Neoadjuvant chemoradiotherapy with carboplatin and paclitaxel followed by surgery improves overall survival compared to surgery alone for resectable esophageal cancer. In this randomized controlled trial, the median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24 months in the surgery alone group. The chemoradiotherapy regimen was associated with a low rate of toxicity. A pathological complete response was more common in the chemoradiotherapy group. Long-term follow-up confirmed the survival benefit and lower rates of locoregional and distant disease progression for chemoradiotherapy plus surgery.

1. Preoperative Chemoradiotherapy for Esophageal or
Junctional Cancer
• P. van Hagen et al. Department of Medical Oncology, Erasmus University Medical Center/Daniel den Hoed Cancer
Center, Netherlands
• N Engl J Med 2012;366:2074-84.
• Multicenter , randomized, controlled, phase 3 study
• MODERATOR : PROF VISHAL GUPTA

2. • Despite adequate preoperative staging, 25% of patients treated with primary surgery have R1 margin, and 5-year survival rate
rarely exceeds 40%
• Same group previously reported a phase 2 trial of neoadjuvant chemoradiotherapy with same regimen and was associated with a
low rate of serious toxic effects, and a complete resection with R0 margins
• Most RCTs criticized for inadequate trial design, no survival benefit could be shown, and samples that were too small, and poor
outcomes in the surgery-alone group.
• Meta-analyses suggested a survival benefit from neoadjuvant chemoradiotherapy, albeit frequently at the cost of increased
postoperative morbidity and mortality.

3. Inclusion Criteria
• 18 to 75 years of age
• Performance status score of 2 or lower
• lost 10% or less of body weight
• Histologically confirmed, potentially curable squamous-cell carcinoma, adenocarcinoma,or large-cell
undifferentiated carcinoma of the esophagus or esophagogastric junction
• N1 or T2-3
• Upper border of the tumor had to be at least 3 cm below the upper esophageal sphincter.
• Adequate hematologic, renal, hepatic, and pulmonary function,

4. Exclusion Criteria
• Proximal gastric tumors with minimal invasion of the esophagus were excluded.
• The length and width of the tumor could not exceed 8 cm and 5 cm, respectively.
• Metastatic tumors
• No history of other cancer or previous radiotherapy or chemotherapy

5. TREATMENT
Chemotherapy
• Days 1, 8, 15, 22, and 29, Carboplatin targeted at an area under the curve of 2 mg per milliliter per minute
• Paclitaxel at a dose of 50 mg per square meter of body-surface area
• All patients were intravenously premedicated with dexamethasone, clemastine, and ranitidine and antiemetic
agents.

6. Radiotherapy
• Totally 41.4 Gy
• 23 fractions
• 1.8 Gy each
• 5 fractions per week, starting on the first day of the first chemotherapy cycle.
• All patients were treated by means of external-beam radiation.

7. STUDY ENROLLMENT

8. Chemoradiotherapy group f/b surgery
• 7 patients (4%) in the chemoradiotherapy–surgery group did not receive any chemoradiotherapy:
5 patients- disease progression before commencing therapy
2 patients declined the therapy.
• 162 patients (91%) received the full treatment regimen of five cycles of chemoradiotherapy
• Most common reason for not completing all chemotherapy cycles was a low platelet count.
• 164 (92%) received the full dose of radiotherapy.
• Two patients (1%) received a higher dose of radiotherapy (45.0 and 54.0 Gy, respectively)
• 168 patients (94%) underwent surgery
2 patients declined
1 died due to toxic effects of chemoradiotherapy.
• A resection was not possible in 7 patients due to unresectability at surgery

9. • 12 of 171 patients (7%) who received treatment in the chemoradiotherapy–surgery group, grade 3 hematologic
toxic effects were observed;
• 1 patient- Grade 4 hematologic toxic effect and neutropenic fever
• One patient died while awaiting surgery after chemo radiotherapy, probably owing to a perforation of the
esophagus, accompanied by major hemorrhage in the absence of thrombocytopenia.
• All other major nonhematologic toxic effects of grade 3 or higher occurred in less than 13% of patients in this
group.
• The most common grade 3 or worse toxicities were leucopenia in 11 (6%) of 171 patients, anorexia in nine (5%),
and fatigue in five (3%).

