Neoadjuvant Neoadjuvant approaches for approaches for

localized cancers localized cancers of the esophagus of the esophagus and GE junctionand GE junction

Safa Najafi M.DSafa Najafi M.D..

Medical Oncologist & Medical Oncologist & HematologistHematologist

Assistant professor Assistant professor ACECR,JDTUMSACECR,JDTUMS

��According to data from the According to data from the Surveillance, Epidemiology and End Surveillance, Epidemiology and End Results (SEER) Program, the five-year Results (SEER) Program, the five-year survival for all patients with esophageal survival for all patients with esophageal cancer improved modestly over the last cancer improved modestly over the last 30 years, from 5 percent in the years 30 years, from 5 percent in the years 1975 to 1977, to 17 percent during the 1975 to 1977, to 17 percent during the period 1996 to 2004period 1996 to 2004

���������� Jemal A; Siegel R; Ward E; Hao Y; Xu J; Thun MJJemal A; Siegel R; Ward E; Hao Y; Xu J; Thun MJ

Cancer J Clin. 2009 Jul-Aug;59(4):225-49. Epub 2009 May 27.Cancer J Clin. 2009 Jul-Aug;59(4):225-49. Epub 2009 May 27.

only 30 to 40 percent of patients only 30 to 40 percent of patients have potentially resectable diseasehave potentially resectable disease

Data from contemporary surgical Data from contemporary surgical series report five-year survival rates series report five-year survival rates of 5 to 20 percent for surgery aloneof 5 to 20 percent for surgery alone

TI - Chemoradiotherapy followed by surgery compared with TI - Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus.surgery alone in squamous-cell cancer of the esophagus.

AU - Bosset JF; Gignoux M; Triboulet JP; Tiret E; Mantion AU - Bosset JF; Gignoux M; Triboulet JP; Tiret E; Mantion G; Elias D; Lozach P; Ollier JC; Pavy JJ; Mercier M; G; Elias D; Lozach P; Ollier JC; Pavy JJ; Mercier M; Sahmoud TSahmoud T

SO - N Engl J Med 1997 Jul 17;337(3):161-7.SO - N Engl J Med 1997 Jul 17;337(3):161-7.

It has been proposed that the difference in It has been proposed that the difference in tumor location also has implications for tumor location also has implications for the choice of therapy. Some suggest that the choice of therapy. Some suggest that induction chemotherapy alone may suffice induction chemotherapy alone may suffice for adenocarcinomas, while results are for adenocarcinomas, while results are superior with chemoradiotherapy for SCCs superior with chemoradiotherapy for SCCs because of the greater need for tumor because of the greater need for tumor downsizing to achieve a complete radical downsizing to achieve a complete radical resection .resection .

TI - Are squamous and adenocarcinomas of the esophagus the same TI - Are squamous and adenocarcinomas of the esophagus the same disease?disease?

AU - Siewert JR; Ott KAU - Siewert JR; Ott K SO - Semin Radiat Oncol. 2007 Jan;17(1):38-44.SO - Semin Radiat Oncol. 2007 Jan;17(1):38-44.

Before the era of modern Before the era of modern chemotherapy and combined chemotherapy and combined chemoradiotherapy, RT alone (60 to chemoradiotherapy, RT alone (60 to 66 Gy over a period of 6 to 6.6 66 Gy over a period of 6 to 6.6 weeks) was associated with five-year weeks) was associated with five-year survival rates of 5 to 20 percent, survival rates of 5 to 20 percent, depending upon tumor extent depending upon tumor extent

Choi, NC. The role of radiation therapy in the management Choi, NC. The role of radiation therapy in the management of malignant neoplasms of the esophagus. In: Current of malignant neoplasms of the esophagus. In: Current Therapy in Cardiothoracic Surgery, Grillo, HC, Austen, WG, Therapy in Cardiothoracic Surgery, Grillo, HC, Austen, WG, Wilkins, EW Jr (Eds), BC Decker Inc., Toronto 1989. p.197.Wilkins, EW Jr (Eds), BC Decker Inc., Toronto 1989. p.197.

