Esophageal carcinoma is an aggressive
cancer with a poor prognosis. In 2000, an estimated 12,300 Americans will be
diagnosed with this tumor, with approximately 12,100 deaths. Traditionally,
patients with localized esophageal cancer, treated with either surgery alone or
radiation therapy alone, have had a 5-year survival rate of 5% to 10%.[2,3] More
recently, in large phase III trials, patients treated with combined-modality
therapy or surgery alone have had 5-year survival rates of 25% to 27%.[4,5]
Despite this improvement in overall survival, most patients with
locally advanced disease will have a recurrence. These patients and those
presenting with metastatic disease require palliative chemotherapy. These
disappointing results have stimulated the search for more aggressive
multimodality therapy with more effective chemotherapeutic agents in the
treatment of esophageal cancer.
Irinotecan (Camptosar) has a novel mechanism of action. Once it
is converted to its active metabolite SN-38, irinotecan binds to the
topoisomerase I-DNA cleavable complex, stabilizes this cleavable complex, and
inhibits reannealing of the parent DNA.[6-8] These single-strand breaks are
converted to irreversible double-strand breaks when a DNA replication fork
encounters a cleavable complex. This process halts the synthesis of nucleic acid
in the cell, leading to cell death.[7,8]
Preclinical and Clinical Studies
Ikeda et al examined the antitumor activity of four camptothecin
analogs, including SN-38, against six human esophageal cancer cell lines. The
authors noted significant antitumor activity for all four camptothecin analogs.
In addition, all the cell lines expressed high levels of topoisomerase I, the
target of these camptothecin compounds.
Only a small number of patients with esophageal cancer have been
treated with single-agent irinotecan. Hecht et al reported their results in 13
patients with previously treated esophageal adenocarcinoma. Of seven evaluable
patients treated with weekly irinotecan at 125 mg/m2,
they noted one complete response and five patients with stable disease.
At the Dana-Farber Cancer Institute, a more recent trial of
single-agent irinotecanthis time for previously untreated, advanced
adenocarcinoma of the esophagus and stomachfound an objective response rate
of 15% among 34 evaluable patients. Another recent study of the drug in 21
patients with advanced adenocarcinoma of the gastroesophageal junction showed a
14% response rate. In both of these phase II trials, irinotecan was
administered at a dosage of 125 mg/m2 in cycles
of 4 weeks of treatment followed by 2 weeks of rest.
Cisplatin (Platinol) forms the backbone of many combination
regimens used today. Toxicities associated with cisplatin, including neurologic
and renal effects, do not overlap with those of irinotecan, which makes this
combination attractive. Furthermore, cisplatin acts differently from irinotecan
by forming displacement reactions, in which platinum forms a stable bond with
DNA, RNA, or other proteins. Intrastrand binding causes kinking of the DNA
helix and is associated with limited unwinding. This process disrupts the local
structure of DNA and appears to inhibit a number of enzymes important to the
cell, leading to apoptosis and cell death.
Cisplatin and irinotecan have demonstrated sequence-dependent
synergy in a variety of cancer cell lines in vitro. Kano et al showed that
simultaneous administration of irinotecan or SN-38 with cisplatin produced
synergistic cytotoxicity in a human T-cell leukemia cell line. Peak synergy
was achieved in a human squamous cell carcinoma cell line when cisplatin was
given immediately prior to or in combination with SN-38. Sequences in which
SN-38 was given prior to cisplatin showed no statistical synergy.
The mechanism of synergy between cisplatin and irinotecan
remains unclear at this time. A number of theories based on interesting
laboratory findings have been advanced. As quantified by a DNA alkaline elution
technique, Masumoto et al found that SN-38 has no effect on the uptake of
cisplatin or on the rate of formation of cisplatin-induced DNA interstrand
cross-links. Instead, SN-38 appears to reduce the rate of removal of these
cross-links. These results were confirmed by Fukuda et al. Cells treated
with SN-38 in addition to cisplatin eluted greater amounts of intrastrand
cross-linked DNA. This increase persisted at 24 and 48 hours after cisplatin
washout, suggesting interference with a DNA repair protein that removes
cisplatin-induced DNA adducts.
Fukuda et al also demonstrated a second possible mode of synergy
for these two agents. Their experiments suggested that cisplatin increases
SN-38 inhibition of topoisomerase I. Nuclear extracts from cells treated with
both agents showed decreased quantities of relaxed, uncoiled DNA when compared
with untreated cells or cells treated with SN-38 alone. Based on evidence
obtained from x-ray diffraction, the authors speculated that severe distortion
or kinking of the DNA double helix, caused by intrastrand cisplatin cross-links,
might modulate the stabilization of the topoisomerase I-drug-DNA cleavable
Recently, similar results were reported in the ABC-1 lung cancer
cell line by Aoe et al. On median-effect plot analysis and combination-index
isobologram, synergism was observed when cisplatin was given prior to SN-38.
Using a supercoiled-DNA relaxation assay, these authors noted decreased activity
of topoisomerase I for 2 to 4 hours after administration of cisplatin and
postulated that down-regulation of topoisomerase I by cisplatin contributed to
the synergistic effect of these two drugs.
