proton therapy for prostate cancer

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TITLE: Proton Therapy for Prostate Cancer

AUTHOR: Judith Walsh, MD, MPH

Professor of Medicine

Division of General Internal Medicine

Department of Medicine

University of California San Francisco

PUBLISHER: California Technology Assessment Forum

DATE OF

PUBLICATION: October 17, 2012

PLACE OF

PUBLICATION: San Francisco, CA

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PROTON BEAM THERAPY FOR PROSTATE CANCER

A Technology Assessment

INTRODUCTION

The California Technology Assessment Forum is requested to review the scientific

evidence for the use of proton therapy for the treatment of localized prostate cancer. This

is the first time that CTAF has addressed this topic.

BACKGROUND

Epidemiology of Prostate Cancer

Prostate cancer is the most commonly diagnosed cancer in U.S. men and is second

only to lung cancer as a cause of cancer death in U.S. men. It is estimated that in the year

2012, there will be 241,170 new cases in the U.S. and that 28,170 men will die from prostate

cancer.1

Treatment options for prostate cancer depend on extent of disease at diagnosis. For

men with clinically localized prostate cancer (cancer confined to the prostate), treatment

options focus on more local approaches, whereas systemic approaches, such as androgen

deprivation therapy, are used in men with more distant disease. For men who have

prostate cancer that extends beyond the prostatic capsule, into the seminal vesicles or the

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adjacent nodes, radical prostatectomy is sometimes combined with adjuvant radiation

therapy.

A particular challenge in the treatment of prostate cancer is that because of the

prolonged natural history of prostate cancer, many men will die WITH but not FROM

prostate cancer, whereas some will develop metastatic and potentially fatal disease. Risk

stratification helps identify which patients are low versus high risk and can be helpful in

guiding therapy. Risk stratification for prostate cancer includes the following: clinical stage

of disease, baseline serum prostate specific antigen (PSA) level, the Gleason score and the

extent of prostatic involvement. The Gleason score is a grading scale (2-10) for prostate

cancer tissue and indicates the likelihood that the cancer tumor will spread. Higher

Gleason scores show greater differences between the cancer tissue and normal prostate

tissue and indicates greater likelihood of the cancer tissue to metastasize.

Very low risk clinically localized prostate cancer is defined as disease detected by

biopsy only (no abnormalities detected on rectal examination or imaging), Gleason score

of 6 or less on biopsy and a serum PSA <10ng/ml. Within the prostate, the extent of

disease must be limited (fewer than three positive biopsy cores with less than 50%

involvement in any core and a PSA density of less than 0.15 ng/mL/gram.)2

Low risk, clinically localized prostate cancer is disease limited to one lobe of the

prostate or with no apparent tumor (diagnosis based only on biopsy, serum PSA < 10

ng/ml and a Gleason score ≤ 6.)

Men with low or very low risk prostate cancer are typically offered treatment options

that include active surveillance, radiotherapy and radical prostatectomy.

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Treatment of Localized Prostate Cancer

Standard treatment options for men diagnosed with localized prostate cancer include

radiation therapy (external beam or brachytherapy), radical prostatectomy and for some

patients, active surveillance. When disease has spread through the prostatic capsule,

prostatectomy may be combined with adjuvant radiation therapy or androgen deprivation

therapy may be added to radiation therapy.

1. Role of prostatectomy for treatment of localized prostate cancer

Radical prostatectomy is an established treatment option for localized prostate cancer.

The entire prostate is removed. Prostatectomy has been associated with high rates of long

term cancer control, but is also associated with significant complications including

incontinence and impotence.

2. Role of external beam radiation therapy for localized prostate cancer

The overall goal of radiation therapy for prostate cancer is to deliver a therapeutic

dose of radiation to the tumor while minimizing radiation of surrounding normal tissue.

External beam radiotherapy uses an external radiation source to radiate the prostate and a

small amount of surrounding tissue. Intensity modulated radiation therapy is the standard

technique by which radiation is administered and is an advanced type of three dimensional

conformal radiation therapy (3D-CRT). This technique has replaced the previously used

two dimensional approaches, which are now considered outdated. The radiation beam

varies in intensity with the goal of targeting a complex tumor more effectively and

minimizing the impact on surrounding tissues.

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In addition to recommending the use of 3D conformal techniques, the National

Comprehensive Cancer Network (NCCN) Guidelines in Oncology recommends that a

conventional dose of 70 Gy is not considered adequate and recommends doses between

75.6 and 79 Gy for individuals with low risk prostate cancer. For patients with intermediate

or higher risk disease, they recommend that doses up to 81 Gy are appropriate.2

3. Role of brachytherapy for the treatment of localized prostate cancer.

Brachytherapy involves the implantation of a radioactive source directly into the

prostate. Since the radiation source is within the tumor, the goal is to maximize the

radiation to the tumor, while minimizing the effect on surrounding normal tissues.

Treatment options include implanting a permanent radiation source, usually using iodine-

125 or palladium-103 or a temporary radiation source such as iridium -192.

Technologic Advances in Prostate Cancer Treatment

Prostate cancer treatment is an area where there have been many recent technologic

advances. These advances include minimally invasive radical prostatectomy, intensity

modulated radiation therapy (IMRT) and proton therapy. Adoption of these technologies

resulted in a $350 million increase in health care expenditures in 2005.3 The Institute of

Medicine has recommended that the treatment of localized prostate cancer be considered

one of the first quartile priorities for comparative effectiveness research.4

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Proton beam therapy

Proton beam therapy is a type of external beam radiotherapy using ionizing radiation.

The theoretic advantage of using protons for radiotherapy is that because of their

relatively large mass, there is less scatter and therefore the radiation dose can be more

concentrated on the tumor. As charged particles move through the tissue, they slow down

and energy is transferred to adjacent tissues. Most of the energy gets deposited at the

end of a “linear track.” known as the “Bragg Peak.” For protons, the dose of radiation

beyond the Bragg peak drops quickly to zero (exit dose) thereby limiting the impact of the

radiation on tissue beyond the Bragg peak. Thus, tissue that is beyond or distal to the

tumor receive minimal radiation, whereas tissues that are closer to the body surface than

the tumor will still receive some radiation.

