CA Esophagus – Role of Chemoirradiation WH Chan Pamela Youde Nethersole Eastern Hospital

Ca Esophagus Incidence: 4.5 cases per 100,000 in one year in Europe 1 8th commonest cause of cancer death in 2011 in HK (4.8 per 100,000) 2 Squamous cell carcinoma Adenocarcinoma 1.Esophageal Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up. M. Stahl; C. Mariette; K. Haustermans; A. Cervantes & D. Arnold, on behalf of the ESMO Guidelines Working Groups. Annals of Oncology 24 (Supplement 6), vi51-vi56, Hong Kong Cancer Registry

Surgery High morbidity and mortality  Worsened physical function, social function, long lasting deterioration in health-related quality of life 3 Recurrence Complete Resection may not be possible 3. Meta-analysis shows clinically relevant and long-lasting deterioration in health-related quality of life after esophageal cancer surgery. M. Jacobs; R.C. Macefield; R.G. Elbers; M.A.G. Sprangers. Qual Life Res (2014) 23:

286 patients had surgery alone Median FU period: 49 months 30-day mortality: 3.7% Recurrence: - Stage I: 7.1%; Stage II/III/IV: 50.5% 5 year disease free survival: - Stage I: 76.3%; Stage II/III/IV: 30.8%

Chemoirradiation Introduced in 1980s  5-FU, cisplatin  Radiation of Gy Improves survival, complete resection rate Surgically not fit patient ?Increase surgical morbidity

20 RCTs were included  9 comparing neoadjuvant CRT vs surgery  8 comparing neoadjuvant chemotherapy vs surgery  3 comparing definitive CRT vs surgery

Neoadjuvant CRT vs surgery alone 9 RCTs included 1099 patients: 554 received neoadjuvant CRT, 545 received surgery alone Mean age 60.8 Surgery performed 2-8 weeks after CRT (mean 3 weeks) Median FU time: months

R0 resection rate p-value = 0.043

Morbidity p-value = 0.363

30-day mortality p-value = 0.692

Overall survival p-value = 0.008

Conclusion Neoadjuvant chemoradiotherapy improved R0 resection and overall survival, but does not increase post-op morbidity or mortality

Definitive chemoRT vs surgery 3 RCTs included All squamous cell carcinoma 512 patients: 252 received definitive chemoRT; 260 received surgery

Morbidity p-value = 0.332

30-day mortality p-value = 0.007

Overall survival

Conclusion Definitive chemoRT has lower 30-day mortality compared with surgery, but overall survival is similar

Neoadjuvant chemotherapy vs surgery Neoadjuvant chemotherapy improved R0 resection rate, but no improvement in overall survival

Definitive chemoirradiation Efficacy Tolerance and toxicity Any new regimen

Traditionally is radiotherapy + 5-FU + cisplatin Cisplatin is difficult to administer as requiring prolonged hydration, nephrotoxic, emetogenic

Study period Exclusion:  Metastasis  Contraindication to chemoRT: tracheoesophageal fistula, recent AMI, etc 131 patients in FOLFOX; 128 patients in 5- FU + cisplatin

Regimen Radiotherapy: 50Gy in 25 fractions Chemotherapy:  FOLFOX: 6 cycles (each cycle 2 days), one cycle every 2 week, first 3 cycles concurrent with RT  5-FU + cisplatin: 4 cycles (each cycle 4 days), first 2 cycles with RT Completion rate:  FOLFOX: 90/131 (68.7%)  5-FU + cisplatin: 96/128 (75%)

No difference in progression free or overall survival Median survival: FOLFOX 20.2 months 5-FU + cisplatin 17.5 months P = 0.70

Morbidity FOLFOX group:  More paraesthesia, sensory neuropathy, elevation of liver enzyme 5-FU + cisplatin group:  More mucositis, alopecia, renal impairment

Mortality 1 in FOLFOX group (0.76%): pneumopathy plus denutrition 6 in 5-FU + cisplatin group (4.69%): 5 neutropenic sepsis, 1 cardiac ischemia p-value = 0.066

Conclusion FOLFOX is a more convenient option, similar efficacy to 5-FU + cisplatin, with probably lower mortality

New development

Retrospective review 204 patients: 75 had neoadjuvant chemoRT, 129 had surgery alone Propensity score matching: 75 patients in each group with similar demographics and tumor staging 41.4 Gy, Paclitaxel and carboplatin

Neoadjuvant chemoRT had better disease free and overall survival

Distant recurrence Locoregional recurrence Complete Response

Neoadjuvant chemoRT could improve disease free survival, overall survival and locoregional recurrence free survival Not improved distant recurrence free survival

Future Development Any method to predict complete response to chemoRT EGFR inhibitors, HER-2 receptor inhibitors Adjuvant agents to reduce distant metastases

Conclusion Neoadjuvant chemoirradiation improves survival of CA esophagus without increasing post-op morbidities Definitive chemoRT is an effective alternative to patients who are not fit for surgery New agents are needed to improve the complete response rate and survival of patients

Reference 1. Esophageal Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up. M. Stahl; C. Mariette; K. Haustermans; A. Cervantes & D. Arnold, on behalf of the ESMO Guidelines Working Groups. Annals of Oncology 24 (Supplement 6), vi51- vi56, Meta-analysis shows clinically relevant and long-lasting deterioration in health-related quality of life after esophageal cancer surgery. M. Jacobs; R.C. Macefield; R.G. Elbers; M.A.G. Sprangers. Qual Life Res (2014) 23: Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for esophageal squamous cell cancer. M. Kranzfelder; T. Schuster; H. Geinitz; H. Friess; P. Buchler. British Journal of Surgery 2011; 98: Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with esophageal cancer (PRODIGE5/ACCORD17): final results of a randomized phase 2/3 trial. Thierry Conroy; Marie-Pierre Galais; Antonie Adenis. Lancet Onco 2014; 15: Different Recurrence Pattern After Neoadjuvant Chemoradiotherapy Compared to Surgery Alone in Esophageal Cancer Patients. Justin K. Smit, MD; Sahin Guler, Bsc; John Th. M. Plukker, MD, PhD. Annals of Surgical Oncology (2013) 20;

Thank You

Staging method: CT scan, PET, EUS 752 clinical staging of T2N0 disease 482 underwent surgery directly 27.4% confirmed T2N0 disease 25.9% downstaged 46.7% upstaged