improving outcomes in esophageal cancers thruogh clinical trials

Clinical Trials In Esophageal
Cancer
Presenter-Dr Manoj Aher
Moderator-Dr Sitaram Yadav

Introduction & Historic treatment
• "The main goal of surgery in esophageal cancer was good palliation and that cure
is an accident.’’
-Ronald H. Belsey (1910-2007)
• Lack of serosa & rich submucosal lymphatics network- lead to high occult nodal
metastases- account for high local recurrence rates.

 Cervical ca -Definitive Chemoradiation is the standard care (CR)
 Upper Thoracic & Middle Thoracic ca -SCC is more common .LR spread more
common (RT > CT)
 Lower Thoracic & OG junction ca - ADC is more common . Distant metastases
more common (CT > RT)

T and N staging of Esophageal cancer

Evolution of trials in esophageal cancer
1.RTOG 1999 RT alone versus CRT (no surgery in both groups)
2.MRC/OE2 2002 Cisplatin,5FU, cycles preop
3.MAGIC 2006 Cunningham et al, Epirubicin, cisplatin, 5FU, 3 cycles preop and postop
4.FFCD 9102 2007
5.OEO5 2008 Neoadj CT(CF) versus neoadj ECX
6.CROSS TRIAL 2008(2015) CRT plus Surgery versus Surgery alone
7.STAHL/POET 2009 preop CT versus preop CRT
8.FNCLCC/FFCD 2011 periop CT with CF
9.NExT (JCOG1109) trial Arm A: 2 cycles preop cisplatin 5FU, Arm B: 3 cycles preop
docetaxel, cisplatin, 5FU Arm C: 2 cycles preop cisplatin, 5FU + 30 Gy
10. NeoAEGIS 2014 MAGIC vs. CROSS
11.(PRODIGE5/ ACCORD17) 2014 FOLFOX + 50 Gy vs. 5FU, cisplatin + 50 Gy
12.TOPGEAR 2015 Chemo: 3 cycles epirubicin, cisplatin, and 5FU 3 cycles preop and
3 cycles postop VS CRT: 2 cycles ECF preop + 45 Gy + 3 cycles ECF postop.
13.ESOPEC 2016 FLOT Vs CROSS

Neoadjuvant chemoradiotherapy—preferred treatment paradigm
for localized esophageal cancer (T3Nx)
• Dutch CROSS trial ,low-dose weekly carboplatin plus paclitaxel regimen was
used concurrently with 41.4 Gy radiation, while
• cisplatin plus fluorouracil (5-FU)/50.4 Gy protocol was used in CALGB 9781
and
• vinorelbine and cisplatin/40 Gy in the NEOCRTEC5010 trial

Perioperative chemotherapy—alternative for adenocarcinoma of the
lower esophagus or GEJ
• MAGIC trial three cycles of both pre and post-operative epirubicin/cisplatin/5-
FU (ECF) were superior to surgery alone.
• Subsequently, the FLOT4 trial from Germany enrolled patients with GEJ (66%)
or gastric (34%) adenocarcinoma, and reported superior results with four cycles of
perioperative infusional-5-FU, oxaliplatin and docetaxel, as compared with the
MAGIC regimen
• Furthermore,perioperative chemotherapy with cisplatin and fluorouracil (CF) is
another viable option for both GEJ and lower esophageal adenocarcinoma, as
shown in the FNCLCC ACCORD 07 trial

Neoadjuvant chemotherapy—acceptable alternative for
adenocarcinoma
• OEO2 trial, a median OS benefit of 16.8 vs. 13.3 months was gained after
preoperative CT compared to surgery alone
• There is established efficacy of chemoradiation in SCC makes neoadjuvant
chemotherapy a feasible approach in adenocarcinoma
• Notably, triplet chemotherapy did not have an OS advantage in the OEO5 trial

Adjuvant chemotherapy/ chemoradiotherapy for high risk GEJ
• CRITICS study, which showed no survival benefit for the addition of
postoperative chemoradiotherapy to perioperative chemotherapy in patients with
GEJ or gastric carcinoma
• It is important to note that to date, survival benefit of post-operative
chemoradiation has not been demonstrated in a randomized trial in the
subpopulation of esophageal cancer.
• Taken together, there is evidence to employ adjuvant chemoradiation only for
high risk patients with GEJ cancer who have not received preoperative therapy.

Definitive chemoradiotherapy—unresectable disease or poor
surgical candidates, particularly SCC
• the landmark Radiation Therapy Oncology Group (RTOG) 85-01 trial enrolled
patients with both SCC and adenocarcinoma and was closed prematurely due to
significant survival advantage
• A non-operative approach should be indicated for SCC located in the cervical
esophagus.

