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Title: Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma

Abstract

Purpose: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. Methods and Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m{sup 2} and paclitaxel 50 mg/m{sup 2} weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. Results: Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. Conclusions: Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies withoutmore » an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2]
  1. Brown University Oncology Group, Providence, RI (United States). E-mail: hsafran@lifespan.org
  2. Brown University Oncology Group, Providence, RI (United States)
Publication Date:
OSTI Identifier:
20944680
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 67; Journal Issue: 2; Other Information: DOI: 10.1016/j.ijrobp.2006.08.076; PII: S0360-3016(06)02832-X; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CARCINOMAS; ESOPHAGUS; EVALUATION; FLUORESCENCE; GENE AMPLIFICATION; GENES; IN-SITU HYBRIDIZATION; METASTASES; PATIENTS; RADIATION DOSES; RADIOTHERAPY; TOXICITY

Citation Formats

Safran, Howard, Di Petrillo, Thomas, Akerman, Paul, Ng, Thomas, Evans, Devon, Steinhoff, Margaret, Benton, David, Purviance, John, Goldstein, Lisa, Tantravahi, Umadevi, and Kennedy, Teresa R.N.. Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma. United States: N. p., 2007. Web. doi:10.1016/j.ijrobp.2006.08.076.
Safran, Howard, Di Petrillo, Thomas, Akerman, Paul, Ng, Thomas, Evans, Devon, Steinhoff, Margaret, Benton, David, Purviance, John, Goldstein, Lisa, Tantravahi, Umadevi, & Kennedy, Teresa R.N.. Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma. United States. doi:10.1016/j.ijrobp.2006.08.076.
Safran, Howard, Di Petrillo, Thomas, Akerman, Paul, Ng, Thomas, Evans, Devon, Steinhoff, Margaret, Benton, David, Purviance, John, Goldstein, Lisa, Tantravahi, Umadevi, and Kennedy, Teresa R.N.. Thu . "Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma". United States. doi:10.1016/j.ijrobp.2006.08.076.
@article{osti_20944680,
title = {Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma},
author = {Safran, Howard and Di Petrillo, Thomas and Akerman, Paul and Ng, Thomas and Evans, Devon and Steinhoff, Margaret and Benton, David and Purviance, John and Goldstein, Lisa and Tantravahi, Umadevi and Kennedy, Teresa R.N.},
abstractNote = {Purpose: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. Methods and Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m{sup 2} and paclitaxel 50 mg/m{sup 2} weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. Results: Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. Conclusions: Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.},
doi = {10.1016/j.ijrobp.2006.08.076},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 2,
volume = 67,
place = {United States},
year = {Thu Feb 01 00:00:00 EST 2007},
month = {Thu Feb 01 00:00:00 EST 2007}
}
  • Purpose: Preoperative paclitaxel-based chemoradiotherapy may improve the response rates and survival in patients with localized esophageal cancer. We evaluated paclitaxel-based induction chemoradiotherapy in patients with localized esophageal cancer to determine its feasibility, clinical response, pathologic response, and overall survival. Methods and Materials: Between 1995 and 1998, 50 patients were enrolled in this study. At study entry, patients were categorized as either resectable or unresectable according to evaluation by an experienced thoracic surgeon. All patients were treated with paclitaxel 175 mg/m{sup 2} and cisplatin 75 mg/m{sup 2} on Day 1, 29 with radiotherapy to 3,000 cGy in 15 fractions. Resectable patientsmore » underwent esophagectomy 4 weeks later. Postoperatively, patients received two cycles of paclitaxel 175 mg/m{sup 2} on Day 1 and 5-fluorouracil 350 mg/m{sup 2} and leucovorin 300 mg on Days 1-3, given every 28 days. Patients who were deemed unsuitable for resection from the outset continued radiotherapy to a total dose of 6,000 cGy. Results: Of the 50 patients, all began neoadjuvant chemoradiotherapy, 40 patients underwent surgery, and 25 patients completed postoperative chemotherapy. A pathologic complete response was seen in 7 patients (17.5%). Patients with a pathologic response had a median survival of 32.4 months vs. 14.4 months for nonresponders (p <0.001). Patients with a clinical response had a median survival of 25.2 months compared with 15.6 months for nonresponders (p = 0.002). At a median follow up of 19.8 months (range 2.4-100.8), the median survival was 20.4 months and the 3-year overall survival rate was 23.2%. Conclusion: Although preoperative cisplatin/paclitaxel with 3,000 cGy was tolerable, this multimodality regimen did not appear to be superior to standard cisplatin/5-fluorouracil-containing regimens and its use is not recommended.« less
