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Irinotecan, Cisplatin, and Radiation in Esophageal Cancer

Irinotecan, Cisplatin, and Radiation in Esophageal Cancer

ABSTRACT: The limited effectiveness of currently available chemotherapy in the treatment of advanced esophageal cancer, and the poor survival achieved in locally advanced disease with combined chemoradiotherapy with or without surgery, have prompted the evaluation of new agents. Irinotecan (CPT-11, Camptosar) has promising single-agent activity in gastrointestinal cancers. In phase II evaluation of weekly irinotecan plus cisplatin, response rates have exceeded 30% in esophageal and gastric cancers. Irinotecan is an active radiosensitizer in preclinical studies and clinical trials in lung cancer. We performed a phase I trial of weekly irinotecan, cisplatin, and concurrent radiotherapy in locally advanced esophageal cancer. Induction chemotherapy with irinotecan and cisplatin was given prior to radiotherapy, over 6 weeks, cycled on a 2-week-on, 1-week-off schedule to relieve dysphagia. Radiotherapy was given subsequently in 180-cGy daily fractions to a total dose of 5,040 cGy. Doses of chemotherapy, when given with concurrent radiotherapy, were cisplatin at 30 mg/m² followed by irinotecan at escalated doses (40, 50, 65, and 80 mg/m²), on days 1, 8, 22, and 29. Among 18 patients entered in the trial, minimal toxicity has been observed, with no grade 3/4 esophagitis or diarrhea. Hematologic toxicity has been minimal. Dose-limiting toxicity (ie, requiring more than a 2-week delay in radiotherapy) has been seen in one of three patients at the 80-mg/m² irinotecan dose level, and accrual continues at this dose level. Among 13 evaluable patients, five complete responses have been seen (38%), including three pathologic complete responses in 10 patients undergoing surgery (30%). Asymptomatic pulmonary emboli were noted on the posttreatment computed tomography scan in 3 of 15 patients, prompting the addition of warfarin sodium (Coumadin) prophylaxis on protocol. Full doses of weekly irinotecan (65 mg/m²) and cisplatin (30 mg/m²) can be combined safely with concurrent radiotherapy in patients with locally advanced esophageal cancer. [ONCOLOGY 16(Suppl 5):11-15, 2002]

Esophageal carcinoma is an aggressive cancer with a
poor prognosis. In 2002, 13,100 Americans will be diagnosed with esophageal
cancer, and more than 95% of these patients will die of their disease.[1] Half
of patients present with overt metastatic disease, with a median survival of
usually less than 1 year. The remaining half of patients present with locally
advanced disease potentially amenable to surgical- or radiation-based therapy.
Because of the relative rarity of esophageal cancer and the absence of effective
screening, most patients present with symptomatic dysphagia and usually have
locally advanced, transmural, or lymph-node-positive disease.

Despite treatment with surgery, definitive chemoradiotherapy, or combined
preoperative chemoradiotherapy followed by surgery, 5-year survival rates of
less than 20% to 35% are generally achieved.[2-5] The poor survival in locally
advanced disease is due to a high incidence of both distant, metastatic disease
recurrence and local disease recurrence. Conventional chemotherapy combining a
continuous infusion of fluorouracil (5-FU) and cisplatin is associated with
substantial toxicity, including stomatitis, diarrhea, nausea, fatigue, and
myelosuppression. The severe mucosal and gastrointestinal toxicities that occur
when concurrent radiotherapy is combined with 5-FU and cisplatin have led many
investigators to mandate the placement of enteral feeding tubes in patients
prior to therapy. The toxicity and limited effectiveness of currently used
cytotoxic chemotherapy, either to palliate metastatic disease or used in
combination with radiotherapy in locally advanced disease, have mandated the
ongoing investigation of newer cytotoxic agents in esophageal cancer.

Irinotecan

Irinotecan (CPT-11, Camptosar), a semisynthetic camptothecin, has emerged as
a significant new cytotoxic agent with a broad spectrum of antitumor activity.
Early trials in Japan indicated promising antitumor activity for irinotecan in a
number of gastrointestinal malignancies, including colorectal, pancreatic, and
gastric cancer. Irinotecan has a novel mechanism of action. Once it is converted
to its active metabolite SN-38, irinotecan binds to the complex of the enzyme
topoisomerase I and DNA, stabilizing the cleavable complex and inhibiting
reannealing of parent DNA. [6-9] Single-strand DNA breaks are converted to
irreversible double-strand breaks when a DNA replication fork encounters a
cleavable complex, leading to cell death.[7-9] Phase II evaluation of irinotecan
in gastric cancer in Japan indicated a single-agent response rate of 20% to
30%.[10] Recent American trials of single-agent irinotecan, given at a weekly
dose of 125 mg/m², 4 weeks on and 2 weeks off treatment, indicate modest
single-agent activity with a response rate of 15% in gastric and
gastroesophageal junction cancer.[11,12]

