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Irinotecan (Camptosar) has shown activity in several solid tumor malignancies, including gastric and pancreatic cancer. In vitro studies suggest antitumor activity in esophageal cancer cell lines. Sequence-dependent synergy
ABSTRACT: Irinotecan (Camptosar) has shown activity in several solid tumor malignancies, including gastric and pancreatic cancer. In vitro studies suggest antitumor activity in esophageal cancer cell lines. Sequence-dependent synergy has been demonstrated in vitro between irinotecan and cisplatin. A phase I trial conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) has demonstrated the safety and tolerability of cisplatin plus irinotecan. A phase II study of this combination in patients with previously untreated, advanced esophageal cancer, also at MSKCC, has demonstrated promising results. Current trials at MSKCC are attempting to combine this regimen with either paclitaxel (Taxol), fluorouracil (5-FU), or radiation therapy. [ONCOLOGY 14(Suppl 14):26-30, 2000]
Esophageal carcinoma is an aggressivecancer with a poor prognosis. In 2000, an estimated 12,300 Americans will bediagnosed with this tumor, with approximately 12,100 deaths. Traditionally,patients with localized esophageal cancer, treated with either surgery alone orradiation therapy alone, have had a 5-year survival rate of 5% to 10%.[2,3] Morerecently, in large phase III trials, patients treated with combined-modalitytherapy or surgery alone have had 5-year survival rates of 25% to 27%.[4,5]
Despite this improvement in overall survival, most patients withlocally advanced disease will have a recurrence. These patients and thosepresenting with metastatic disease require palliative chemotherapy. Thesedisappointing results have stimulated the search for more aggressivemultimodality therapy with more effective chemotherapeutic agents in thetreatment of esophageal cancer.
Irinotecan (Camptosar) has a novel mechanism of action. Once itis converted to its active metabolite SN-38, irinotecan binds to thetopoisomerase I-DNA cleavable complex, stabilizes this cleavable complex, andinhibits reannealing of the parent DNA.[6-8] These single-strand breaks areconverted to irreversible double-strand breaks when a DNA replication forkencounters a cleavable complex. This process halts the synthesis of nucleic acidin the cell, leading to cell death.[7,8]
Preclinical and Clinical Studies
Ikeda et al examined the antitumor activity of four camptothecinanalogs, including SN-38, against six human esophageal cancer cell lines. Theauthors noted significant antitumor activity for all four camptothecin analogs.In addition, all the cell lines expressed high levels of topoisomerase I, thetarget of these camptothecin compounds.
Only a small number of patients with esophageal cancer have beentreated with single-agent irinotecan. Hecht et al reported their results in 13patients with previously treated esophageal adenocarcinoma. Of seven evaluablepatients 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 ofsingle-agent irinotecanthis time for previously untreated, advancedadenocarcinoma of the esophagus and stomachfound an objective response rateof 15% among 34 evaluable patients. Another recent study of the drug in 21patients with advanced adenocarcinoma of the gastroesophageal junction showed a14% response rate. In both of these phase II trials, irinotecan wasadministered at a dosage of 125 mg/m2 in cyclesof 4 weeks of treatment followed by 2 weeks of rest.
Cisplatin (Platinol) forms the backbone of many combinationregimens used today. Toxicities associated with cisplatin, including neurologicand renal effects, do not overlap with those of irinotecan, which makes thiscombination attractive. Furthermore, cisplatin acts differently from irinotecanby forming displacement reactions, in which platinum forms a stable bond withDNA, RNA, or other proteins. Intrastrand binding causes kinking of the DNAhelix and is associated with limited unwinding. This process disrupts the localstructure of DNA and appears to inhibit a number of enzymes important to thecell, leading to apoptosis and cell death.
Cisplatin and irinotecan have demonstrated sequence-dependentsynergy in a variety of cancer cell lines in vitro. Kano et al showed thatsimultaneous administration of irinotecan or SN-38 with cisplatin producedsynergistic cytotoxicity in a human T-cell leukemia cell line. Peak synergywas achieved in a human squamous cell carcinoma cell line when cisplatin wasgiven immediately prior to or in combination with SN-38. Sequences in whichSN-38 was given prior to cisplatin showed no statistical synergy.
The mechanism of synergy between cisplatin and irinotecanremains unclear at this time. A number of theories based on interestinglaboratory findings have been advanced. As quantified by a DNA alkaline elutiontechnique, Masumoto et al found that SN-38 has no effect on the uptake ofcisplatin or on the rate of formation of cisplatin-induced DNA interstrandcross-links. Instead, SN-38 appears to reduce the rate of removal of thesecross-links. These results were confirmed by Fukuda et al. Cells treatedwith SN-38 in addition to cisplatin eluted greater amounts of intrastrandcross-linked DNA. This increase persisted at 24 and 48 hours after cisplatinwashout, suggesting interference with a DNA repair protein that removescisplatin-induced DNA adducts.
