 2007;25(15):2035-2041.

14. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291(11):1325-1332.

15. Bernard JR, Jr., Buskirk SJ, Heckman MG, et al. Salvage radiotherapy for rising prostate-specific antigen levels after radical prostatectomy for prostate cancer: dose-response analysis. Int J Radiat Oncol Biol Phys. 2010;76(3):735-740.

16. Cozzarini C, Fiorino C, Da Pozzo LF, et al. Clinical factors predicting late severe urinary toxicity after postoperative radiotherapy for prostate carcino-ma: a single-institute analysis of 742 patients. Int J Radiat Oncol Biol Phys. 2012;82(1):191-199.

17. Feng M, Hanlon AL, Pisansky TM, et al. Predictive factors for late genitourinary and gastrointestinal toxicity in patients with prostate cancer treated with adjuvant or salvage radiotherapy. Int J Radiat Oncol Biol Phys. 2007;68(5):1417-1423.

18. Pearse M, Choo R, Danjoux C, et al. Prospective assessment of gastrointesti-nal and genitourinary toxicity of salvage radiotherapy for patients with pros-tate-specific antigen relapse or local recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys. 2008;72(3):792-798.

19. Peterson JL, Buskirk SJ, Heckman MG, et al. Late toxicity after postprostatec-tomy salvage radiation therapy. Radiother and Oncol. 2009;93(2):203-206.

20. Boonsirikamchai P, Kaur H, Kuban DA, et al. Use of maximum slope images generated from dynamic contrast-enhanced MRI to detect locally recurrent prostate carcinoma after prostatectomy: a practical approach. AJR Am J Roentgenol. 2012;198(3):W228-W236.

21. Casciani E, Polettini E, Carmenini E, et al. Endorectal and dynamic con-trast-enhanced MRI for detection of local recurrence after radical prostatec-tomy. AJR Am J Roentgenol. 2008;190(5):1187-1192.

22. Sciarra A, Panebianco V, Salciccia S, et al. Role of dynamic contrast-en-hanced magnetic resonance (MR) imaging and proton MR spectroscopic imaging in the detection of local recurrence after radical prostatectomy for prostate cancer. Eur Urol. 2008;54(3):589-600.


Adjuvant Radiotherapy in Low-Risk Breast Cancer Patients: Review and

Clinical ImplicationsChirag Shah, MD, Vivek Verma, MD, Michelle Frances Barrord, BS, Frank Vicini, MD

ABSTRACT

Breast conserving therapy (BCT) offers women the ability to preserve their breast without sacrificing local control or survival. Since its inception, a key component of BCT has been the delivery of adjuvant radiotherapy following breast-conserving surgery (BCS). However, a growing interest remains in determining if there exists a subset of women with low-risk features for whom adjuvant radiotherapy may be omitted following BCS. To date, the data are consistent in demonstrating that adjuvant radiotherapy reduces the rate of local re-currences in all risk groups. In lower-risk groups, modern trials have failed to demonstrate a survival advantage from the local control benefit derived from radiotherapy. Currently, studies are being performed to identify low-risk patients based on tumor genetics, nomo-grams, and other techniques. In the interim, clinicians now have alternative techniques including hypofractionated whole breast irradiation as well as accelerated partial breast irradiation which allows for a reduction in treatment duration (and possibly treatment volume) while still maintaining local control.

David E. Wazer, MD, FACRO, FACR, FASTRO

Department of Radiation OncologyTufts University School of MedicineAlpert Medical School of Brown University

Why is this article contemporary?Contemporary risk-adapted local therapy for early breast cancer is a complex and evolving paradigm. Shah et al do an excellent job in summariz-ing the multitude of evidence-based approaches related to risk stratifica-tion, treatment options, and results. By also placing these in the context of real-world case examples, clinicians can gain valuable insight into the ap-propriate application of these multi-faceted clinical trial data to manage the individual patient. This review highlights the enormous progress that has been achieved in recent years toward providing women with local therapy options that are safe, effec-tive, convenient, and cost efficient.


Chirag Shah, MDDepartment of Radiation OncologySumma Health System

IntroductionOver the past several decades, breast-con-serving therapy (BCT) has emerged as the standard of care in the management of early-stage breast cancer. With greater than twenty-five years of follow-up, mul-tiple randomized trials have demonstrat-ed equivalence in outcomes between mas-tectomy and BCT, with BCT being shown to improve the quality of life of breast cancer survivors compared with mas-tectomy.1-4 A key component in the BCT arms of the randomized trials was stan-dard fractionation whole-breast irradia-tion (WBI) delivered over 5 to 6 weeks. In the decades since the initial randomized trials, adjuvant radiation therapy (RT) has continued to be a key component of the BCT technique to optimize local con-trol. While RT has been shown to enhance local control following breast-conserving surgery (BCS), concerns exist, including acute/chronic toxicities associated with treatment, the duration of treatment,

and the potential for overtreatment.5,6 A key question being considered is the role of RT in patients who will not manifest large local control benefits with adjuvant RT compared with BCS with or without endocrine therapy. Multiple attempts have been made to omit RT following BCS, with mixed results. In spite of the lack of clarity, clinicians are facing pres-sure to tailor RT recommendations based on patient (age, performance status), pathologic (tumor size, margin status, grade, hormone receptor status, lymph node status), and systemic treatment (tamoxifen/aromatase inhibitor utiliza-tion) characteristics and to identify low-risk patients for whom RT may not be required. Therefore, the purpose of this clinical review is to evaluate the role of RT in low-risk patients (based on patient and pathologic features) following BCS and to provide common scenarios and recommendations based on current data and guidelines.



