Esophageal carcinoma is an aggressive cancer with a poor prognosis. In the year 2003, 13,900 Americans will be diagnosed with esophageal cancer, and more than 93% of patients will die of their disease.[ 1] One-half of patients present with overt metastatic disease, and systemic chemotherapy is the mainstay of palliative treatment. The remaining one-half of patients present with locally advanced disease that is potentially amenable to treatment with surgery or radiation-based therapy. Because of the absence of effective screening, most patients present with locally advanced, transmural, or lymph node-positive disease. Treatment with surgery, definitive chemoradiotherapy, or preoperative chemoradiotherapy followed by surgery yields a 5-year survival of less than 20% to 35%.[2-5] The toxicity of conventional chemotherapy, combining a continuous infusion of fluorouracil(Drug information on fluorouracil) (5-FU) and cisplatin(Drug information on cisplatin), is substantial and includes stomatitis, diarrhea, nausea, fatigue, and myelosuppression. The severe gastrointestinal toxicity is amplified when concurrent radiotherapy is combined with 5-FU and cisplatin. The limited effectiveness and toxicity of conventional chemotherapy have mandated the investigation of new agents in esophageal cancer. Irinotecan in Advanced Esophageal Cancer Irinotecan(Drug information on irinotecan) (CPT-11, Camptosar), a semisynthetic camptothecin, is an inhibitor of the enzyme topoisomerase I. Irinotecan has emerged as a significant new chemotherapeutic agent with a broad spectrum of antitumor activity, including effectiveness against esophageal and gastric cancer. An outline of recent clinical trials of irinotecan- based chemotherapy in esophageal and gastric cancer is shown in Table 1. Phase II evaluation of irinotecan in gastric and gastroesophageal junction cancer in recent US trials, using a dose of 125 mg/m2 given weekly for 4 weeks, indicates modest single- agent activity with a response rate of 14% to 15%.[6,7] Irinotecan has also been combined with 5-FU in recent trials in gastric and esophageal cancer. The combination of weekly irinotecan at 125 mg/ m2 with bolus 5-FU at 500 mg/m2 and leucovorin at 20 mg/m2 IV weekly * 4 every 6 weeks, the US schedule developed in colorectal cancer, yielded a response rate of only 22% in 119 patients treated on two phase II trials.[ 8,9] Other investigators have combined irinotecan with a continuous infusion schedule of 5-FU. A recent randomized phase II trial conducted in Europe evaluated irinotecan at a dose of 80 mg/m2 combined with leucovorin at 500 mg/m2 and continuous infusion 5-FU at 2,000 mg/m2, given over 24 hours, cycled once weekly, for 6 weeks on and 1 week off. The regimen of irinotecan and infusional 5-FU was compared to an every- 3-week treatment with irinotecan at 200 mg/m2 and cisplatin at 60 mg/ m2. In 146 patients treated with advanced gastric or gastroesophageal junction cancer, the two treatment arms had equivalent response rates- 34% for the 5-FU combination and 28% for the cisplatin combination. The median survival for the 5-FU-containing arm was higher (10.7 vs 6.9 months for the cisplatin arm). Based on the superior survival observed, the infusional 5-FU and irinotecan arm is now being compared in a phase III trial to conventional 5-FU and cisplatin in advanced gastric and GE junction cancers. A recently reported trial evaluated the combination of infusional 5-FU and irinotecan in the salvage setting, as second-line treatment after prior chemotherapy. Irinotecan at 180 mg/m2 was given on an every-2-week schedule along with leucovorin at 125 mg/m2 and combined with 5-FU (400-mg/m2 bolus) followed by continuous infusion 5- FU (1,200 mg/m2 over 48 hours), with a response rate of 20% observed in 25 patients. The combination of irinotecan and cisplatin, initially evaluated in phase I and II trials in gastric cancer in Japan, has been evaluated in two recent phase II trials in esophageal and gastric cancer in the United States. Both trials used a weekly schedule of relatively low doses of cisplatin and irinotecan, initially reported by Saltz and colleagues in a phase I trial. In these trials, cisplatin at 30 mg/m2 was combined with irinotecan at 65 mg/ m2, cycled for 4 weeks on and 2 weeks off. The report of this regimen in esophageal cancer noted an encouraging response rate of 57% in 35 patients, with comparable activity for adenocarcinoma and squamous cell carcinoma. The median duration of response was 4.2 months, and the median survival was 14.6 months. Dysphagia relief (either improvement or resolution of dysphagia) was achieved in 90% of patients. Qualityof- life indices showed significant improvement in responding patients. The second trial of the weekly regimen, conducted in metastatic gastric and GE junction cancer, also reported an encouraging response rate of 58% in 36 evaluable patients treated. In both trials, there were frequent treatment delays due to hematologic toxicity. Because of the need for delay in therapy with weekly irinotecan and cisplatin using 4 consecutive weeks of treatment, a change in the schedule to 2 weeks on, 1 week off is now being evaluated in a phase II multicenter national trial in advanced esophageal cancer. A recent report evaluating weekly irinotecan at 50 mg/ m2 and cisplatin at 30 mg/m2 weekly * 4 every 6 weeks as second-line salvage chemotherapy in gastric cancer also showed significant activity with a response rate of 31% in 29 patients.