The use of proton beams or particle therapy as an oncologic treatment was initially

proposed in 1946 by Dr. Robert Wilson.5 During the 1950s, particle therapy use began at

the Lawrence Berkeley Laboratory, the Harvard Cyclotron and in Uppsala, Sweden.6-8

Loma Linda University opened the first hospital based facility and started treating patients

in the 1990s.9 Massachusetts General Hospital also has a proton facility.

Proton beam therapy can be given either by itself or as a boost to x-ray external beam

radiotherapy. Proton beam therapy boost can be compared with either no boost or an x-

ray boost. Proton beam therapy (alone or as a boost) can be compared with other

prostate cancer treatments including brachytherapy, watchful waiting, radical

prostatectomy or standard radiotherapy.

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Radiation therapy dose is typically measured in Gray units (eg total dose was 70 Gy).

The relative biological effectiveness (RBE) is the ratio of the photon dose to the particle

dose required to produce the same biological effect. For proton beams, the relative

biological effectiveness is 1.1. To measure the total radiation dose with proton beams, Gray

equivalents (GyE) or cobalt Gray equivalents (CGE) are often used with protons. The CGE is

the Gray multiplied by the RBE factor specific for the beam used.

Proton beam therapy has been used for the treatment of many cancers, including

lung, hepatocellular, head and neck, cervical, renal cell, bone and soft tissue sarcomas,

melanoma, chordoma and chondrosarcomas of the skull base, prostate cancer and

pediatric malignancies. For some of these cancers, such as large uveal melanomas and

selected pediatric malignancies, particle therapy is considered the standard of care, but for

other cancers, the use of proton beam therapy has been more controversial. The use of

proton beam therapy is increasing as more proton beam treatment centers are opening,

and direct to consumer advertising is likely to lead to an increase in use.10,11 The goal of

this assessment is to evaluate the evidence for the use of proton beam therapy in the

treatment of localized prostate cancer.

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TECHNOLOGY ASSESSMENT (TA)

TA Criterion 1: The technology must have final approval from the appropriate

government regulatory bodies.

Proton beam therapy is a form of external radiotherapy using ionizing radiation. It is a

procedure and therefore not under FDA regulations and oversight. The equipment used

to create and deliver the proton beam (cyclotron, synchrotron, magnets, and other pieces

of equipment to modify the range of protons and to shape/focus the beam) is considered

a medical device and under FDA regulations and oversight.

TA Criterion 1 is met.

TA Criterion 2: The scientific evidence must permit conclusions concerning the

effectiveness of the technology regarding health outcomes.

The Medline database, Cochrane clinical trials database, Cochrane reviews database

and the Database of Abstracts of Reviews of Effects (DARE) were searched using the key

words: “prostate cancer ” and “proton therapy” or “protons.” The search was performed

from database inception through August, 2012. The bibliographies of systematic reviews

and key articles were manually searched for additional references. The abstracts of

citations were reviewed for relevance and all potentially relevant articles were reviewed in

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full.

Study had to evaluate proton beam therapy as a treatment for prostate cancer

Study had to evaluate clinical outcomes

Included only humans

Published in English as a peer reviewed article

Our search revealed 250 potentially relevant articles. We reviewed all the titles and

identified 22 potentially relevant abstracts. Abstracts were reviewed in full and we

identified 13 studies as potentially relevant for inclusion. Reasons for exclusion included

not focusing on clinically relevant outcomes, or being a duplicate of an earlier publication.

A total of 14 studies evaluated the use of proton beam therapy for the treatment of

prostate cancer and assessed clinical outcomes. Seven of these studies were non-

comparative studies.12-18 and seven were comparative19-26 (Table 3). Of the non-

comparative studies, two were randomized19,21,22 and the remaining five were not.23-25,27

Level of Evidence: 2,3,5

TA Criterion 2 is met

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Table 1: Non-com

parative studies of the use of Proton Beam Therapy for the Treatm

ent of Prostate Cancer Study

Type N

Location

Intervention Inclusion Criteria

Outcom

es M

ayahara, 2007

Retrospective cohort

287 Japan

Proton therapy 74GyE T1-4N

oMo prostate

cancer and treated with proton therapy (Dose 76Gye)

Acute Genitourinary morbidity

Acute Gastrointestinal Morbidity

Mendenhall,

2012 Retrospective cohort:

211 Florida

78-82 CGE 78 CGE for low risk disease 78-82 CGE for interm

ediate risk disease 78 CGE for high risk with docetaxel and androgen deprivation

Patients on approved protocols with low risk, interm

ediate risk and high risk prostate cancer with at least 2 year follow up

Disease progression GI toxicity GU toxicity

Nihei, 2005

Phase II 30

Japan 76 Gy XRT plus proton boost

T1-3N0M

0 GI toxicities GU toxicities

Nihei, 2011

Multi-

institutional Phase II

151 Japan

74Gye proton therapy (included boost with interm

ediate risk patients)

T1-2 N0M

0 Late Grade 2 or greater Rectal Toxicity at 2 years

Gardner, 2002

Subgroup analysis in long term

survivors of Phase II study and experim

ental arm

of RCT

39 Boston, M

A XRT plus photon boost 77.4Gy

T3-4 survivors of Phase II study and experim

ental arm

of RCT (Duttenhaver, 1983; Shipley, 1979)

Late normal tissue sequelae

Slater, 2004 Retrospective Cohort

1255 Lom

a Linda, CA

XRT plus proton boost 75Gy

Localized prostate cancer (stages Ia-III)