Adjuvant Radiotherapy in Low-Risk Breast Cancer Patients: Review and Clinical Implications

DiscussionThe role of adjuvant RT in patients undergoing BCS has been evaluated as part of the randomized trials compar-ing mastectomy and BCT. NSABP B-06 randomized 1861 women (stage I/II, < 4cm, 62% node negative, all under-went axillary dissection) to mastectomy, BCS, or BCS with adjuvant RT. With 20 years follow-up, the omission of RT following BCS increased the rate of local recurrence, 39% vs 14%.1 Further, the Milan III study randomized nearly 579 women (tumor size <2.5 cm, <70 years old, majority <55 years old, 32% to 44% endocrine therapy, 67% to 72% node negative, all underwent axillary dissection, nodal positivity allowed) to adjuvant RT or observation following quadrantectomy; at 10 years follow-up, adjuvant RT had

Table 1. Trials Evaluating the Omission of Radiotherapy With Endocrine TherapyStudy Arms Number

of Patients

Follow-up (years)

Size Hormones/Systemic Therapy

Lymph Node Status

Grade Margin Age Outcomes

NSABP B-21 Tamoxifen vs RT vs Tamoxifen + RT

1009 7.2 <1 cm ER status not required; 54-59% ER positive, 28-32% unknown

ALND, pathologically negative

Not provided

Negative 20% <50 years old

Ipsilateral breast tumor recurrence: 16.5% vs 9.3% vs 2.8%

CALGB 9343 Tamoxifen +/- RT

636 10.5 T1-2, revised to T1 (98% <2 cm)

97% ER positive; all received Tamoxifen

ALND discouraged (63% did not); clinical node negative

Not provided

Negative 70 years or older

Local recurrence: 9% vs 2%; no difference in survival

Canadian Multi-Institutional

Tamoxifen +/- RT

769 5.6 T1-2, median 1.4 cm, 17% >2 cm

81% ER positive, all received Tamoxifen

Node negative; 83% pathologically negative

15-18% Grade 3

Negative Median 68 years old

Local recurrence: 7.7% vs 0.6%; DFS 84% vs 91%

German 2x2 study; +/- Tamoxifen, +/- RT

361 10 T1 ER positive Pathologically negative

Grade 1-2

Negative 45-75, 54% >60 years old

Local recurrence: 34% BCS vs 10% RT vs 7% Tamoxifen vs 5% both

Austrian Tamoxifen/ Anastrazole +/- RT

869 4.5 T1-2, <3 cm

ER and/or PR positive

Pathologically negative

Grade 1-2, 5% unknown

Negative Median 66 years old, 1-2% <50 years old

Local recurrence: 5.1% vs 0.4%

ALND indicates axillary lymph node dissection; DFS, disease-free survival; ER, estrogen receptor, PR, progesterone receptor; RT, radiation therapy.

reduced local recurrences (from 23% to 6%) with the great-est benefit noted in women under 45 years of age.7.

Similar results were seen with a trial from Sweden, which randomized 381 women (<2cm, node negative) to receive RT following BCS; at 10 years, RT had reduced the rate of local recurrence, from 24% to 8.5%.8 These findings have been replicated by other randomized trials, which have consistently demonstrated an improvement in local control with RT.9-12 As well, the Early Breast Cancer Tri-alists Group (EBCTG) meta-analysis has confirmed the improvement in local control and breast cancer mortality with adjuvant RT.13

It should be noted that most patients in the older ran-domized trials did not consistently receive endocrine ther-



apy. With the advent of tamoxifen and aromatase inhib-itors and the subsequent publication of NSABP B-14 and the EBCTG meta-analysis, trials were developed evaluat-ing the role of RT in patients receiving endocrine therapy (Table 1).14, 15 NSABP B-21 randomized 1009 women with node negative (following pathologic evaluation) tumors less than 1 cm to tamoxifen, RT, or RT and tamoxifen. At 8 years, the lowest rate of local recurrence was seen in the RT and tamoxifen arm (2.8%), with higher rates seen in the radiation alone (9.3%) and tamoxifen arms (16.5%). Com-pared with tamoxifen alone, RT reduced the rate of ipsilat-eral breast tumor recurrence (IBTR) by 49%.16 The CALGB 9343 trial randomized a potentially lower risk group of 636 women over 70 years of age with T1N0 estrogen receptor positive tumors to tamoxifen with or without adjuvant RT following BCS with negative surgical margins. At 10 years, RT further reduced the rate of local recurrence compared with tamoxifen alone (9% vs 2%), although no difference in cause-specific or overall survival (OS) was noted.17 These results were mirrored by a Canadian study that randomized 769 women 50 years or older with node negative tumors less than 5 cm to tamoxifen with or without RT following BCS with negative surgical margins. While an increase in local recurrence was noted in patients receiving tamoxifen alone (8% vs 1%), an increase in disease-free survival was noted, which may be due to the inclusion of younger patients than in the CALGB trial.18 A German 2×2 randomized trial eval-uated 361 low-risk women (pT1, estrogen receptor positive, margin negative, node negative) with a randomization for adjuvant RT and tamoxifen. While underpowered, at 10 years, the rates of local recurrence were 34%, 10%, 7%, and 5% for the BCS, BCS + RT, BCS + tamoxifen, and BCS + RT + tamoxifen arms, respectively.19 A more recent Austrian study evaluated 869 women with low-risk breast cancer (tumor <3 cm, ER/PR positive, grade 1/2, node negative, margins negative) and randomized women following BCS to hormonal therapy (tamoxifen or Arimidex) with or with-out adjuvant RT. At 5 years, RT significantly reduced local recurrences (5.1% vs 0.4%) and overall relapses (6.1% vs 2.1%).20 Taken together, the data support the premise that even with the additional benefit of endocrine therapy, ad-juvant RT provides a local control benefit even in low-risk patients.