[ 15] Recent trials have explored novel combinations of irinotecan and other agents in gastric and esophageal cancer. One trial combined mitomycin(Drug information on mitomycin) (Mutamycin) 7 mg/m2 on day 1 and irinotecan at 140 mg/m2 on days 1 and 15, repeated every 28 days. Sixty- five percent of patients (11/17) achieved a major response. Other investigators have combined irinotecan and docetaxel(Drug information on docetaxel) (Taxotere) on an every-3-week schedule, based on a phase I trial establishing treatment doses of 160 mg/m2 for irinotecan and 65 mg/m2 for docetaxel. Two phase II trials in advanced esophageal cancer have indicated prohibitive hematologic toxicity for this combination.[ 18,19] In these trials, irinotecan at 130 to 160 mg/m2 was combined with docetaxel at 50 to 60 mg/m2, cycled every 21 days. Response rates were not reported in these preliminary reports. An alternative schedule, combining irinotecan at 50 to 65 mg/m2 preceded by docetaxel at 35 mg/m2 administered for 2 consecutive weeks followed by a 1-week rest, is also under investigation in gastrointestinal cancers, given the potential for a lesser degree of myelosuppression using weekly therapy. Another recent trial evaluated the combination of every-3-week irinotecan at 225 mg/ m2 and the taxane paclitaxel(Drug information on paclitaxel) at 100 mg/m22, with a response rate of 29% reported in 23 patients treated. Phase I Combination of Irinotecan and Radiotherapy Preclinical studies have demonstrated the radiation-sensitizing effect of the camptothecins,[22-25] with data obtained from cell line and xenograft models. The degree of radiosensitization appears to be similar to that of other standard drugs used in combined- modality therapy. Evidence to support several potential mechanisms of radiosensitization by the camptothecins has been described, including an increase in the proportion of cells in the G2/M phase (the most radiosensitive phase of the cell cycle), a potentiation of the formation of DNA-protein crosslinks, and enhancement of the conversion of single- strand DNA breaks to double-strand breaks by the inhibition of topoisomerase I. Investigators at The University of Texas M. D. Anderson Cancer Center conducted a phase I trial combining weekly irinotecan with concurrent radiotherapy dosed from 4,500 to 5,040 cGy in cancers of the upper gastrointestinal tract. The data suggested that irinotecan at a dose of 60 mg/m2 given weekly for 5 to 6 weeks could be combined safely with concurrent radiotherapy. A phase I trial combining concurrent radiation therapy with weekly irinotecan and cisplatin in locally advanced esophageal cancer was recently completed at the Memorial Sloan-Kettering Cancer Center. In this trial, cisplatin was given at a fixed dose of 30 mg/m2 weekly with irinotecan at escalating doses (40, 50, 65, and 80 mg/m2) on days 1, 8, 22, and 29 of radiotherapy. Radiation was administered in 180- cGy daily fractions Monday through Friday to a total dose of 5,040 cGy. Induction chemotherapy was given prior to the start of combined chemoradiotherapy with weekly irinotecan (65 mg/m2) and cisplatin (30 mg/m2), 2 weeks on and 1 week off, for two 3- week cycles. Induction chemotherapy was administered primarily to relieve dysphagia prior to the start of combined chemoradiotherapy. The 2- week-on, 1-week-off schedule of weekly chemotherapy was employed during both the induction chemotherapy and during the combined chemoradiotherapy. Patients with previously untreated, locally advanced esophageal squamous or adenocarcinoma, without evidence of distant metastatic disease, were eligible for treatment. Patients were staged with computed tomography scan imaging and positron emission tomography scanning, and local tumor staging with endoscopic ultrasound. Surgery after treatment on protocol was not mandated, with surgery performed at the discretion of the treating physician and surgeon. Dose-limiting toxicity was defined as the need for a 2-week treatment delay during radiotherapy due to toxicity. Patient demographics are outlined in Table 2. Nineteen patients were entered; all have completed therapy and are evaluable for both response and toxicity. The majority were males with adenocarcinoma, and the majority had stage III (T3, N1) disease as determined by pretreatment endoscopic ultrasound. Therapy was remarkably well tolerated, with minimal hematologic toxicity observed. At the irinotecan 80 mg/m2 dose level, two of six patients had hematologic doselimiting toxicity (a 2-week delay in radiotherapy due to neutropenia and thrombocytopenia). The recommended phase II dose of irinotecan to combine with weekly cisplatin and radiotherapy is 65 mg/m2. Seven patients treated at the 65 mg/m2 dose level of irinotecan tolerated therapy well and had minimal myelosuppression. No significant grade 3 or 4 toxicity, including esophagitis or diarrhea, was observed, with the exception of one patient treated at the irinotecan 50 mg/m2 dose level who developed reversible grade 3 pneumonitis (which resolved). An unexpected toxicity that cannot clearly be explained and whose relation to therapy is uncertain is an observation in 3 of the first 15 patients treated. Asymptomatic pulmonary emboli were documented on the posttherapy CT scan of the chest and abdomen. A coincident deep venous thrombosis was documented in only one of the three patients, and there was probable progression of disease on therapy in this patient. In prior phase I/II trials of weekly irinotecan and cisplatin, we did not observe an increase in the incidence of thromboembolic events, including deep venous thrombosis or pulmonary embolism.