Chemo-(radiation) Chemo-(radiation) studiesstudies

Chemoradiation studies as non-Chemoradiation studies as non-operative treatmentoperative treatment

Preoperative chemoradiotherapyPreoperative chemoradiotherapy NEOADJUVANT CHEMOTHERAPYNEOADJUVANT CHEMOTHERAPY

Chemoradiation studies as Chemoradiation studies as non-operative treatmentnon-operative treatment

  A landmark RTOG trial compared RT alone (64 Gy in 32 A landmark RTOG trial compared RT alone (64 Gy in 32 fractions over 6.5 weeks) versus concurrent fractions over 6.5 weeks) versus concurrent chemoradiotherapy (two cycles of infusional 5-FU [1000 chemoradiotherapy (two cycles of infusional 5-FU [1000 mg/m2 per day, days 1 to 4, weeks 1 and 5] plus cisplatin 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 [75 mg/m2 day 1 of weeks 1 and 5] and RT [50 Gy in 25 fractions over five weeks]) in patients with locoregional fractions over five weeks]) in patients with locoregional thoracic esophageal cancer thoracic esophageal cancer ..

RTOG 85-01RTOG 85-01  N Engl J Med 1992 Jun 11;326(24):1593-8.N Engl J Med 1992 Jun 11;326(24):1593-8. In the US Intergroup Study 0123 (INT 0123), 236 patients with In the US Intergroup Study 0123 (INT 0123), 236 patients with

nonmetastatic SCC or adenocarcinoma of the thoracic esophagus nonmetastatic SCC or adenocarcinoma of the thoracic esophagus received concurrent cisplatin and 5-FU (as in RTOG 85-01), but 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 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 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) (36 fractions of 1.8 Gy each, five fractions per week)

Intergroup 0123J Clin Oncol 2002 Mar 1;20(5):1167-74Intergroup 0123J Clin Oncol 2002 Mar 1;20(5):1167-74

Preoperative Preoperative chemoradiotherapychemoradiotherapy  

Irish trialIrish trial —— In an early trial, 113 patients with esophageal or GEJ In an early trial, 113 patients with esophageal or GEJ adenocarcinoma were randomly assigned to surgery alone or preceded by adenocarcinoma were randomly assigned to surgery alone or preceded by chemoradiotherapy [41] . Preoperative treatment consisted of two courses of 5-FU 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), (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 both administered during weeks 1 and 6 of concurrent RT (40 Gy in 15 fractions over three weeks).over three weeks).

Michigan study Michigan study —— In a second trial, 100 patients with locoregional In a second trial, 100 patients with locoregional esophageal or GEJ cancer (25 SCC, 75 adenocarcinoma) were randomly assigned esophageal or GEJ cancer (25 SCC, 75 adenocarcinoma) were randomly assigned to surgery with or without induction chemoradiotherapy [37] . Neoadjuvant 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 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 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 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, 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 using 3D-CRT treatment planning). Surgery was performed on day 42, after a three week rest.week rest.

. At a median follow-up of 8.2 years, the median . At a median follow-up of 8.2 years, the median survival was similar (16.9 versus 17.6 months survival was similar (16.9 versus 17.6 months for multimodality therapy and surgery for multimodality therapy and surgery respectively)respectively)

Necessity for surgeryNecessity for surgery Nearly all reports note a higher rate of locally Nearly all reports note a higher rate of locally

persistent/recurrent disease when surgery is persistent/recurrent disease when surgery is not a component of treatment .not a component of treatment .

J Clin Oncol. 2007 Nov 1;25(31):4895-901.J Clin Oncol. 2007 Nov 1;25(31):4895-901.

In general, there is a lack of data on In general, there is a lack of data on nonsurgical management for patients with nonsurgical management for patients with adenocarcinoma.adenocarcinoma.