Clinicians continue to search for a group of low-risk pa-tients for whom RT may not be required following BCS. One method is to apply the clinical and pathologic crite-ria utilized in the trials themselves, such as those from the CALGB 9343 trial.17 These strategies have been incorporated into evidence-based guidelines, including the Nation-al Comprehensive Cancer Network (NCCN) guidelines, which provide a category 1 recommendation to omit radia-

tion in women 70 years of age or older with T1N0 (clinical-ly negative) estrogen receptor positive tumors should they receive adjuvant endocrine therapy. No mention is made of the role of grade or margin status.21 Similarly, nomograms have been developed using clinical and pathologic charac-teristics to help risk-stratify patients and provide clinicians with an estimate of the risk of local recurrence. One exam-ple is the IBTR! nomogram, which includes age, size, mar-gins, lymphovascular invasion, tumor grade, and the utili-zation of chemotherapy and endocrine therapy.22,23 A more recent technique to identify patients who may not need adjuvant RT is to use tumor genetics rather than clinical and pathologic characteristics. Panels have been developed to evaluate the benefit of systemic therapy and have been validated.24, 25 Studies are currently looking to utilize simi-lar gene panels to identify those patients who benefit most and least from adjuvant RT. Studies with ductal carcinoma in situ (DCIS) scoring, demonstrating an ability to stratify by risk of recurrence in some groups, have been presented recently.26,27 Beyond omitting RT in low-risk patients, new treatment schedules and techniques are available to shorten the duration of treatment and the volume of normal breast tissue irradiated. One alternative gaining acceptance is the use of hypofractionated whole-breast irradiation (Table 2).28,29 A study from the Ontario Clinical Oncology Group randomized 1234 women with T1-2N0 (node dissection re-quired) breast cancer to whole-breast irradiation with either 50 Gy in 25 fractions or 42.5 Gy in 16 fractions. Forty-one percent of women received tamoxifen and 11% received che-motherapy. At 10 years, no difference in local control (7.4% vs 7.5%) or OS was noted and toxicities and cosmesis (70% excellent/good) were comparable.30 These findings were consistent with follow-up from the START A and B trials, which demonstrated comparable local control with hypof-ractionated regimens compared with standard schedules.31 The START A trial randomized 2236 women (pT1-3a, 30% node positive) to 39 Gy in 13 fractions, 41.6 in 13 fractions or 50 Gy in 25 fractions with all delivered over 5 weeks; no difference in local recurrence (5.2% vs 3.5% vs 3.6%) was noted. The START B trial randomized 2215 women (pT1-3a, 21.5% node positive) to 40 Gy in 15 fractions in 3 weeks or 5 Gy in 25 fractions, with no difference in local recurrence (2.2% vs 3.3%) with reduced adverse events in the hypofrac-tionated arm. Accelerated partial breast irradiation (APBI) is another option that shortens treatment duration and reduc-es the amount of normal breast tissue treated by irradiation to the lumpectomy cavity and the area surrounding it. APBI can be delivered with interstitial brachytherapy, applicator brachytherapy, or external beam techniques. Randomized data from Hungary have demonstrated equivalence in local control and survival compared with standard fractionation



WBI, as has a matched-pair analysis from William Beaumont Hospital with long-term follow-up.32, 33 More recently, appli-cator-based brachytherapy has emerged as the predominant brachytherapy technique, with follow-up demonstrating low rates of local recurrence and, with the development of multilumen applicators, reduced toxicities.34-36 Modern ran-domized studies comparing APBI with WBI are either under way or completed with results expected in the years to come, including the NSABP B-39 and GEC-ESTRO trials.

Clinical Implications and CasesWhen evaluating the clinical implications of modern data, it is imperative to utilize the data in conjunction with a multidisciplinary evaluation of the patient. The following examples will present common clinical scenarios and treat-ment recommendations.

Scenario 1: Age 70 years or greater, T1N0, estrogen receptor positiveThis group currently represents the subset of patients for whom omitting RT has the greatest support based on the find-

Table 2: Randomized Hypofractionated Radiation Therapy TrialsStudy Arms Number of

PatientsFollow-Up (years)

Size Hormones/Systemic Therapy

Lymph Node Status

Grade Margin Age Outcomes

Ontario Clinical Oncology Group

42.56 Gy/16 fractions vs 50 Gy/25 fractions

1234 12 T1-2 (<5 cm) 71% ER positive; 41% in both arms received Tamoxifen; 11% chemotherapy

Level I/II dissection required; node negative

19% Grade 3 in both arms

Negative 25% <50 years old in both arms

Local recurrence: 7.4% vs 7.5%; Cosmesis 70% vs 71%

MRC START A

39 Gy/13 fractions vs 41.6 Gy/13 fractions vs 50 Gy/25 fractions (5 weeks)

2236 5 pT1-3a (16% mastectomy)