[ 12,13] Because of this potential complication experienced during combined chemoradiotherapy, we have incorporated the use of daily, low-dose warfarin(Drug information on warfarin) (Coumadin) prophylaxis during combined chemoradiotherapy. In the additional 10 patients treated on study after the adoption of coumadin prophylaxis (including six patients treated with the addition of 1-hour paclitaxel discussed below), no thromboembolic complications have been observed. Fifteen patients were referred for surgical resection. Pathologic complete responses were observed in four patients (27%), including two patients treated at the irinotecan dose level of 40 mg/m2 and two patients treated at the irinotecan dose level of 80 mg/m2. Four patients were not treated surgically, two with progressive disease outside of the radiotherapy field, and two who achieved clinical complete responses to chemoradiotherapy without surgery. Overall, six complete responses (clinical and pathologic) were observed in 19 patients, for an overall complete response rate of 32%. We have continued this trial with the addition of weekly paclitaxel to the irinotecan/cisplatin/radiation regimen, based on the results of a phase I trial indicating the feasibility of combining the three agents in advanced disease. During concurrent radiotherapy, weekly 1-hour paclitaxel at 40 mg/m2 was combined with concurrent radiotherapy, weekly irinotecan at 50 mg/m2, and cisplatin at 30 mg/ m2 on days 1, 8, 22, and 29 of radiotherapy. Three of six patients treated experienced dose-limiting toxicity, a delay in radiotherapy due to neutropenia or thrombocytopenia, with one patient hospitalized for neutropenic fever. It is unclear whether it will be feasible to add a third agent-paclitaxel- to cisplatin, irinotecan, and radiotherapy because of severe myelosuppressive toxicity. Another recently reported phase II trial employed induction chemotherapy with irinotecan at 70 mg/m2 plus cisplatin at 20 mg/m2 weekly * 2 then 1 week off, followed by combined radiotherapy (45 Gy in 25 fractions) with weekly paclitaxel at 45 mg/m2 and continuous infusion 5-FU at 300 mg/m2/d, 5 days/wk. The regimen was tolerable, with a reported pathologic complete response rate of 27% in 22 patients. Future Directions The activity, ease of administration, and excellent tolerance of weekly cisplatin, irinotecan, and concurrent radiotherapy compare favorably to infusional 5-FU and cisplatin with radiotherapy, and to regimens used in more recent trials combining paclitaxel, cisplatin, and radiotherapy. We plan a formal phase II trial of this regimen as preoperative therapy in locally advanced esophageal cancer. Other trials will employ alternative combination therapy with weekly irinotecan, including weekly irinotecan plus docetaxel and radiation therapy to be studied at the Memorial Sloan-Kettering Cancer Center, and the combination of weekly irinotecan, docetaxel, continuous infusion 5-FU, and radiation therapy to be studied at The University of Texas M.D. Anderson Cancer Center. Given the minimal toxicity of therapy, further studies building on the combination of weekly irinotecan, cisplatin, and radiotherapy are planned or have recently opened. Such trials include the addition in phase I and II trials of new molecularly targeted agents, including the cyclooxygenase- 2 inhibitor celecoxib(Drug information on celecoxib) (Celebrex), and the epidermal growth factor receptor inhibitor cetuximab(Drug information on cetuximab) (Erbitux) and the VEGF inhibitor bevacizumab(Drug information on bevacizumab) (Avastin). The treatment schema for adding targeted agents to induction chemotherapy and combined chemoradiotherapy with weekly irinotecan and cisplatin is outlined in Figure 1.Recently, the Eastern Cooperative Oncology Group (ECOG) has also opened a randomized phase II trial comparing paclitaxel and cisplatin to irinotecan and cisplatin with concurrent radiotherapy in locally advanced esophageal cancer. Conclusion Irinotecan possesses activity in a number of gastrointestinal cancers, including esophageal cancer. Phase II evaluation of the combination of weekly irinotecan and cisplatin has shown response rates exceeding 30% to 50% in esophageal and gastric cancer. Novel investigative regimens include irinotecan combined with mitomycin, the taxanes, and continuous infusion 5-FU. Clinical trials have also evaluated concurrent radiotherapy with irinotecan to study its radiosensitizing properties. Phase II evaluation of weekly irinotecan, cisplatin, and concurrent radiotherapy as preoperative therapy is planned. Further phase I and II investigation is ongoing with the addition of targeted agents, as are studies using other combinations of irinotecan with radiotherapy, including the addition of docetaxel and continuous infusion 5-FU.