Fukuda et al also demonstrated a second possible mode of synergyfor these two agents. Their experiments suggested that cisplatin increasesSN-38 inhibition of topoisomerase I. Nuclear extracts from cells treated withboth agents showed decreased quantities of relaxed, uncoiled DNA when comparedwith untreated cells or cells treated with SN-38 alone. Based on evidenceobtained from x-ray diffraction, the authors speculated that severe distortionor kinking of the DNA double helix, caused by intrastrand cisplatin cross-links,might modulate the stabilization of the topoisomerase I-drug-DNA cleavablecomplex.
Recently, similar results were reported in the ABC-1 lung cancercell line by Aoe et al. On median-effect plot analysis and combination-indexisobologram, synergism was observed when cisplatin was given prior to SN-38.Using a supercoiled-DNA relaxation assay, these authors noted decreased activityof topoisomerase I for 2 to 4 hours after administration of cisplatin andpostulated that down-regulation of topoisomerase I by cisplatin contributed tothe synergistic effect of these two drugs.
Early Clinical Studies
In Japan, phase I and II trials have evaluated the combinationof irinotecan and cisplatin for many solid tumor malignancies, especially non-small-celllung 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 80mg/m2) on day 1 of each treatment cycle.Responses in patients with previously untreated non-small-cell lung cancerranged from 43% to 54%.[19-22]
Based on these preclinical and clinical findings, Saltz et alinitiated a phase I study of weekly irinotecan and cisplatin for advanced solidtumor malignancies at Memorial Sloan-Kettering Cancer Center (MSKCC). Thisschedule was developed to maximize the opportunity for synergy between the twoagents.
Patients received cisplatin over 30 minutes (immediatelyfollowed by irinotecan over 90 minutes) weekly for 4 weeks on days 1, 8, 15, and22. One cycle was defined as 4 weekly treatments, followed by a 2-week restperiod. For previously untreated patients, the maximum tolerated doses were 30mg/m2 for cisplatin and 65 mg/m2for irinotecan. Encouraging antitumor activity was noted, including a partialresponse lasting 5 months in a patient with a gastroesophageal junction tumor.Neutropenia was the main dose-limiting toxicity, and other toxic effects wereminimal.
Phase II Trial of Weekly Cisplatin and Irinotecan
In a follow-up study at MSKCC, we initiated a phase II trial ofweekly cisplatin 30 mg/m2 and irinotecan 65mg/m2 for unresectable, locally recurrent, ormetastatic esophageal adenocarcinoma or squamous cell carcinoma.[24,25] Patientswith a performance status of at least 60% and no prior chemotherapy orradiotherapy had adequate renal, hematologic, and hepatobiliary function. Forpatients with cancer of the gastroesophageal junction, there was at least 50%involvement of the esophagus. Serial dysphagia and quality-of-life assessmentswere also made at regular intervals.
Of 38 patients entered in the study to date, 35 are evaluablefor response and toxicity. Two poorly differentiated cancers were found to haveneuroendocrine features on follow-up biopsy, and one gastroesophageal junctioncancer appeared to be a gastric cancer on follow-up endoscopy. Accrual continuesfor patients with squamous cell carcinoma. As outlined in Table1, patients were typically middle-aged men with an excellent performancestatus. Almost all patients had metastatic, bidimensionally measurable disease,with involvement of the lymph nodes in 80%, liver metastases in 50%, and lungnodules in 20%. Two-thirds of patients had adenocarcinoma and one-third hadsquamous 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 respondersrequired only one cycle of chemotherapy to reach a partial response. Asignificant number of minor responses were also recorded (7 patients, 20%). Fewpatients failed to benefit from this therapy; only one patient had outrightprogression of disease. Similar response rates were seen with adenocarcinoma (12of 23 patients, 52%) and squamous cell carcinoma (8 of 12 patients, 66%). Themedian 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+months).
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 EuropeanOrganization for Research and Treatment of Cancer (EORTC) Quality-of-LifeQuestionnaire (QLQ)-C30, and Functional Assessment of Cancer Therapy-General(FACT-G), were noted. Specifically, FACT-G emotional well-being scores as wellas EORTC pain, emotional, and work-related functioning scores improved frombaseline in responders.