11. Surgery group
• 1- disease progression during treatment
1- diagnosis of a second cancer before surgery
• 25 identified as unresectable during surgery

12. Surgery
• Patients in the chemoradiotherapy–surgery group underwent surgery preferably, within 4 to 6 weeks
• Median time between randomization and surgery was 97 days in the chemoradiotherapy–surgery group and 24 days
in the surgery group.
• The median time between the end of chemoradiotherapy and surgery was 6.6 weeks
• A transthoracic approach with two-field lymph-node dissection was performed for tumors extending proximally to
the tracheal bifurcation.
• For tumors involving the esophagogastric junction, a trans hiatal resection was preferred.

13. PATHOLOGICAL ANALYSIS
• Reports on pathological examination had to describe the tumor type and extension, lymph nodes , and resection
margins.
• In the absence of macroscopic tumor , any abnormal-appearing tissue was paraffin-embedded in total in order to
make an adequate assessment for the presence of residual tumor and the effects of therapy.
• Response to therapy gradation was classified into four categories as follows:
Grade 1: no evidence of vital residual tumor cells (pathological complete response)
Grade 2: <10% vital residual tumor cells;
Grade 3: 10 - 50%;
Grade 4: > 50%.
• If a vital tumor was present at 1 mm or less from the proximal, distal, or circumferential resection margin, it was
considered to be microscopically positive (R1).

14. FOLLOW-UP
• Every 3 months in 1st year
• Every 6 months in 2nd year
• End of each year for next 3yrs

15. STATISTICAL ANALYSIS
• Block randomization was performed centrally by telephone or at the central trial office according to computer-generated
randomization lists for each stratum, with random block sizes of 4 or 6.
• Data were analyzed according to the intention to-treat principle.
• Primary end point was overall survival.
• All other described outcomes were secondary end points.
• Survival was calculated from the date of randomization until death with Kaplanan–Meier method
• Log-rank test to determine significance.
• Cox proportional-hazards model was used to estimate the treatment effect with adjustment for prognostic factors for survival.
• Statistical analysis was performed with the use of SPSS software, version 17.0

16. Results

19. • In 7 of 168 patients (4%) in the chemoradiotherapy–surgery group, as compared with 25 of 186 patients (13%) in
the surgery group a resection was not possible because the primary tumor or lymph nodes were identified during
surgery as unresectable, (P = 0.002).
• No significant differences in the occurrence of complications were found between the two treatment groups.
• Six of 168 patients (4%) in the chemoradiotherapy–surgery group died in the hospital, as did 8 of 186 (4%) in the
surgery group (P = 0.70).
• Four patients (2%) in the chemoradiotherapy– surgery group died within 30 days after surgery, as compared with 5
(3%) in the surgery group (P = 0.85)

20. PATHOLOGICAL ASSESSMENT
• A pathological complete response was observed in versus
neoadjuvant chemoradiotherapy plus surgery surgery alone
R0 resection (P<0.001). 148 of 161 patients (92%) 111 of 161 (69%)
A pathological complete response (P = 0.008). adenocarcinoma squamous-cell carcinoma
28 of 121 (23%) 18 of 37 (49%)
lymph nodes (P = 0.77). 15 18
One or more positive lymph nodes (P<0.001). 50 patients (31%) 120 patients (75%)

21. SURVIVAL
• For surviving patients, the median follow-up was 45.4 months .
• Of the 61 patients in the chemoradiotherapy–surgery group who underwent resection and died after having been
discharged, 52 (85%) died from recurrent cancer
2 from sepsis
2 from cardiac failure
2 from respiratory insufficiency
1 from kidney failure
1 from a second primary tumor,
1 after reconstructive surgery for a persistent postoperative neo-esophago tracheal fistula.

