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Safa Najafi M.D. Medical Oncologist & Hematologist

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1 Neoadjuvant approaches for localized cancers of the esophagus and GE junction
Safa Najafi M.D. Medical Oncologist & Hematologist Assistant professor ACECR,JDTUMS

2 َََََ Jemal A; Siegel R; Ward E; Hao Y; Xu J; Thun MJ
َAccording to data from the Surveillance, Epidemiology and End Results (SEER) Program, the five-year survival for all patients with esophageal cancer improved modestly over the last 30 years, from 5 percent in the years 1975 to 1977, to 17 percent during the period 1996 to 2004 َََََ Jemal A; Siegel R; Ward E; Hao Y; Xu J; Thun MJ Cancer J Clin Jul-Aug;59(4): Epub 2009 May 27.

3 only 30 to 40 percent of patients have potentially resectable disease
Data from contemporary surgical series report five-year survival rates of 5 to 20 percent for surgery alone TI - Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. AU - Bosset JF; Gignoux M; Triboulet JP; Tiret E; Mantion G; Elias D; Lozach P; Ollier JC; Pavy JJ; Mercier M; Sahmoud T SO - N Engl J Med 1997 Jul 17;337(3):161-7.


5 It has been proposed that the difference in tumor location also has implications for the choice of therapy. Some suggest that induction chemotherapy alone may suffice for adenocarcinomas, while results are superior with chemoradiotherapy for SCCs because of the greater need for tumor downsizing to achieve a complete radical resection . TI - Are squamous and adenocarcinomas of the esophagus the same disease? AU - Siewert JR; Ott K SO - Semin Radiat Oncol Jan;17(1):38-44.

6 Before the era of modern chemotherapy and combined chemoradiotherapy, RT alone (60 to 66 Gy over a period of 6 to 6.6 weeks) was associated with five-year survival rates of 5 to 20 percent, depending upon tumor extent Choi, NC. The role of radiation therapy in the management of malignant neoplasms of the esophagus. In: Current Therapy in Cardiothoracic Surgery, Grillo, HC, Austen, WG, Wilkins, EW Jr (Eds), BC Decker Inc., Toronto p.197.


8 Chemo-(radiation) studies
Chemoradiation studies as non-operative treatment Preoperative chemoradiotherapy NEOADJUVANT CHEMOTHERAPY

9 Chemoradiation studies as non-operative treatment
 A landmark RTOG trial compared RT alone (64 Gy in 32 fractions over 6.5 weeks) versus concurrent chemoradiotherapy (two cycles of infusional 5-FU [1000 mg/m2 per day, days 1 to 4, weeks 1 and 5] plus cisplatin [75 mg/m2 day 1 of weeks 1 and 5] and RT [50 Gy in 25 fractions over five weeks]) in patients with locoregional thoracic esophageal cancer . RTOG 85-01 N Engl J Med 1992 Jun 11;326(24): In the US Intergroup Study 0123 (INT 0123), 236 patients with nonmetastatic SCC or adenocarcinoma of the thoracic esophagus received concurrent cisplatin and 5-FU (as in RTOG 85-01), but they were randomly assigned to one of two different RT doses: 50.4 Gy (28 fractions of 1.8 Gy each, five fractions per week) or 64.8 Gy (36 fractions of 1.8 Gy each, five fractions per week) Intergroup 0123J Clin Oncol 2002 Mar 1;20(5):

