Concurrent RT With 5-FU/Epirubicin and Cisplatin or Irinotecan for Locally Advanced Upper GI Adenocarcinoma
Concurrent RT With 5-FU/Epirubicin and Cisplatin or Irinotecan for Locally Advanced Upper GI Adenocarcinoma
From the results of recent studies, it is likely that multimodality therapy with chemotherapy and radiation treatment may improve the overall outcome of locally advanced upper gastrointestinal (GI) malignancies, including esophageal, gastric, pancreatic, and biliary tract carcinomas. However, more effective, more optimal, and less toxic chemotherapy regimen(s) with concomitant radiotherapy are needed beyond the concurrent continuous-infusion fluorouracil (5-FU) with radiation that is commonly applied in general practice. Epirubicin (Ellence), cisplatin, and irinotecan (Camptosar) are all active cytotoxic chemotherapy agents in upper GI cancers. Two phase I studies were designed to test the tolerability of the combination of radiotherapy with infusional 5-FU, epirubicin, and cisplatin (ECF) or 5-FU, irinotecan, and epirubicin (EIF) in the treatment of locally advanced upper GI malignancies.
Upper gastrointestinal (GI) cancers are a group of common and highly virulent diseases that include esophageal, gastric, pancreatic, and biliary tract cancers. Based on the American Cancer Society's estimates, there will be 14,250 esophageal, 22,710 gastric, and 31,860 pancreatic cancers diagnosed in 2004 in the United States. The majority of patients present with advanced disease, and the prognosis for all sites is poor. Even for patients with resected disease, the rate of recurrence-including local failure and distant metastasis- is very high. Improvement in survival will rely on the development of effective multimodality treatment plans. Although recently developed chemotherapy regimens have shown some improvement in the treatment of advanced upper GI adenocarcinoma, most have only modest clinical efficacy. Combined chemotherapy and radiotherapy has demonstrated survival benefits in patients with locally advanced unresectable adenocarcinomas of the esophagus, gastroesophageal junction, stomach, and pancreas.[2-4] Survival advantages have also been shown with chemoradiation in the perioperative setting in upper GI cancers.[ 5-7] Infusional fluorouracil (5-FU) concurrent with radiation has been accepted as the standard treatment for locally advanced upper GI adenocarcinomas. Epirubicin (Ellence) is a semisynthetic derivative of doxorubicin. The antitumor activity of epirubicin, like that of other anthracyclines, is thought to result from intercalation between DNA base pairs and stabilization of the topoisomerase II DNA complexes, leading to irreversible DNA strand breakage. It has been estimated that epirubicin is about 75% as myelotoxic and 50% as cardiotoxic as doxoru bicin. Cisplatin is a heavy metal compound, which has the activity of a bifunctional alkylating agent and a broad spectrum of antitumor activity. The combination of 5-FU and cisplatin has been considered the reference regimen for advanced gastric cancer. The ECF regimen of epirubicin, cisplatin, and 5-FU has resulted in a significant response and survival benefit for advanced unresectable esophagogastric cancer.[9-12] Long-term follow-up of a prospectively randomized study demonstrated an advantage with the ECF combination compared with FAMTX (5-FU, doxorubicin [Adriamycin], methotrexate).[ 13] The overall response rate was 46% with ECF and 21% with FAMTX; the median survival was 8.7 vs 6.1 months; and the 2-year survival was 14% vs 5%. Preliminary results of a phase III study showed that pre- and postoperative ECF increases the rate of complete resection of locally advanced gastric cancer. The study also demonstrated improved disease-free survival in patients who had ECF treatment before and after surgery, compared to those who had surgery alone. Although the study has not shown the survival benefit of perioperative ECF treatment, disease-free survival is improved in the ECF treatment arm. Re sults from several phase II studies suggest that ECF may prolong survival in patients with locally advanced or metastatic pancreatic cancer with tolerable toxicities.[15,16] Irinotecan (Camptosar), a camptothecin derivative, is a topoisomerase I inhibitor that traps the topoisomerase I/DNA cleavable complex following cleavage of single-strand DNA. Collision of the replication fork converts the single-strand break into a doublestrand break, thus inducing apoptosis. The antitumor activity of irinotecan has been well documented in colorectal cancer. In upper GI malignancies, irinotecan has shown significant activity as a single agent and also in combination with 5-FU. In vitro and animal studies with epirubicin and camptothecins have demonstrated synergistic antitumor activity with enhanced DNA damage and tumor cell killing. A recent randomized study compared concurrent chemoradiation with epirubicin (60 mg/m2) and externalbeam radiotherapy (40 Gy in fractions of 2.5 Gy four times a week for 4 consecutive weeks) to radiation alone in 220 patients with locally advanced cervical cancer. The result demonstrated a survival benefit in the chemoradiation arm, with increased mild to moderate marrow suppression (no grade 4 leukopenia or grade 3 thrombocytopenia). There was no difference in treatment delays observed between the two arms, and no increased skin or normal organ toxicity. Therefore, the combination of radiotherapy with ECF (epirubicin, cisplatin, and 5-FU) or EIF (epirubicin, irinotecan, and 5-FU) chemotherapy for treatment of locally advanced upper GI adenocarcinoma holds promise. Ongoing Phase I Studies We are conducting two open-label phase I studies to evaluate concurrent, ascending doses of the combination of ECF or EIF with concurrent radiation when administered to patients with locally advanced upper GI adenocarcinoma. The primary end points are to find the dose for a phase II study, dose-limiting toxicity, and maximum tolerable dose. The response of these two combinations will also be determined for those patients with measurable or evaluable diseases. Trial Design Fluorouracil is administered as a continuous intravenous infusion via a Port-a-Cath through a portable infusion pump for 5.5 weeks during radiation treatment. Epirubicin and cisplatin or irinotecan is administered as a 60- to 90-minute infusion weekly for 5 weeks; administration is started on day 1 of radiation (days 1, 8, 15, 22, and 29 of the treatment plan) (Figure 1). All patients undergo treatmentplanning computed tomography and simulation. For nutritional support, most patients have feeding tubes (either G- or J-tubes) placed during chemoradiation treatment. Patients with histologically confirmed adenocarcinoma of the esophagus, stomach (including gastroesophageal junction), pancreas, and biliary tract, which is locally advanced unresectable or in whom postsurgery pathology showed positive margins, or with gross regional residual disease, are eligible for these two studies. Patients with adenocarcinoma of the esophagus, pancreas, and biliary tract status postresection and who are considered to have a high risk of recurrence (T3, T4, and/or lymph node metastases) are also acceptable. They should be older than 18 years old with relatively good overall performance status and reasonable liver and kidney function, with a left ventricular ejection fraction of at least 50%. Patients who had previous chemotherapy or radiation treatment are not qualified for either trial. Formal consent forms are signed by all patients undergoing treatment. The dose-escalation schedules of the studies are listed in Tables 1 and 2. Dose-limiting toxicities attributed to the study are defined as toxicities related to the treatment requiring discontinuation or significant dose reduction in study drugs. Toxicities are to be assessed according to the National Cancer Institute Common Toxicity Criteria scale. The maximum tolerated dose is defined as one dose level below the dose that induced dose-limiting toxicity in greater than one-third of patients in a given cohort. The dose modification is designed based on the type (hematologic vs nonhematologic) and grade of toxicities a patient may have. Results Both trials are at level 2 of their dose-escalating schedules. To date, there have been seven patients enrolled to the ECF trial and eight patients to the EIF trial. The characteristics of those patients are listed in Tables 3 and 4. Neutropenia, thrombocytopenia, nausea, vomiting, and diarrhea/dehydration are the main treatment-related toxicities for both trials. In the ECF trial, there was no doselimiting toxicity at level 1. One patient developed grade 3 dehydration at level 2 of the study, which is considered a dose-limiting toxicity. Three more patients will be added on that level for further evaluation. In the EIF trial, a 79-year-old patient with locally advanced biliary cancer at level 1 developed severe diarrhea (grade 3) and dehydration (grade 4) after her third dose of chemotherapy. She did not follow medical advice and was then admitted to the intensive care unit. She recovered from the event and was taken off study. Because of this case, four extra patients were added to that level, and no dose-limiting toxicity has been reached. There has been one patient enrolled on level 2, and so far there is no dose-limiting toxicity reported. There are three cases of Port-a- Cath-related upper extremity deepvein thrombosis in the EIF trial (two in level 1 and one in level 2), but not in the ECF trial. Although antitumor efficacy is not the primary end point of either trial, preliminary data are encouraging. In the ECF trial, among five enrolled locally advanced pancreatic cancer patients (three with unresectable disease and two with locally advanced disease post-operations), two patients had their diseases stabilized with de- creasing CA 19-9 and one patient achieved at least minimal response with normalized CA 19-9. One patient with T4, N1 duodenal adenocarcinoma, which was considered unresectable from prechemoradiation assessment, had curative surgical resection after treatment. The final pathology suggested that the disease was downstaged to T3, N0. The patient then had three more treatments of infusional 5-FU and cisplatin after surgery. There is still no evidence of disease. Another patient with a T3, N2 adenocarcinoma of gastroesophageal junction had his disease completely resected after therapy. In the EIF trial, all seven evaluable patients-including three cases of locally advanced pancreatic cancer, three cases of unresectable locally advanced cholangiocarcinoma, and one patient with T3, N2 gastroesophageal junction adenocarcinoma-achieved at least stable disease. The patient with gastroesophageal junction adenocarcinoma had complete surgical resection for his disease. Conclusion/ Both trials are actively ongoing, and no maximum tolerated dose has been reached.