Freedom from

biochemical

evidence of disease Failure: 3 consecutive rises in PSA levels with the date of failure being m

idway between the nadir and the first rise

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Study Type

N

Location Intervention

Inclusion Criteria O

utcomes

Johannson, 2012


278 Sweden

XRT plus proton boost 70 Gy

Low, medium

and high risk localized prostate cancer

5 year PSA progression free survival GI and GU toxicities

GyE: Gray Equivalents

CGE: Cobalt Gray Equivalents T_N

_M_: A staging system

for prostate cancer. T=measures the extent of the prim

ary tumor, N

= whether the cancer has spread to nearby lymph

nodes, and M = absence or presence of m

etastases GI: Gastrointestinal

GU: Geniturinary XRT: X-ray therapy

PSA: Prostate Specific Antigen

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Table 2: O

utcomes of non-com

parative studies of the use of proton beam therapy for the treatm

ent of prostate cancer

Study Type

N

Duration of follow-up

Main O

utcomes

Comm

ents

Mayahara,

2007 Retrospective cohort

287

No grade 2 or higher GI m

orbidity 39%

and 1% had Grade 2 and Grade 3 GU m

orbidities 87%

of patients with GU sym

ptoms had relief with

alpha blocker therapy M

endenall, 2012


211 M

inimum

2 years m

ean not reported

1/82 intermediate risk patients with disease progression

2/40 high risk patients with disease progression 1.9%

Grade 3 GU symptom

s ,0.5%

Grade 3 GI toxicities

Early outcomes

Nihei, 2005

Phase II 30

30 months

No Grade 3 or greater acute or late toxicities

6 patients had biochemical relapse

Feasibility study

Nihei, 2011

Multi-Institutional

Phase II 151

43.4 months

At two years, incidence of late Grade 2 or greater: rectal toxicity 2%

(95% C.I. 0-4.3%

) and bladder toxicity 4.1%

(95% C.I. 0.9-7.3%

)

Gardner, 2002

Subgroup analysis in long term

survivors of Phase II study and experim

ental arm

of RCT

39 13.1years

Grade 2 or greater GU morbidity at 15 years: 59%

Grade 2 or greater hem

aturia at 5 years: 21%; at 15

years: 47%

Grade 2 or greater GI morbidity at 5 years: 13%

; at 15 years: 13%

Long term follow up of

patients already included in other studies Few serious effects

Slater, 2004 Retrospective cohort

1,255 63 m

onths O

verall biochemical disease free survival 73%

Johansson, 2012


278 57 m

onths 5 year PSA progression free survival: 100%

, 95% and

74% for low, interm

ediate and high risk Bladder toxicities (not GI) were dose lim

iting

GI: Gastrointestinal

GU: Genitourinary

C.I.: Confidence Interval

RCT: Random

ized Controlled Trial


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Table 3: Description of Comparative Studies of the Use of Proton Beam

Therapy for the Treatment of Prostate Cancer

Study Type

N

Location Inclusion Criteria

Intervention O

utcomes

Randomized

PROG/ACR 95-

09, [Zietman,

2010; Zietman,

2005; Talcott, 2010]

RCT 393

Loma Linda

University, CA and M

assachusetts General, Boston M

A

Stage T1b through T2b prostate cancer and PSA <15 ng/m

l

External radiation with a com

bination of conformal

photon and proton beams

to a total dose of 70.2Gy (conventional dose) or 79.2 Gy (high dose) .

Biochemical Failure (Increasing PSA

level 5 years after treatment)

Local Failure GI and GU m

orbidity O

verall survival

Shipley, 1995 Phase III

202 Boston, M

A Stage T3-T4, N

x0-2, M

o 10-25 M

V photons with conform

al protons to total dose of CGE or XRT to dose of 67.2 Gy

Overall survival (O

S), disease specific survival (DSS) and total recurrence-free survival (TRFS) Local control (digital rectal and rebiopsy negative)

Nonrandom

ized Studies Sheets, 2012

Population based registry- propensity score m

atched com

parison

1,368 U.S. 16 population based cancer registries

Patients with nonm

etastatic prostate cancer

IMRT versus proton therapy

Rates of GI and urinary morbidity,

erectile dysfunction, hip fractures and additional cancer therapy

Duttenhaver, 1983

Phase I/II com

parison 180

Boston, MA

Localized prostate cancer (T1-4)

XRT 50Gy versus protons plus XRT50Gy plus 74 CGE proton boost

Survival, disease free survival and local recurrence free survival

Galbraith, 2001 Survey

185 Lom

a Linda, M

en with prostate cancer who had

1) watchful waiting, 2) surgery, 3) conventional

Quality of Life Index

Medical O

utcomes study General

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Study Type

N

Location Inclusion Criteria

Intervention O

utcomes

received various treatm

ents external beam

radiation (65-70 Gy), 4) proton-beam

radiation (74-75Gy), 5) com

bination of conventional external beam

radiation and proton beam

or mixed beam

radiation (74-75Gy) ,

Health Survey Southwest O

ncology Group Prostate Treatm

ent-specific symptom

s M

easure (PTSS)

Coen, 2012 Case-m

atched analysis

282 (141 part of the PRO

G/ACR 95-09,trial)

Loma Linda

and Boston Localized Prostate cancer

141 patients in high dose proton/XRT arm

of PRO

G/ACR95-09 matched

with 141 patients who received brachytherapy

Biochemical Failure

Jabbari, 2010 Two retrospective cohorts com

pared with published results of a trial

249 (PPI) 195 (CPBRT) 124 (CD-CRT)

UCSF, University of M

ichigan , Lom

a Linda and M

assachusetts General Hospital

Localized prostate cancer

249 patients who received PPI at UCSF were com

pared with 124 patients from

a 3D-CRT cohort and 195 patients enrolled in a published trial of CPBRT

Biochemical control (biochem

ical no evidence of disease (bN

ED) and PSA nadir

PROG/ACR: Proton Radiation O

ncology Group (PROG)/Am

erican College of Radiology (ACR) 95-09 (a randomized trial)

RCT: Randomized Controlled Trial

T_N_M

_: A staging system for prostate cancer. T=m

easures the extent of the primary tum

or, N = whether the cancer has spread to nearby lym

ph nodes, and M

= absence or presence of metastases

Gy: Gray PSA: Prostate Specific Antigen GI: Gastrointestinal GU: Genitourinary

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MV: M

egavolts XRT: X-ray Therapy PPI: Perm

anent Prostate Implant Brachytherapy

3D-CRT: Three Dimensional Conform

al Radiotherapy CPBRT: Conform

al proton beam radiotherapy

UCSF: University of California, San Francisco bN

ED: Biochemical N

o Evidence of Disease

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Table 4: Outcom

es of Comparative Studies of Proton Beam

Therapy for the Treatment of Prostate Cancer

Study M

ean Age Average Duration of Follow-Up

Results Com

ments

Randomized

PROG/ACR 95-09;

Zeitman, 2010;

Zeitman, 2005;

Talcott, 2010]

67 in conventional group and 66 in high dose group

8.9 years Proportion free from

BF at 5 years: 61.4% for conventional dose

versus 80.4% for high dose (p<0.001)

10 year BF rates: 32.4% for conventional dose and 16.7%

for high dose (p<0.0001) N

o difference in overall survival at either time point

GU toxicity ≥3: 2% in each arm

GI toxicity ≥3: 1%

in high dose arm

Mainly com

pared two doses of x-ray therapy. Both groups received proton therapy.

