Topoisomerase inhibitors have been widely studied for the treatment of refractory or recurrent cervical cancer. Various schedules have been used, with response rates ranging from 13% to 20%. The combination of cisplatin and irinotecan (CPT-11, Camptosar) is being studied in cervical cancer.
ABSTRACT: Topoisomerase inhibitors have been widely studied for the treatment of refractory or recurrent cervical cancer. Various schedules have been used, with response rates ranging from 13% to 20%. The combination of cisplatin and irinotecan (CPT-11, Camptosar) is being studied in cervical cancer. Hematologic and gastrointestinal toxicities have been observed. Gastrointestinal toxicities have been particularly problematic at high irinotecan doses. Further studies of irinotecan in combination with other drugs and radiotherapy are warranted. [ONCOLOGY 16(Suppl 5):32-34, 2002]
Topoisomerases are essential nuclear enzymes with amultiplicity of cellular functions involving DNA replication, RNA transcription,mitosis, and chromosome condensation. Two classes have been identified inmammalian cells: the class I topoisomerases, so named because such agents inducesingle-strand breaks and reunions of the DNA double helix; and the class IItopoisomerases, so named because such agents induce double-strandbreakage-reunion reactions with the DNA double helix. Both enzymes catalyze theinterconversion of various topologic isomers of DNA.[2,3]
Camptothecin, an alkaloid from the tree Camptotheca acuminata (Nyssaceae), isthe parent compound of topotecan (Hycamtin), irinotecan (CPT-11, Camptosar),9-aminocamptothecin, 9-nitrocamptothecin, and other analogs. Topotecan andirinotecan are commercially available water-soluble derivatives of camptothecin.The active form of the camptothecins is the closed lactone ring, which ispH-dependent. Preclinical activity screening of camptothecin and its analogshas been demonstrated in several models including gynecologic tumors. Inaddition, irinotecan is a prodrug and needs to be metabolized for optimalactivity. A carboxylesterase catalyzes the conversion of irinotecan to itsactive metabolite SN-38 (7-ethyl-10-hydroxycamptothecin). Using a subrenalcapsule assay, irinotecan showed growth-suppressive effects of greater than 50%in two cervical cell lines.
Camptothecin analogs also augmented the activity of cisplatin, fluorouracil(5-FU), and etoposide in HST-1, a human squamous cell carcinoma cell line.[8-11]This may result from inhibition of the removal of cisplatin DNA adducts.These compounds appear to have radiosensitization properties in small-cell andadenocarcinoma lung cancer cell lines, which has also been demonstrated inpatients. The addition of recombinant tumor necrosis factor and irinotecanto several gynecologic cancer cell lines also demonstrated synergisticeffects.
Therapy for cervical cancer is chosen according to the clinical stage. Mostpatients with early-stage disease (IA, IB1) are cured by surgery orradiotherapy; chemotherapy has no role in this setting. For patients withhigher-stage disease (IB2 to IVA) or positive lymph nodes, chemoradiation is thetreatment of choice. Irinotecan has not been studied in combination withradiotherapy for the treatment of cervical cancer. In animal studies, however,the combination is synergistic.
Experimental modalities for the primary treatment of cervical cancer stagesIB to IVA include neoadjuvant chemotherapy followed by radical surgery.Sugiyama et al tested the combination of cisplatin (60 mg/m² on day 1) andirinotecan (60 mg/m² on days 1, 8, and 15) administered prior to surgery to 23patients with stage IB2 to IIIB cervical cancer. The patients werechemotherapy-naive and had a median age of 59 years. Eighty-seven percent ofpatients had squamous cell histology. The overall response rate was 78%, with 3complete remissions, 15 partial remissions, 4 stabilizations, and 1 progressionof disease. Median survival has not yet been reached.
In contrast to the first-line setting, chemotherapy is used to treatrecurrent or metastatic cervical cancer. Single-agent chemotherapy yieldssurvival benefits similar to that of chemotherapy combination regimens;single-agent treatment is preferred because it is associated with fewer sideeffects. Response rates to single agents vary from 15% to 30% and completeresponses are rare. Cisplatin and carboplatin (Paraplatin) are considered themost active single drugs. Patients with renal failure or poor performance statusrarely benefit from chemotherapy. Combination chemotherapy has been tested innumerous trials. While high response rates have been documented even in heavilytreated patients, response durations are short and survival is not improved overthat achieved with single-agent treatment. Furthermore, results from randomizedtrials comparing single-agent and combination therapy demonstrated nosignificant benefits for the combination.
