OPTIMIZED RADIOTHERAPY STRATEGIES

Gastric cancer

Karin Haustermans

University Hospitals Leuven

DISCLOSURE OF INTEREST

No conflicts of interest

◆ Ultimate goal of radiation therapy:

◆ To maximize tumor control → better survival

◆ While sparing the surrounding normal tissue → less

side-effects and better QoL

◆ Inevitably some radiation dose is always deposited in the

healthy tissues…

Therapeutic ratio

TCP NTCP

THERAPEUTIC RATIO

◆ High chance of tumor control

◆ Low risk of side effects

THERAPEUTIC RATIO

◆ High chance of tumor control

◆ High risk of side effects

Barker et al. Nat Rev Cancer 2015

RADIATION SIDE EFFECTS

EVOLUTION IN TECHNOLOGY

2D conventional

radiotherapy

(2D RT)

3D conformal

radiotherapy

(3D CRT)

Image Guided

Radiotherapy

(IGRT)

Intensity Modulated

Radiotherapy

(IMRT)

Better 3D control of the dose distribution

Target volume adapted to tumor volume

Less dose to the surrounding normal tissues

Therapeutic ratio

EVOLUTION IN TECHNOLOGY

Tha

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ratio

EVOLUTION IN TECHNOLOGY

GOAL OF RADIOTHERAPY IN GEJ AND GASTRIC CANCER

◆ Downstage the tumour

◆ Increase R0 resection rate

◆ Decrease locoregional recurrence

◆ Improve survival

Recurrences Mean Range

Locoregional - only 54% (29-72%)

Locoregional - total 88% (38-94%)

Distant - only 25% (18-35%)

Gunderson et al. Int J Radiat Oncol Phys 1982; Smalley et al. Int J Radiat Oncol Phys 2002; Lim et al. Br J Cancer 2004

UICC TNM 8TH EDITION (2017)

◆ GEJ tumors involving the GEJ whose epicenter is

within the proximal 2 cm of the cardia (Siewert types

I/II)

◆ Cancers whose epicenter is more than 2 cm distal

from the GEJ will be staged using the Stomach

Cancer TNM even if the GEJ is involved

◆ All cardia cancers not involving the GEJ will be staged

using the Stomach Cancer TNM

Ajani et al. Nat Rev Dis Primers 2017

Lordick et al. Ann Oncol 2016

ESOPHAGEAL AND GEJ CANCER

CROSS TRIAL

◆ Randomized phase III trial with 366 patients

◆ Stage II or III: cT2-3/N0-1/M0

◆ AC (75%) or SCC (23%) esophagus (+/- 73%) or GEJ (+/- 24%)

◆ Primary objective: OS

Van Hagen et al. N Engl J Med 2012

Surgery

SurgeryCRT:

paclitaxel 50mg/m² + carboplatin AUC2 weekly

+ radiotherapy 41.4 Gy

CROSS TRIAL

Shapiro et al. Lancet Oncol 2015

POET TRIAL

◆ Randomized phase III trial with 126 patients

◆ uT3-4NxM0

◆ AC GEJ (100%)

Primary objective: OS

Stahl et al. J Clin Oncol 2009

GEJ cancer

Chemotherapy

2x cisplatin + 5FU + LV

CRT30.0 Gy + cisplatin

+ etoposide

Surgery

Chemotherapy2,5x cisplatin + 5FU

Surgery

POET TRIAL

Stahl et al. J Clin Oncol 2009

Arm A Arm B P-value

Treatment No. % No. % P

Patients with

resection

49 100.0 45 100.0

pT0 N0 M0 1 2.0 7 15.6 .03*

pT1-4 N0 M0 17 34.7 22 48.9

pT0-4 N0 M0† 18 36.7 29 64.4 .01*

pTall N M0 27 55.1 14 31.1

pTall N M1 4 8.2 2 4.5

Fisher´s exact test.

† Bold text indicates data summarized from patients with pT0 N0 M0 and pT1-4 N0 M0.

