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)

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