Anna Dorothea Wagner, PD & MER Department of...

Neo- and adjuvant treatment for gastric and GE junction cancer: The role of radiotherapy

Anna Dorothea Wagner, PD & MER Department of Oncology University of Lausanne

Overview

1. Background: 2. Rationale: Why to irradiate? 3. Methods: How to irradiate? 4. Timing: When to irradiate? 5. Patient selection: Whom to irradiate?

1. Backgroud:

To be considered when discussing (neo-) adjuvant radiotherapy : a) Results of surgery alone b) Localisation: gastric vs GE-junction c) Histological subtype: intestinal versus

diffuse

1. Background: Results for surgery alone – the Dutch gastric cancer study as example

Songun, Lancet Oncol 2010

5-year survival rate in both arms > 40% for surgery alone in

Recruitment between 1998 - 1993

1. Background: recurrence rates in the Dutch gastric cancer study

Songun, Lancet Oncol 2010

1. Background: ESMO Guidelines

Neoadjuvant treatment:

Adjuvant treatment:

Overview

1.Background: Heterogeneity of GC 2. Rationale: Why to irradiate? 3. Methods: How to irradiate? 4. Timing: When to irradiate? 5. Patient selection: Whom to irradiate? 6. Perspectives

2. Rationale: Why to irradiate?Retrospective analysis, n=60 EBRT (external beam irradiation) or IOERT (EBRT+intraoperative IRRADIATION) 39.8-57.6 Gy (median 48.6), with 5-FU (92%)

Henning et al, I J Radiat Oncol Biol Physics 2000

70% loco-regional control rates (defined as lack of progression based

on radiographic evaluation, clinical exam, or local symptoms)

2. Rationale: Intergroup 0116

Macdonald et al, NEJM 2001

Patients with R0-resected

gastric cancer


Patient characteristics: ▪ N= 559 patients randomized between 1991-1998 ▪ R0 resected cancer of stomach or GEJ ▪ T1-2: 31% N1-3: 85% ▪ T3: 61% ▪ T4: 7% type of lymphadenectomy: D1: 36% D2: 10% D0: 54%



Treatment: Chemotherapy: 5-FU 425mg/m2, LV 20mg/m2, d1-5q 4 weeks, one cycle before RT: day 1- 25: 1.8 Gy/d day 1-5 every week (45 Gy in total), with chemotherapy on days 1-5 and 23-25 followed by 2 monthly cycles of chemotherapy



Smalley et al., J Clin Oncol 2012

Updated analysis HR for OS: 1.32 (95% CI 1.10-1.60)

p=.0046

But: 17% stopped treatment

due to toxicity 1% treatment related

deaths Second malignancies:

7.4% vs 3.5%


Smalley et al., J Clin Oncol 2012

Overview

1.Background: Heterogeneity of GC 2. Rationale: Why to irradiate? 3. Methods: How to irradiate? 4. Timing: When to irradiate? 5. Patient selection: Who to irradiate? 6. Perspectives

3. Methods: How to irradiate?

From: Lee et al., Cancer Res and Treatment, 2014

Example for 2D-RT (AP/PA)

OBSOLETE IN 2015

GEJ-cancer, 4 fields (AP/PA + 2 lat)



Recommended radiation dose and schedule: 45 Gy at 1.8 Gy/day on day 1-5 for 5 weeks Linear accelerator with 3D-CRT or IMRT capability with energy of 4-18 mv

3. Methods: How to irradiate

Gross tumor volume (GTV): macroscopically visible tumor Clinical target volume (CTV): includes GTV + safety margin for microscopic invasion of about 1 cm. Planning target volume (PTV): takes into account the precision of the patient’s position, as well as the motility of the organ


- One volume should be used throughout RT - endoscopy, EUS and CT should be used prior to induction chemotherapy and assign the tumor to one of the following six locations: tumors of the GEJ (type I-III) or proximal/middle/distal third of the stomach - No boost recommended


- Advanced treatment planing techniques allow

calculation of 3D DVH for any organ at risk - Tolerance doses for critical organs are well

known (TD 5/5= dose which causes 5% grade III/IV toxicity after 5 years)


▪ Type I: More than 1 cm above GEJ

▪ Type II: True carcinomas of the cardia

▪ Type III: Tumor center more than 2,

but not more than 5 cm below the GEJ

From: Matzinger et al., 2009


Less than 5% of the patients have tumor cells more than 3 cm from the macroscopic edge of the primary lesion

Bozzetti, Eur J Surg Oncol 1992; Matzinger, 2009

Examples for current RT plans

(GE-junction carcinoma)

Courtesy to M. Oszahin


Courtesy to M. Oszahin

Overview

1.Background: Heterogeneity of GC 2. Rationale: Why to irradiate? 3. Methods: How to irradiate? 4. Timing: When to irradiate? 5. Patient selection: Who to irradiate? 6. Perspectives

4. When to irradiate?

▪ not delayed by surgical complications ▪ patient in better general condition ▪ smaller treatment volumes ▪ intact vascularization and oxygenization ▪ no anatomical deviations ▪ tumor downsizing may facilitate surgery

Advantages of NEOadjuvant RT:

4. When to irradiate?

▪Precise pathological staging is available ▪No risk of disease progression during

neoadjuvant treatment

Advantages of adjuvant RT:

4. When to irradiate?Neoadjuvant studies

▪ In GASTRIC cancer, studies on neoadjuvant chemoradiation are limited to single-arm phase II studies, which demonstrate high clinical and pathological response rates

(eg Ajani, 2005)

▪ In GEJ cancer, one randomized phase III trial comparing chemoradiotherapy versus chemotherapy alone has been published (Stahl, 2009)

4. When to irradiate?Neoadjuvant chemoradiation

N= 41 two 28 days cycles of 5-CDDP, 5-FU, paclitaxel, followed by 45 Gy+paclitaxel+5-FU

Ajani 2005

▪N= 119, phase III

Stahl, JCO 2009

R

PLF regimen (weekly 5-FU 2mg/m2, LV 500mg/m2 + biweekly CDDP 50mg/m2 q 6 weeks for 2.5 cycles

2 cycles PLF as above, followed by chemoradiation (CDDP 50mg/m2

d1+8 plus etoposide 80mg/m2 d 3+5)+ 30 Gy

ARTIST-trial

2000 - 2005

4."POET"– trial: Neoadjuvant radiochemotherapy in GEJ-cancer

1 treatment-related death with chemotherapy alone

Stahl, J Clin Oncol 2009

Overall survival 27.7 vs 47.4 % at 3 years (n.s.)

4. "POET"– trial: neoadjuvant radiochemotherapy in GEJ-cancer

Path. CR 15.6 vs 2 %

Surgery aloneChemoradiation

« POET »- trial: neoadjuvant chemoradiotherapy in GEJ-cancer

▪Underpowered trial, patient numbers were too small ▪Chemotherapy does not correspond

to current standards ▪Radiation dose (30 Gy) lower than

usually used

▪N= 458, phase III

Lee, JCO online2011

R

6 cycles of XP (capecitabine 2000mg/m2 d1-14+ CDDP 60 mg/m2 q d 21 Treatment completed as planned: 75.4 %

2 cycles of XP, followed by 45 Gy XRT with capecitabine 1.650 mg/m2 for 5 weeks and 2 cycles FP Treatment completed as planned 81.7 %

4. « ARTIST »-trial: adjuvant chemoradiation

2004 - 2008

« ARTIST » : safety

XP▪ Dose modifications: 52% ▪ 1 treatment related death ▪ Major grade III/IV

toxicities: nausea 12%, neutropenia 41%

XP+RT▪ Dose modifications: 35% ▪ 1 treatment related death (non-neutropenic

pneumonia) ▪ Major grade III/IV

toxicities: nausea 12%, neutropenia 49%

Conclusion : adjuvant chemoradiotherapy feasible and well tolerated


Lee, JCO online2011

« ARTIST »

Primary endpoint : DFS at 3 years: 78.2 vs 74.2% for XP/RT vs XP, p= 0.862

Subgroup with pos. lymph nodes (n= 396): 77.5 vs.72.3 % ; p=0.356


Lee, JCO online2011

Disease free survival

Overall survival

4. « ARTIST »-trial: adjuvant chemoradiation- long term follow up

Park, J Clin Oncol 2015

subgroup analyses at long-term

follow-up: no benefit for

diffuse-type carcinoma and patients with

negative lymph nodes

4. « ARTIST »-trial: adjuvant chemoradiation- long term follow up

Overview

1.Background: Heterogeneity of GC 2. Rationale: Why to irradiate? 3. Methods: How to irradiate? 4. Timing: When to irradiate? 5. Patient selection: Whom to irradiate? 6. Perspectives

5. Patient selection

According to subgroup analyses of Intergroup 0116 and ARTIST-trials, patients with diffuse-type

gastric cancers do not benefit

from adjuvant chemoradiation

Currently ongoing trials: TOPGEAR


Two parts: Part I: phase II component (n=120) - Toxicity - Surgical morbidity - Path. response

Part II: phase III (n=752) - Overall survival ongoing

Conclusions of phase II-part (ECCO 2015) - Preoperative CRT is safe and feasible - Does not increase surgical morbidity - Chemo dose reductions in 40% in CRT

arm versus 48% in CT arm - 98% of patients completed full

radiotherapy dose - Comprehensive QA program ensures high

quality trial conduct


Lleong, ECCO 2015

Currently ongoing trials: CRITICS

R

ECCx3

S U R G E R Y

ECCx3

ECCx3S U R G E R Y

INT -0116 regimen (« Macdonald »)

Currently ongoing trials: ARTIST-2

R

S U R G E R Y

Adjuvant SOX (6 months)

Adjuvant S-1 (12 months)

S1-RT SOX SOX

N=900 D-2-resected GC pN2-3

Conclusions

- The role of chemoradiation in the curative treatment of GC is controversial

- Modern RT has acceptable toxicities - After D2-resected GC, chemoradiation has no

benefit in the overall patient population (« ARTIST »)

- Current studies investigate the role of adjuvant and neoadjuvant chemoradiation in comparison to perioperative chemotherapy

Anna Dorothea Wagner, PD & MER Department of...

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