22. • Of the 83 patients in the surgery group who underwent resection and died after having been discharged,
78 (94%) died from recurrent cancer,
2- cardiac failure
1-respiratory failure
1-thromboembolic event
1 from an unknown cause (P = 0.14).
• median overall survival was 49.4 months in the chemoradiotherapy–surgery group versus 24.0 months in the
surgery group (P = 0.003)
• The respective overall survival rates at 1, 2, 3, and 5 years were 82%, 67%, 58%, and 47% in the
chemoradiotherapy–surgery group, as compared with 70%, 50%, 44%, and 34% in the surgery group.

23. Long term follow up
• Baseline characteristics were well balanced between the two treatment groups
• 1 patient in the neo adjuvant chemoradiotherapy plus surgery group moved abroad and was therefore lost to follow-
up 73 months after randomization.
• Median follow-up for surviving patients was 84.1 months
Median survival neoadjuvant chemoradiotherapy plus
surgery
surgery alone
73 [41%] of 178 53 [28%] of 188
Overall 48.6 months 24 months
squamous cell carcinomas 81.6 months 21.1 months
adenocarcinoma 43.2 months 27.1 months

24. • During follow-up, 16 patients died from treatment-related causes (ie, during neoadjuvant chemoradiotherapy or
during postoperative hospital stay), of whom nine were in the neoadjuvant chemoradiotherapy plus surgery group
and seven in the surgery alone group.
• 23 patients died from non-disease-related causes beyond the first 90 days postoperatively (13 in the neoadjuvant
chemoradiotherapy plus surgery group and ten in the surgery alone group).
OVERALL SURVIVAL neoadjuvant chemoradiotherapy plus
surgery
surgery alone
1 year 81% 70%
2 years 67% 50%
3 years 58% 44%
5 years 47% 33%

25. •Disease free

26. Disease progression
neoadjuvant chemoradiotherapy plus surgery surgery alone
Locoregional progression 39 72
Distant progression 70 90
Both 22 38

27. Discussion
• Trial showed significantly better overall and disease-free survival among patients who received a
chemoradiotherapy regimen as compared with those treated with surgery alone.
• Chemoradiotherapy was associated with a low frequency of high-grade toxic effects and could be given as an
outpatient treatment
• The preoperative treatment did not result in higher postoperative morbidity or early mortality.
• Patients treated with neoadjuvant chemoradiotherapy followed by surgery had a 34% lower risk of death during
follow-up
• Study was designed to detect a difference in median survival of 6 months in favor of the combined regimen of
chemoradiotherapy and surgery, as compared with surgery alone (22 months vs. 16 months).
• The observed survival in both groups was superior to the anticipated survival probably owing to ongoing
improvements in surgical techniques, patient selection, and staging methods over the years

28. • In the chemoradiotherapy–surgery group, 94% of patients underwent surgery, and 90% of tumors could be resected.
In the surgery group,99% of patients underwent surgery, and 86% underwent resection.
• These percentages indicate that the preoperative chemoradiotherapy did not significantly change the individual
chance of undergoing a resection.
• Postoperative complication rates, although similar between groups , were higher than expected and higher than
reported in other studies
• The substantial downstaging as a result of chemoradiotherapy is also reflected in the significantly higher percentage
of R0 resections in the chemoradiotherapy–surgery group
• 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.

29. • Improvement in locoregional control continued for a longer period. These findings further support the clinical value
of this multimodality treatment strategy.
• The overall survival benefit and the progression-free survival benefit were confirmed for both histological subtypes
• Further more, Stahl et al and Burmeiter et al reported similar R0 resection rates between treatment groups but
significantly higher pathologically complete response rates and lower locoregional recurrence rates in the
neoadjuvant chemoradiotherapy plus surgery groups.
• Therefore, the results from these trials point towards neoadjuvant radiotherapy combined with sensitizing
chemotherapy rather than neoadjuvant chemotherapy alone as the likely cause of improved locoregional control, as
achieved in the CROSS trial.