Shipley, 1995 70 in proton arm

and 68.6 in conventional arm

61 months

No differences in O

S, DSS, TRFS or local control Increase in local control only in patients with poorly differentiated tum

ors (5 year local control rate: 94% versus 64%

: p<0.01) Rectal bleeding higher in proton group (32%

versus 12%:

p=0.002) Urethral stricture nonsignificantly higher in proton group (19%

versus 8%

)

Nonrandom

ized Studies Sheets, 2012

Not calculated-

propensity m

atched

Propensity m

atched GI m

orbidity: 12.2 per 100 person years for IMRT versus 17.8 per

100 person years for proton: RR 0.66 (95% C.I. 0.55-0.79)

No differences in other m

orbidities

Proton therapy only available in few places so propensity m

atching Duttenhaver, 1983

67.7 N

ot reported N

o differences in survival, disease free survival and local recurrence free survival

Nonrandom

ized early study

Galbraith, 2001 68

18 months

No overall differences in health status or health related quality of

life Survey Patients not random

ized

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Study M

ean Age Average Duration of Follow-Up

Results Com

ments

Coen, 2012 67 in EBRT and 65 in brachytherapy arm

8.6 years for EBRT and 7.4 years for brachytherapy

No difference in 8 year biochem

ical failure rates ((7.7% for EBRT

and 16.1% for brachytherapy (p=0.42)

Jabbari, 2010 63 (PPI) 66 (CPBRT) 70 (3D-CRT)

5.3 years for PPI 58 m

onths for 3D-CRT 5.5 years for CPBRT

5 year bNED rate after a CPBRT 91%

vs 93% for sim

ilar group of PPI patients 91%

of PPI patients achieved a lower PSA nadir compared with

those in the CPBRTB trial (PSA nadir ≤0.5 ng/ml, 91%

vs 59%

Similar outcom

es for PPI vs CPBRTB in nonrandom

ized retrospective cohorts

PROG/ACR: Proton Radiation O

ncology Group (PROG)/Am

erican College of Radiology (ACR) 95-09 (a randomized trial)

BF: Biochemical Failure

GI: Gastrointestinal GU: Genitourinary O

S: Overall Survival

DSS: Disease Specific Survival TRFS: Total Recurrence Free Survival IM

RT: Intensity Modulated Radiation Therapy

RR: Relative Risk

EBRT: External Beam Radiation Therapy

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TA Criterion 3: The technology must improve the net health outcomes.

Health Outcomes

Ideally, studies of prostate cancer treatments would measure clinically significant long

term outcomes such as total or prostate cancer mortality, and prostate cancer survival.

Other clinically significant outcomes include quality of life and treatment related side

effects. However, many of the studies of prostate cancer treatment measure intermediate

outcomes, which are of less clear clinical significance, such as “biochemical failure.”

Biochemical failure as defined by the Phoenix definition is a rise in the PSA of 2 ng/ml or

more about the nadir after EBRT with or without hormonal therapy, with the date of failure

being the date that failure is defined.28 An earlier, alternative definition the ASTRO

definition is three consecutive increases in PSA.29 The ASTRO definition has been replaced

by the Phoenix definition due to statistical shortcomings.28 Biochemical failure has been

defined as an “appropriate early endpoint for clinical trials,” but it is not equivalent to

clinical failure.

Important outcomes in prostate cancer treatment are treatment related side effects.

Toxicity is typically graded on a standard scale based on the RTOG Radiation Toxicity

Grading Criteria30. Toxicities are graded from level 1 (lowest severity) to level 4 (highest

severity). Most studies use these criteria for grading toxicities and typically consider

toxicities of Grade 2 or greater or Grade 3 or greater as clinically significant.

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Table 5: RTOG Radiation Toxicity Grading Criteria

Genitourinary Tract Gastrointestinal System

Grade 1 Frequency of urination or nocturia twice pretreatment habit and/or dysuria, urgency not requiring medication

Increased frequency or change in quality of bowel habits not requiring medication and rectal discomfort not requiring analgesics

Grade 2 Frequency of urination or nocturia that is less frequent than every hour. Dysuria, urgency, bladder spasm requiring local anesthetic (e.g. Pyridium);

Diarrhea requiring parasympatholytic drugs (e.g. Lomotil), mucous discharge not necessitating sanitary pads or rectal or abdominal pain requiring analgesics

Grade 3 Frequency with urgency and nocturia hourly or more frequently/dysuria, pelvis pain or bladder spasm requiring regular, frequent narcotic/gross hematuria with or without clot passage

Diarrhea requiring parenteral support, sever mucous or blood discharge necessitating sanitary pads, abdominal distention (flat plate radiograph demonstrates distended bowel loops)

Grade 4 Hematuria requiring transfusion/acute bladder obstruction not secondary to clot passage, ulceration or necrosis

Acute or subacute obstruction, fistula or perforation: Gi bleeding requiring transfusion: abdominal pain or tenesmus requiring tube decompression or bowel diversion.

Potential Benefits

The goal of proton beam therapy is to prolong overall and disease specific survival, to

delay progression of disease and to improve quality of life. Because proton beams can

theoretically be more concentrated on the tumor and less concentrated on the

surrounding normal tissues, theoretically it could be a treatment option for patients with

localized prostate cancer that maximizes the effect on the tissue while limiting effects on

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adjacent tissue.

