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.
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/mÂ² followed by irinotecan at escalated doses (40, 50, 65, and 80 mg/mÂ²), 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/mÂ² 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/mÂ²) and cisplatin (30 mg/mÂ²) 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 apoor prognosis. In 2002, 13,100 Americans will be diagnosed with esophagealcancer, and more than 95% of these patients will die of their disease. Halfof patients present with overt metastatic disease, with a median survival ofusually less than 1 year. The remaining half of patients present with locallyadvanced disease potentially amenable to surgical- or radiation-based therapy.Because of the relative rarity of esophageal cancer and the absence of effectivescreening, most patients present with symptomatic dysphagia and usually havelocally advanced, transmural, or lymph-node-positive disease.
Despite treatment with surgery, definitive chemoradiotherapy, or combinedpreoperative chemoradiotherapy followed by surgery, 5-year survival rates ofless than 20% to 35% are generally achieved.[2-5] The poor survival in locallyadvanced disease is due to a high incidence of both distant, metastatic diseaserecurrence and local disease recurrence. Conventional chemotherapy combining acontinuous infusion of fluorouracil (5-FU) and cisplatin is associated withsubstantial toxicity, including stomatitis, diarrhea, nausea, fatigue, andmyelosuppression. The severe mucosal and gastrointestinal toxicities that occurwhen concurrent radiotherapy is combined with 5-FU and cisplatin have led manyinvestigators to mandate the placement of enteral feeding tubes in patientsprior to therapy. The toxicity and limited effectiveness of currently usedcytotoxic chemotherapy, either to palliate metastatic disease or used incombination with radiotherapy in locally advanced disease, have mandated theongoing investigation of newer cytotoxic agents in esophageal cancer.
Irinotecan (CPT-11, Camptosar), a semisynthetic camptothecin, has emerged asa significant new cytotoxic agent with a broad spectrum of antitumor activity.Early trials in Japan indicated promising antitumor activity for irinotecan in anumber of gastrointestinal malignancies, including colorectal, pancreatic, andgastric cancer. Irinotecan has a novel mechanism of action. Once it is convertedto its active metabolite SN-38, irinotecan binds to the complex of the enzymetopoisomerase I and DNA, stabilizing the cleavable complex and inhibitingreannealing of parent DNA. [6-9] Single-strand DNA breaks are converted toirreversible double-strand breaks when a DNA replication fork encounters acleavable complex, leading to cell death.[7-9] Phase II evaluation of irinotecanin gastric cancer in Japan indicated a single-agent response rate of 20% to30%. Recent American trials of single-agent irinotecan, given at a weeklydose of 125 mg/m², 4 weeks on and 2 weeks off treatment, indicate modestsingle-agent activity with a response rate of 15% in gastric andgastroesophageal junction cancer.[11,12]
Cisplatin is an alkylating agent commonly used in combination chemotherapyfor upper gastrointestinal malignancies. Cisplatin acts through a mechanismdifferent from that of irinotecan, forming platinum adducts with DNA leading toinhibition of DNA synthesis and repair. In vitro, cisplatin and irinotecan havedemonstrated sequence-dependent synergy in a variety of cancer cell lines. Peaksynergy appears to be achieved in cell lines when cisplatin is given immediatelyprior to or in combination with SN-38.[13,14] One potential mechanism of synergybetween cisplatin and irinotecan is for SN-38 to reduce the rate of removal ofcisplatin-induced DNA interstrand cross links.[15,16] Cisplatin may alsoincrease SN-38 inhibition of topoisomerase I.
Saltz et al conducted a phase I trial combining weekly irinotecan andcisplatin. The weekly schedule was developed to optimize potential synergybetween the two agents. Patients received cisplatin over 30 minutes immediatelyfollowed by irinotecan over 90 minutes weekly, for 4 consecutive weeks, followedby a 2-week rest; this 6-week period comprised one treatment cycle. Neutropeniawas the dose-limiting toxicity; other toxicities were minimal, and includedmanageable diarrhea, nausea, and fatigue. Doses recommended for phase II studiesin previously untreated patients were cisplatin at 30 mg/m² and irinotecan at 65mg/m².