Landmark studies evaluating treatment approach in locoregional esophageal/GEJ
cancer.

RTOG
(Radiation Therapy Oncology Group ) 85-01
Cooper, J. S., Guo, M. D., Herskovic, A., Macdonald, J. S., Martenson, Jr, J. A., Al-Sarraf, M., … Leichman, L. L.
(1999). Chemoradiotherapy of Locally Advanced Esophageal Cancer. JAMA, 281(17).
doi:10.1001/jama.281.17.1623
10.1001/jama.281.17.1623

 prospective, randomized, phase 3 trial
 concurrent chemoradiotherapy followed by adjuvant chemotherapy could
improve the overall survival rate compared with RT alone.
 The essential hypothesis of this trial was that concurrently administered chemo-
therapy would act as a promoter of the local-regional effects of RT as well as
having direct cytotoxic effects on its own.

Design and Protocol Population
 Randomized controlled trial conducted 1985 to 1990 with follow-up of at least 5
years, followed by a prospective cohort study conducted between May 1990 and
April 1991.
 Squamous or adenocarcinoma of the thoracic esophagus
 Karnofsky score of at least 50
 No prior or concurrent other malignancy
 No prior chest irradiation or chemotherapy
 T1-3 N0-1 M0
 Adequate renal and bone marrow reserve

Treatment Plan
 The combined modality therapy-
• continuous infusion of fluorouracil, 1 g/m2
, for the first 4 days of weeks 1, 5, 8,
and11.
• cisplatin, 75 mg/m2
intravenously, on the first day of weeks 1, 5, 8, and 11.
• Radiation 30 Gy in 15 fractions over 3 weeks starting on day 1, followed by 20 Gy
in 10 fractions over 2 weeks .
 The RT - consisted of 50 Gy in 25 fractions over 5 weeks starting on day 1 and
followed by 14 Gy in 7 fractions over 1.4 weeks

Outcomes
•End Points
• The primary outcome measure for this study was overall survival. Secondary
end points were patterns of treatment failure, and acute and late toxic effects
• Long-term overall survival was associated with combined modality therapy
than RT group.
• By 5 years, 26% of the randomized combined modality group and 14% of the
nonrandomized combined modality group were alive vs none in the RT group.
• 22% of the randomized combined modality group survived at least 8 years
following therapy , to project that the 10-year survival rate may be as high as
20% .

Treatment failure
•Persistence of disease was the greatest cause of treatment failure in every group of
patients . However, it was 40% more common in the group receiving RT alone
(37% following RT only; 25% and 28% following combined modality therapy in
the randomized and nonrandomized cohorts, respectively).

Toxic effects
 8% patient randomly assigned to combined modality therapy experienced acute
life-threatening ( grade 4) toxic effects on the RTOG acute morbidity scale . 2%
died as a direct consequence of treatment
 In contrast, only 2% of patients receiving RT alone experienced acute grade 4
toxic effects and there were no fatalities due to toxic effects.

 Interestingly, the nonrandomized combined modality group experienced a lower
grade 4 toxicity rate (4% vs 8%) and no fatalities, perhaps reflecting greater
experience with this management plan (despite receiving more drugs).
 In contrast, once patients survived more than 90 days based on time from the
beginning of treatment, there were no significant differences in (late RTOG scale)
toxic effects between the groups.

 Pros-
1. First randomized prospective trial showing efficacy of chemoradiation.
2. Interim analysis done which showed early advantage of chemoradiation.
 Cons-
1.The trial may have handicapped the efficacy of chemoradiation by using a
smaller dose of RT than was used for patients treated by RT alone(50 Gy vs 64
Gy).
2.Trial did not address the potential role of surgery in combination with
chemoradiotherapy.

Conclusion
 Combined therapy increases the survival of patients who have squamous cell or
adenocarcinoma of the esophagus, T1-3 N0-1 M0, compared with RT alone.
 Chemoradiotherapy - a standard of care for patients who have carcinoma of the
esophagus.
 Since local-regional persistence of disease accounted for the majority of treatment
failures in the trial, surgery might be able to eradicate some of these tumors.

POET/Stahl TRIAL
PreOperative therapy in Esophagogastric adenocarcinoma Trial (POET)

Study design
 unblinded, prospective and randomised phase III study
 Between November 2000 and December 2005, 126 patients were enrolled from
19 German centres
 The POET was the first randomised controlled phase III study to compare
induction chemotherapy with induction chemoradiotherapy (CRT) followed by
surgery.
 Aim of the study is for an improvement of 10% in 3-year survival rate (from 25%
to 35%) by adding radiation therapy to preoperative chemotherapy.