Irinotecan and Cisplatin

Cisplatin is an alkylating agent commonly used in combination chemotherapy
for upper gastrointestinal malignancies. Cisplatin acts through a mechanism
different from that of irinotecan, forming platinum adducts with DNA leading to
inhibition of DNA synthesis and repair. In vitro, cisplatin and irinotecan have
demonstrated sequence-dependent synergy in a variety of cancer cell lines. Peak
synergy appears to be achieved in cell lines when cisplatin is given immediately
prior to or in combination with SN-38.[13,14] One potential mechanism of synergy
between cisplatin and irinotecan is for SN-38 to reduce the rate of removal of
cisplatin-induced DNA interstrand cross links.[15,16] Cisplatin may also
increase SN-38 inhibition of topoisomerase I.[16]

Saltz et al conducted a phase I trial combining weekly irinotecan and
cisplatin.[17] The weekly schedule was developed to optimize potential synergy
between the two agents. Patients received cisplatin over 30 minutes immediately
followed by irinotecan over 90 minutes weekly, for 4 consecutive weeks, followed
by a 2-week rest; this 6-week period comprised one treatment cycle. Neutropenia
was the dose-limiting toxicity; other toxicities were minimal, and included
manageable diarrhea, nausea, and fatigue. Doses recommended for phase II studies
in previously untreated patients were cisplatin at 30 mg/m² and irinotecan at 65
mg/m².

Ilson and colleagues subsequently performed a phase II trial of weekly
cisplatin and irinotecan in patients with metastatic esophageal cancer, using
the weekly schedule.[18] A response rate of 57% was observed in 35 patients. The
median response duration was 4.2 months, and median actuarial survival was 14.6
months. Dysphagia relief—either improvement or resolution of dysphagia—was
achieved in 90% of patients. Treatment delays due to prolonged blood count
recovery were common, affecting 66% of patients; most commonly, treatment was
delayed in week 3 or 4 of therapy, and less commonly, the treatment cycle was
shortened from 4 to 3 weeks.

Another trial in metastatic gastric and gastroesophageal junction cancer was
reported by Ajani and colleagues at The University of Texas M. D. Anderson
Cancer Center. An overall response rate of 54% among 39 patients was
observed.[19] A smaller trial of weekly irinotecan and cisplatin conducted at
Memorial Sloan-Kettering Cancer Center (MSKCC) in gastric cancer also
demonstrated significant hematologic toxicity, with a response rate of 33% in 18
patients treated.[20] Because of the need to delay therapy when irinotecan and
cisplatin are administered weekly for 4 consecutive weeks, a change in the
schedule to 2 weeks on and 1 week off has been proposed. A phase II multicenter
trial exploring this alternative schedule has recently opened in patients with
metastatic esophageal cancer.

Phase I/II Trials of Irinotecan Combined With Radiotherapy

Numerous studies conducted in cell line and xenograft models have
demonstrated the radiation-sensitizing effect of the camptothecins.[21,22]
Results of several studies have demonstrated that synergy is greatest when
camptothecins are given concurrently with or within a short period of radiation
therapy.[23] In one study, the peak sensitization enhancement ratio was reached
when radiotherapy was used concurrently with or immediately after camptothecin
treatment.[24] The degree of radiosensitization appears to be similar to that of
other standard drugs used in combined-modality therapy.[25,26] The mechanism of
radiosensitization of the camptothecins is unclear at this time. The
radiosensitization effect may be cell-cycle specific; one xenograft study
demonstrated a significant increase in the proportion of cells in the G2/M
phase, the most radiosensitive phase of the cell cycle after treatment with
SN-38.[27]

Another trial in cell lines showed an increase in the number of DNA-protein
cross links formed, exceeding that expected by the additive damage from
radiotherapy and irinotecan, suggesting a synergistic effect.[28] Others have
speculated that topoisomerase I inhibitors given shortly after irradiation may
cause conversion of single-strand DNA breaks to double-strand breaks, resulting
in synergistic lethality to cultured malignant cells.[29]

Few clinical studies have evaluated the combination of irinotecan and
radiation therapy. Phase I/II studies of weekly irinotecan and radiation therapy
for locally advanced non-small-cell lung cancer have been conducted in Japan;
an initial phase I trial established a phase II dose of 45 mg/m² of irinotecan
when given once weekly with 6,000 cGy of once-daily fractionated
radiotherapy.[30] Dose-limiting toxicities on this trial included esophagitis,
pneumonitis, and diarrhea.

A phase II trial conducted in Japan combined 60 mg/m² of once-weekly
irinotecan with 6,000 cGy of radiotherapy given in single daily fractions.[31]
Observed toxicities included neutropenia, pneumonitis, and esophagitis. Clinical
trials in non-small-cell lung cancer, combining radiation therapy and weekly
irinotecan with either weekly carboplatin (Paraplatin) or cisplatin, are
currently being conducted in the United States at Vanderbilt University in
Nashville, and Fox Chase Cancer Center in Philadelphia.

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