Ilson and colleagues subsequently performed a phase II trial of weeklycisplatin and irinotecan in patients with metastatic esophageal cancer, usingthe weekly schedule. A response rate of 57% was observed in 35 patients. Themedian response duration was 4.2 months, and median actuarial survival was 14.6months. Dysphagia reliefeither improvement or resolution of dysphagiawasachieved in 90% of patients. Treatment delays due to prolonged blood countrecovery were common, affecting 66% of patients; most commonly, treatment wasdelayed in week 3 or 4 of therapy, and less commonly, the treatment cycle wasshortened from 4 to 3 weeks.
Another trial in metastatic gastric and gastroesophageal junction cancer wasreported by Ajani and colleagues at The University of Texas M. D. AndersonCancer Center. An overall response rate of 54% among 39 patients wasobserved. A smaller trial of weekly irinotecan and cisplatin conducted atMemorial Sloan-Kettering Cancer Center (MSKCC) in gastric cancer alsodemonstrated significant hematologic toxicity, with a response rate of 33% in 18patients treated. Because of the need to delay therapy when irinotecan andcisplatin are administered weekly for 4 consecutive weeks, a change in theschedule to 2 weeks on and 1 week off has been proposed. A phase II multicentertrial exploring this alternative schedule has recently opened in patients withmetastatic esophageal cancer.
Numerous studies conducted in cell line and xenograft models havedemonstrated the radiation-sensitizing effect of the camptothecins.[21,22]Results of several studies have demonstrated that synergy is greatest whencamptothecins are given concurrently with or within a short period of radiationtherapy. In one study, the peak sensitization enhancement ratio was reachedwhen radiotherapy was used concurrently with or immediately after camptothecintreatment. The degree of radiosensitization appears to be similar to that ofother standard drugs used in combined-modality therapy.[25,26] The mechanism ofradiosensitization of the camptothecins is unclear at this time. Theradiosensitization effect may be cell-cycle specific; one xenograft studydemonstrated a significant increase in the proportion of cells in the G2/Mphase, the most radiosensitive phase of the cell cycle after treatment withSN-38.
Another trial in cell lines showed an increase in the number of DNA-proteincross links formed, exceeding that expected by the additive damage fromradiotherapy and irinotecan, suggesting a synergistic effect. Others havespeculated that topoisomerase I inhibitors given shortly after irradiation maycause conversion of single-strand DNA breaks to double-strand breaks, resultingin synergistic lethality to cultured malignant cells.
Few clinical studies have evaluated the combination of irinotecan andradiation therapy. Phase I/II studies of weekly irinotecan and radiation therapyfor 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 irinotecanwhen given once weekly with 6,000 cGy of once-daily fractionatedradiotherapy. Dose-limiting toxicities on this trial included esophagitis,pneumonitis, and diarrhea.
A phase II trial conducted in Japan combined 60 mg/m² of once-weeklyirinotecan with 6,000 cGy of radiotherapy given in single daily fractions.Observed toxicities included neutropenia, pneumonitis, and esophagitis. Clinicaltrials in non-small-cell lung cancer, combining radiation therapy and weeklyirinotecan with either weekly carboplatin (Paraplatin) or cisplatin, arecurrently being conducted in the United States at Vanderbilt University inNashville, and Fox Chase Cancer Center in Philadelphia.