Eligibility criteria
• Untreated locally advanced (category T3 and T4 ) adenocarcinoma of oesophagogastric
junction(Siewert 1 to 3) in good performance status (WHO Grade 0 or 1)
• Arm A - CT (PLF)15 wks → Surgery
Weekly 5-fluorouracil (2000 mg/m2, 24 h infusion)/folinic acid (500 mg/m2, 2 h infusion)
Biweekly cisplatin (50 mg/ m2, 1 h infusion),f/b another 3-weekly applications.
 Arm B - CT(12 wks) → CRT(3wks) → Surgery
12 wks chemotherapy(PLF) for induction, f/b 3-wks combined CRT(3 wks of 30 Gy using
15 fractions of 2 Gy) with cisplatin (50 mg/m2, 1 h infusion, days 2 and 8) and etoposide
(80 mg/m2, 1 h infusion, days 3 to 5).

Trial profile Patient characteristic

Surgery results Pathological response

Pros cons
Only randomized controlled
phase III study to compare
chemotherapy with CRT,
followed by surgery in ACs of
the oesophagogastric
junction.
1. Limited number of study
population
2. Low power of the study
3. Unconventional chemotherapy
regimen is used in the trial
(cisplatin + etoposide in CRT
arm)

Conclusion
The study did not show significant increase in overall survival but,
- improvement in both local tumor free and overall survival adds to the knowledge
that preoperative chemoradiotherapy appears most valuable to cure patients with
localized esophagogastric adenocarcinoma.

CROSS TRIAL
ChemoRadiotherapy for Oesophageal cancer f/b Surgery Study

Design and Participants
 Multicenter, open label, randomized, controlled, phase 3 study.
 Enrolled 368 patients between March 2004 and Dec 2008, from eight Dutch
participating centers .
 Eligibility
1. adequate haematological, renal, hepatic, and pulmonary function;
2. WHO performance score of 2 or better,
3. 75 years or younger;
4. without a past or present history of other malignancy.

5. locally advanced (clinical stage T1N1M0 or clinical stage T2–3N0–1M0)
6. histologically proven, and SCC or ADC of the oesophagus or OG junction
Exclusion criteria-
1. past or current history of malignancy other than the oesophageal malignancy,
2. previous chemotherapy and/or radiotherapy,
3. weight loss of more than 10% of the original bodyweight

Procedure
 Neoadjuvant chemoradiotherapy
Carboplatin (2 mg/ml/min) and Paclitaxel (50 mg/m² BSA)5 cycles on days 1,8,15,22,28.
 Radiation dose
41·4Gy in 23 fractions of 1·8 Gy on 5 days/week on 1st day of CT cycle for 23 days
 Surgery
Surgery in CRT group  Preferably within 4 to 6 weeks
Surgery alone group  As soon as possible after randomization

PATHOLOGICAL ANALYSIS
 To grade the response to therapy, the degree of histomorphologic regression
was classified:
• Grade 1: No evidence of vital residual tumor cells (pathological
complete response);
• Grade 2: Less than 10% vital residual tumor cells
• Grade 3: 10 to 50%
• Grade 4: More than 50%
 Microscopically radical resection (R0) was deﬁned as a tumor-free
resection margin of at least 1 mm.

Follow up
After completion of treatment
• First year  Every 3 months
• Second year  Every 6 months
• Up to 5 years  Yearly once

Outcomes
Primary endpoint
• Overall survival
• From the date of randomization to the date of all-cause death or to the last day of
follow-up
Secondary endpoints
• Progression-free survival
• Progression-free interval

Surgical assessment
 Unresectable tumour
• 7 of 168 patients (4%) in the chemoradiotherapy–surgery group
• 25 of 186 patients (13%) in the surgery group

Survival
• Median follow-up was 45.4 months
• Patients who underwent resection and died after having been discharged:
• 52 (85%) died from recurrent cancer and 9 (15%) from other causes in the
chemoradiotherapy–surgery group.
• 78 (94%) died from recurrent cancer, 4 (5%) from other causes
• Median overall survival of 49.4 months in the chemoradiotherapy–surgery group
versus 24.0 months in the surgery group.

Overall survival
• 48.6 months in the NACTRT + Surgery group
• 24.0 months in the Surgery alone group
• SCC 81.6 months in the NACTRT + Sx gp & 21.1
months in Sx alone gp
• ADC 43.2 months in the NACTRT + Sx gp & 27.1
months in Sx alone gp

Progression free survival
• 37.7 months in the NACTRT + Surgery group
• 16.2 months in the Surgery alone group
• SCC 74.7 months in the NACTRT + Sx gp &11.6 months in Sx
alone gp
• ADC 29.9 months in the NACTRT + Sx gp &17.7 months in Sx
alone gp

Locoregional /Distant Progression

Discussion
• The chemoradiotherapy was associated with a low frequency of high-
grade toxic effects and could be given as an outpatient treatment.
• The observed survival in both groups was superior to the anticipated
survival and to that reported in earlier randomized trials.
• The preoperative chemoradiotherapy did not significantly change the
individual chance of undergoing a resection.

