Neoadjuvant chemoradiotherapy plus surgery versussurgery alone for oesophageal or junctional cancer (CROSS):

long-term results of a randomised controlled trial

Shapiro et al

Problem statement

• aggressive disease with high degree of locoregional and distant recurrence after primary surgical resection

• Despite adequate preoperative staging, 25% of patients treated with primary surgery have microscopically positive resection margins (R1), and the 5-year survival rate rarely exceeds 40%.

Rationale

• Before 2004, four randomised trials comparing neoadjuvant concurrent chemoradiotherapy plus surgery to surgery alone - cisplatin and fluorouracil with concurrent radiation (40 to 45 Gy) – no benefit

• CROSS TRIAL group - non-randomised phase 2 feasibility trial (weekly administrations of carboplatin and paclitaxel with 41·4 Gy concurrent radiotherapy) – R0 resection rate of 100% & low treatment-related toxicity

Introduction

• The trial enrolled 368 patients between March 30, 2004, and Dec 2, 2008, from eight Dutch participating centers (five academic centers and three large non-academic teaching hospitals).

• 2 years follow up results were published in 2012

Objectives • Primary objective – Overall Survival - calculated from the

date of randomisation to the date of all-cause death or to the last day of follow-up.

• Secondary objective - Progression Free Survival - defined as the interval between randomisation and the earliest occurrence of locoregional progression or distant dissemination or death from any cause. Progression-free interval - similar to progression-free survival, with the difference that treatment-related deaths and non-oesophageal cancer-related deaths were not counted as events

Definitions • Locoregional progression - either progression of locoregional

disease during treatment (resulting in irresectability) or as locoregional recurrence after completion of treatment. Locoregional sites included the mediastinum, the supraclavicular region, and the celiac trunk region.

• Distant progression - as occurrence of disseminated disease, either during or after completion of treatment. Distant disease included cervical and (para-aortic) lymph node dissemination below the level of the pancreas, malignant pleural effusions, peritoneal carcinomatosis, and further hematogenous (organ) dissemination

Inclusion Criteria

1. 18 to 75 years of age2. ECOG <3,3. Locally advanced (clinical stage T1N1M0 or clinical

stage T2–3N0–1M0, according to TNM 6th edition), 4. Histologically proven - squamous cell carcinoma or

adenocarcinoma of the oesophagus or oesophago-gastric junction

5. The length and width of the tumor should not exceed 8 cm and 5 cm, respectively

Exclusion Criteria

1. A past or present history of other malignancy,2. Serious systemic disease3. The upper border of the tumor less than 3

cm below the upper esophageal sphincter4. Proximal gastric tumors with minimal

invasion of the esophagus

Sample size calculation

• To detect a difference of 6 months in median overall survival (22 months in the neoadjuvant chemoradiotherapy plus surgery group v/s 16 months in the surgery alone group, according to a two-sided test with α level 0.05 and β level 0.80), sample size was at least 175 patients in each treatment group. The statistical significance level was set to 0.05.

Sampeling

• Sampeling :- Computer-generated randomisation with random permuted block sizes of four or six

• No. of groups :- 2, one NACRT followed by surgery & second surgery alone

• Masking

Procedure • Pretreatment staging – UGIE with biopsy, EUS, CT scan of the neck, chest,

and upper abdomen and USG neck with FNAC suspected lymph nodes on indication

• Other tests – Pulmonary function tests, routine hematologic and biochemical tests

• Protocol - Carboplatin (AUC 2 mg/mL per min) and Paclitaxel (50 mg/m2 of body-surface area) intravenously for five cycles, on days 1, 8, 15, 22, and 29. A total concurrent radiation dose of 41.4 Gy in 23 fractions of 1.8 Gy on 5 days per week (excluding weekends), starting on the first day of the first chemotherapy cycle.

• Total duration of neoadjuvant treatment - 23 days (5 days per week in weeks 1, 2, 3 and 4, then 3 days in week 5).

• Interim biochemistry - on days 8, 15, 22 & 29 (weekly), blood counts & serum creatinine

• Treatment delay for 1 week – TLC <1000, Platelet <50000, Mucositis with oral ulcers or protracted vomiting

• Treatment stopped - febrile neutropenia (neutrophils <500 and a body temperature >38.5°C), persistent creatinine clearance of less than 50% of the pretreatment level, symptomatic cardiac arrhythmia or atrio-ventricular block ( not first-degree atrio-ventricular block), or any toxicity at grade 3 or worse

• Surgery – immediate in surgery alone group and after 4 to 6 weeks in NACRT group

• TTE with two-field lymph node dissection - for upper esophagus carcinomas (at or above the level of the carina)

• Either a TTE with two-field lymph node dissection or a THE – for ca below the level of the carina,

• THE for junctional tumors• Gastric-tube reconstruction with a cervical anastomosis -

preferred technique for restoring the continuity of the digestive tract

• Pathological analysis - 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, - classified the degree of histomorphologic regression into four categories as follows:

• (1) grade 1 - no evidence of vital residual tumor cells (pathological complete response);

• (2) grade 2 - less than 10% vital residual tumor cells; • (3) grade 3 - 10 to 50% vital residual tumor cells• (4) grade 4 - more than 50% vital residual tumor cells

• Pathological staging based on TNM 6th edition• R0 resection - defined as a tumour-free resection margin of

at least 1 mm• Follow up - in first year every 3 months, In the second year

every 6 months and annually thereafter until 5 years after treatment.