A phase I trial combining concurrent radiation therapy with weekly irinotecanand cisplatin in patients with locally advanced esophageal cancer is nearcompletion at MSKCC. The primary study end point is to establish the maximumtolerated dose of weekly irinotecan that can be combined with weekly cisplatinand concurrent radiotherapy in esophageal cancer. Eligible patients havepreviously untreated, locally advanced esophageal squamous or adenocarcinomawithout evidence of distant metastatic disease. Adequate performance status andorgan function are required. Patients are staged with computed tomography (CT)scan and positron emission tomography scan to evaluate for metastatic disease.All patients undergo local tumor staging with endoscopic ultrasound, andpatients with early-stage T1, N0 tumors are excluded. Surgery is not mandated aspart of the study, but may be considered after treatment.
The treatment schema for the trial is shown in Figure1. Dose-limitingtoxicity is defined as toxicity that necessitates a 2-week treatment delayduring radiotherapy. Induction chemotherapy consists of weekly irinotecan (65mg/m²) and cisplatin (30 mg/m²), 2 weeks on and 1 week off, for two 3-weekcycles. Induction chemotherapy is given primarily to allow for relief ofdysphagia prior to beginning the combined chemoradiotherapy. Inductionchemotherapy is followed by 6 weeks of radiotherapy, with radiation administeredin 180-cGy daily fractions from Monday to Friday to a total dose of 5,040 cGy.During radiation treatment, cisplatin is administered concurrently at a fixeddose of 30 mg/m² followed by escalating doses of irinotecan (40, 50, 65, and 80mg/m²), once weekly on days 1, 8, 22, and 29 of radiation therapy. The doselevel of 80 mg/m² was included given the 2-week-on, 1-week-off chemotherapyschedule during radiation, potentially permitting further irinotecan doseescalation.
Patient demographics are outlined in Table1. Of 18 patients entered so far,15 have completed therapy. Therapy has been remarkably well tolerated, withminimal hematologic toxicity noted in treated patients even to a dose level of65 mg/m² of irinotecan. Median absolute neutrophil and platelet nadirs at eachdose level are shown in Table 2. No significant grade 3 or 4 toxicity, includingesophagitis or diarrhea, has been observed, with the exception of one patienttreated with irinotecan at 50 mg/m² who developed reversible grade 3 pneumonitis(which resolved). At the 80 mg/m² irinotecan dose level, one of three patientscompleting therapy has had dose-limiting hematologic toxicity (a 2-week delay inradiotherapy due to neutropenia and thrombocytopenia). Three additional patientsare currently completing therapy at this dose level.
An unexpected toxicity, which cannot clearly be explained and whose relationto therapy is uncertain, is the observation (in 3 of 15 patients) ofasymptomatic pulmonary emboli documented on the posttherapy CT scan of the chestand abdomen. A coincidental deep venous thrombosis was documented in only one ofthese three patients. In previous phase I/II trials of weekly irinotecan andcisplatin that have included more than 100 patients, no increase in theincidence of thromboembolic events, including deep venous thrombosis orpulmonary embolism, has been observed.[17,18,20,32] Because of this potentialcomplication, the protocol was revised to include daily, low-dose warfarinsodium (Coumadin) prophylaxis during combined chemoradiotherapy.
Thirteen patients are evaluable for response to therapy, of whom 10 haveundergone surgery. Five clinical complete responses have been observed (38%).Pathologic complete response was observed in 3 of 10 patients (30%). Anadditional two patients had only microscopic residual cancer (20%).
The preliminary activity and excellent tolerability of weekly irinotecan,cisplatin, and radiation compare favorably with older regimens combininginfusional 5-FU and cisplatin with radiotherapy, and more recent trialscombining paclitaxel, cisplatin, and radiotherapy. We plan to conduct a formalphase II trial of this regimen of induction chemotherapy followed bychemoradiotherapy, with weekly cisplatin and irinotecan as preoperative therapy,in locally advanced esophageal cancer. Given the minimal toxicity observed,further exploration of other phase I combinations employing thischemoradiotherapy regimen is planned.