• Postoperative complication rates, although similar between groups, were higher
than reported in other studies. (A plausible explanation for this finding, other than
the fact that all postoperative events were meticulously recorded).
• Complete Response in both the primary tumor and the lymph nodes is the best
possible pathological outcome of CTRT.

• The observed percentage of patients with a pathological complete response - 29%.
• Despite the higher rate of pathological complete response among patients with
squamous cell carcinoma, as compared with those with adenocarcinoma,
histologic tumor type was not a prognostic factor for survival.

PROS
• Well randomized multi-
institutional trial
• High pCR rate compared to
other similar trials
CONS
• Treatment protocol does not
vary with histological type of
cancer

Conclusion
 Preoperative chemoradiotherapy (five courses of carboplatin and paclitaxel, with
41.4 Gy of concurrent radiotherapy) is safe and leads to a significant increase in
overall survival among patients with adenocarcinoma or squamous-cell carcinoma
of the esophagus or esophagogastric junction.
 Chemoradiotherapy improves long-term overall and progression-free survival in
patients with oesophageal and junctional cancer.

Magic trial
Medical Research Council Adjuvant Gastric Infusional Chemotherapy.

Background
This study demonstrates that a perioperative chemotherapy regimen of epirubicin,
cisplatin, and fluorouracil (ECF) combined with surgery improves outcomes for
patients with resectable gastric or esophagogastric adenocarcinoma compared to
surgery alone.
 Benefits of preop ECF
• increasing the likelihood of curative resection by down staging the tumor,
• eliminating micrometastases,
• rapidly improving tumor-related symptoms, and
• determining whether the tumor is sensitive to the chemotherapy.

Eligibilty
 Inclusion criteria
• WHO P.S. of 0 or 1
• Stage 2 ADC of the stomach or lower
third of the esophagus or higher with
• No evidence of distant metastases, or
• No locally advanced inoperable
disease
 Exclusion criteria
• Previously received cytotoxic
chemotherapy or radiotherapy,
• Uncontrolled cardiac disease, or
• Creatinine clearance of <60 ml/min .

Methods
 Study Groups:
• Perioperative-chemotherapy group: 3 cycles of ECF before surgery and 3
cycles after surgery.
• Preop CT  after 3 to 6 wks  Surgery after 6 to 12 wks Postop CT
• Surgery-only group: No chemotherapy, surgery alone.
• Sx done within 6 weeks after randomization
 Chemotherapy details:
• Epirubicin (50 mg/m² IV) and cisplatin (60 mg/m² IV) on day 1.
• Continuous infusion of fluorouracil (200 mg/m²/day) for 21 days.

 Surgery:
• Radical total/subtotal gastrectomy with resection lines had to be at least 3 cm
from the edge of the macroscopic tumor.
• The resection included the greater and lesser omenta and any other organs in
volved by extension of the primary growth (e.g., pancreas, spleen, mesocolon,
colon, or left lobe of liver).
• Lymph nodes along the lesser and greater curvatures and at the origin of the left
gastric artery were to be included.
• Transhiatal esophagectomy with removal periesophageal nodes with separate
sampling of the subcarinal and celiac axis lymph nodes was recommended.

 Primary Endpoint: Overall survival.
• Overall survival was calculated from randomization to death.
 Secondary Endpoint: Progression-free survival and tumor characteristic.
• Progression-free survival was calculated from randomization to the first event
(i.e., local recurrence or progression, distant recurrence, or death from any cause).

 Adverse Effects and Complications:
• ECF-related adverse effects were consistent
with previous studies.
• Postoperative complication rates were similar
(46% vs. 45%).
• 30-days postoperative mortality was
comparable in both groups.

• Tumor Characteristics :Tumors in
the perioperative group were
smaller and less advanced after
surgery.

Progression-free and overall survival
Peri operative-chemotherapy group had a
significantly higher likelihood of progression-free
survival (hazard ratio for progression of 0.66 )
Peri operative-chemotherapy group had a significantly
higher likelihood of overall survival (hazard ratio for
death, 0.75)

There was no clear evidence of heterogeneity of treatment effect according to the site of the
primary tumor, age group, sex, or the WHO performance status.