81% received hormonal therapy; 35% chemotherapy

pN0-1; 29.6% node positive


>1 mm Mean 57.2 years old

Local recurrence: 5.2% vs 3.5% vs 3.6%; reduced adverse events in 39 Gy arm

MRC START B

40 Gy/15 fractions vs 50 Gy/25 fractions

2215 6 pT1-3a (8% mastectomy)

89% received hormonal therapy; 23% chemotherapy

pN0-1, 21.5% node positive


>1 mm Mean 57.0 years old

Local recurrence: 2.2% vs 3.3%; decrease late adverse events

ings of the CALGB trial as well as the evidence-based NCCN guidelines.17,21 Patients should have negative margins or un-dergo re-excision, as trials consistently included patients with negative margins. With regard to grade, the majority of pa-tients were grade ½ or grade but not evaluated while there was a subset of high-grade patients in the Canadian trial (Ta-ble 1). It should be noted that current guidelines do not incor-porate grade into the recommendations. For patients seeking an alternative to simply omitting RT, hypofractionation or APBI are reasonable alternatives to standard fractionation, though a subset analysis did find higher local recurrence with hypofractionation in high-grade tumors.30

Scenario 2: Age 70 years or greater, T1N0, estro-gen receptor negativeIn light of estrogen receptor negativity, utilizing endocrine therapy alone following BCS is not an option for this subset of patients. While omitting RT may be an option in patients with poor performance status or significant comorbidities, RT remains the standard for patients in this group includ-ing standard fractionation WBI, hypofractionated WBI,



and APBI as trials had limited numbers of receptor nega-tive patients.37 While some concern has been raised about estrogen receptor negativity and APBI, current guidelines support the use of APBI in estrogen receptor negative pa-tients.38 With regard to margin status, negative margins should be achieved if feasible prior to initiation of RT. Lim-ited data are available on the role of grade in this subset of patients.

Scenario 3: Age 70 years or greater, T2N0, estro-gen receptor positive/negativeIn patients with larger tumors (T2N0), there are limited data on omitting RT at this time. While some studies in-cluded T2 patients, most studies limited tumor size to less than 3 cm, with the exception of the Canadian trial, in which 17% of cases were >2 cm. As such, RT following BCS remains the standard with options including standard fractionation WBI, hypofractionated WBI, and APBI (<3 cm).37,38 For those patients requiring systemic therapy, less data are available regarding hypofractionated WBI, and subset analysis has shown higher recurrence rates with higher-grade tumors.37 In patients with positive margins, re-excision should be performed if feasible prior to RT with limited data available regarding grade and the omission of RT in this subset of patient.

Scenario 4: Age 50-70 years, T1N0, estrogen recep-tor positiveTo date, the data do not support the omission of RT in this subset of patients. As noted in Table 1, subsets of patients from each trial with the exception of CALGB 9343 included women in this group, though there were small numbers, particularly less than 60 years old. The Canadian trial that included women 50 years or older not only demonstrated a local recurrence increase but a decrement in disease-free survival and as such it is not considered a standard option in evidence-based guidelines.18,21 For women 60 to 69 years of age, there are data evaluating the omission of RT, but this is still evolving in light of evidence-based guidelines focusing on women over age 70 years.21 Treatment options include standard fractionation WBI, hypofractionated WBI, and APBI. While the ASTRO guidelines puts patients ages 50 to 59 as a cautionary risk for APBI, the ABS and ASBS consensus statements do not.38-40 As noted above, margin status should be considered as well as grade, par-ticularly in high-grade patients for whom hypofractionated RT is considered.

Scenario 5: Age 50-70 years, T1N0, estrogen recep-tor negative Adjuvant RT remains an essential component of BCT in

this subset of patients. While standard fractionation WBI remains the standard for these patients, hypofractionated WBI represents an option for those not requiring systemic therapy.37 APBI also represents an option for appropriately selected patients though concerns regarding estrogen re-ceptor negativity exists.38 Margins should be negative.

Scenario 6: Age 50-70 years, T2N0, estrogen re-ceptor positive/negativeIn this subset of patients, RT remains the standard of care following BCS. Conventional fractionation represents the standard, but hypofractionated RT can be considered in women based on national guidelines as well as dosimetric constraints.37 APBI also represents an option for appropri-ately selected patients in this subset with tumors less than 3 cm though there remains some debate over suitability in this subset.38-40 Surgical margins should be negative prior to proceeding with RT.

ConclusionsTrials have confirmed that adjuvant RT following BCS im-proves local control. However, new data allow for stratifying patients into low-risk cohorts (clinical/pathologic, molecu-lar) who may not require RT or who may be able to receive alternatives to standard RT (eg, hypofractionated or acceler-ated partial breast irradiation). Future studies are required to provide long-term outcomes for patients in whom RT is omitted based on such stratification criteria.

ABOUT THE AUTHORSSumma Health System and Northeast Ohio Medical University (CS, MFB), University of Nebraska Medical Center (VV), 21st Century Oncology/Michigan Healthcare Professionals (FV).

Address correspondence to: Chirag Shah, MD, Department

of Radiation Oncology, Summa Health System, 161 North Forge,

Suite G90, Akron, OH 44304, Phone: (330) 375-3557, Fax: (330)

375-3072. E-mail: [email protected].

REFERENCES

1. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347:1233-1241.

2. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a random-ized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347:1227-1232.

3. Litiere S, Werutsky G, Fentiman IS, et al. Breast conserving therapy versus mastectomy for stage I-II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial. Lancet Oncol. 2012;13:412-419.