Potential Harms

The main harms associated with radiotherapy of the prostate are toxicities to the

genitourinary and gastrointestinal systems. Genitourinary toxicities include urethral

stricture, urinary incontinence or retention, frequency, hematuria or impotence. Toxicities

of the gastrointestinal system include diarrhea, proctitis and rectal bleeding or pain. Hip

fractures have also been associated with radiotherapy for prostate cancer.

Outcomes of Non-comparative studies

A total of seven non-comparative studies evaluated proton therapy for the treatment

of prostate cancer. The description of these studies is included in Table 1 and the main

study outcomes are described in Table 2. Study size ranged form 30 to 1,255 participants.

Three studies were done in Japan,12,14,15 one in Sweden18 and the remaining three in the

U.S.13,16,17 Two of the studies used proton therapy alone12,13, four used proton therapy with

a boost14,16-18 and one used a boost in intermediate risk but not low risk patients.15 All used

radiation doses ranging form 70 to 82 Gy or CGE. The most common outcomes evaluated

were GI and GU toxicities, biochemical failure (defined by rises in PSA levels) and

progression free survival.

The largest non-comparative study of proton beam therapy is a retrospective cohort

from Loma Linda University, where proton beam therapy for localized prostate cancer has

been used since 1991.17 They evaluated all patients treated between 1991 and 1997 at Loma

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Linda. The main outcomes were toxicities and biochemical relapse. Patients were treated

with both photons and protons. Initially, the treatment was a conformal boost of 30 CGE

in 15 fractions and was then followed by 45 Gy of photon radiation therapy. Later during

the study period, participants were divided into low or high risk categories. Those

considered high risk continued to receive the combined proton-photon treatment and

those considered low risk were treated with protons alone. Biochemical failure was

defined using the consensus definition in place at the time by the American Society for

Therapeutic Radiology (ASTRO), which was defined as three consecutive rises in PSA levels,

with the date of failure being midway between the nadir and the first rise.29 Participants

were followed for an average of 62 months. Seven hundred thirty one patients received a

combination of protons and photos and 524 received all their treatments with protons to

the prostate and seminal vesicle(s) only. Biochemical disease free survival was measured at

five and eight years and were 75% and 73% respectively. For both GI and GU toxicities, the

rate of RTOG Grade 3 or greater toxicities was <1%. Late GI toxicity was relatively rare but

there was one small bowel obstruction requiring a diverting colostomy and two episodes

of bleeding and pain. GU toxicity late in the treatment course was more common. A total

of 14 patients developed late GU toxicity, including eight urethral strictures, four with

hematuria and two with dysuria. One patient developed necrosis of the symphisis pubis.

There were no differences in toxicity between those treated with photons and protons

versus those treated with protons alone.

Johansson and colleagues recently reported on five year outcomes from a cohort of

patients in Sweden treated with proton boost therapy. A total of 278 patients with

localized prostate cancer received XRT plus a proton boost to a total of 70 Gy. Five year

survival for the cohort was 89% and eight year survival was 71%. Patients were divided into

three risk categories based on the NCCN guidelines and were classified as low,

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intermediate or high risk.31 They analyzed survival and PSA relapse separately by risk

group. There were no significant differences in overall survival by risk group. They also

evaluated the likelihood of PSA relapse by risk group. Five year actuarial relapse was 0%,

5% and 26% for low, intermediate and high risk groups (p<0.001).18

In all of the non-comparative studies, GI and GU toxicities were assessed. Except for

the one study that measured late outcomes in long term survivors,16 GI and GU toxicities

were generally less than 5%. In the one study that measured GU and GI morbidity, at five

and 15 years,16 rates were higher. They found that the incidence of Grade 2 or greater GU

morbidity at 15 years was 59% but that the symptoms persisted to the time of interview in

only 18% of patients. The actuarial incidence of Grade 2 or greater hematuria at 15 years

was 47%, but the incidence of Grade 3 or greater hematuria was 8%. The actuarial

incidence of Grade 2 or greater GI morbidity was 13% at five and 15 years, although Grade

1 rectal bleeding occurred in 41% of men. Thus, although there were long term sequelae

after proton beam treatment, most of the toxicities were not severe.

The studies did not assess the impact on prostate cancer mortality or total mortality,

although three studies assessed the impact on survival, progression free survival or

freedom from biochemical evidence of disease.13,17,18 At Loma Linda, Slater and colleagues

found that the five and eight year biochemical disease free survival rates were 75% and

73%.17 Mendenhall and colleagues at the University of Florida, found that at two year

follow up, the overall survival rate for treated patients was 96%, and that progression free

survival was 99% at two years.13 Finally, Johansson and colleagues reported a five year

progression free survival of 100% for low risk patients, 95% for intermediate risk patients

and 74% for high risk patients.18 Although there are no comparison groups in these

studies, these outcomes are similar to those see for IMRT treatment of prostate cancer.32.

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Summary

In summary, seven non-comparative studies have evaluated the use of proton beam

therapy for the treatment of localized prostate cancer. Rates of disease free progression

seem to be relatively high, and comparable to rates seen with other treatments of localized

prostate cancer. Although low grade toxicities are somewhat common, rates of higher

grade toxicities are relatively low. Overall, the net benefits appear to outweigh the risks

such that there is a net benefit for the use of proton beam therapy to treat prostate

cancer.

TA Criterion 3 is met

TA Criterion 4: The technology must be as beneficial as any established alternatives.

A total of seven studies have compared proton beam therapy to an alternative (Table

3). Two of these studies were randomized.19,22 The other five studies were not

randomized.23-27 In the earliest randomized study, published by Talbot and colleagues in

1995, a Phase III trial was conducted where patients with Stages T3-T4, Nx0-2 prostate

cancer received a treatment combining 10-25 MV photons with conformal protons to a

total dose of 75.6 CGE or conventional external beam radiation therapy t a total dose of

67.2 Gy. There were 103 patients in the proton arm and 99 patients in the conventional

therapy arm. Patients were followed for an average of 61 months. There were no

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differences in overall survival, disease free survival or total recurrence-free survival. The

rates of local control at five and eight years for the proton group was 94% and 84% and

80% and 60% for those receiving proton therapy (p=0.090). There were higher rates of

Grade 2 or less rectal bleeding in the proton group (32% versus 12%: p=0.002) and a

nonsignificant increase in urethral stricture (19% versus 8%).