French trial FFCD 9102:French trial FFCD 9102: At a median follow-up of At a median follow-up of 47 months, the surgically treated patients had similar two-year 47 months, the surgically treated patients had similar two-year (34 versus 40 percent) and median survival (17.7 versus 19.3 (34 versus 40 percent) and median survival (17.7 versus 19.3 months) as compared to those assigned to continue months) as compared to those assigned to continue chemoradiotherapy. Surgically treated patients had significantly chemoradiotherapy. Surgically treated patients had significantly lower rates of locoregional recurrence (34 versus 43 percent) lower rates of locoregional recurrence (34 versus 43 percent) and were significantly less likely to require palliative and were significantly less likely to require palliative intervention for dysphagia (24 versus 46 percent).intervention for dysphagia (24 versus 46 percent).

Induction chemotherapy Induction chemotherapy and concurrent and concurrent

chemoradiotherapychemoradiotherapy In a phase II trialIn a phase II trial, , 38 patients with resectable 38 patients with resectable

esophageal or GEJ cancer received one or two courses of esophageal or GEJ cancer received one or two courses of infusional 5-FU (750 mg/m2 daily on days 1 to 5) plus 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 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 (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 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 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 5 of RT), and then surgery. Potentially curative resection was possible in 35, and a pCR was noted in eight (23 percent) . possible in 35, and a pCR was noted in eight (23 percent) . At a median follow-up of 58 months, three- and five-year At a median follow-up of 58 months, three- and five-year survival estimates were 63 and 39 percent, respectivelysurvival estimates were 63 and 39 percent, respectively

TI - A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in 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.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 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 JAR; Lahoti S; Raijman I; Swisher S; Martin FD; Roth JA

SO - Cancer 2001 Jul 15;92(2):279-86.SO - Cancer 2001 Jul 15;92(2):279-86.

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

0.07).0.07).

NEOADJUVANT NEOADJUVANT CHEMOTHERAPYCHEMOTHERAPY  

United Kingdom MAGIC trialUnited Kingdom MAGIC trial ——study of study of preoperative chemotherapy, included patients with resectable preoperative chemotherapy, included patients with resectable gastric (74 percent), GEJ (15 percent), or distal esophageal (11 gastric (74 percent), GEJ (15 percent), or distal esophageal (11 percent) adenocarcinomas . A total of 503 patients were randomly percent) adenocarcinomas . A total of 503 patients were randomly assigned to surgery with or without perioperative chemotherapy assigned to surgery with or without perioperative chemotherapy (consisting of three preoperative plus three postoperative cycles of (consisting of three preoperative plus three postoperative cycles of ECF [epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2 day 1 and 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]). infusional 5-FU 200 mg/m2/day days 1 to 21]).

French FNLCC/FFCD trial French FNLCC/FFCD trial —— A similar benefit for A similar benefit for preoperative chemotherapy was noted in a French preoperative chemotherapy was noted in a French multicenter trial in which 224 patients with potentially multicenter trial in which 224 patients with potentially resectable stage II or greater adenocarcinoma of the GE resectable stage II or greater adenocarcinoma of the GE junction (n = 144), distal esophagus (n = 25), or stomach (n junction (n = 144), distal esophagus (n = 25), or stomach (n = 55) were randomly assigned induction chemotherapy = 55) were randomly assigned induction chemotherapy versus surgery alone [89] . The induction chemotherapy versus surgery alone [89] . The induction chemotherapy consisted of two to three cycles of preoperative consisted of two to three cycles of preoperative chemotherapy (infusional 5-FU 800 mg/m2 daily for five chemotherapy (infusional 5-FU 800 mg/m2 daily for five days plus cisplatin 100 mg/m2 on day 1 or 2, every four days plus cisplatin 100 mg/m2 on day 1 or 2, every four weeks).weeks).