4. Sun Y, Kim SW, Heo CY, et al. Comparison of quality of life based on surgical technique in patients with breast cancer. Jpn J Clin Oncol. 2014;44:22-27.

5. Jagsi R. Progress and controversies: radiation therapy for invasive breast cancer. CA Cancer J Clin. 2014;64:135-152.

6. Yao N, Matthews SA, Hillemeier MM, et al. Radiation therapy resources and guideline-concordant RT for early-stage breast cancer patients in an under-



served region. Health Serv Res. 2013;48:1433-1449.7. Veronesi U, Marubini E, Mariani L, et al. Radiotherapy after breast-conserving

surgery in small breast carcinoma: long-term results of a randomized trial. Ann Oncol. 2001;12:997-1003.

8. Liliegren G, Holmberg L, Bergh J, et al. 10-year results after section resection with or without postoperative RT for stage I breast cancer: a randomized trial. J Clin Oncol. 1999;17:2326-2333.

9. Renton SC, Gazet JC, Ford HT, et al. The importance of the resection margin in conservative surgery for breast cancer. Eur J Surg Oncol. 1996;22:17-22.

10. Clark RM, Whelan T, Levine M, et al. Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: an update. Ontario Clinical Oncology Group. J Natl Cancer Inst.1996;88:1659-1664.

11. Forrest AP, Stewart HJ, Everington D, et al. Randomised controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial. Scottish Cancer Trials Breast Group. Lancet. 1996;348:708-713.

12. Holli K, Hietanen P, Saaristo R, et al. Radiotherapy after segmental resection of breast cancer with favorable prognostic features:12-year follow-up results of a randomized trial. J Clin Oncol. 2009;27:927-932.

13. Clarke M, Collins R, Darby S, et al. Effects of RT and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomized trials. Lancet. 2005;366:2087-2106.

14. Fisher B, Jeong JH, Bryant J, et al. Treatment of lymph-node-negative, estrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. Lancet. 2004;364:858-868.

15. Davies C, Godwin J, Clarke M, et al. Relevance of breast cancer hormone re-ceptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomized trials. Lancet. 2011;378:771-784.

16. Fisher ER, Constantino JP, Leon ME, et al. Pathobiology of small invasive breast cancers without metastases (T1a/b, N0, M0): National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-21. Cancer. 2007;110:1929-1936.

17. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast can-cer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31:2382-2387.

18. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med. 2004;351:963-970.

19. Winzer KJ, Sauerbrei W, Braun M, et al. Radiation therapy and tamoxifen after breast-conserving surgery updated results of a 2X2 randomised clinical trial in patients with low risk of recurrence. Eur J Cancer. 2010;46:95-101.

20. Potter R, Gnant M, Kwasny W, et al. Lumpectomy plus tamoxifen or anastra-zole with or without whole-breast irradiation in women with favorable early breast cancer. Int J Radiat Oncol Biol Phys. 2007;68:334-340.

21. National Comprehensive Cancer Network. Breast Cancer (Version 1.2015). http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Ac-cessed February 22, 2015.

22. Sanghani M, Balk E, Cady B, et al. Predicting the risk of local recurrence n patients with breast cancer: an approach to a new computer-based predic-tive tool. Am J Clin Oncol. 2007;30:473-480.

23. Sanghani M, Truong PT, Raad RA, et al. Validation of a web-based predictive nomogram for ipsilateral breast tumor recurrence after breast conserving therapy. J Clin Oncol. 2010;28:718-722.

24. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26:721-728.

25. Brufsky AM. Predictive and prognostic value of the 21-gene recurrence score in hormone receptor-positive, node-positive breast cancer. Am J Clin Oncol. 2014;37:404-410.

26. Solin LJ, Gray R, Baehner FL, et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2013;105:701-710.

27. Rakovitch E, Nofech-Mozes S, Hanna W, et al. A large prospectively-designed study of the DCIS score: Predicting recurrence risk after local excision for ductal carcinoma in situ patients with and without irradiation. Presented at the San Antonio Breast Conference, December 12, 2014, San Antonio, Texas.

28. Jagsi R, Falchook AD, Hendrix LH, et al. Adoption of hypofractionated radiation therapy for breast cancer after publication of randomized trials. Int J Radiat Oncol Biol Phys. 2014;90:1001-1009

29. Jagsi R, Griffith KA, Heimburger D, et al. Choosing wisely? patterns and correlates of the use of hypofractionated whole-breast-radiation therapy in the state of Michigan. Int J Radiat Oncol Biol Phys. 2014;90:1010-1016.

30. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362:513-520.

31. Haviland JS, Owen JR, Dewar JA, et al. The UK standardisation of breast RT (START) trials of RT hypofractionation for treatment of earl breast cancer: 10-year follow-up results of two randomized controlled trials. Lancet Oncol. 2013;14:1086-1094.

32. Polgar C, Fodor J, Major T, et al. Breast-conserving therapy with partial or

whole-breast irradiation: ten-year results of the Budapest randomized trial. Radiother Oncol. 2013;108:197-202.

33. Shah C, Antonucci JV, Wilkinson JB, et al. Twelve-year clinical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast irradiation: results of a matched-pair analysis. Radiother Oncol. 2011;100:210-214.

34. Shah C, Badiyan S, Wilkinson J, et al. Treatment efficacy with accelerated partial breast irradiation (APBI): final analysis of the American Society of Breast Surgeons MammoSite breast brachytherapy registry trial. Ann Surg Oncol. 2013;20:3279-3285.