Dr. Sun has received research support from Pfizer.
1. Jemal A, Tiwari RC, Murray T, et al: Cancer statistics, 2004. CA Cancer J Clin 54:8-29, 2004.
2. Moertel CG, Frytak S, Hahn RG, et al: Therapy of locally unresectable pancreatic carcinoma: A randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil. Cancer 48:1705-1710, 1981.
3. Klaasen DJ, MacIntyre JM, Catton GE, et al: Treatment of locally unresectable cancer of the stomach and pancreas: A randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil. J Clin Oncol 3:373-378, 1985.
4. Gastrointestinal Tumor Study Group: Treatment of locally unresectable carcinoma of the pancreas: Comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 80:751-755, 1988.
5. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-730, 2001.
6. Whittington R, Neuberg D, Tester WJ, et al: Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: A phase I Eastern Cooperative Oncology Group trial. J Clin Oncol 13:227-232, 1995.
7. Lee JH, Whittington R, Williams NN, et al: Outcome of pacreaticoduodenectomy and impact of adjuvant therapy for ampullary carcinoma. Int J Radiat Oncol Biol Phys 47:945- 953, 2000.
8. Bonadonna G, Gianni L, Santor A, et al: Drugs ten years later: Epirubicin. Ann Oncol 4:359-369, 1993.
9. Webb A, Cunningham D, Scarffe JH, et al: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261- 267, 1997.
10. Cascinu S, Labianca R, Alessandroni P, et al: Intensive weekly chemotherapy for advanced gastric cancer using fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione, and filgrastim: A report from the Italian group for the study of digestive tract cancer. J Clin Oncol 15:3313-3319, 1997.
11. Eatock MM, Anthony DA, El-Abassi M, et al: A dose-finding study of raltitrexed (Tomudex) with cisplatin and epirubicin in advanced gastro-oesophageal adenocarcinoma. Br J Cancer 82:1925-1931, 2000.
12. Chi KH, Chao Y, Chan WK, et al: Weekly etoposide, epirubicin, cisplatin, 5-fluorouracil and leucovorin: An effective chemotherapy in advanced gastric cancer. Br J Cancer 77:1984- 1988, 1998.
13. Water JS, Norman A, Cunningham D, et al: Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: Results of a randomized trial. Br J Cancer 80:269-272, 1999.
14. Allum W, Cunningham D, Weeden S, et al: Perioperative chemotherapy in operable gastric and lower oesophageal cancer: A randomized, controlled trial (the MAGIC trial, ISRCTN 93793971) (abstract 998). Proc Am Soc Clin Oncol 22:249, 2003.
15. Evans TRJ, Lofts FJ, Mansi JL, et al: A phase II study of continuous-infusion 5-fluorouracil with cisplatin and epirubicin in inoperable pancreatic cancer. Br J Cancer 73:1260- 1264, 1996.
16. Wagener DJ, Hoogenraad WJ, Rougier P, et al: Results of a phase II trial of epirubicin and cisplatin (EP) before and after irradiation and 5-fluorouracil in locally advanced pancreatic cancer: An EORTC GITCCG study. Eur J Cancer 32A(8):1310-1313, 1996.
17. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343(13):905-914, 2000.
18. Bleiberg H: CPT-11 in gastrointestinal cancer. Eur J Cancer 35(3):371-379, 1999.
19. Blanke CD, Haller DG, Benson AB, et al: A multicenter phase II study of CPT-11, 5- fluorouracil, and leucovorin (LCV) in patients with previous untreated adenocarcinoma of the stomach or GE junction (abstract 1141). Proc Am Soc Clin Oncol 19:292a, 2000.
20. Karaberis E, Mourelatos D: Enhanced cytogenetic and antitumor effects by 9- nitrocamptothecin and antineoplastics. Teratog Carcinog Mutagen 20(3):141-146, 2000.
21. Wang LC, Ngan HYS, Cheung ANY, et al: Chemoradiation and adjuvant chemotherapy in cervical cancer. J Clin Oncol 17:2055-2060, 1999.