Early Clinical Studies
In Japan, phase I and II trials have evaluated the combination
of irinotecan and cisplatin for many solid tumor malignancies, especially non-small-cell
lung cancer. These studies typically administered irinotecan (30 to 100 mg/m2)
on days 1, 8, and 15, followed by a 1-week rest period, and cisplatin (60 to 80
mg/m2) on day 1 of each treatment cycle.
Responses in patients with previously untreated non-small-cell lung cancer
ranged from 43% to 54%.[19-22]
Based on these preclinical and clinical findings, Saltz et al
initiated a phase I study of weekly irinotecan and cisplatin for advanced solid
tumor malignancies at Memorial Sloan-Kettering Cancer Center (MSKCC). This
schedule was developed to maximize the opportunity for synergy between the two
Patients received cisplatin over 30 minutes (immediately
followed by irinotecan over 90 minutes) weekly for 4 weeks on days 1, 8, 15, and
22. One cycle was defined as 4 weekly treatments, followed by a 2-week rest
period. For previously untreated patients, the maximum tolerated doses were 30
mg/m2 for cisplatin and 65 mg/m2
for irinotecan. Encouraging antitumor activity was noted, including a partial
response lasting 5 months in a patient with a gastroesophageal junction tumor.
Neutropenia was the main dose-limiting toxicity, and other toxic effects were
Phase II Trial of Weekly Cisplatin and Irinotecan
In a follow-up study at MSKCC, we initiated a phase II trial of
weekly cisplatin 30 mg/m2 and irinotecan 65
mg/m2 for unresectable, locally recurrent, or
metastatic esophageal adenocarcinoma or squamous cell carcinoma.[24,25] Patients
with a performance status of at least 60% and no prior chemotherapy or
radiotherapy had adequate renal, hematologic, and hepatobiliary function. For
patients with cancer of the gastroesophageal junction, there was at least 50%
involvement of the esophagus. Serial dysphagia and quality-of-life assessments
were also made at regular intervals.
Of 38 patients entered in the study to date, 35 are evaluable
for response and toxicity. Two poorly differentiated cancers were found to have
neuroendocrine features on follow-up biopsy, and one gastroesophageal junction
cancer appeared to be a gastric cancer on follow-up endoscopy. Accrual continues
for patients with squamous cell carcinoma. As outlined in Table
1, patients were typically middle-aged men with an excellent performance
status. Almost all patients had metastatic, bidimensionally measurable disease,
with involvement of the lymph nodes in 80%, liver metastases in 50%, and lung
nodules in 20%. Two-thirds of patients had adenocarcinoma and one-third had
squamous cell carcinoma.
As described in Table 2,
the major response rate for all patients was 57%, including 2 complete responses
(6%), 1 in each histology, and 18 partial responses (51%). Most major responders
required only one cycle of chemotherapy to reach a partial response. A
significant number of minor responses were also recorded (7 patients, 20%). Few
patients failed to benefit from this therapy; only one patient had outright
progression of disease. Similar response rates were seen with adenocarcinoma (12
of 23 patients, 52%) and squamous cell carcinoma (8 of 12 patients, 66%). The
median duration of response was 4.2 months (range: 1.0 to 8.8+
months), and the median actuarial survival was 14.6 months (range: 1.0 to 15.2+
Of 20 patients with evaluable dysphagia at baseline, 18 (90%)
noted either improvement or resolution of dysphagia with chemotherapy.
Significant improvements in overall quality of life, as measured by the European
Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life
Questionnaire (QLQ)-C30, and Functional Assessment of Cancer Therapy-General
(FACT-G), were noted. Specifically, FACT-G emotional well-being scores as well
as EORTC pain, emotional, and work-related functioning scores improved from
baseline in responders.
The toxicity profile of the weekly combination of cisplatin and
irinotecan is listed in Table 3. Grade 4
neutropenia was seen in 9% of patients. Grade 3 toxic effects included
neutropenia (37%), diarrhea (11%), nausea (6%), and fatigue (3%). Six patients
(17%) were hospitalized for toxicity, most commonly for neutropenic fever. There
were no treatment-related deaths. Delay in treatment occurred at some point
during therapy in 23 patients (66%), and attenuation of the dose was required in
7 patients (20%). Overall, 96% of planned treatments were given.
To a certain extent, these findings are being confirmed by Ajani
et al at the M. D. Anderson Cancer Center. These investigators are employing
the same weekly regimen of cisplatin and irinotecan for gastric and
gastroesophageal junction cancers. The preliminary major response rate was 51%
in 25 evaluable patients. Similar to the study previously described,
gastroesophageal junction cancer accounts for a substantial number of cases in
this trial. Neutropenia and diarrhea were again the dominant toxic effects. One
of these authors has suggested that perhaps a modification of the schedule to a
2-week-on, 1-week-off cycle might reduce the neutropenia, which typically arises
in the third week (J.A. Ajani, personal communication, 1999).
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