Survival Outcomes:
 5-year survival: 36% in the perioperative group vs. 23% in the surgery-only group
 Curative resection rate: 69% in perioperative group vs 66% in surgery only group

Limitations of MAGIC
 Non standard surgery
 Inaccurate pre-op Staging
 Higher % pts in chemo arm underwent Curative Sx (79% v 70%)
 T1/2 and NO/1 more in chemo arm
 Only 42% completed protocol Rx

Conclusions
• The perioperative ECF regimen:
1.Reduced tumor size and stage preoperatively.
2.Improved overall survival and progression-free survival.
3.Was well-tolerated without increasing postoperative complication or mortality
rates.
• This supports the use of perioperative chemotherapy with ECF as a standard
approach for improving outcomes in operable gastric or lower esophageal
adenocarcinomas.

CRITICS Trial
ChemoRadiotherapy after Induction chemoTherapy In Cancer of the Stomach.

Background
• Gastric cancer: 5th leading cause of cancer mortality globally.
• Poor prognosis post-surgery alone, with frequent relapses within 2 years.
• Objective: Optimize perioperative and adjuvant treatments to improve survival.

Study Objective
• Compare perioperative chemotherapy (standard) with a combined strategy of
preoperative chemotherapy and postoperative chemoradiotherapy.
 Trial Type:
• investigator-initiated, open- label, randomised phase 3 trial, with patients
recruited from the Netherlands (44 hospitals), Sweden (11 hospitals), and Denmark
(one hospital)

Study Design
 Inclusion criteria:
• 788 patients with stage IB-IVA gastric or gastroesophageal adenocarcinoma,
• Siewert types II and III tumors.
• 18 years or older, have a WHO performance status of 0 or 1, have adequate
cardiac, bone marrow, liver, and kidney function, and have had no previous
radiotherapy or chemotherapy

• T1N0 tumors
• solitary functioning kidney that would be located within the radiation field,
• major surgery within 4 weeks before start of study treatment, or
• lack of complete recovery from previous surgery,
• uncontrolled cardiac or infectious disorders,
• continuous use of immunosuppressive drugs, or
• other conditions preventing the safe use of study drugs and treatment methods.

 Intervention Groups:
• Group 1: Perioperative chemotherapy (3 cycles pre- and post-surgery).
• Group 2: Preoperative chemotherapy + postoperative chemoradiotherapy

Randomisation and masking
 ALEA Randomisation computer programme
 Stratified according to
• Histological subtype @Lauren classification: (intestinal vs diffuse vs mixed vs
unknown)
• Tumour location (gastro-oesophageal junction vs proximal stomach vs middle
stomach vs distal stomach)
 Patients and investigators were not masked to treatment allocation.

Procedure
 Preoperative chemotherapy –
• Three 21-day cycles of epirubicin, cisplatin or oxaliplatin, and capecitabine.
• Epirubicin 50 mg/m², cisplatin 60 mg/m², and oxaliplatin 130 mg/m² were given
intravenously on day 1 of each 21-day cycle.
• Capecitabine was administered at doses of 1000 mg/m² orally two times per day
as tablets for 14 days
• Response assessment with CT scan was done after two chemotherapy cycles to
exclude early progression

 Surgery
• radical resection of the primary tumour (by means of a total gastrectomy, subtotal
gastrectomy, or oesophagocardiac resection) en bloc
D1+ i.e. N1 and N2 LN(stations 1–9 &11) and a minimum of 15 LN
• macroscopic proximal and distal margin of 5 cm.

 Postoperative chemotherapy
• within 4–12 weeks after surgery
• Capecitabine was administered at a dose of 575 mg/m² orally twice daily on
radiotherapy days, for 5 weeks,
• Cisplatin was administered at a dose of 20 mg/m² intravenously on the first day of
each 5 weeks of radiotherapy treatment.
• The radiation dose was 45 Gy, 25 # of 1·8 Gy, for 5 weeks.

• Follow up
• every month during the first 3 months,
• every 3 months during the first year,
• every 6 months until 5 years.
• CT scans of the thorax, abdomen, and pelvis were done every 6 months during the
first 2 years and then once per year until 5 years

Outcomes
• The primary endpoint was overall survival, defined as the time from
randomisation to death from any cause.
• Secondary endpoints were event-free survival, toxicity, and health-related quality of
life.

Surgical and pathological outcomes

Overall survival and event free survival
Overall Survival (OS): 43 months (chemotherapy) vs. 37
months (chemoradiotherapy).
Event-Free Survival (EFS):28 months (chemotherapy) vs. 25
months (chemoradiotherapy).

Subgroup analysis of overall survival

 After preoperative chemotherapy
In the total safety population of 781 patients
• 368 (47%) grade 3 adverse events
• 130 (17%) grade 4 adverse events
• 13 (2%) deaths.
 Causes of death during preoperative treatment were diarrhoea (n=2), dihydropyrimidine
deficiency (n=1), sudden death (n=1), cardiovascular events (n=8), and functional bowel
obstruction (n=1).
.