  • Purpose: Toxicity, pathologic complete response, and long-term outcomes are reported for the neoadjuvant therapies assessed in a randomized phase 2 Eastern Cooperative Oncology Group and American College of Radiology Imaging Network trial for operable esophageal adenocarcinoma, staged as II-IVa by endoscopy/ultrasonography (EUS). Methods and Materials: A total of 86 eligible patients began treatment. For arm A, preoperative chemotherapy was cisplatin, 30 mg/m{sup 2}, and irinotecan, 50 mg/m{sup 2}, on day 1, 8, 22, 29 during 45 Gy radiation therapy (RT), 1.8 Gy per day over 5 weeks. Adjuvant therapy was cisplatin, 30 mg/m{sup 2}, and irinotecan, 65 mg/m{sup 2} daymore » 1, 8 every 21 days for 3 cycles. Arm B therapy was cisplatin, 30 mg/m{sup 2}, and paclitaxel, 50 mg/m{sup 2}, day 1, 8, 15, 22, 29 with RT, followed by adjuvant cisplatin, 75 mg/m{sup 2}, and paclitaxel, 175 mg/m{sup 2}, day 1 every 21 days for 3 cycles. Stratification included EUS stage and performance status. Results: In arm A, median overall survival was 35 months, and 5-, 6-, and 7-year survival rates were 46%, 39%, and 35%, respectively, whereas for arm B, they were 21 months and 27%, 27%, and 23%, respectively. Median progression- or recurrence-free survival (PFS) was 39.8 months with a 3-year PFS of 50% for arm A and 12.4 months (P=.046) with 3-year PFS of 28% for arm B. Eighty percent of the observed incidents of progression occurred within 19 months. Survival did not differ significantly by EUS and performance status strata. Conclusions: Long-term survival was similar for both arms and did not appear superior to results achieved with other standard regimens.« less
  • Purpose: Phase I-II data regarding neoadjuvant cisplatin, 5-fluorouracil (5-FU), paclitaxel, and radiation (PFT-R) from our institution demonstrated encouraging pathologic complete response (pCR) rates. This article updates our experience with PFT-R, and compares these results to our experience with cisplatin, 5-FU, and radiation therapy (PF-R) in locally advanced esophageal cancer. Patients and Methods: We searched the Massachusetts General Hospital cancer registry for esophageal cancer patients treated with radiation therapy and chemotherapy between 1994-2002. Records of patients treated with curative, neoadjuvant therapy were examined for chemotherapeutic regimen. Outcomes of patients treated with PF-R or PFT-R were assessed for response to therapy, toxicity,more » and survival. Results: A total of 177 patients were treated with neoadjuvant therapy with curative intent; 164 (93%) received PF-R (n = 81) or PFT-R (n = 83). Median overall survival was 24 months. After a median follow-up of 54 months for surviving patients, 3-year overall survival was 40% with no significant difference between PF-R (39%) and PFT-R (42%). Conclusions: Our findings failed to demonstrate an improvement in pCR or survival with PFT-R vs. PF-R. These results do not support this regimen of concurrent neoadjuvant PFT-R in esophageal cancer, and suggest that further investigations into alternative regimens and novel agents are warranted.« less
  • Hyperthermia is now being widely used to treat clinical malignancies, especially combined with radiotherapy and more rarely with chemotherapy. The combination of heat, radiation, and chemotherapy (trimodality) can lead to potent interaction. The present Phase I-II study was conducted to evaluate the feasibility and acute toxicity of a combination of cisplantin, hyperthermia, and irradiation in the treatment of superficial cervical nodal metastases from head and neck cancer. Eighteen patients with measurable neck metastases from previously untreated squamous cell head and neck tumors were entered into the trial. Therapy consisted of a conventional irradiation (total dose 70 Gy, 2 Gy fivemore » times a week) combined with a weekly administration of 20 mg/m[sup 2] iv of cisplatin and a total of two sessions of local external microwave hyperthermia (desired temperature of 42.5[degrees]C for 30 min). Feasibility of the treatment was demonstrated. Acute local toxicity was mild; no thermal blisters or ulcerations were reported and only two patients experienced local pain during hyperthermia. Cutaneous toxicity appeared greater than in previous studies with irradiation plus hyperthermia and irradiation plus cisplatin. Systematic toxicity was moderate with major toxic effects observed in three patients (World Health Organization (WHO) grade 3 anaemia). Even though it was not an aim of the study to evaluate the nodal response, they observed a complete response rate of 72.2% (95% confidence interval 51-93.4%), 16.6% of partial response and 11.1% of no change. The study confirms the feasibility of the combination of cisplantin, heat, and radiation with an acceptable toxicity profile. The trimodal therapy deserves further evaluation as a way to enhance the efficacy of irradiation in the treatment of nodal metastases from head and neck tumors. 43 refs., 3 figs., 4 tabs.« less
  • Purpose: To determine in a Phase II trial whether preoperative irinotecan-cisplatin (IC) followed by concurrent IC therapy and radiotherapy (IC/RT) improved outcome in patients with resectable, locally advanced gastric adenocarcinoma (GC) or esophagogastric junction cancer (EGJC). Patients and Methods: Patients with resectable Stage II-IV, M0 GC or EGJC made up the study population. The primary endpoint was pathologic complete response (pCR). Two courses of IC (irinotecan, 65mg/m{sup 2}; cisplatin, 30mg/m{sup 2} on Days 1 and 8 every 21 days) were given. Patients without progression then received IC/RT, consisting of daily radiotherapy (45Gy) with concurrent IC (irinotecan, 65mg/m{sup 2}; cisplatin, 30mg/m{supmore » 2} on Days 1, 8, 15, and 22). Surgical resection was performed, if feasible, 5-8 weeks after the end of radiotherapy. Results: Twenty-three patients were included in the study: 10 with EGJC and 13 with GC. Two patients (9%) achieved pCR. The incidences of Grade 3-4 toxicities were as follows: IC: neutropenia 35% (febrile 13%), anemia 22%, diarrhea 22%, emesis 8%; IC/RT: neutropenia 52% (febrile 5%), asthenia 19%, anemia 9%, emesis 9%, diarrhea 5%, cardiotoxicity 5%. No patients died during IC or IC/RT. R0 resection was achieved in 15 patients (65%). Median survival was 14.5 months, and the actuarial 2-year survival rate was 35%. Conclusions: Preoperative IC followed by IC/RT resulted in moderate response and resection rates with mild toxicity in patients with GC and EGJC.« less