Upcoming trials in the phase I setting include addition of weekly paclitaxel(given over 1 hour) to weekly irinotecan, cisplatin, and radiotherapy, as wellas the addition of some of the new molecular-targeted therapies. Given thepotential role of angiogenesis in tumor growth and metastasis, a planned phase Itrial will combine irinotecan, cisplatin, and radiation with the novelantiangiogenic agent SU5416 (Iressa). SU5416 inhibits the tyrosine kinaseinvolved in signal transduction via the angiogenic growth factor receptors flk-1(fetal liver kinase-1), PDGF (platelet-derived endothelial growth factor), andVEGF (vascular endothelial growth factor).
1. Greenlee R, Hill-Harmon M, Murray T, et al: Cancer Statistics, 2001. CACancer J Clin 51:15-36, 2001.
2. Walsh TN, Noonan N, Hollywood D, et al: A comparison of multimodal therapyand surgery for esophageal adenocarcinoma. N Engl J Med 335:462-467, 1996.
3. Kelsen DP, Ginsberg R, Pajak T, et al: Chemotherapy followed by surgerycompared with surgery alone for localized esophageal cancer. N Engl J Med339:1979-1984, 1998.
4. Cooper J, Guo M, Herskovic A, et al: Chemoradiotherapy of locally advancedesophageal cancer: Long-term follow-up of a prospective randomized trial (RTOG85-01). JAMA 281:1623-1627, 1999.
5. Urba SG, Orringer MB, Turrisi A, et al: Randomized trial of preoperativechemoradiation versus surgery alone in patients with locoregional esophagealcarcinoma. J Clin Oncol 19:305-313, 2001.
6. Chen AY, Liu LF: DNA topoisomerases: Essential enzymes and lethal targets.Annu Rev Pharmacol Toxicol 34:191-218, 1994.
7. Hsiang YH, Hertzberg R, Hecht S: Camptothecin induces protein-linked DNAbreaks via mammalian DNA topoisomerase I. J Biol Chem 260(14):873-878, 1985.
8. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as anintracellular target of the anticancer drug camptothecin. Cancer Res48(1):722-726, 1988.
9. Creemers CJ, Lund B, Verwij J: Topoisomerase I inhibitors: Topotecan andirinotecan. Cancer Treat Rev 20:73-96, 1994.
10. Kambe M, Wakui A, Nakano I, et al: A late phase II study of irinotecan(CPT-11) in patients with advanced gastric cancers. Proc Am Soc Clin Oncol12:198, 1993.
11. Lin L, Hecht J: A phase II trial of irinotecan in patients with advancedadenocarcinoma of the gastroesophageal (GE) junction. Proc Am Soc Clin Oncol19:1130, 2000.
12. Enzinger P, Kulke M, Clark J, et al: Phase II trial of CPT-11 inpreviously untreated patients with advanced adenocarcinoma of the esophagus andstomach. Proc Am Soc Clin Oncol 19:1243, 2000.
13. Kano Y, Suzuki K, Akutsu M, et al: Effects of CPT-11 in combination withother anti-cancer agents in culture. Int J Cancer 50:604-610, 1992.
14. Masumoto N, Nakano S, Esaki T, et al: Sequence-dependent modulation ofanticancer drug activities by 7-ethyl-10-hydroxycamptothecin in an HST-1 humansquamous carcinoma cell line. Anticancer Res 15:405-410, 1995.
15. Masumoto N, Nakano S, Esaki T, et al: Inhibition of cis-diamminedichloroplatinum(II)-induced DNA interstrand cross-link removal by7-ethyl-10-hydroxy-camptothecin in HST-1 human squamous-carcinoma cells. Int J Cancer 62:70-75, 1995.
16. Fukuda M, Nishio K, Kanzawa F, et al: Synergism between cisplatin andtopoisomerase I inhibitors, NB-506 and SN-38, in human small cell lung cancercells. Cancer Res 56:789-793, 1996.
17. Saltz LB, Spriggs D, Schaaf LJ, et al: Phase I clinical and pharmacologicstudy of weekly cisplatin combined with weekly irinotecan in patients withadvanced solid tumors. J Clin Oncol 16:3858-3865, 1998.