Rotterdam trial Rotterdam trial —— In a multicenter trial from the Medical Research In a multicenter trial from the Medical Research Council in the United Kingdom, 802 patients with operable esophageal Council in the United Kingdom, 802 patients with operable esophageal or GEJ cancer (two-thirds adenocarcinoma) were randomly assigned to or GEJ cancer (two-thirds adenocarcinoma) were randomly assigned to resection alone or resection preceded by two courses of cisplatin (80 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 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 to 4) given three weeks apart . Preoperative radiation, administered at the discretion of the treating clinician, was received by 9 percent of the the discretion of the treating clinician, was received by 9 percent of the patients in each group. The percentage of patients undergoing surgery patients in each group. The percentage of patients undergoing surgery was similar for the two groups, 92 versus 97 percent, as was the was similar for the two groups, 92 versus 97 percent, as was the curative resection rate (ie, R0 resection), 60 versus 54 percent.curative resection rate (ie, R0 resection), 60 versus 54 percent.

Meta-analysesMeta-analyses — —  A survival benefit for neoadjuvant A survival benefit for neoadjuvant chemotherapy relative to surgery alone was also suggested in a chemotherapy relative to surgery alone was also suggested in a review of eight randomized trials of surgery alone or review of eight randomized trials of surgery alone or chemotherapy followed by surgery for esophageal cancer (n = chemotherapy followed by surgery for esophageal cancer (n = 1724 patients, any histology, excluding cervical esophageal 1724 patients, any histology, excluding cervical esophageal cancers) [44] . cancers) [44] . The hazard ratio for all-cause survival at two The hazard ratio for all-cause survival at two years favored chemotherapy followed by surgery (hazard years favored chemotherapy followed by surgery (hazard ratio [HR] for all-cause mortality 0.90, 95% CI 0.81 to 1.0), ratio [HR] for all-cause mortality 0.90, 95% CI 0.81 to 1.0), a difference which translated into a two-year absolute a difference which translated into a two-year absolute survival benefit of 7 percent. There was no significant survival benefit of 7 percent. There was no significant benefit for chemotherapy among patients with SCC, while benefit for chemotherapy among patients with SCC, while there was a significant benefit for those with there was a significant benefit for those with adenocarcinoma, which was based only on data from the adenocarcinoma, which was based only on data from the United Kingdom MRC trial [81] (HR 0.78, 95% CI 0.64-United Kingdom MRC trial [81] (HR 0.78, 95% CI 0.64-0.95).0.95).

INDUCTION INDUCTION CHEMORADIOTHERAPY CHEMORADIOTHERAPY

VERSUS CHEMOTHERAPYVERSUS CHEMOTHERAPY   German POET (PreOperative chemotherapy or German POET (PreOperative chemotherapy or

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

J Clin OncolJ Clin Oncol . 2009 . 2009 Feb 20;27(6):851-6. Epub 2009 Feb 20;27(6):851-6. Epub 2009 Jan 12Jan 12 . .

Patients with locally advanced (uT3-4NXM0) adenocarcinoma of Patients with locally advanced (uT3-4NXM0) adenocarcinoma of the lower esophagus or gastric cardia were randomly allocated to the lower esophagus or gastric cardia were randomly allocated to one of two treatment groups: induction chemotherapy (15 weeks) one of two treatment groups: induction chemotherapy (15 weeks) followed by surgery (arm A); or chemotherapy (12 weeks) followed followed by surgery (arm A); or chemotherapy (12 weeks) followed by chemoradiotherapy (3 weeks) followed by surgery (arm B). by chemoradiotherapy (3 weeks) followed by surgery (arm B). Primary outcome was overall survival time. Primary outcome was overall survival time.

A total of 354 patients were needed to detect a 10% increase in 3-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. year survival from 25% to 35% by addition of radiation therapy. The study was prematurely closed due to low accrual.The study was prematurely closed due to low accrual.

Although the study was closed early and Although the study was closed early and statistical significance was not achieved, statistical significance was not achieved, results results point to a survival advantage for preoperative point to a survival advantage for preoperative chemoradiotherapy compared with preoperative chemoradiotherapy compared with preoperative chemotherapy in adenocarcinomas of the chemotherapy in adenocarcinomas of the esophagogastric junction.esophagogastric junction.