10 Preoperative chemoradiotherapy
Irish trial — In an early trial, 113 patients with esophageal or GEJ adenocarcinoma were randomly assigned to surgery alone or preceded by chemoradiotherapy [41] . Preoperative treatment consisted of two courses of 5-FU (15 mg/kg by bolus days 1 to 5) and cisplatin (75 mg/m2, on day 7 of each cycle), both administered during weeks 1 and 6 of concurrent RT (40 Gy in 15 fractions over three weeks). Michigan study — In a second trial, 100 patients with locoregional esophageal or GEJ cancer (25 SCC, 75 adenocarcinoma) were randomly assigned to surgery with or without induction chemoradiotherapy [37] . Neoadjuvant treatment consisted of infusional cisplatin (20 mg/m2 per day, days 1 to 5, and 17 to 21), infusional 5-FU (300 mg/m2 per day, days 1 to 4 and 17 to 20), and vinblastine (1 mg/m2 per day, on days 1 to 4, and 17 to 20) plus concurrent accelerated fraction RT (45 Gy in 1.5 Gy twice daily fractions for three weeks, using 3D-CRT treatment planning). Surgery was performed on day 42, after a three week rest. . At a median follow-up of 8.2 years, the median survival was similar (16.9 versus 17.6 months for multimodality therapy and surgery respectively)


12 Necessity for surgery Nearly all reports note a higher rate of locally persistent/recurrent disease when surgery is not a component of treatment . J Clin Oncol Nov 1;25(31): In general, there is a lack of data on nonsurgical management for patients with adenocarcinoma. French trial FFCD 9102: At a median follow-up of 47 months, the surgically treated patients had similar two-year (34 versus 40 percent) and median survival (17.7 versus 19.3 months) as compared to those assigned to continue chemoradiotherapy. Surgically treated patients had significantly lower rates of locoregional recurrence (34 versus 43 percent) and were significantly less likely to require palliative intervention for dysphagia (24 versus 46 percent).

13 Induction chemotherapy and concurrent chemoradiotherapy
In a phase II trial, 38 patients with resectable esophageal or GEJ cancer received one or two courses of infusional 5-FU (750 mg/m2 daily on days 1 to 5) plus cisplatin (15 mg/m2 daily bolus, days 1 to 5) and paclitaxel (200 mg/m2 over 24 hours on day 1) . This was followed by RT (45 Gy) and concurrent infusional 5-FU (300 mg/m2 daily on days 1 to 5 weekly) plus cisplatin (20 mg/m2 on days 1 to 5 of RT), and then surgery. Potentially curative resection was possible in 35, and a pCR was noted in eight (23 percent) . At a median follow-up of 58 months, three- and five-year survival estimates were 63 and 39 percent, respectively TI - A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophageal junction. AU - Ajani JA; Komaki R; Putnam JB; Walsh G; Nesbitt J; Pisters PW; Lynch PM; Vaporciyan A; Smythe R; Lahoti S; Raijman I; Swisher S; Martin FD; Roth JA SO - Cancer 2001 Jul 15;92(2):

14 In the POET trial, described in detail below, 126 patients with GEJ adenocarcinoma were randomly assigned to 16 weeks of chemotherapy alone (cisplatin plus short-term infusional leucovorin-modulated 5-FU) or 12 weeks of the same chemotherapy regimen followed by low-dose RT (15 Gy over three weeks) concurrent with cisplatin and etoposide . The pCR rate was significantly higher after induction chemotherapy followed by chemoradiotherapy (16 versus 2 percent), and there was a nonsignificant trend towards better median and three-year survival in this group as well (47 versus 28 percent, p = 0.07).

United Kingdom MAGIC trial —study of preoperative chemotherapy, included patients with resectable gastric (74 percent), GEJ (15 percent), or distal esophageal (11 percent) adenocarcinomas . A total of 503 patients were randomly assigned to surgery with or without perioperative chemotherapy (consisting of three preoperative plus three postoperative cycles of ECF [epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2 day 1 and infusional 5-FU 200 mg/m2/day days 1 to 21]). French FNLCC/FFCD trial — A similar benefit for preoperative chemotherapy was noted in a French multicenter trial in which 224 patients with potentially resectable stage II or greater adenocarcinoma of the GE junction (n = 144), distal esophagus (n = 25), or stomach (n = 55) were randomly assigned induction chemotherapy versus surgery alone [89] . The induction chemotherapy consisted of two to three cycles of preoperative chemotherapy (infusional 5-FU 800 mg/m2 daily for five days plus cisplatin 100 mg/m2 on day 1 or 2, every four weeks).