35. Shah C, Khwaja S, Badiyan S, et al. Brachytherapy-based partial breast irradiation is associated with low rates of complications and excellent cosmesis. Brachytherapy. 2013;12:278-284.

36. Arthur DW, Vicini FA, Todor DA, et al. Contura multilumen balloon breast brachytherapy catheter: comparative dosimetric findings of a phase 4 trial. Int J Radiat Oncol Biol Phys. 2013;86:264-269.

37. Smith BD, Bentzen SM, Correa CR, et al. Fractionation for whole-breast irra-diation: an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011;81:59-68.

38. Shah C, Vicini F, Wazer DE, et al. The American Brachytherapy Society con-sensus statement for accelerated partial breast irradiation. Brachytherapy 2013;12:267-277.

39. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradia-tion consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74:987-1001.

40. American Society of Breast Surgeons. Consensus statement for accelerated par-tial breast irradiation. https://www.breastsurgeons.org/statements/PDF_State-ments/APBI_statement_revised_100708.pdf. Accessed February 22, 2015.


S T R A T E G I C A L L I A N C E P A R T N E R S H I P P R O G R A M

Liposomal Encapsulation of Radiotherapeutics Holds Promise in Treating Glioblastoma

By Andrew Brenner, MD, PhD

Neuro-Oncologist, Medical Oncologist Cancer Therapy & Research Center Assistant Professor School of Medicine, UT Health Science Center San Antonio, TX

Primary brain tumors are a cause of marked debility and are characterized by poor survival. In 2015, an estimated 23,180 new cases of primary malignant brain tumors will be diagnosed and 16,570 patients will die from these tu-mors.1 Glioblastoma (GBM, grade IV astrocytoma) is the most common and most aggressive of the primary ma-lignant brain tumors in adults, with historical 1-year and 5-year survival rates of 29.3% and 3.3%, respectively.1

Currently, frontline treatment consists of a multi-modality approach that includes maximal surgical resection and adjuvant radiation therapy with con-current temozolomide. This multimodal approach has been the standard of care since the EORTC phase III trial demonstrated a median survival of 14.6 months in the temozolomide group versus 12.1 months in the radiation alone group.2 While this was a significant improvement, it is clear that radiation remains the most effective component of the combined approach on median survival with multiple randomized studies showing a 5-month improvement in survival with XRT alone3 compared to an additional 2.5 months with the addition of temozolomide.

Theoretically, any tumor can be controlled if a suf-ficient dose of radiation is delivered to the tumor. The main limiting factor in delivering a tumoricidal dose is the toxicity to surrounding normal tissue. As the tra-ditional x-ray radiation beam passes through the skull

and brain to reach the tumor it is absorbed by the body and shows exponential decrease in the dose delivered with tissue depth. Even using highly conformal appli-cations such as TomoTherapy or Intensity Modulated Radiation Therapy, doses are limited to less than 80 Gy4 due to progressive toxicity with increasing dose. With brachytherapy, the most successful example has been in the use of radioactive iodine to treat thyroid cancer, which can be completely ablated with doses of nearly 1000 Gy with almost no toxicity to surrounding normal tissue. The reason that other therapeutic ra-dionuclides have not been successfully developed for other types of cancer is due to an inability to specifi-cally deliver these isotopes.

Rhenium-186 (186Re) is a reactor-produced iso-tope with great potential for medical therapy if it can be successfully delivered. It is in the same chemi-cal family as technetium-99m (99mTc), which is a commonly used isotope for diagnostic imaging. The average 186Re beta particle path length in tissue of 2 mm is ideal for treatment of solid tumors and the half-life of 90 hours is clinically meaningful. However, a carrier is needed to deliver the isotope to the brain and maintain its localization at the desired site, as it would otherwise quickly disperse and be carried away from the site of injection by the circulatory system.

Liposomes, spontaneously forming lipid nanoparti-cles, have rapidly evolved as carriers of cancer thera-peutics. They consist of naturally occurring lipid bi-layers that are nearly identical to the lipid membranes of normal cells. The list of FDA-approved liposomal drugs includes Doxil (liposomal doxorubicin) and De-pocyt (liposomal cytarabine) to just name two.

For treatment of locally invasive tumors, liposomal encapsulation of radiotherapeutics holds significant promise. To achieve this, we have developed a propri-etary encapsulation method using a custom lipophilic molecule that carries radionuclides into the aqueous compartment of the liposomes. The final investiga-tional product is BMEDA-chelated-186Rhenium en-capsulated within liposomes. These rhenium-labeled nanoliposomes (RNL) have shown great promise in preclinical studies for the treatment of cancer by re-gional and local administration.5-8



To better char-acterize the poten-tial delivery, toxic-ity, and efficacy of these high specific activity RNL, in-tracranial applica-tion by convection enhanced delivery (CED) in a U87 gli-oma rat model was investigated. RNL remained confined to the site of injec-tion over 96 hours, and doses of up to 1850 Gy were ad-ministered without evidence of toxici-ty. Animals treated with RNL had a me-dian survival of 126 days (95% CI, 78.4-173 days) compared to 49 days (95% CI, 44-53 days) in con-trols. Log rank analysis between these two groups was highly significant (P = .0013), and was even higher when 100 Gy was used as a cutoff (P <.0001). MRI and luciferase imaging showed significant difference in tumor size (Figure), with many tumors completely ablated. Duplication of tumor volume differences and survival benefit was possible in a more invasive U251 orthotopic model with median survival in treated an-imals not reached at 120 days due to lack of mortali-ty, and log rank analysis of survival highly significant (P = .0057). Analysis of tumors by histology revealed minimal areas of necrosis and gliosis.