The toxicity profile of the weekly combination of cisplatin andirinotecan is listed in Table 3. Grade 4neutropenia was seen in 9% of patients. Grade 3 toxic effects includedneutropenia (37%), diarrhea (11%), nausea (6%), and fatigue (3%). Six patients(17%) were hospitalized for toxicity, most commonly for neutropenic fever. Therewere no treatment-related deaths. Delay in treatment occurred at some pointduring therapy in 23 patients (66%), and attenuation of the dose was required in7 patients (20%). Overall, 96% of planned treatments were given.
To a certain extent, these findings are being confirmed by Ajaniet al at the M. D. Anderson Cancer Center. These investigators are employingthe same weekly regimen of cisplatin and irinotecan for gastric andgastroesophageal 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 inthis trial. Neutropenia and diarrhea were again the dominant toxic effects. Oneof these authors has suggested that perhaps a modification of the schedule to a2-week-on, 1-week-off cycle might reduce the neutropenia, which typically arisesin the third week (J.A. Ajani, personal communication, 1999).
With the promising phase II results of our weeklycisplatin-irinotecan combination, it was logical to add another antitumor agentto this regimen to improve the response further, and paclitaxel (Taxol) was anobvious choice. Paclitaxel is active in many solid tumors, and in combinationwith cisplatin, it is considered standard therapy for ovarian, lung, and headand neck cancers.
The mechanism of synergy between paclitaxel and cisplatin is notclear. Jekunen et al found that paclitaxel, at a concentration at which itdemonstrates synergy with cisplatin, is capable of altering microtubularmorphology but not capable of causing arrest of the cell cycle. Even less isknown about the combination of irinotecan and paclitaxel. There appears to be nocross resistance between these two antitumor agents, yet antagonism has beenreported in an ovarian cancer cell line.
Dosing considerations are critical when combining threechemotherapeutic agents. A weekly 1-hour regimen of paclitaxel and cisplatin hasnever been evaluated, yet a weekly 3-hour regimen of paclitaxel and cisplatinwas tested in a phase I study of patients with solid tumors. The maximumtolerated dose was 30 mg/m2 of cisplatin and 65mg/m2 of paclitaxel in chemotherapy-naivepatients. Neutropenia was the main dose-limiting toxic effect.
Gollerkeri et al studied escalating doses of weekly irinotecanand a 1-hour regimen of paclitaxel in patients with advanced solid tumors.The maximum tolerated dose was 50 mg/m2 ofirinotecan and 75 mg/m2 of paclitaxel,with neutropenia as the dose-limiting toxic effect.
Citardi et al demonstrated that a 24-hour regimen of paclitaxelfollowed by a 30-minute regimen of cisplatin had a greater antitumor effect thana 30-minute regimen of cisplatin followed by a 24-hour regimen of paclitaxel orconcurrent cisplatin and paclitaxel in murine leukemia cells. In patientswith solid tumors, Rowinsky et al found that the occurrence of neutropenia wassignificantly greater when cisplatin preceded paclitaxel than in the reverseorder.
Based on these data, we initiated a phase I study of a combinedweekly 1-hour regimen of paclitaxel, cisplatin, and irinotecan for previouslyuntreated solid tumors. The starting doses and sequence follow: first paclitaxelat 40 mg/m2, then cisplatin at 30 mg/m2,followed by irinotecan at 50 mg/m2. At thislevel, one patient had a dose-limiting toxic effect in the form of nausea.Expansion of the study to six patients at this dose level is near completion.
Using a similar rationale, we will soon test the combination ofirinotecan, cisplatin, and fluorouracil (5-FU) for solid-tumor malignancies.Again, 5-FU has broad activity in a variety of solid tumors and has shownsynergy with both cisplatin and irinotecan in vitro. A phase I study tocombine cisplatin, irinotecan, and concurrent radiation therapy for locallyadvanced esophageal cancer is also planned. Irinotecan has been shown to be aradiation sensitizer in vitro and in vivo. In combination with cisplatinand radiation, irinotecan has shown activity in a phase I/II adjuvant non-small-celllung cancer study in Japan.
The combination of weekly cisplatin and irinotecan is active inthe treatment of previously untreated, advanced esophageal carcinoma. Thisregimen has similar activity for both adenocarcinoma and squamous cellcarcinoma. Therapy was well tolerated. Toxicity appears to be limited mostly tograde 3 neutropenia and grade 2/3 diarrhea. Significant relief of dysphagia wasnoted by almost all patients with symptoms at baseline. Quality-of-life indicesshowed improvement in responding patients. Further exploration of thiscombination and schedule (or modified schedule as Ajani has suggested) iswarranted for other solid-tumor malignancies. This couplet forms an ideal basefor the addition of other chemotherapeutic agents (ie, paclitaxel or 5-FU) orthe addition of radiation therapy for locally advanced disease.
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