Irinotecan is the only active agent in platinum-refractory disease. Thisagent has been tested as a single agent in cervical cancer patients refractoryto platinum-based therapy in five trials (Table1). The first phase II trial inthe United States used a schedule of 125 mg/m²/wk for 4 weeks followed by a2-week rest. A total of 42 patients with a median age of 44 years (range: 24-59years) were treated for a median of 2 cycles (range: 1-14 cycles). Allpatients had failed previous chemotherapy. The response rate was 21% with amedian time to response of 6 weeks and a response duration of 12 weeks. Themajor dose-limiting side effects were nausea and vomiting (45%), diarrhea (24%),and myelosuppression (36%). Myelosuppression did not decrease when theirinotecan dose was reduced, whereas gastrointestinal side effects did. Theinvestigators concluded that irinotecan had significant clinical activity andwarranted further investigation, although hematologic and gastrointestinal sideeffects were problematic.
The Gynecologic Oncology Group (GOG) conducted another trial of single-agentirinotecan in 54 patients with recurrent or refractory disease. Most patientshad received previous radiotherapy and 12 had also received chemotherapy. Of 45evaluable patients for response (49 for toxicity), 6 (13%) responded, including1 with a complete response. Grade 3/4 gastrointestinal toxicity occurred in 19(39%) patients. The authors concluded that the drug had modest activity andmoderate toxicity, and should be combined with cisplatin for future study.
In one study of irinotecan in patients with recurrent cervical cancer, noresponse was observed. However, a few patients had subjective improvement andthe authors conclude that further exploration of this drug was warranted.
The European Organization for Research and Treatment of Cancer (EORTC) hasconducted a trial of irinotecan as primary chemotherapy in cervical cancer.Patients were stratified according to whether measurable disease was presentoutside (group A) or within (group B) the previously radiated area. Irinotecanat 350 mg/m² was administered every 3 weeks. Responses occurred in 5 of 21 (24%)group A patients and in none of the 13 group B patients, for an overall responserate of 15%. The duration of response was 6+ months. However, two patients diedfrom toxic effects related to myelosuppression, diarrhea, or dehydration. Theauthors recommended further studies to define better the gastrointestinal sideeffects.
The Japanese have had extensive experience with irinotecan in gynecologiccancers. In one study of 24 patients who received 100 mg/m² weekly for fourdoses, 5 (21%) responded. Among another 31 patients who received 150 mg/m² every2 weeks for three courses, 8 (26%) responded. It is notable that the majority ofpatients in both groups had received previous radiotherapy and chemotherapy.Myelosuppression and gastrointestinal side effects were significant andtreatment-related deaths occurred. No recommendation was made regarding furtherstudy.[26,27]
Irinotecan has not been extensively studied in combination with other agentsin the treatment of cervical cancer. Sugiyama et al studied irinotecan given ondays 1, 8, and 15, combined with cisplatin administered on day 1 only. Cycleswere repeated every 29 days. The recommended doses were cisplatin at 60 mg/m²and irinotecan at 60 mg/m². Of 29 patients treated, 17 (59%) had majorresponses. There is also potential for this combination to be applied in theneoadjuvant and adjuvant settings.
The topoisomerase I inhibitors have not been extensively studied in somegynecologic cancers. Single-agent activity is definite but modest with all ofthe analogs. Most investigators recommend studying the combination of irinotecanand cisplatin, and such studies are underway. Laboratory data indicatepotentially interesting interactions of irinotecan with radiotherapy andcytokines. Such findings need further refinement within the conduct ofcorrelative clinical studies.
1. Liu LF, Desai SD, Li TK, et al: Mechanism of action of camptothecin. AnnNY Acad Sci 922:1-10, 2000.
2. Covey JM, Jaxel C, Kohn KW, et al: Protein-linked DNA strand breaksinduced in mammalian cells by camptothecin, an inhibitor of topoisomerase I.Cancer Res 49:5016-5022, 1989.
3. Jaxel C, Kohn KW, Wani MC, et al: Structure-activity study of the actionsof camptothecin derivatives on mammalian topoisomerase I: Evidence for aspecific receptor site and a relation to antitumor activity. Cancer Res49:1465-1469, 1989.