 During postoperative treatment,
• Grade 3 and 4 adverse events
113 (48%) and 22 (9%) of 233 patients in the chemotherapy group, respectively.
101 (41%) and 10 (4%) of 245 patients in the chemoradiotherapy group,
respectively.
• Non-febrile neutropenia occurred more frequently during postoperative chemotherapy
(79 [34%] of 233) than during postoperative chemoradiotherapy (11 [4%] of 245).
• No deaths were observed during postoperative treatment.

Conclusion
• This trial did not find better efficacy of postoperative chemoradiotherapy
compared with postoperative chemotherapy in patients with resectable gastric
cancer treated with preoperative chemotherapy and adequate surgery.
• In view of the poor postoperative patient compliance in both treatment groups,
future studies should focus on optimising preoperative treatment strategies.
• Docetaxel might be a better chemotherapy backbone than epirubicin and might
therefore be a better option in future trials.

Future
• Furthermore, classification of gastric cancer on the basis of histological response,
completeness of surgical resection, or nodal positivity, as well as molecular
subtypes, such as HER2 12 overexpression, MSI, EBV, or TCGA signature, in this
and other studies, could provide the opportunity to individualise treatment in
future studies.

Classic trial
Capecitabine And Oxaliplatin Adjuvant Study In Stomach Cancer (CLASSIC)
Study

 Surgery is the main treatment for operable gastric cancer; however, recurrence rates
are high (about 40–80%) in advanced cases.
 Adjuvant chemotherapy is a standard component of resectable gastric cancer
therapy and improves patient outcomes
 The Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC)
study was designed to compare the effect of adjuvant capecitabine plus oxaliplatin
after D2 gastrectomy with surgery alone on disease-free survival in patients with
stage II or III gastric cancer

Methods
 Study design
• Randomised, open-label, multicentre, parallel-group, phase 3 study.
• Done in 37 centres in South Korea, China, and Taiwan.

 Inclusion criteria
• Ambulatory
• Aged 18 years or older;
• Histologically confirmed,
• Stage II (T2N1, T1N2, T3N0), IIIA (T3N1, T2N2,T4N0), or IIIB (T3N2)
• Gastric adenocarcinoma with no evidence of metastatic disease;
• Undergone D2 surgery and achieved R0 resection
• Karnofsky performance status of 70% or more
• Adequate renal ,hepatic and hematological function

chemotherapy, immunotherapy, or radiotherapy for gastric cancer
 Randomisation
a centralised interactive computerised system and stratified by country and disease
stage (II, IIIA, and IIIB)

Procedure
 Surgery
• Curative D2 gastrectomy within 6 weeks before randomisation.
• At least 15 lymph nodes were examined
 Chemotherapy
• Total eight 3-week cycles of oral capecitabine (1000 mg/m² twice daily on days
1–14 of each cycle) plus
• intravenous oxaliplatin (130 mg/m²) on day 1 of each cycle .

 Prespecified tumour assessments
• abdominal CT or MRI every 6 months during the first 3 years and yearly
thereafter,
• chest radiograph every 3 months for the first 2 years, every 6 months for the
subsequent year, and yearly thereafter.

 Primary endpoint
• 3year disease-free survival
time from randomisation to the time of recurrence of the original gastric cancer,
development of a new gastric cancer, or death from any cause.
 Secondary endpoints
• overall survival
the time from the date of randomisation to date of death (from any cause) and
safety (any adverse event).

Result
 The median duration of follow-up was 34·2 months in the chemotherapy group
and 34·3 months in the surgery only group
 3year disease-free survival was 74 %in the chemotherapy group and 59% in the
surgery only group
 disease-free survival was 74% in the chemotherapy group and 59% n the surgery
only group
 65patients (13%) died in the chemotherapy group compared with 85 (17%) in
the surgery only group.
 3year overall survival was 83% in the chemotherapy group and 78% in the
surgery only group

• In the chemotherapy group, 96 patients (18%) developed recurrences or new occurrences of gastric cancer
compared with 155 patients (30%) in the surgery only group.

Discussion
• This study shows that a 6month course of chemotherapy after D2 gastrectomy
improves 3year disease-free survival compared with surgery only.
• Adjuvant capecitabine and oxaliplatin was beneficial for all disease stages (II,
IIIA or IIIB).
• In conclusion, findings from the CLASSIC trial support the use of adjuvant
capecitabine and oxaliplatin as a new treatment option for patients with resectable
disease.