Good Laboratory Practice (GLP) toxicology studies in beagles have shown that intracranial administra-tion of RNL up to 360 Gy produced no significant test article-related pathologic changes in the brains of dogs at 24 hours or 14 days, supporting the study of RNL in humans. I am currently leading a phase I clin-ical trial of RNL in patients with glioblastoma sup-ported by NanoTx Therapeutics at the CTRC in San Antonio, Texas.

REFERENCES1. Ostrom QT, et al. CBTRUS statistical report: primary brain and

central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol. 2014;16 Suppl 4:iv1-63.

2. Stupp R, et al. Radiotherapy plus concomitant and adjuvant

temozolomide for glioblastoma. N Engl J Med. 2005;352(10): 987-996.

3. Chang JE, et al. Radiotherapy and radiosensitizers in the treatment of glioblastoma multiforme. Clin Adv Hematol Oncol. 2007;5(11):894-902, 907-915.

4. Werner-Wasik M, et al. Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malig-nant gliomas. Radiation Therapy Oncology Group Study 83-02. Cancer. 1996;77(8):1535-1543.

5. Bao A, et al. A novel liposome radiolabeling method using 99mTc-”SNS/S” complexes: in vitro and in vivo evaluation. J Pharm Sci. 2003;92(9):1893-1894.

6. French JT, et al. Interventional therapy of head and neck can-cer with lipid nanoparticle-carried rhenium 186 radionuclide. J Vasc Interv Radiol. 2010;21(8):1271-1279.

7. Wang SX, et al. Intraoperative 186Re-liposome radionu-clide therapy in a head and neck squamous cell carcinoma xenograft positive surgical margin model. Clin Cancer Res. 2008;14(12):3975-3983.

8. Wang SX, et al. Intraoperative therapy with liposomal drug delivery: retention and distribution in human head and neck squamous cell carcinoma xenograft model. Int J Pharm. 2009;373(1-2):156-164.

Figure. Response on MRI to Rhenium Nanoliposomes

Arrows show tumors established in the brains of athymic rats 1 day prior to treatment, 14 days after treatment, and at day 72 after treatment. No control animals were alive at 72 days.


By Steven Eric Finkelstein, MD

Chief Science Officer21st Century OncologyScottsdale, AZ

S T R A T E G I C A L L I A N C E P A R T N E R S H I P P R O G R A M

Radiotherapy’s Immunologic Properties Offer Paradigm-Changing Potential

Radiation-driven immunotherapy (RDI) is an exciting area of research where evidence is accumulating sug-gesting that this biological process may have important ramifications for the future of clinical radiotherapy. In patients undergoing radiation, the complex interplay of tumor cell death, antigen expression, inflammatory signals, and lymphocyte and dendritic cell (DC) acti-vation presents a unique therapeutic opportunity. To-gether, the whole therapeutic effect can exceed the sum of its parts and can present the potential for further improvement of immunotherapy effects arising from tumor irradiation to generate RDI—in effect providing immunologic-mediated, radiation-driven personalized systemic therapy.

The fundamental mechanism of tumor control through radiotherapy is through induction of DNA damage in can-cer cells. However, this view is not a complete picture of the time course of cellular events within the tumor. There are as-sociated changes in the microenvironment, tumor-associ - ated endothelial cells, inflammatory infiltrates, and sys-temic responses to the tumor destruction. Areas of high-er dose exposure inside the bulk of the tumor may have markedly different pathways to cell death, emphasizing necrosis mechanisms. Additionally, the time course of changes of antigen expression during the cell-killing pro-cess and differences among radiotherapy techniques can be relevant.1

Several events have been studied for their specific immunotherapy relevance beyond the phenomenon of cells dying within the radiated tumor. Some of the downstream events relate to inflamma-tion and clearance of antigens within the

irradiated volume; those of most interest influence ac-quisition of a more activated general or more activated tumor-specific phenotype. The most dramatic outcome is when a distant tumor mass regresses as a consequence of this, known as the abscopal effect. Examples of this effect are described in case reports2-4 and preclinical studies,5 which have led to recently completed clinical trials.6-12 Other less apparent outcomes as a consequence of the radiation-triggered immune activation include acceleration or completion of definitive clearance of the irradiated tumor or clearance of microscopic or other metastatic disease that was not clinically apparent.

Incorporating RDI Into Therapy Indeed, there are abundant opportunities to transform the phenomenon of radiotherapy-induced antican-cer immune response from the realm of isolated case report into a predictable, directed therapeutic goal. What are the key components to make this a reality?

Priming the SystemOne component is the understanding of how to use system-ic therapies to transform the host lymphocyte compartment and antigen-presenting cell compartments so that they be-come primed to be stimulated. Some examples of immune modulators with the potential of having a significant impact on the phenotypes of the DC compartment include TLR9 ag-onists,13,14 all trans retinoic acid,15 and inhibitors of VEGF, TGF-β, or of other cytokines.16-18 Comparably, stimulation of the lymphocyte compartment with checkpoint inhibitors (PD-1, CTLA-4) and cytokines also appears poised to make a significant contribution to clinical practice.

