long term results of cross trial

1. Neoadjuvant chemoradiotherapy
plus surgery versus
surgery alone for oesophageal or
junctional cancer (CROSS):
long-term results of a randomised
controlled trial
Shapiro et al

2. 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%.

3. 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

4. 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

5. 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

6. 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

7. Inclusion Criteria
1. 18 to 75 years of age
2. 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

8. Exclusion Criteria
1. A past or present history of other malignancy,
2. Serious systemic disease
3. The upper border of the tumor less than 3
cm below the upper esophageal sphincter
4. Proximal gastric tumors with minimal
invasion of the esophagus

9. 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.

10. 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

11. 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).

12. • 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

13. • 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

14. • 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

15. • 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

16. 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.

17. • Registration - with the Netherlands Register,
number NTR487

18. 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

19. Trial profile

20. Baseline characteristics

22. 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)

23. 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%.

24. • 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).

25. • 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.

26. Results for overall survival
Median 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]

27. Results for progression free survival
Median
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%,

28. Disease progression

29. 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.

30. 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.

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

32. (3) distant disease control :- improved
significantly. Potential explanation –
direct systemic effect of chemotherapy.

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

34. 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
•

35. • 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