ESOPEC TRIAL
Esophageal Cancer Study on PErioperative Chemotherapy

Study and Design
• The present trial was initiated to obtain valid information whether neoadjuvant
chemoradiation(CROSS) or perioperative chemotherapy(FLOT) yields better
survival in the treatment of localized esophageal adenocarcinoma.
• two-arm randomized phase III study
• 16 trial centers in Germany
• Randomization is performed in blocks concealed from the investigator

Arm A (FLOT -PERIOP CHEMO)
• 4 Cycles of FLOT -SURGERY -4
Cycles of FLOT
• FLOT REGIMEN * every 2 weeks
• 5-FU 2600 mg/m2 (24 h) day 1
• Leucovorin 200 mg/m2 (2 h), day 1
• Oxaliplatin 85 mg/m2 (2 h) day 1
• Docetaxel 50 mg/m2 (1 h), every 2
weeks
Arm B ( NACRT-CROSS protocol)
• 5 weeks of radiation therapy and 5
concurrent weekly cycles of
chemotherapy
• EBRT , using 3D conformal radiation
technique
• 41.4Gy given in 23 fractions of 1.8Gy
• Chemotherapy: weekly paclitaxel 50
mg/m2 (1h) and carboplatin (2
mg/ml/min AUC) (1h) .

Inclusion criteria
1. Histologically-proven adenocarcinoma of the esophagus cT1N+ M0 or cT2-4a
N0/N+, M0
2. Age ≥ 18 years
3. No prior abdominal or thoracic radiotherapy
4. ECOG performance status 0–2
5. Adequate cardiac ,respiratory, pulmonary ,bone marrow ,renal, liver function

Exclusion criteria
1. Squamous, adenosquamous or other non-adenocarcinoma histology
2. Advanced inoperable or metastatic esophageal adenocarcinoma
3. ADC cT1N0 and cT4b
4. ADC cT4a deemed inoperable by operating team
5. Gastric carcinoma
6. Prior chemotherapy for gastrointestinal cancer
7. Clinical significant cardiac and/or lung disease
8. Peripheral neuropathy grade >1
9. Pregnant and lactating women

Study objectives and Endpoints
 Primary endpoint
• Overall survival time -It is time from start of study treatment to death due to any
cause.
 Secondary endpoints
• Progression-free survival (PFS) time -Time interval from randomization to the
first event of locoregional failure, metastatic recurrence/progression or death.
• Recurrence-free survival (RFS) time: defined in resected patients who achieved an
R0 or R1 resection as the time interval from surgery to the date of first recurrence
(local, regional or distant) or death, whichever comes first.

Follow up
• The first follow-up visit is performed 6 months after start of treatment
• every 3 months in the first year
• every 6 months from the second year after treatment until the end of follow-up
(min. 3 years)

Statistics
• Sample size calculation is based on primary end point-OS.
• The effect of treatment with respect to the primary end point OS will be estimated
and tested by Cox regression
• Overall survival rates in both arms will be estimated by the Kaplan-Meier method.

Discussion
• Although different studies have been carried out there is no prospective data
comparing the contemporary regimens of neoadjuvant chemoradiation and
perioperative chemotherapy in patients with esophageal adenocarcinoma are
available.
• The present trial was started to obtain valid information whether neoadjuvant
chemoradiation or perioperative chemotherapy yields superior benefits for the
curative treatment of esophageal adenocarcinoma.

Conclusion
• It is hypothesized that perioperative chemotherapy will result in increased overall
survival due to a comparable local effect and a better control of micrometastatic
distant disease.
• Perioperative FLOT improved median overall survival (OS) by 29 months when
compared with neoadjuvant CROSS.
• Surgical complications and postoperative mortality were similar in both arms.

NeoAEGIS trial
NEOADJUVANT TRIAL IN ADENOCARCINOMA OF THE ESOPHAGUS AND ESOPHAGO-GASTRIC JUNCTION INTERNATIONAL STUDY

Methods and design
• Multicentre phase III open-labelled, randomised controlled trial
• 25 institutions and 5 countries
• The aim of this study is to compare the two Level-1 evidence based regimens
exclusively in patients defined as high-risk for relapse.