Providing AntigensAnother component is development of further effec-tive ways to provide tumor-associated antigen to the



immune system. While recombinant vaccines, tumor lysates, and synthetic peptides have attributes of con-venience and definable antigen sets, they cannot be considered interchangeable with tumor irradiation as a source. Unique features of tumor irradiation include si-multaneous elaboration of subtle microenvironmental changes with the capacity to improve antigen presen-tation, total tumor as a source of antigen, production of radiation-induced antigens, and provision of antigen even before overt or immediate cell killing occurs.

Further, evolving flexibility of radiation technique, particularly in relation to conventional fractionation, hypofractionation, brachytherapy, stereotactic radio-surgery techniques, and high intratumoral dose ex-posure may be of particular interest for optimization with respect to the potential to trigger an abscopal re-sponse. This may be related to tumor effect, DC effect, lymphocyte effects, or indirect modulation of the way the tumor is affecting leukocyte compartments.

Cellular TherapyA third component of interest is cellular therapy, particularly DC injection. Many questions about timing with respect to irradiation and details of ex vivo preparation remain to be addressed em-pirically. Appropriate patient preparation, se-lection, and antigen loading could improve outcomes as well. In addition, the optimal vol-ume and number of cells merits empiric study. Finally, as a necessary part of clinical development, there must be some focus on specific cancer diagnoses.

In summary, it is clear that radiation is a modulator of the interaction of the tumor and immune compart-ments. Careful study of the microenvironment of the irradiated tumor in involution should create some ex-citing future opportunities for RDI.

REFERENCES

1. Finkelstein SE, Timmerman R, McBride WH, et al. The confluence of stereotactic ablative radiotherapy and tumor immunology [pub-lished online November 15, 2011]. Clin Dev Immunol. 2011:439752. doi:10.1155/2011/439752.

2. Kingsley DP. An interesting case of possible abscopal effect in malig-nant melanoma. Br J Radiol. 1975;48(574):863-866.

3. Stamell EF, Wolchok JD, Gnjatic S, Lee NY, Brownell I. The abscopal ef-fect associated with a systemic anti-melanoma immune response [pub-lished online May 5, 2012]. Int J Radiat Oncol Biol Phys. 2013;85(2):293-295.

4. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925-931.

5. Finkelstein SE, Heimann DM, Klebanoff CA, et al. Bedside to bench and back again: how animal models are guiding the development of new immunotherapies for cancer [published online May 20, 2004]. J Leukoc Biol. 2004;76(2):333-337.

6. Gulley JL, Arlen PM, Bastian A, et al. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer [published correction appears in Clin Cancer Res.

2006;12(1):322]. Clin Cancer Res. 2005;11(9):3353-3362.7. Finkelstein SE, Rodriguez F, Dunn M, et al. Serial assessment of

lymphocytes and apoptosis in the prostate during coordinated intra-prostatic dendritic cell injection and radiotherapy. Immunotherapy. 2012;4(4):373-382

8. Finkelstein SE, Iclozan C, Bui MM, et al. Combination of external beam radiation (EBRT) with intratumoral injection of dendritic cells as neo-adju-vant treatment of high-risk soft tissue sarcoma patients [published online March 11, 2011]. Int J Radiat Oncol Biol Phys. 2012;82(2):924-932.

9. Finkelstein SE, Trotti A, Rao N, et al. The Florida Melanoma Trial I: A prospective multicenter phase I/II trial of postoperative hypofrac-tionated adjuvant radiotherapy with concurrent interferon-alpha-2b immunotherapy in the treatment of advanced stage III melanoma with long term toxicity follow-up. ISRN Immunology. 2012; article ID 324235. doi:10.5402/2012/324235.

10. Kamrava M, Kesarwala AH, Madan RA, et al. Long-term follow-up of prostate cancer patients treated with vaccine and definitive radiation therapy [published online March 6, 2012]. Prostate Cancer Prostatic Dis. 2012;15(3)289-295.

11. Redman BG, Hillman GG, Flaherty L, et al. Phase II trial of sequential radiation and interleukin 2 in the treatment of patients with metastatic renal cell carcinoma. Clin Cancer Res. 1998;4(2):283-286.

12. Kerst JM, Bex A, Mallo H, et al. Prolonged low dose IL-2 and thalido-mide in progressive metastatic renal cell carcinoma with concurrent radiotherapy to bone and/or soft tissue metastasis: a phase II study [published online May 19, 2005]. Cancer Immunol Immunother. 2005;54(9):926-931.

13. Brody JD, Ai WZ, Czerwinski DK, et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study [pub-lished online August 9, 2010]. J Clin Oncol. 2010;28(28):4324-4332.

14. Kim YH, Gratzinger D, Harrison C, et al. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study [published online November 1, 2011]. Blood. 2012;119(2):355-363.

15. Mirza N, Fishman M, Fricke I, et al. All-trans-retinoic acid improves dif-ferentiation of myeloid cells and immune response in cancer patients. Cancer Res. 2006;66(18):9299-9307.

16. Zeng R, Spolski R, Finkelstein SE, et al. Synergy of IL-21 and IL-15 in regulat-ing CD8+ T cell expansion and function. J Exp Med. 2005;201(1):139-48.

17. Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostat-ic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202(7):907-912.

18. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal ef-fect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):5379-5388.

21st Century Oncology provides cancer care through a network of nearly 180 treatment centers, including 140 in the United States. Its corporate headquarters, above, is in Fort Myers, Florida.






This activity is supported by educational grants from Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Biodesix Inc., Bristol-Myers Squibb, Celgene Corporation, Clovis Oncology, Lilly, and Novartis Pharmaceuticals Corporation.

For further information concerning Lilly grant funding visit www.lillygrantoffice.com.


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