Cross trial esophagus updated result

JOURNAL CLUB
Dr Bharti Devnani
Moderator- Dr Neeraj Rastogi
Lancet Oncol 2015,August 6, 2015

LAYOUT
 Preamble
 Present study
 Review of literature
 Ongoing trials

4
PRE OP.CT+RT+S VS S
AUTHOR MEDI
AN
FOLL
OW
UP
REGIMEN NO
OF
PTS
Ro
resection/
Dist Met
PATH CR LOCOREG
FAILURE
3-Yr
Surviv
al
SURVIVAL
DIFF
Urba et al 8.2 5fu+cddp+Vbl+R
T+S
S
50
50
90 60%
90 65%
28
-
19%
42%
P=0.02
30
16
p=0.15
Boset et
al
4.6 Cddp+RT+S
S
143
138
81
69
26
---
34
36
NS
Walsh et
al
1.5 5fu+cddp+RT+S
S
58
58
NR
NR
25 32
6
P+0.01
Burmeiste
r et al
5.4 5fu+cddp+RT+S
S
128
128
80
59
16
---
35
30
NS
Tepper et
al
6.0 5fu+cddp+RT+S
S
30
26
NR
NR
33 13
15
39
16
P=0.008

METAANALYSIS OF NACTRT F/B SX VS SX
ALONEAuthors Trials Results Journal
John D .
Urschel et
al
9 RCTs
N=1116
3 year survival better in CTRT
f/b sx (p=0.016)
Locoregional reccurence less in
CTRT f/b sx (p=0.0002)
American jr of
sx(2003)185;5
38-543
Fiorica et
al
6 RCT
N=764
3 year mortality rate less with
CTRT f/b Sx (p=0.03)
Post op mortality high in CTRT
f/b sx (p=0.01)
Gut
2004;53:925-
930
Kaklaman
os I et al
11 RCTs
N=2311
2 year OS absolute diff 4.4% in
CTRT f/b sx
Treatment related mortality 3.4%
vs 1.7%( NACTRT vs NACT f/b
Sx)
Annals of sx
oncology
(2003)10(7);75
4-761
Val
Gebski et
al
10 RCTs
N=1209
2 year OS absolute difference
13% (p=0.04)
Lancet
oncology
2007;8:226-
234 5

Sajoquist et alLancet Oncol 2011; 12: 681–92

Provides strong evidence for a survival benefit of neoadjuvant
chemoradiotherapy or chemotherapy over surgery alone in patients with
oesophageal carcinoma. clear advantage of
neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy has not
been established.

 The role of neoadjuvant chemoradiotherapy has
been debated for several decades.
 In most randomized trials, no survival benefit could
be shown, and the trials were criticized for
 Inadequate trial design,
 Small sample size,
 Poor outcomes in the surgery-alone group.
 Meta-analyses suggest a survival benefit at the cost
of increased postoperative morbidity and mortality.

AIM
To report long term results of ChemoRadiotherapy for
Oesophageal cancer followed by Surgery Study
(CROSS )comparing neoadjuvant
chemoradiotherapy plus surgery versus surgery
alone in patients with squamous cell carcinoma and
adenocarcinoma of the oesophagus or
oesophagogastric junction at a minimum follow-up
of 5 years.

Study design
 Phase III randomised controlled trial
 368 patients
 2004-2008
 By eight Dutch participating centres (5 academic
and 3 large non academic centers)

INCLUSION CRITERIA
 Age 18- 75 years
 Adequate haematological, renal, hepatic & pulmonary function
 WHO PS of 2 or better
 Locally advanced T1N1M0 or T2–3N0–1M0 (6th E)
 Histologically proven potentially curable SCC /
adenocarcinoma or large cell undifferentiated
 Oesophagus or GE junction (ie, tumours involving both the
cardia and the oesophagus on endoscopy)

EXCLUSION CRITERIA
 Past or current history of malignancy other than the
oesophageal malignancy
 Previous chemotherapy and/or radiotherapy
 Weight loss of > 10% of the original bodyweight.
 Length and width of tumor more than 8cm and 5 cm
respectively.

PRETREATMENT STAGING
 History /Physical examination
 Routine hematological and biochemical tests
 Upper GI endoscopy with histological biopsy
 EUS
 CT scan of the neck, chest, and upper abdomen
 USG of the neck
 FNAC of suspected lymph nodes on indication
 PFT

TREATMENT
Radiotherapy
 41.4 Gy/ 23 # @1.8 Gy
 5 fractions /week
Chemotherapy
 Carboplatin - AUC 2 mg /ml/min
 Paclitaxel - 50 mg /m2
 On days 1, 8, 15, 22, and 29

Surgery
In surgery arm-ASAP
In CT-RT arm-4-6 wks after completion of chemoRT
 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
transhiatal resection was preferred.
 In both approaches, an upper abdominal
lymphadenectomy, including resection of nodes along
the hepatic artery, splenic artery, and left gastric artery,
was done.