30. • Not only locoregional control, but also distant disease control improved significantly in the neoadjuvant
chemoradiotherapy plus surgery group.
1. If fewer locoregional recurrences occur, then possibly less distant dissemination develops
2. A mechanism by which improved locoregional control might improve distant disease control could be merely
control of the primary tumor itself, thereby removing a presently unknown stimulus for disseminated tumor
outgrowth.
3. Improved distant disease control could be caused by a direct systemic effect of chemotherapy.
• In the present study, we recorded a significant reduction in distant disease progression already within the first 6
months after randomisation. Such an early reduction in distant disease progression, without evidence of a reduction
beyond the first 24 months, supports a direct systemic effect of this neoadjuvant chemotherapy regimen.

31. For multimodal therapy, prior to the CROSS trial,
• RCTs tended to be small and underpowered
• Inclusive of both EAC and (SCC) subtypes
• Variation in dose and fractionation
Post Cross trial
1. No neoadjuvant approach is without risk
2. Increased risk of postoperative morbidity and mortality.
3. Some will be completely resistant to therapy and may progress during therapy.

32. • Walsh et al with 113 patients of adenocarcinoma, showing a highly significant
improvement in 3-year survival (32% vs. 6%; P=0.01) compared with surgery
alone
• CALBG 9781, where (n=56 of planned 540) patients treated with 5-FU/Cisplatin
and 50.4Gy RT had a 5 year overall survival of 39% compared with 16% in
surgery only P<0.008) with pCR of 40%
• RTOG 8911/ Intergroup 0113 RCT randomised 440 patients, 54% with
adenocarcinoma, to pre- and postoperative 5-Fluorouracil and cisplatin, or surgery
alone. No improvement in survival was evident

33. • OEO2 Trial with 802 patients where 66% of patients had adenocarcinoma, and patients
were randomised to two cycles of pre-operative Cisplatin and 5-FU, or surgery alone.
The treatment arm had a 23% 5-year overall survival compared with 17% in the surgery
alone group .
• MAGIC trial of 503 patients for gastric adenocarcinoma, included 11% with junctional
and 14% with lower esophageal adenocarcinoma, and compared 3 cycles of ECF before
and after surgery with surgery alone. Grade 3-4 hematologic toxicities were evident in
24% of patients. Pathologic down-staging in tumor and nodal sites were evident, and the
5-year survival rate was 36% vs 23% (P=0.009). Efficacy was independent of site.
• French ACCORD-07 recruited 224 of planned 250, with 64% having junctional
adenocarcinoma, and 11% with lower esophageal adenocarcinoma. Two pre- and four
postoperative cycles of Cisplatin and 5-FU were given, and the 5 year survival was 38%
vs 24%
• in Japan, where adjuvant chemotherapy was standard of care for stage II or II esophageal
squamous cell carcinoma based largely on the results of the RCT JCOG 9204 , a trial of
330 patients comparing 2 cycles of neoadjuvant cisplatin and 5-FU versus post-operative
CF terminated early as the 5 year overall survival in the neoadjuvant group were
superior

34. • Recent FLOT4 study, in patients with gastric or junctional adenocarcinoma with
300 patients compared ECF/ECX (3 cycles pre and post operatively) with FLOT 4
cycles pre and 4 postoperatively junctional cancers. Primary end point was pCR,
16% for the FLOT to 6% for ECF/ECX overall pathological response rate of 37%
with FLOT
• OE05 trial randomised 897 with lower esophageal or junctional tumours to 2
cycles of CF and surgery versus 4 cycles ECX followed by surgery. There no
differences in overall survival at 3 years between the arms. There were more
complete responses and a longer interval to disease recurrence in the ECX arm
but there were more grade 3 toxicities