The other randomized trial, PROG-95-09, actually compared “low dose” and “high

dose” conformal radiation therapy that used a combination of proton and photon

beams.20 The PROG-95-09 study randomized 393 patients to receive either 70.2 Gy of

combined photons plus protons versus 79.2 Gy of combined photons plus protons. All

received conformal photon therapy at a dose of 50.4 Gy. The boost dose was protons and

was either 19.8 Gy or 28.8 Gy. The main measured outcome was “biochemical failure” as

measured by an increased PSA level at five years after treatment. At five years, there were

more men in the high dose group free from biochemical failure than there were in the

conventional dose group, resulting in a 49% reduction in the risk of failure in the high dose

group. There was no difference in overall survival between the two treatment groups.

Only one percent of patients in the conventional group and two percent in the high dose

group experienced acute urinary or rectal morbidity of RTOG Grade 3 or greater.20 The

authors subsequently reported on longer term follow-up. After a median of 8.9 years of

follow-up, those receiving the high dose treatment had a significantly lower likelihood of

local failure (HR 0.57). The ten year rates of biochemical failure were 32.4% for the

conventional dose group versus 16.7% for the high dose group. There was no difference in

overall survival when comparing the two treatment groups.19

Finally, the PROG 9509 Group also reported on long term patient reported outcomes

of combined proton and photon therapy. They conducted a survey of 280 of the surviving

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337 patients enrolled in this protocol. The main outcomes were Prostate Cancer Symptom

Indices, a validated measure of urinary incontinence, urinary obstruction and irritation,

bowel problems and sexual dysfunction, and other quality of life measures. The study was

conducted a median of 9.4 years after treatment. Rates of symptoms were not statistically

different between treatment groups. These symptoms included urinary obstruction and

irritation, urinary incontinence, bowel problems, and sexual dysfunction.

In summary, the results of this randomized trial showed that higher dose combined

proton and photon therapy is associated with improved rates of biochemical survival, with

no significant difference in treatment related side effects including long term patient

reported outcomes between treatment group. Thus, higher dose combined proton and

photon therapy leads to improved outcomes compared with lower dose. However, since

participants in both study arms received proton therapy, this study did not compare

proton therapy with photon therapy alone, which limits conclusions.

Five nonrandomized studies have compared proton beam therapy to another

treatment in the earliest study. Duttenhaver and colleagues compared outcomes among

patients with localized prostate cancer receiving either 50 Gy of conventional therapy

alone versus receiving a proton boost to reach a total dose of 74 CGE.24 There were no

significant differences in patient survival, disease free survival or local recurrence free

survival. However, the doses used in this study are much lower than currently used doses

and the techniques used in that study are now outmoded and so not relevant to current

practice.

In a recent case-matched analysis, high dose external beam proton and photon XRT

(79.2 GYE) was compared with brachytherapy for treatment of localized prostate cancer.

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The 199 participants who received high dose proton and photon therapy were those in the

PROG 95-09 high dose arm, all recruited form Loma Linda University and Massachusetts

General Hospital (MGH) during 1996-1999 were eligible for inclusion. After excluding those

with a Gleason Score of greater than seven, there were 177 left for case matching. A total

of 203 similar patients were treated at MGH with brachytherapy from 1997-2002 by one

brachytherapist. Case matching, which included T stage, Gleason Score, PSA and age

resulted in 141 matched cases. Median follow up was 8.6 years for EBRT and 7.4 years for

brachytherapy. The primary endpoint was biochemical failure. Median age was 67 years

old. The eight year rates of biochemical failure were not significantly different between the

two groups (7.7% for EBRT versus 16.1% for brachytherapy: p=0.42). There was also no

difference in overall survival at eight years (93% versus 96%: p=0.45). Analysis by

subgroup (low versus intermediate risk; there were no high risk patients) also showed no

significant differences between groups. The results suggest that outcomes are similar for

men treated with proton therapy or with brachytherapy, although this was a case matched,

non-randomized analysis among patients treated at different time periods.

Galbraith and colleagues assessed the impact of different prostate cancer treatments

on health outcomes in five different treatment groups. They conducted a longitudinal

survey of 185 men treated for prostate cancer at one tertiary care medical center (Loma

Linda University). There were a total of 185 men, all of whom had received different

treatments for prostate cancer. These treatments included watchful waiting (n=30),

surgery (n=59), conventional external beam radiotherapy (n=25), proton beam

radiotherapy (n=24) or mixed beam radiation (n=47). At six months, 163 of the patients

completed another survey and at 12 months, 154 completed another survey and at 18

months, 153 completed a survey. The main outcomes were health related quality of life,

health status and prostate treatment specific symptoms and sex role identity. Health

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related quality of life was measured using the Quality of Life Index (QLI), a measure to

assess health related quality of life that was designed specifically for patients with cancer.33

Overall , the five groups did not differ in measures of health related quality of life during

the 18 months following prostate cancer treatment. Post hoc analyses showed that at 12

months, the mixed beam radiation group and the proton beam radiation group reported

better health related quality of life than those in the watchful waiting group (p=0.02 and

p=0.05 respectively). Health status was measured with the Medical Outcomes Study

General Health Survey. At 18 months, there were no overall differences in health status

among the five groups. Prostate treatment related symptoms were measured using the

Southwest Oncology Group Prostate Treatment Specific Symptoms Measure (PTSS). The

PTSS is a 19 item scale which was developed to measure and compare treatment related

symptoms that can occur after any treatment for prostate cancer.34 Symptoms are related

to bowel, bladder and sexual functioning. At 18 month follow-up, there were differences

among the five treatment groups in prostate treatment specific symptoms. Each group

was compared to every other group at multiple time periods. At 18 months, there were

differences in sexual and GI symptoms among groups, but no differences in urinary

symptoms. Multiple post hoc analyses were done at different time points (6 months and

12 months). Of note, at 12 months, the men who had mixed beam radiation reported

more symptoms than those who received watchful waiting (p=0.005), but there were still

no differences in urinary symptoms among groups. In summary, in this study of 185

patients who had received various treatments, there was no difference in health related

quality of life or health status at 18 month follow-up. There were more GI symptoms with

radiation treatment.