ChemoRadiotherapy for Oesophageal cancer followed by
Surgery Study (CROSS) trial
368 pts. (2004-2008)
Surgery alone
Preop
ChemoRT
followed by
surgery
RT dose -41.4 Gy/ 23# @ 1.8 Gy # 5 days a week
NACT- Carboplatin AUC 2 & Paclitaxel (50 mg/m2 of body-surface area) on
days 1, 8, 15, 22, and 29
Surgery-4–6 weeks after completion

Toxicity monitoring- NCI-CTCAE Version-3
Weekly laboratory tests
 CBC
 S. Creatinine
Chemo delayed if
 WBC < 1・0 × 10⁹ cells/ L
 Platelet count <50 × 10⁹ per L
 Mucositis with oral ulcers or protracted vomiting
despite antiemetic premedication.

Further chemotherapy was withheld
 Febrile neutropenia (ANC <500,temp >38・5°C)
 Persistent creatinine clearance of < 50% of the
pretreatment level
 Symptomatic cardiac arrhythmia or AV block
 Major organ toxicity at grade 3 or worse
(except oesophagitis).

PATHOLOGICAL ANALYSIS
 Tumor type and extension
 Lymph nodes,
 Resection margins-R1 if tumor present at <1mm
from the proximal, distal, or circumferential margin
Response to therapy
 Grade 1 (pCR)-no evidence of vital residual tumor
cells
 Grade 2-- < 10% vital residual tumor cells
 Grade 3-- 10 to 50%
 Grade 4 --> 50%.

Stratified according to
 Histological tumour type (adenocarcinoma vs
squamous cell carcinoma),
 Treatment centre
 Clinical nodal status (cn0 vs cn1),
 WHO performance score (WHO-0 vs WHO-1 vs
WHO-2)
No post hoc analyses were performed.

FOLLOW-UP
 I yr- every 3 months
 II-yr - every 6 month
 II-V yrs- annually.
 Interim visits were - if complaints
(dysphagia ,unexplained weight loss , pain)
Adverse events were collected till the initial report
of this trial (2012)
Diagnostic investigations were only
undertaken as necessary during follow-up.

Primary end point
 Overall survival- Date of randomisation to the date of all-cause
death or to the last day of follow-up.
Secondary end points
 Progression free survival- Defined as the interval between
randomisation and the earliest occurrence of disease
progression resulting in primary (or peroperative)
irresectability of disease, locoregional recurrence (after
completion of therapy), distant dissemination (during or after
completion of treatment), or death from any cause.
 Progression free interval-treatment-related deaths
and non-oesophageal cancer-related deaths were not
counted as events.

Locoregional sites
 Mediastinum
 Supraclavicular region
 Coeliac trunk region.
Distant disease
 Cervical and (para-aortic) lymph node
 Dissemination below the level of the pancreas
 Malignant pleural eff usions
 Peritoneal carcinomatosis
 Haematogenous (organ) dissemination.

STATISTICAL ANALYSIS
 Kaplan-Meier method –OS and PFS
 Log-rank test – to ascertain signifi cance.
 Univariable and multivariable cox proportional
hazards models to establish the effect of
neoadjuvant chemoradiotherapy in subgroups,
adjusting for baseline covariates.

 Minimum follow-up- 60 months
 Median follow-up-84.1 months (range 61.1–116.8)
 162 (95%) were able to complete the entire
neoadjuvant chemoradiotherapy regimen.

Grade 3 or worse haematological toxicity
13/171 pts (8%)
 Most common leucopenia in 11 (6%)
Grade 3 or worse non-haematological toxicity.
18 /171(11%)
 Anorexia in 9 (5%)
 Fatigue in 5(3%).
 Treatment related deaths
16 (9 v/s 7)

Median OS
48.6 v/s 24.0 months
HR 0・68
[95% CI 0.53-0.88]

Median OS –SCC
HR 0.48(95% CI 0.28-
0.83 )
Median OS-Adenoca
HR 0.73 (95% CI 0.55-
0.98)

Median PFS
37.7 v/s 16.2
months
HR 0・64
[95% CI 0.49-0.82]

Median PFS –SCC
HR-0.48 [95% CI 0.28–0.82]
Median PFS-Adenoca
HR-0・69 [95% CI 0.52–0.92]

LOCOREGIONAL PROGRESSION
Reduction in locoregional progression was already apparent during the first 6
months & remained significant after the first 24 months of followup
Effect of reduction in locoregional progression continued for an extended period
after randomisation.