UnansweredUnanswered questions in questions in chemotherapychemotherapy

To date there is no standard To date there is no standard chemotherapy regimen for use in chemotherapy regimen for use in neoadjuvantneoadjuvant ,combined modality ,combined modality setting.setting.

Several ongoing studies are evaluating Several ongoing studies are evaluating the feasibility of incorporating the feasibility of incorporating targeted targeted therapiestherapies in chemotherapy regimens. in chemotherapy regimens.

These chemotherapy regimens are not These chemotherapy regimens are not as effective as neoadjuvant therapy as effective as neoadjuvant therapy when they use as adjuvant.when they use as adjuvant.

Standard Chemotherapy Standard Chemotherapy regimensregimens

5FU Based:5FU Based:

5FU+Cis ,ECF ,TCF ,Etoposid CF, 5FU+Cis ,ECF ,TCF ,Etoposid CF,

FOLFOXFOLFOX Capcitabin basedCapcitabin based

TCX ,ECX ,TCX ,ECX ,…….... Other Platiniums: Other Platiniums:

Carboplatin,Oxaloplatin.Carboplatin,Oxaloplatin. Irinotecan,Irinotecan,…… Tegafur & S1Tegafur & S1

Targeted agentsTargeted agentsBevacizomab & ErlotinibBevacizomab & Erlotinib

This phase II study evaluated the combination of carboplatin, This phase II study evaluated the combination of carboplatin, paclitaxel, 5-FU, bevacizumab, and erlotinib with RT as paclitaxel, 5-FU, bevacizumab, and erlotinib with RT as preoperative treatment of localized esophageal cancerspreoperative treatment of localized esophageal cancers. .

Eligibility included previously untreated stage I, II, Eligibility included previously untreated stage I, II, or III surgical candidates with histologically or III surgical candidates with histologically confirmed cancer of the esophagus or confirmed cancer of the esophagus or gastroesophageal junction. The treatment regimen gastroesophageal junction. The treatment regimen was: carboplatin AUC 5.0 d 1, 22, paclitaxel was: carboplatin AUC 5.0 d 1, 22, paclitaxel 200mg/m2 d 1, 22, 5-FU 225 mg/m2/d IVCI d 1-35, 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 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 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 45 Gy. Patients were restaged between weeks 9-11 and had surgical resection between weeks 12-14. and had surgical resection between weeks 12-14.

Abst 48 ASCO 2010Abst 48 ASCO 2010

GefitinibGefitinib Eligibility required T3, N1, or M1a esophageal or Eligibility required T3, N1, or M1a esophageal or

gastroesophageal junction squamous cell or adenocarcinoma gastroesophageal junction squamous cell or adenocarcinoma staged by esophageal ultrasound and positron emission staged by esophageal ultrasound and positron emission tomography/computed tomographytomography/computed tomography. .

Four-day continuous intravenous infusions of Four-day continuous intravenous infusions of cisplatin (20 mg/m/d) and fluorouracil (1000 mg/m/d) cisplatin (20 mg/m/d) and fluorouracil (1000 mg/m/d) began on day 1 of preoperative radiation (30 Gy and began on day 1 of preoperative radiation (30 Gy and 1.5 Gy bid). Surgery followed in 4 to 6 weeks, and an 1.5 Gy bid). Surgery followed in 4 to 6 weeks, and an identical course of CCRT 6 to 10 weeks identical course of CCRT 6 to 10 weeks postoperatively. G 250 mg/d was given with postoperatively. G 250 mg/d was given with preoperative CCRT for 4 weeks and restarted with preoperative CCRT for 4 weeks and restarted with postoperative therapy for 2 years. Results were postoperative therapy for 2 years. Results were retrospectively compared with our historical series retrospectively compared with our historical series of 93 patients given CCRT without G.of 93 patients given CCRT without G.

Abst 49 ASCO 2010Abst 49 ASCO 2010 J Thorac Oncol. 2010 Feb;5(2):229-35.J Thorac Oncol. 2010 Feb;5(2):229-35.