16 Rotterdam trial — In a multicenter trial from the Medical Research Council in the United Kingdom, 802 patients with operable esophageal or GEJ cancer (two-thirds adenocarcinoma) were randomly assigned to resection alone or resection preceded by two courses of cisplatin (80 mg/m2 on day 1) and 5-FU (1000 mg/m2 by continuous infusion days 1 to 4) given three weeks apart . Preoperative radiation, administered at the discretion of the treating clinician, was received by 9 percent of the patients in each group. The percentage of patients undergoing surgery was similar for the two groups, 92 versus 97 percent, as was the curative resection rate (ie, R0 resection), 60 versus 54 percent. Meta-analyses — A survival benefit for neoadjuvant chemotherapy relative to surgery alone was also suggested in a review of eight randomized trials of surgery alone or chemotherapy followed by surgery for esophageal cancer (n = 1724 patients, any histology, excluding cervical esophageal cancers) [44] . The hazard ratio for all-cause survival at two years favored chemotherapy followed by surgery (hazard ratio [HR] for all-cause mortality 0.90, 95% CI 0.81 to 1.0), a difference which translated into a two-year absolute survival benefit of 7 percent. There was no significant benefit for chemotherapy among patients with SCC, while there was a significant benefit for those with adenocarcinoma, which was based only on data from the United Kingdom MRC trial [81] (HR 0.78, 95% CI ).

German POET (PreOperative chemotherapy or radiochemotherapy in Esophagogastric adenocarcinoma Trial) trial: which focused exclusively on GE junction adenocarcinomas . Patients were randomly assigned to 16 weeks of chemotherapy alone (cisplatin plus short-term infusional leucovorin-modulated 5-FU) or 12 weeks of the same chemotherapy regimen followed by RT (15 Gy over three weeks) concurrent with cisplatin (50 mg/m2 on days 2 and 8) and etoposide (80 mg/m2 on days 3 to 5). The trial was closed because of poor accrual after only 126 of the planned 394 patients were enrolled. Microscopically complete (R0) resection was possible in a similar proportion of each group (70 and 72 percent after chemotherapy and chemoradiotherapy, respectively), although the pCR rate was significantly higher after chemoradiotherapy (16 versus 2 percent). At a median follow-up of 46 months, patients undergoing chemoradiotherapy had better median (33 versus 21 months) and three-year survival (47 versus 28 percent, p = 0.07), but these potentially clinically meaningful differences were not statistically significant. One reason may have been the relatively low RT dose and the substitution of etoposide for 5-FU during the RT. Although low in both groups, postoperative mortality was nonsignificantly higher after chemoradiotherapy (10.2 versus 3.8 percent, respectively)

18 J Clin Oncol. 2009 Feb 20;27(6):851-6. Epub 2009 Jan 12.
Patients with locally advanced (uT3-4NXM0) adenocarcinoma of the lower esophagus or gastric cardia were randomly allocated to one of two treatment groups: induction chemotherapy (15 weeks) followed by surgery (arm A); or chemotherapy (12 weeks) followed by chemoradiotherapy (3 weeks) followed by surgery (arm B). Primary outcome was overall survival time. A total of 354 patients were needed to detect a 10% increase in 3-year survival from 25% to 35% by addition of radiation therapy. The study was prematurely closed due to low accrual. Although the study was closed early and statistical significance was not achieved, results point to a survival advantage for preoperative chemoradiotherapy compared with preoperative chemotherapy in adenocarcinomas of the esophagogastric junction.

19 Unanswered questions in chemotherapy
To date there is no standard chemotherapy regimen for use in neoadjuvant ,combined modality setting. Several ongoing studies are evaluating the feasibility of incorporating targeted therapies in chemotherapy regimens. These chemotherapy regimens are not as effective as neoadjuvant therapy when they use as adjuvant.

