Cross trial esophagus updated result

Cross trial esophagus updated result

1. Journal club Dr Bharti Devnani Moderator- Dr Neeraj Rastogi Lancet Oncol 2015, August 6, 2015

2. Layout Preamble Present study Review of literature Ongoing trials

3. Oesophageal cancer is an aggressive disease, characterised by a high degree of locoregional & distant recurrence after primary surgical resection Highly lethal disease,with a poor 5-year survival that rarely exceeds 40%. Incidence of esophageal adenocarcinoma is rapidly rising

4. 4 Pre op.CT+RT+S Vs S AUTHOR MEDIAN 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+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 Burmeister 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

5. Metaanalysis of NACTRT f/b sx vs Sx alone Authors 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;538-543 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 Kaklamanos 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);754-761 Val Ge bski et al 10 RCTs N=1209 2 year OS absolute difference 13% (p=0.04) Lancet oncology 2007;8:226-234 5

6. Sajoquist et alLancet Oncol 2011; 12: 681–92

7. 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.

8. 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.

9. Rationale of pre-op chemort Downstage the disease:- Enhances resectability Drugs enhances radiosensitivity Reduced dissemination of tumor cells during surgery :- Hence reduces distant metastasis Remove microscopic persistant disease

10. 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.

11. Materials and Methods

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

13. 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 (6 th 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)

14. 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.

15. 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

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

17. 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.

18. 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

19. 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.

20. 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 ).

21. 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%.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. results

28. Trial profile 90 % 86%

29. Patient characterstics

30. Tumor characterstics

31. 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.

32. 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)

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

34. Median OS –SCC 81.6 v/s 21.1 months HR 0.48(95% CI 0.28-0.83 ) Median OS- Adenoca 43.2 v/s 27.1 months HR 0.73 (95% CI 0.55-0.98)

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

36. Median PFS –SCC 74.7 v/s 11.6 months HR- 0.48 [95% CI 0.28–0.82] Median PFS- Adenoca 29.9 v/s 17.7 months HR- 0・69 [95% CI 0.52–0.92]

37. 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.

38. 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

39. Sub-group analysis

40. Sub-group analysis

41. Although 75% of enrolled patients had an adenocarcinoma , the effect of neoadjuvant chemoradiotherapy was much greater in the smaller subgroup of patients with squamous cell carcinoma. CI (0·56–1·01) of the adjusted hazard ratio (0·75) does not allow for a defi nitive conclusion to be drawn (p=0·059). Ideal neoadjuvant (or perioperative ) chemotherapy regimen to use in this subpopulation of patients with adenocarcinoma remain

42. 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

43. 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)

44. 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.

45. The CROSS trial provides robust evidence in support of a neoadjuvant chemoradiotherapy treatment strategy, especially for locally advanced squamous cell carcinomas.

46. Discussion and review of literature

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

48. Applicablility for oesophageal and junctional cancers is questionable due to small no of this group P reoperative or perioperative chemotherapy is still regarded as standard of care in some countries for patients with oesophageal and junctional cancer. P ublished 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

49. 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).

50. Carboplatin-Paclitaxel as Neoadjuvant Therapy for Esophageal Ca Keresztes et al. JTCVS 2003 Carbo AUC 6, Taxol 200 mg/m 2 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/m 2 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

51. 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

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