HerceptinHerceptin About 22% of patients with advanced About 22% of patients with advanced

gastroesophageal cancer were found to have gastroesophageal cancer were found to have tumors that overexpress human epidermal tumors that overexpress human epidermal growth-factor receptor 2 (HER2), and these growth-factor receptor 2 (HER2), and these patients had significantly improved overall patients had significantly improved overall survival when trastuzumabsurvival when trastuzumab ( (HerceptinHerceptin) ) was was added to chemotherapy, compared with added to chemotherapy, compared with chemotherapy alonechemotherapy alone. .

American Society of Clinical Oncology (ASCO) American Society of Clinical Oncology (ASCO) 45th Annual Meeting: 45th Annual Meeting: Abstract LBA4509. .

Presented June 2, 2009.Presented June 2, 2009.

CetoximabCetoximab Whether these results are better than can be Whether these results are better than can be

achieved with chemotherapy alone is unclear. The achieved with chemotherapy alone is unclear. The benefit of adding cetuximab to cisplatin plus 5-FU benefit of adding cetuximab to cisplatin plus 5-FU was addressed in a randomized phase II German was addressed in a randomized phase II German trial of 66 previously untreated patients with trial of 66 previously untreated patients with metastatic squamous cell cancer (SCC) .metastatic squamous cell cancer (SCC) .

TI - Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-TI - Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie.the Arbeitsgemeinschaft Internistische Onkologie.

AU - Lorenzen S; Schuster T; Porschen R; Al-Batran SE; AU - Lorenzen S; Schuster T; Porschen R; Al-Batran SE; Hofheinz R; Thuss-Patience P; Moehler M; Grabowski P; Hofheinz R; Thuss-Patience P; Moehler M; Grabowski P; Arnold D; Greten T; Muller L; Rothling N; Peschel C; Langer Arnold D; Greten T; Muller L; Rothling N; Peschel C; Langer R; Lordick FR; Lordick F

SO - Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23.SO - Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23.

Conclusion 1Conclusion 1 combined modality therapy using preoperative combined modality therapy using preoperative

chemoradiotherapy followed by surgery rather than chemoradiotherapy followed by surgery rather than either surgery alone or definitive chemoradiotherapy for either surgery alone or definitive chemoradiotherapy for patients with stages IIA, IIB, and III esophageal SCC or patients with stages IIA, IIB, and III esophageal SCC or adenocarcinoma of the distal esophagus or GEJadenocarcinoma of the distal esophagus or GEJ (Grade (Grade 2B).2B).

We also suggest induction chemoradiotherapy instead of We also suggest induction chemoradiotherapy instead of chemotherapy alone followed by surgerychemotherapy alone followed by surgery (Grade 2B).(Grade 2B).

The benefit of preoperative chemoradiotherapy The benefit of preoperative chemoradiotherapy for patients with stage I esophageal or GEJ for patients with stage I esophageal or GEJ adenocarcinoma or SCC is less clear. We adenocarcinoma or SCC is less clear. We recommend surgery alone in these patients . recommend surgery alone in these patients . (Grade 1B).(Grade 1B).

Conclusion 2Conclusion 2

However, combined modality therapy is a However, combined modality therapy is a reasonable approach for patients who are not reasonable approach for patients who are not surgical candidatessurgical candidates..

Although the optimal type, dose, combination, Although the optimal type, dose, combination, and schedule of drugs is unclear, we suggest and schedule of drugs is unclear, we suggest multiagent chemotherapy rather than single multiagent chemotherapy rather than single

agent cisplatinagent cisplatin (Grade 2B). (Grade 2B). We suggest not administering concurrent We suggest not administering concurrent

chemoradiotherapy with a taxane or irinotecan-chemoradiotherapy with a taxane or irinotecan-containing regimen outside of the context of a containing regimen outside of the context of a

clinical trialclinical trial (Grade 2C). (Grade 2C).