DISTANT PROGRESSION
Reduction in distant progression remained significant during
the first 24 months of follow-up but not thereafter.
 Systemic effect of chemotherapy
 Fewer local recurrence , less distant dissemination

OS ACCORDING TO DEGREE OF TUMOUR
REGRESSION
Pts with > 50% residual tumour had a significantly worse OS as
compared to patients without residual tumour or patients with 1% - 49%
residual
No significant difference b/w patients without residual tumour and
patients with 1% - 49% residual tumour

LIMITATIONS OF THE STUDY
?? Applicable to
Poorer performance status
 PS 0 (84%) or PS1 (16%)
Middle and upper 1/3 of the oesophagus
 82% of patients had lower third or junctional tumours.
Early oesophageal cancer
 Only 14% patients
Raised risk of postoperative mortality without survival
benefit after NACT-RT in stage I–II oesophageal
cancers (FFCD 9901)

CONCLUSION OF THIS STUDY
 CROSS chemoradiotherapy regimen improves
long-term overall & progression-free survival in
patients with oesophageal and junctional cancer.
 Improvement is statistically significant and clinically
relevant for both squamous cell carcinoma and
adenocarcinoma subtypes.
 This should be viewed as a standard of care for
patients with resectable locally advanced
oesophageal or junctional cancer.

DISCUSSION AND REVIEW OF
LITERATURE

?? Ideal neoadjuvant strategy
CF+ RT
ECF perioperatively
Pacli+Carbo+RT
RT- high dose / low dose
Chemo alone or chemoRT

Applicablility for oesophageal and junctional cancers is questionable due
to small no of this group
Preoperative or perioperative chemotherapy is still regarded
as standard of care in some countries for patients with
oesophageal and junctional cancer.
Published in 2006 after a minimum follow-up of < 2 years, has not yet
reported its long-term results,
??survival benefit of perioperative chemotherapy will sustaine or not
MAGIC TRIAL

Comparable outcome, in terms of DFS and OS
A higher percentage of patients completed the carboplatin/paclitaxel regimen
(82% versus 57%, P = 0.010).
Hematological and nonhematological toxicity (≥grade 3) in the
carboplatin/paclitaxel group (4% and 18%) was significantly lower than in the
cisplatinum/5-FU (19% and 38%, P = 0.001).

CARBOPLATIN-PACLITAXEL AS NEOADJUVANT
THERAPY FOR ESOPHAGEAL CA
Keresztes et al. JTCVS 2003
• Carbo AUC 6, Taxol 200 mg/m2 q3wk x 2 cycles  surgery
• 26 pts – 100% completion full course
- 12% grade III/IV leucopenia
-95% improvement dysphagia w/in 1 wk
-61% major clinical response, 11% pathCR
-3 yr OS 64% for resected patients
D’Addario et al. Onkol 2002
• Carbo AUC 3, Taxol 75 mg/m2 days 1, 8, 15 q4wks x 2  surgery
• 19 pts -15.2% grade III/IV leucopenia, 3.2% grade III/IV
thrombocytopenia
- 83% overall RR, 17% pathCR
- 70% RR adenoca, 87% RR SCC esophagus
- median F/U 19 mo – 11/19 pts alive

Higher radiation dose more toxic
Three early postoperative deaths were seen, due in
part to acute respiratory distress syndrome and
all three patients received 50–50.4 Gy

A- pacli+ Carbo+41.4 Gy
B-Cis+5FU+50.4 Gy
Arm –A Less toxic
No difference in response or survival

MAGIC VS. CROSS UPPER GI. ICORG
(NEO-AEGIS TRIAL)
 Adenocarcinoma of the Oesophagus
Adenocarcinoma of the Oesophago-gastric Junction
 cT2-3 N0-1 M0
 CT- 18FDG-PET and EUS in all patients
 WHO Performance Status 0, 1 or 2
 Experimental: A (MAGIC)MAGIC regimen: 3 cycles
ECF/X-Surgery-ECF/X
 Capecitabine (625 mg/m2 twice daily orally)for 21
days/3 weeks also allowed (modification)
 Experimental: B (CROSS)Arm B consists of the CROSS
protocol,

PREOPERATIVE CHEMORADIATION (PACLITAXEL-
CARBOPLATIN OR FOLFOX) FOR RESECTABLE
ESOPHAGEAL AND JUNCTIONAL CANCER
(PROTECT)

Cross trial esophagus updated result

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