Jabbari and colleagues compared a cohort of 249 patients who were treated with

permanent prostate implant brachytherapy at UCSF with a cohort of individuals treated

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with 3D-CRT at the University of Michigan and the published results of a high dose CPBRT

boost trial.26 Patients in the CPBRT trial20 received a combination of conformal photon and

proton beams to a total dose of or 79.2 Gy.20 The main outcomes were biochemical no

evidence of disease (bNED) and PSA nadir achieved. For each of the two comparisons,

they selected subsets of the PPI cohort who had similar patient and disease criteria to the

reference group. The five year bNED rate was 91% for those who received CPBRT and 93%

for those who received PPI. More PPI patients reached a PSA nadir of <0.5 ng/ml than did

those in the CPBRT trial (91% vs 59%). In this nonrandomized study, men treated with PPI

had similar outcomes when compared with those treated with high dose CPBRT in a

published trial .

Finally, a recent study evaluated the comparative efficacy of IMRT, proton therapy and

conformal radiation therapy for primary treatment of prostate cancer.23 This was a

population based study using data from the Surveillance, Epidemiology, and End Results

(SEER) Medicare-linked data from 2000-2009 for patients with non-metastatic prostate

cancer. SEER-Medicare links the registry data to Medicare claims data. The main

outcomes were rates of GI and GU morbidity, erectile dysfunction, hip fractures and need

for additional cancer therapy. Overall, they identified 6,666 patient treated with IMRT and

6,310 treated with conformal radiation therapy. For the proton versus IMRT comparison,

they identified 684 men treated with proton therapy from 2002 to 2007. Because there

were so few institutions that offered proton therapy, baseline characteristics between

proton therapy and IMRT patients were very different, primarily because of two variables -

SEER region and institutional affiliation with the RTOG. To overcome this, they used

propensity score matching to compare the patients who received proton therapy with

those who received IMRT. Median follow-up for this comparison was 46 months for IMRT

and 50 months for proton therapy. Comparing those who received proton therapy with

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the propensity matched IMRT patients, there was a lower rate of GI morbidity in those who

received IMRT (absolute risk 12.2 versus 17.8 per 100 person-years: RR 0.66: 95%; C.I. 0.55-

0.79). There were no significant differences in rates of other morbidities or need for

additional therapies between IMRT and proton therapy. Proton therapy was not compared

with conformal radiation therapy in this analysis.

In summary, seven studies have compared proton beam therapy for prostate cancer

to another treatment. Only two of these have been randomized. The first of the two

randomized studies included 202 patients was done 15 years ago and found no evidence

of differences in survival although there were higher rates of rectal bleeding in the proton

beam treated group. The second study actually compared low to high dose photons plus

protons. Although they found that high dose combined therapy was better, there was no

comparison group that did not receive proton therapy. The one study that compared

proton beam therapy to brachytherapy was a non-randomized case matched study and

the study that compared proton beam therapy to IMRT was a case matched propensity

analysis among patients treated at different time periods, thus limiting the conclusions that

can be drawn from these studies.

TA Criterion 4 is not met.

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TA Criterion 5: The improvement must be attainable outside the investigational

settings.

Despite limited evidence of efficacy, the use of new technologies for prostate cancer

treatment, proton therapy has spread widely. Proton therapy is widely used in specialized

centers. However, since an improvement has not been shown in the investigational

setting, improvement cannot be attained outside the investigational setting.

TA Criterion 5 is not met

CONCLUSION

In summary, proton beam therapy has been widely used for the treatment of localized

prostate cancer. In nonrandomized studies, rates of disease free progression appear to be

favorable and although side effects are common, rates of significant toxicity are relatively

low. However, there is limited evidence of comparative efficacy with other prostate cancer

treatments. The main recent RCT evaluating proton beam therapy actually compared low

dose with high dose proton beam therapy and did not include a group that did not receive

proton beam therapy. The comparisons with other treatments (brachytherapy, IMRT) have

been limited by being retrospective case matched analyses and have included patients

treated during different time periods. Thus the role of proton beam therapy for localized

prostate cancer within the current list of treatment options remains unclear.

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RECOMMENDATION

It is recommended that proton beam therapy for localized prostate cancer does not meet

CTAF criteria 4 or 5 for safety, efficacy and improvement in health outcomes.

The CTAF Panel voted nine in favor of the recommendation as written and none

opposed.

,

October 17, 2012

This is the first review of this technology by CTAF.

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RECOMMENDATIONS OF OTHERS

Blue Cross Blue Shield Association Technology Evaluation Center (BCBSA TEC)

BCBSA TEC performed an assessment on this technology is June 2011. The assessment

noted that “Good comparative studies are lacking for…comparisons addressed in the

Assessment”, that “There is inadequate evidence from comparative studies to permit

conclusions….” and therefore the technology did not meet BCBSA TEC criteria. The

assessment can be found at http://www.bcbs.com/blueresources/tec/vols/25/proton-

beam-therapy-for-1.html

Canadian Agency for Drugs and Technologies in Health (CADTH)

In 2008, CADTH published a limited literature search to address the following

four questions:

1. What is the clinical effectiveness of proton beam therapy for various indications

including different types of cancer?

2. Is there evidence that proton beam therapy is clinically more effective for specific

indications when compared with conventional treatment options?

3. What is the cost effectiveness of proton beam therapy?

4. What are the guidelines for use of proton beam therapy?

The list of documents can be found at http://www.cadth.ca/media/pdf/htis/Proton%20Beam%20Therapy%20Clinical%20and%20Cost-Effectiveness%20and%20Guidelines%20for%20Use.pdf

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National Institute for Health and Clinical Excellence (NICE)

There is no specific mention of proton beam therapy in the NICE clinical guideline

published in February, 2008: CG58: Prostate Cancer – diagnosis and treatment. The

clinical guideline can be found at http://publications.nice.org.uk/prostate-cancer-cg58.