35. What approach, multimodal or chemotherapy-only, is superior in the neoadjuvant or perioperative approach to locally advanced
esophageal and junctional cancer?
• Whereas the superiority of multimodal therapy firmly established from Level 1
evidence, in contrast, no conclusions can be drawn from the limited data on direct
comparisons between the two.
• The POET trial had 119 patients with EUS staged (uT3-4, Nx, Mo) adenocarcinoma
received either preoperative induction chemotherapy (Cisplatin, 5-FU and leucovorin) or
induction chemotherapy followed by chemoradiation [Cisplatin and etoposide with
30Gy in 15 fractions of radiation therapy (RT)], and then surgery.
The trial was closed prematurely due to slow accrual, 3 year survival was 47.4% vs 27.7%
(P=0.07)
pCR rate was 15.6% vs 2% (P=0.03)
pathological node negative rate was 64.4% vs. 37.7%; P=0.01.
• RCT from Scandanavia of 181 patients, 131 with adenocarcinoma, and powered on pCR,
compared 3 cycles of CF alone with RT (40Gy). pCR was 28% vs 9% in chemotherapy
alone (P=0.002), with corresponding nodal metastases of 35% and 62%, respectively,
there was no difference in OS

36. Targeted therapies and immune based approaches in esophageal cancer
• The ToGA trial patients with HER-2-positive metastatic gastric and junctional cancers, where targeted therapy with
Herceptin has impacted on outcome and is included in current treatment guidelines
• A study at lapatinib for HER2 positive cancer, patients with esophageal and junctional adenocarcinoma of stomach
or junction were randomised to ECX chemotherapy or ECX in combination with the VEGF inhibitor bevacizumab,
for 3 cycles before and after surgery, with a further 6 maintenance doses in the bevacizumab arm showed no
differences in survival were reported, a high anastomotic leak rate (23%) in patients undergoing esophageal
surgery on the experimental arm, compared with 9% in the ECX arm, with 30 day mortalities of 11% and 5%.

37. Does cT2N0 represent a disease stage that justifies inclusion in trials of locally advanced disease?
• It is uncertain from published trials whether patients with this disease stage derive any benefit from neoadjuvant
therapy.
• At this point it is reasonable to conclude that there is no compelling evidence to support neoadjuvant therapy in
this cohort, notwithstanding the limitations of even modern staging with EUS and CT-PET with understaging in
approximately half of patients and overstaging in about one quarter of tumors in this group
• RCTs powered on predicted node negative disease in adenocarcinoma and including surgery only arms would be
of interest and should be developed.

38. Is there a role for a “watch and wait” policy in patients with a predicted complete clinical response following
neoadjuvant therapy?
• No single best answer for the entire group of patients.
• Of available evidence, our ability to predict the likelihood of true pCR, the risk of an operation, and the risks associated with a
surveillance strategy are less than ideal.
• pre-SANO trial concluded clinical response evaluation comprising EUS with bite-on-bite biopsies and FNAC of suspicious
lymph nodes for detection of locoregional residual disease in combination with PET–CT for detection of interval metastases
after neoadjuvant chemoradiotherapy is an adequate strategy for clinical response evaluation
• For a fit patient, a risk of persistent cancer in the range of 30–40% may be too high, even with an aggressive surveillance
strategy and plan for salvage operation if recurrence is detected. Avoiding surgery and surgical complications may not be worth
the risk of progression to unresectability or metastasis, or the burden of anxiety
• Conversely, in the older or sicker, a 60–70% chance that the cCR patient truly has a pCR may be good enough.
• For patients that fall in the middle, clinical decision is more complicated. No studies currently capture all of these patient-
important factors, so clinical judgment and experience remain at the center of these decisions which results in wide variability of
care.