Study objectives
• The primary objective is overall survival, from the date of randomisation and an
event registered on the date of death from any cause.
• Secondary objectives
• clinical response rate (relief of dysphagia, improvement in health related quality
of life, endoscopic regression, radiological response),
• tumour regression grade,
• surgical resection rate,
• pathological R0 resection,
• post-operative pathology including nodal involvement,
• disease-free survival, time to treatment failure, site of treatment failure, and
toxicity

Patient selection
 Inclusion criteria-
• adenocarcinoma of the oesophagus or oesophago-gastric junction
• cT2-3, N0-3, M0, and
• tumours less than 8 cm in length,
• ECOG performance status 0-2
• Adequate cardiac,renal ,hepatic,bone marrow, respiratory function,
• prior abdominal or thoracic radiotherapy, chemotherapy for gastrointestinal cancer,
• peripheral neuropathy,
• HIV
• other malignancies within 5 years

Arm A - Modified Magic regimen

Arm B – CROSS ,Chemotherapy and Radiotherapy Regimen

MUNICON I & II trial
• It studied the role of FDG-PET-CT in response to assessment following NA
treatment.
• Both trials showed that the continuation of neoadjuvant chemotherapy in metabolic
responders resulted in a favourable outcome.
• However, the poor prognosis of metabolic non-responders could not be improved
by Immediate surgery (MUNICON I) or addition of neoadjuvant radiation therapy
(MUNICONII) indicating dismal tumor biology of these tumors.

Checkmate trial(2021)
• Study Design: Phase III trial of adjuvant nivolumab (Opdivo) vs. placebo post-
surgery and chemoradiotherapy.
• Findings:
• Significant improvement in disease-free survival (22.4 vs. 11.0 months).
• First trial showing benefit of adjuvant immunotherapy.
• Impact: FDA approved nivolumab as an adjuvant therapy.
• Reference: ASCO 2021.

KEYNOTE-590 (2021) trial
• Study Design: Phase III trial of pembrolizumab + chemotherapy vs. chemotherapy
alone for advanced esophageal cancer.
• Findings:
• Improved overall survival in PD-L1-positive patients.
• Durable responses in metastatic settings.
• Impact:
• FDA approved pembrolizumab as first-line therapy.

Toga trial(2010)
• Phase III study of trastuzumab + chemotherapy vs. chemotherapy alone in HER2-
positive gastroesophageal cancers.
• Findings: Significant survival benefit (median OS: 13.8 vs. 11.1 months).
• Established HER2 as a critical biomarker.
• Impact: HER2 testing became standard for gastroesophageal cancers.

Sano trial
 Background:
• One-third of patients with oesophageal cancer has a pathologically complete
response after neoadjuvant chemoradiotherapy (nCRT) plus oesophagectomy.
• Active surveillance may be an alternative for patients with clinically complete
response (CCR)

• A noninferiority stepped-wedge cluster randomised trial was performed.
• Patients with CCR (i.e. no residual disease 6 and 12 weeks after nCRT) underwent
active surveillance (surgery only when locoregional regrowth was detected) or
standard surgery.

• Primary endpoint was overall survival (OS) from day of CCR. Non inferiority was
defined as Hazard Ratio (HR) ) <1.77 for mortality.
• Secondary endpoints were operative outcomes, disease-free survival(DFS), distant
dissemination rate and quality of life (HRQOL, EORTC QLQ-C30).

• Patient Groups: 198 patients underwent active surveillance, and 111 patients
underwent standard surgery.
• Follow-Up: Median follow-up was 34 months for active surveillance and 50
months for standard surgery.
• Overall Survival (OS): Active surveillance showed non-inferior overall survival
compared to standard surgery , indicating that survival rates were not worse with
active surveillance.

 Disease Progression:
•35% of patients in active surveillance maintained complete clinical remission (CCR).
•48% developed locoregional regrowths.
•17% developed distant metastases.
 Surgical Outcomes:
•The R1 rate (positive surgical margins) was 2% in both groups.
•Postoperative 90-day mortality was 4% for active surveillance versus 5% for standard
surgery.

 Disease-Free Survival (DFS):Median DFS was 35 months for active surveillance
versus 49 months for standard surgery with no statistically significant difference.
 Metastasis Development: 43% of patients in active surveillance developed distant
metastases at 30 months after nCRT, compared to 34% in the standard surgery
group , again with no statistically significant difference.
 Health-Related Quality of Life (HRQOL): Active surveillance resulted in
significantly better quality of life at 6 months and 9 months .

Conclusion
• After a follow-up of two years, patients undergoing active surveillance had
noninferior OS and improved short-term HRQOL compared to standard surgery.
• Postponed esophagectomy for locoregional regrowth was safe.
• Extended follow-up is required to assess long-term efficacy of active surveillance.
• Concept is similar to Habr Gama approach for rectal cancer.

TIME trial
It compared minimally invasive surgery (MIS) vs open surgery for esophageal
cancers. MIS was found to be associated with better short term recovery outcomes
(less blood loss, less pain, less pulmonary morbidity, shorter length of hospital stay)
with equivalent long term oncological outcomes.

ROBOT trial
It compared robotic vs open esophagectomy for resectable
esophageal cancer. Robotic esophagectomy was found to be associated
with better short term recovery outcomes (less pain, less post-operative
complications) with equivalent long term oncological outcomes.

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