18. Ilson DH, Saltz L, Enzinger P, et al: Phase II trial of weekly irinotecanplus cisplatin in advanced esophageal cancer. J Clin Oncol 17:3270-3275, 1999.
19. Ajani J, Fairweather J, Pisters P, et al: Phase II study of CPT-11 pluscisplatin in patients with advanced gastric and GE junction carcinomas. Proc AmSoc Clin Oncol 18:927, 1999.
20. Ilson D, Enzinger P, Saltz L, et al: Phase II trial of weekly irinotecan+ cisplatin in advanced gastric cancer. Proc Am Soc Clin Oncol 18:994, 1999.
21. Lamond JP, Wang M, Kinsella TJ, et al: Radiation lethality enhancementwith 9-aminocamptothecin: Comparison to other topoisomerase I inhibitors. Int JRadiat Oncol Biol Phys 36(2):369-376, 1996.
22. Roffler SR, Chan J, Yeh MY: Potentiation of radioimmunotherapy byinhibition of topoisomerase I. Cancer Res 54:1276-1285, 1994.
23. Wang DS, Ueno Y, Oyamada H, et al: Enhancement of the antitumor effect ofgamma-ray irradiation in combination with camptothecin against human colorectaladenocarcinoma. Biolog Pharmaceut Bull 19(3):354-359, 1996.
24. Kirichenko AV, Rich TA, Newman RA, et al: Potentiation of murine MCA-4carcinoma radioresponse by 9-amino-20(S)-camptothecin. Cancer Res 57:1929-1933,1997.
25. Okishio K, Kudoh S, Kurihara N, et al: Irinotecan (CPT-11) enhances theradiosensitivity of lung cancer in vitro. Proc Am Soc Clin Oncol 14:1109, 1995.
26. Watanabe A, Nishiwaki K, Hasegawa Y, et al: Effects of taxotere(docetaxel) and of irinotecan (CPT-11) combined with radiation on lung cancercell lines. Proc Am Soc Clin Oncol 14:1617, 1995.
27. Tamura K, Takada M, Kawase I, et al: Enhancement of tumor radio-responseby irinotecan in human lung tumor xenografts. Jpn J Cancer Res 88:218-223, 1997.
28. Szumiel I, Buraczewska I, Gradzka I, et al: Effects of topoisomeraseI-targeted drugs on radiation response of L5178Y sublines differentiallyradiation and drug sensitive. Int J Radiat Biol 67(4): 441-448, 1995.
29. Chen AY, Okunieff P, Pommier Y, et al: Mammalian DNA topoisomerase Imediates the enhancement of radiation cytotoxicity by camptothecin derivatives.Cancer Res 57:1529-1536, 1997.
30. Kudoh S, Kurihara N, Okishio K, et al: A phase I-II study of weeklyirinotecan (CPT-11) and simultaneous thoracic radiotherapy (TRT) forunresectable locally advanced non-small cell lung cancer (NSCLC). Proc Am SocClin Oncol 15:1102, 1996.
31. Saka H, Shimokata S, Yoshida K, et al: Irinotecan (CPT-11) and concurrentradiotherapy in locally advanced non-small cell lung cancer (NSCLC): A phase IIstudy of Japan Clinical Oncology Group (JCOG 9504). Proc Am Soc Clin Oncol16:1607, 1997.
32. Maki R, Ilson D, O’Reilly E, et al: Phase I trial of cisplatin,irinotecan, and weekly paclitaxel in patients with solid tumor malignancies.Proc Am Soc Clin Oncol 20:430, 2001.
33. Fong TA, Shawver LK, Sun L, et al: SU5416 is a potent and selectiveinhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) thatinhibits tyrosine kinase catalysis, tumor vascularization, and growth ofmultiple tumor types. Cancer Res 59:99-106, 1999.