Agency for Healthcare Research and Quality (AHRQ)

The AHRQ Technology Assessment Program published the technology assessment in

August 2010: Comparative evaluation of radiation treatments for clinically localized prostate

cancer: an update. The technology assessment noted that “…current review did not

identify any comparative studies evaluating the role of particle radiation therapy (e.g.,

proton) in the treatment of prostate cancer.” The technology assessment can be found at

http://www.cms.gov/medicare-coverage-database/details/technology-assessments-

details.aspx?TAId=69&bc=BAAgAAAAAAAA&

AHRQ funded a systematic review and guide, Comparative Effectiveness of Therapies

for Clinically Localized Prostate Cancer (2008), that was prepared by the Minnesota

Evidence-Based Practice Center. Findings relevant to this assessment include:

“Radiation therapy with protons may improve dose distribution with higher doses

delivered locally to the tumor preserving surrounding healthy tissues. However, no

randomized trials have evaluated the comparative effectiveness of protons vs.

photons in men with localized prostate cancer.

“No randomized trials were found that compared clinical outcomes of proton beam

radiation therapy versus other therapies.”

The review can be found at

http://www.effectivehealthcare.ahrq.gov/repFiles/2008_0204ProstateCancerFinal.pdf

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National Comprehensive Cancer Network (NCCN)

The NCCN Clinical Practice Guidelines In Oncology: Guideline Version 3.2012: Prostate

Cancer states the following regarding proton beam therapy:

“Proton beams can be used as an alternative radiation source. Theoretically,

protons may reach deeply-located tumors with less damage to surrounding tissues.

However, proton therapy is not recommended for routine use at this time, since

clinical trials have not yet yielded data that demonstrates superiority to, or

equivalence of, proton beam and conventional external beam for treatment of

prostate cancer.”

The NCCN guideline can be found at

http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

American Cancer Society (ACS)

The ACS website shows the following information about proton beam therapy:

“Proton beam therapy is related to 3D-CRT and uses a similar approach. But instead of

using x-rays, this technique focuses proton beams on the cancer. Protons are positive

parts of atoms. Unlike x-rays, which release energy both before and after they hit their

target, protons cause little damage to tissues they pass through and then release their

energy after traveling a certain distance. This means that proton beam radiation may

be able to deliver more radiation to the prostate and do less damage to nearby

normal tissues. Although early results are promising, studies are needed to see if

proton beam therapy is better in the long-run than other types of external beam

radiation. Right now, proton beam therapy is not widely available. The machines

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needed to make protons are expensive, and there are only a handful of them in use in

the United States. Proton beam radiation may not be covered by all insurance

companies at this time.”

http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-

treating-radiation-therapy; accessed on 9/26/12.

Centers for Medicare and Medicaid Services (CMS)

There is no National Coverage Determination (NCD) for proton beam therapy for

prostate cancer. Coverage for the procedure is determined under Local Coverage

Determination (LCD).

American College of Radiology (ACR)

ACR did not provide an opinion on this technology nor send a representative to the

CTAF public meeting.

American College of Radiation Oncology (ACRO)

ACRO did not provide an opinion on this technology nor send a representative to the


American Society for Radiation Oncology (ASTRO)

ASTRO provided an opinion on this technology and sent a representative to the CTAF

public meeting.

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American Urological Association (AUA)

AUA did not provide an opinion on this technology nor send a representative to the


In its guideline: Prostate Cancer Guideline for the Management of Clinically Localized

Prostate Cancer: 2007 (reviewed and validity confirmed in 2011), the AUA states that

"External beam radiotherapy is indicated as a curative treatment for prostate cancer in

men who do not have a history of inflammatory bowel disease such as Crohn’s disease,

ulcerative colitis, or a history of prior pelvic radiotherapy….techniques include a CT scan for

treatment planning and either a multileaf collimator, IMRT, or proton radiotherapy….” The

AUA guideline can be found at http://www.auanet.org/content/clinical-practice-

guidelines/clinical-guidelines/main-reports/proscan07/content.pdf

Association of Northern CA Oncologists (ANCO)

ANCO sent an opinion on this technology but did not send a representative to the


California Radiological Society (CRS)

CRS did not send an opinion on this technology nor send a representative to the CTAF

public meeting.

California Urological Association (CUA)

CUA provided an opinion on this technology and sent a representative to the CTAF

public meeting.

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The National Association For Proton Therapy

The National Association for Proton Therapy provided opinions on this technology via

several of its member organizations and sent multiple member organization

representatives to the CTAF public meeting.

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ABBREVIATIONS USED IN THIS ASSESSMENT:

NG: Nanograms


3D-CRT: Three Dimensional Conformal Radiation Therapy

NCCN: National Comprehensive Cancer Network

Gy: Gray

RBE: Relative Biological Effectiveness

GyE: Gray Equivalents (GyE)

CGE: Cobalt Gray equivalents

DARE: Database of Abstracts of Reviews of Effects

EBRT: External Beam Radiation Therapy

GI: Gastrointestinal

GU: Genitourinary

XRT: X-ray Therapy

PPI: Permanent Prostate Implant Brachytherapy

CPBRT: Conformal Proton Beam Therapy

bNED: Biochemical No Evidence of Disease

RTOG: Radiation Therapy Oncology Group

OS Overall Survival

DSS Disease Specific Survival

TRFS Total Recurrence-Free Survival

MV: Megavolts

BF: Biochemical Failure

ASTRO: American Society for Therapeutic Oncology

IMRT: Intensity Modulated Radiation Therapy

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PROG-95-09: Proton Radiation Oncology Group (PROG)/American College of Radiology

(ACR) 95-09 (a randomized trial)

QLI: Quality of Life Index

PTSS: Southwest Oncology Group Prostate Treatment Specific Symptoms Measure

SEER: Surveillance, Epidemiology, and End Results

RR: Relative Risk

C.I.: Confidence Interval

H.R.: Hazard Ratio

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