Download - Cross trial esophagus updated result
JOURNAL CLUB Dr Bharti DevnaniModerator- 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 SAUTHOR MEDI
AN FOLLOW UP
REGIMEN NO OF PTS
Ro resection/Dist Met
PATH CR LOCOREG FAILURE 3-Yr
Survival
SURVIVAL DIFF
Urba et al
8.2 5fu+cddp+Vbl+RT+SS
50
50
90 60%90 65%
28-
19%42%P=0.02
30
16
p=0.15
Boset et al
4.6 Cddp+RT+SS
143138
81 69
26---
3436
NS
Walsh et al
1.5 5fu+cddp+RT+SS
58
58
NR NR
25 32
6
P+0.01
Burmeister et al
5.4 5fu+cddp+RT+SS
128
128
80 59
16
---
35
30
NS
Tepper et al
6.0 5fu+cddp+RT+SS
30
26
NRNR
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 RCTsN=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;538-543
Fiorica et al
6 RCTN=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
Kaklamanos I et al
11 RCTsN=2311
2 year OS absolute diff 4.4% in CTRT f/b sxTreatment related mortality 3.4% vs 1.7%( NACTRT vs NACT f/b Sx)
Annals of sx oncology (2003)10(7);754-761
Val Gebski et al
10 RCTsN=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 neoadjuvantchemoradiotherapy or chemotherapy over surgery alone in patients with oesophageal carcinoma. clear advantage ofneoadjuvant 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.
AIMTo 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.
MATERIALS AND METHODS
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
TREATMENTRadiotherapy 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
SurgeryIn surgery arm-ASAPIn 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 weekNACT- Carboplatin AUC 2 & Paclitaxel (50 mg/m2 of body-surface area) on days 1, 8, 15, 22, and 29Surgery-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.
RESULTS
TRIAL PROFILE
90 %
86%
PATIENT CHARACTERSTICS
TUMOR CHARACTERSTICS
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 –SCC81.6 v/s 21.1 monthsHR 0.48(95% CI 0.28-0.83 )
Median OS-Adenoca43.2 v/s 27.1 monthsHR 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 –SCC74.7 v/s 11.6 monthsHR-0.48 [95% CI 0.28–0.82]
Median PFS-Adenoca29.9 v/s 17.7 monthsHR-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
SUB-GROUP ANALYSIS
SUB-GROUP ANALYSIS
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 toPoorer 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+ RTECF perioperativelyPacli+Carbo+RT
RT- high dose / low doseChemo alone or chemoRT
Applicablility for oesophageal and junctional cancers is questionable due to small no of this group
Preoperative or perioperative chemotherapy is still regardedas standard of care in some countries for patients withoesophageal 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 thecisplatinum/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 GyB-Cis+5FU+50.4 GyArm –A Less toxic No difference in response or survival
ONGOING TRIALS
MAGIC VS. CROSS UPPER GI. ICORG (NEO-AEGIS TRIAL)
Adenocarcinoma of the OesophagusAdenocarcinoma 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)
THANK YOU