20 Standard Chemotherapy regimens
5FU Based: 5FU+Cis ,ECF ,TCF ,Etoposid CF, FOLFOX Capcitabin based TCX ,ECX ,….. Other Platiniums: Carboplatin,Oxaloplatin. Irinotecan,… Tegafur & S1


22 Targeted agents Bevacizomab & Erlotinib
This phase II study evaluated the combination of carboplatin, paclitaxel, 5-FU, bevacizumab, and erlotinib with RT as preoperative treatment of localized esophageal cancers. Eligibility included previously untreated stage I, II, or III surgical candidates with histologically confirmed cancer of the esophagus or gastroesophageal junction. The treatment regimen was: carboplatin AUC 5.0 d 1, 22, paclitaxel 200mg/m2 d 1, 22, 5-FU 225 mg/m2/d IVCI d 1-35, bevacizumab 15 mg/Kg d 1, 22, and erlotinib 100 mg PO d-42. RT was 1.8 Gy M-F to a total dose of 45 Gy. Patients were restaged between weeks 9-11 and had surgical resection between weeks Abst 48 ASCO 2010

23 Gefitinib Abst 49 ASCO 2010 J Thorac Oncol. 2010 Feb;5(2):229-35.
Eligibility required T3, N1, or M1a esophageal or gastroesophageal junction squamous cell or adenocarcinoma staged by esophageal ultrasound and positron emission tomography/computed tomography. Four-day continuous intravenous infusions of cisplatin (20 mg/m/d) and fluorouracil (1000 mg/m/d) began on day 1 of preoperative radiation (30 Gy and 1.5 Gy bid). Surgery followed in 4 to 6 weeks, and an identical course of CCRT 6 to 10 weeks postoperatively. G 250 mg/d was given with preoperative CCRT for 4 weeks and restarted with postoperative therapy for 2 years. Results were retrospectively compared with our historical series of 93 patients given CCRT without G. Abst 49 ASCO 2010 J Thorac Oncol Feb;5(2):

24 Herceptin About 22% of patients with advanced gastroesophageal cancer were found to have tumors that overexpress human epidermal growth-factor receptor 2 (HER2), and these patients had significantly improved overall survival when trastuzumab (Herceptin) was added to chemotherapy, compared with chemotherapy alone. American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract LBA4509. Presented June 2, 2009.

25 Cetoximab Whether these results are better than can be achieved with chemotherapy alone is unclear. The benefit of adding cetuximab to cisplatin plus 5-FU was addressed in a randomized phase II German trial of 66 previously untreated patients with metastatic squamous cell cancer (SCC) . TI - Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. AU - Lorenzen S; Schuster T; Porschen R; Al-Batran SE; Hofheinz R; Thuss-Patience P; Moehler M; Grabowski P; Arnold D; Greten T; Muller L; Rothling N; Peschel C; Langer R; Lordick F SO - Ann Oncol Oct;20(10): Epub 2009 Jun 23.


27 Conclusion 1 combined modality therapy using preoperative chemoradiotherapy followed by surgery rather than either surgery alone or definitive chemoradiotherapy for patients with stages IIA, IIB, and III esophageal SCC or adenocarcinoma of the distal esophagus or GEJ (Grade 2B). We also suggest induction chemoradiotherapy instead of chemotherapy alone followed by surgery (Grade 2B). The benefit of preoperative chemoradiotherapy for patients with stage I esophageal or GEJ adenocarcinoma or SCC is less clear. We recommend surgery alone in these patients . (Grade 1B).

28 Conclusion 2 However, combined modality therapy is a reasonable approach for patients who are not surgical candidates. Although the optimal type, dose, combination, and schedule of drugs is unclear, we suggest multiagent chemotherapy rather than single agent cisplatin (Grade 2B). We suggest not administering concurrent chemoradiotherapy with a taxane or irinotecan-containing regimen outside of the context of a clinical trial (Grade 2C).

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