• Additional interim visits - if complaints such as renewed dysphasia and unexplained weight loss or pain arose before the next scheduled visit.

• Diagnostic investigations - only undertaken as necessary during follow-up

Data collection methods including settings and periodicity

• Pretreatment clinical evaluation, biochemistry and staging evaluation

• Follow up• Follow-up time divided to study the temporal

distribution of disease progression.• Three separate analyses were done, including follow-

up until 6 months, 12 months, and 24 months after randomisation.

• For each time point, the number of events between treatment groups were compared.

• Registration - with the Netherlands Register, number NTR487

Statistical Analysis• Intention-to-treat analysis• Kaplan-Meier method to estimate overall and progression-

free survival, with the log-rank test to ascertain significance. • Univariable and multivariable Cox proportional hazards

models to establish the effect of neoadjuvant chemoradiotherapy in subgroups, adjusting for baseline covariates.

• Univariable Cox regression modeling to analyze differences in progression-free interval between treatment groups, expressed as hazard ratios (HRs)

• Statistical analysis was done by JS and EWS using SPSS version 21.0

Trial profile

Baseline characteristics

Initial results in 2012

• Minimum follow-up of 24 months (median follow-up 45 months [range 25.2–80.9, IQR 32.6–60.6])

• Absolute benefit in 5-year overall survival in favour of the multimodality group

• Treatment completion rate 95%• Rate of occurrence of grade 3 adverse events 17%• R0 resection – 92% in the multimodality group

compared with 69% surgery alone group (p<0.001)

Results

• 95% completed the entire neoadjuvant chemoradiotherapy regimen.

• 8% developed grade 3 or worse haematological toxicity and 11% had grade 3 or worse non-haematological toxicity.

• The most common grade 3 or worse toxicities were leucopenia in 6%, anorexia in 5% and fatigue in 3%.

• In the neoadjuvant chemoradiotherapy plus surgery group 90% patients underwent resection, compared with 86% in the surgery alone group.

• The proportion of patients with THE resections was similar between both treatment groups 45% in the neoadjuvant chemoradiotherapy plus surgery group and 44% in the surgery alone group (p=0.96).

• Median follow-up for surviving patients was 84.1 months (range 61.1 – 116.8; IQR 70.7 – 96.6 months).

• Alive patients at the time of analysis – 41% in the neoadjuvant chemoradiotherapy plus surgery group and 28% in surgery alone group.

Results for overall survivalMedian overall survival

NACRT f/b surgery Surgery alone Stastical significance

overall 48.6 months 24.0 months HR 0.68 with 95% CI, range 0.53–0.88]

squamous cell carcinomas

81.1 months 21.1 months HR 0.48 [95% CI, range 0.28–0.83])

adenocarcinomas 43.2 months 27.1 months HR 0.73 [95% CI, range 0.55 – 0.98

At 1 years 81% 70% HR 0.57 [95% CI, range 0.37 – 0.88]

At 2 years 67% 50% HR 0.59 [CI 95%, range 0.43 – 0.82]

At 3 years 58% 44% HR 0.65 [CI 95% 0.49 – 0.88]

At 5 years 47% 33% HR 0.67 [CI 95% 0.51 – 0.87]

Results for progression free survivalMedian progression free survival

NACRT f/b surgery Surgery alone Stastical significance

overall 37.7 months 16.2 months HR 0.64 [95% CI, range 0.49 – 0.82]

squamous cell carcinomas

74.7 months 11.6 months HR 0.48 [95% CI, range 0.28 – 0.82

adenocarcinomas 29.9 months 17.7 months HR 0.69 [95% CI, range 0.52 – 0.92]

At 1 years 71% 54% HR 0.55 [95% CI, range 0.39 – 0.77

At 2 years 60% 41% HR 0.57 [95% CI, range 0.42 – 0.77]

At 3 years 51% 35% HR 0.62 [CI 95%, range 0.47–0.82]

At 5 years 44% 27% HR 0.61 [CI 95%, range 0.47–0.78]

Disease progression

Disease progression v/s duration• The reduction in locoregional progression was apparent during

the first 6 months of follow-up and remained significant after the first 24 months of follow up. This finding indicates that the effect of reduction in locoregional progression continued for an extended period after randomisation.

• The reduction in distant progression was also already recorded during the first 6 months of follow-up and remained significant during the first 24 months of follow-up but not thereafter, which suggests that the reduction in distant progression mainly occurred within the first 24 months after randomisation.

Discussion

• (1) Differences in treatment effect between subgroups:- no significant interactions in treatment effect for any of the subgroups, which means that differences in treatment effect between subgroups could well have arisen by chance, and the overall treatment effect should be regarded as valid for all considered subgroups.

• (2) better locoregional control in comparison to and chemotherapy followed by surgery trials

(3) distant disease control :- improved significantly. Potential explanation –

direct systemic effect of chemotherapy.

Drawbacks

Relative scarcity of patients with poorer performance status, older patients, or those with tumours located in the proximal or middle oesophagus

Implications of all available evidence for perioperative management

• CROSS v/s MAGIC :- • CROSS – distal oesophageal cancers (56%) or

junctional cancers (26%),• MAGIC - distal oesophageal cancers (14%) or

junctional cancers (12%),• MAGIC – no long term results•

• Japanese randomised NExT trial (JCOG1109) – for preoperative or perioperative treatment for oesophageal squamous cell carcinoma

• Irish randomised Neo-AEGIS trial (ICORG 10-14; NCT01726452) – for preoperative or perioperative treatment oesophageal adenocarcinoma