POET TRIAL

Stahl et al. Eur J Cancer 2017

cT1 N+ or cT2-4a N0/+, M0 adenocarcinoma of esophagus or GEJ

Primary endpoint: OS

594 patients

Reynolds et al. BMC Cancer 2017

Hoeppner et al. BMC Cancer 2016

ESOPEC TRIAL NEO-AEGIS TRIAL

Smyth et al. Ann Oncol 2016

GASTRIC CANCER

SWOG 9008/INT 0116

556 patients

Gastric: +/- 80%

GEJ: +/- 20%

45.0 Gy (1.8 Gy/fx) 2D-RT

5-FU/LV = fluorouracil/leucovorin

Macdonald et al. N Engl J Med 2001

SWOG 9008/INT 0116

Macdonald et al. N Engl J Med 2001

Smalley et al. J Clin Oncol 2002

Surgery CRT + surgery p-value

Median DFS 19 months 30 months 0,001

3 year survival

Median survival

40 %

27 months

50%

36 months0,03

SWOG 9008/INT 0116

◆ Significant improvement in OS and DFS

◆ Effect mainly on local failure rate (19 vs 29%)

◆ Acceptable toxicity

But:

◆ Randomization after surgery

◆ No optimal surgery: 54% < D1 resection

◆ Chemotherapy regimen: not optimal

◆ Few patients in stage IB (n=39)

◆ Results not completely in agreement with what was expected on failure pattern

ARTIST TRIAL

◆ Randomized phase III trial with 458 patients

◆ Excluding cT2aN0

◆ AC gastric (100%)

Primary objective: DFS

Lee et al. J Clin Oncol 2012

Gastric cancer

Surgery

Chemotherapy2x cisplatin + capecitabine

CRT45.0 Gy +

capecitabine

Chemotherapy

2x cisplatin + capecitabine

Surgery

Chemotherapy6x cisplatin + capecitabine

ARTIST TRIAL

Lee et al. J Clin Oncol 2012

DFS LN+ patients

ARTIST II trial

DFS all patients

ARTIST II TRIAL

NCT01761461

Operable GEJ or gastric cancer

D2 surgery

ChemotherapySOX x 2

CRT45.0 Gy + S1

Chemotherapy

SOX x 4

ChemotherapyS1 x 8

ChemotherapySOX x 8

◆ Phase III

◆ 900 patients

◆ Stage II-III N+

◆ AC GEJ or gastric

Primary endpoint: 3y DFS

SOX = S1 + oxaliplatin

ARTIST II TRIAL

Park et al. ASCO 2019; #4001

ARTIST II TRIAL

Park et al. ASCO 2019; #4001

ARTIST II TRIAL

Park et al. ASCO 2019; #4001

ARTIST II TRIAL

Park et al. ASCO 2019; #4001

CRITICS

Dikken et al. BMC Cancer 2011

≥ 87% undergoing D1+

788 patientsGastric: 83%GEJ: 17%

3D-CRT/IMRTECC: epirubine/cisplatin/capectabine

CRITICS

Cats et al. Lancet Oncol 2018

CT CRT

5-year OS

[% (95% CI)]

42 (37-48) 40 (35-46)

Median OS [months

(95% CI)]

43 (31-57) 37 (30-48)

PREOPERATIVE CHEMORADIOTHERAPY?

Rationale/potential advantages◆ Enhance resectability

◆ Assess response in primary tumour

◆ Improve local control

◆ Treat micrometastases early

◆ Better tolerance than postoperative treatment

Potential disadvantages◆ Staging less adequate

◆ Increased postoperative morbidity

◆ Disease progression

PRE- VS. POSTOPERATIVE CRT

Tolerance adjuvant treatment Proportion in study

SWOG/INT 0116 CRT: 65%

ARTIST CT: 75% - CRT 81,7%

CRITICS CT: 47% - CRT 52%

?

TOPGEAR

Leong et al. BMC Cancer 2015

Leong et al. Ann Surg Oncol 2017

Currently recruiting patients

◆ 120 patients phase II

→ results published

◆ 450 patients phase III

◆ cT3-4 or N+

◆ AC GEJ or gastric

Primary endpoint: 5y OS

Estimated Primary Completion Date: December 2020

Operable GEJ or gastric cancer

Chemotherapy

ECF/ECX/EOX x 2 or FLOT x 3

CRT45 Gy + 5FU/X

Surgery

ChemotherapyECF/ECX/EOX x 3

or FLOT x 4

Surgery

Chemotherapy

ECF/ECX/EOX x 3 or FLOT x 4

TOPGEAR: COMPARISON FLOT VS. ECX/F

Michael et al. IGCC 2019

◆ Overall toxicity profile of FLOT regimen was acceptable in the TOPGEAR trial

and did not impact on treatment completion relative to ECF/X regardless of the

treatment groups

◆ Higher febrile neutropenia rates relative to ECF/X (16.2% vs 6.6%. P = 0.036)

◆ No significant FLOT-related toxicity differences between the treatment groups: Group 1

(Chemo + Surgery) vs Group 2 (CRT + surgery)

◆ Surgical completion rates were not influenced by the FLOT regimen relative to ECX/F

overall and regardless of the treatment groups.

CRITICS II

Slachter et al. BMJ Cancer 2018

Marcel Verheij - NCT02931890

Currently recruiting patients

◆ Phase II

◆ 207 patients

◆ Stage Ib-IIIC

◆ AC GEJ or gastric

Primary endpoint:

1y event-free survivalDOC= docetaxel/oxaliplatin/capecitabine

POSTOPERATIVE TARGET VOLUME

According to CRITICS

CTV: ◆ anastomosis

◆ gastric bed/remnant

◆ lymph nodes

PREOPERATIVE

TARGET VOLUME

According to TOPGEAR

RADIATION DELIVERY TECHNIQUE

Hartgrink et al. Lancet 2009

3D VS. IMRT COMPARISON

Chandra et al. Int J Radiat Oncol Phys 2005

“We gave PTV coverage and lung sparing higher priority than the other structures”

IMRT plans reduced the amount of lung treated compared to 3D-CRT“No clinically meaningful differences were observed with respect to irradiated volumes of spinal cord, heart, liver, or total body integral doses”

“In general, V40 and V50 were kept to <50 and <30%, respectively, for the heart.”

IMRT

lower incidence of cardiac and unknown related deaths

Lee et al. Int J Radiat Oncol Phys 2012

HOW ABOUT PROTONS?

Courtesy of Matt Palmer, MD Anderson

Schematic depth dose diagram of a

proton beam Bragg peak, the spread

out Bragg peak and a megavoltage X-

ray beam

The grey shaded areas indicate the

extent of dose reduction

Wang et al. Int J Radiat Oncol Phys 2013

Impact of radiation dose to OAR on postoperative complications and

outcome

Davuluri et al. Int J Radiat Oncol Phys 2017

Lymphopenia - correlation with survival

Predictors G4 lymphopenia:

◆ Distal tumor location

◆ Definitive CRT

◆ Taxane/5-FU chemotherapy

◆ Photon-based radiation (vs.

proton-based)

Shiraishi et al. Radiother Oncol 2017

Lymphopenia - correlation with survival

CONCLUSIONS

◆ The role of radiotherapy in GEJ cancer and gastric cancer needs further study

◆ Perioperative chemotherapy versus preoperative chemoradiotherapy followed by postoperative

chemotherapy

◆ Total dose and fractionation should be standardised

◆ Guidelines for target delineation and OAR with dose constraints should be

implemented

◆ Pretreatment review of radiotherapy treatment plans (contouring and isodose

distribution)

◆ Advanced radiotherapy delivery techniques including image guidance and motion

management

CONCLUSIONS

A multidisciplinary approach is essential in the treatment of this

disease!

◆ Which type of treatment?

◆ Which drugs?

◆ What volume to irradiate, radiation technique?

◆ What type of operation?