4. Arbuck SG, Takimoto CH: An overview of topoisomerase I-targeting agents.Semin Hematol 35:3-12, 1998.
5. Gabr A, Kuin A, Aalders M, et al: Cellular pharmacokinetics andcytotoxicity of camptothecin and topotecan at normal and acidic pH. Cancer Res57:4811-4816, 1997.
6. Kawato Y, Aonuma M, Hirota Y, et al: Intracellular roles of SN-38, ametabolite of the camptothecin derivative CPT-11, in the antitumor effect ofCPT-11. Cancer Res 51:4187-4191, 1991.
7. Wang Y, Inoue K, Shibata H, et al: Preclinical evaluation of a newcamptothecin derivative, CPT-11, on the subrenal capsule assay. Gan To KagakuRyoho 14:1264-1267, 1987.
8. Fukuda M, Nishio K, Ogasawara H, et al: Synergistic effects of cisplatinin combination with topoisomerase I inhibitors, nb506, irinotecan, SN38, notwith topoisomerase II inhibitors in vitro. Proc Am Assoc Cancer Res 36:A1779,1995.
9. Takiyama I, Terashima M, Ikeda K, et al: Remarkable synergisticinteraction between camptothecin analogs and cisplatin against human esophagealcancer cell lines. Proc Am Assoc Cancer Res 38:A101, 1997.
10. 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 JCancer 62:70-75, 1995.
11. Tsunoda T, Tanimura H, Hotta T, et al: In vitro augmentation of antitumoreffect in combination with CPT-11 and CDDP for human colorectal cancer. J SurgOncol 73:6-11, 2000.
12. 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.
13. Yokoyama A, Kurita Y, Saijo N, et al: Dose-finding study of irinotecanand cisplatin plus concurrent radiotherapy for unresectable stage IIInon-small-cell lung cancer [see comments]. Br J Cancer 78:257-262, 1998.
14. Mori H, Sawairi M, Itoh N, et al: Augmentation of antiproliferativeactivity of CPT-11, a new derivative of camptothecin, by tumor necrosis factoragainst proliferation of gynecologic tumor cell lines. Anti-Cancer Drugs2:469-474, 1991.
15. Cannistra SA, Niloff JM:. Cancer of the uterine cervix. N Engl J Med334:1030-1038, 1996.
16. Eifel P, Berek J, Thigpen J: Cancer of the cervix, vagina and vulva, inDeVita V, Hellman S, Rosenberg S (eds): Cancer: Principles and Practice ofOncology, 5th ed, p 1547. Philadelphia, Lippincott, 2001.
17. Greven K, Petereit D, Vermorken JB, et al: Current developments in thetreatment of newly diagnosed cervical cancer. Hematol Oncol Clin North Am13:275-303, 1999.
18. Sugiyama T, Nishida T, Kumagai S, et al. Combination therapy withirinotecan and cisplatin as neoadjuvant chemotherapy in locally advancedcervical cancer. Br J Cancer 81:95-98, 1999.
19. Nguyen HN, Nordqvist SR. Chemotherapy of advanced and recurrent cervicalcarcinoma. Semin Surg Oncol 16:247-250, 1999.
20. Omura GA, Blessing JA, Vaccarello L, et al: Randomized trial of cisplatinversus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advancedsquamous carcinoma of the cervix: A Gynecologic Oncology Group study. J ClinOncol 15:165-171, 1997.
21. Kavanagh JJ, Verschraegen CF, Kudelka AP: Irinotecan in cervical cancer.Oncology 12:94-98, 1998.
22. Verschraegen CF, Levy T, Kudelka AP, et al: Phase II study of irinotecanin prior chemotherapy-treated squamous cell carcinoma of the cervix. J ClinOncol 15:625-631, 1997.
23. Look KY, Blessing JA, Levenback C, et al: A phase II trial of CPT-11 inrecurrent squamous carcinoma of the cervix: A Gynecologic Oncology Group study.Gynecol Oncol 70:334-338, 1998.
24. Irvin WP, Price FV, Bailey H, et al: A phase II study of irinotecan(CPT-11) in patients with advanced squamous cell carcinoma of the cervix. Cancer82:328-333, 1998.
25. Lhomme C, Fumoleau P, Fargeot P, et al: Results of a EuropeanOrganization for Research and Treatment of Cancer/Early Clinical Studies Groupphase II trial of first-line irinotecan in patients with advanced or recurrentsquamous cell carcinoma of the cervix. J Clin Oncol 17:3136-3142, 1999.
26. Takeuchi S, Dobashi K, Fujimoto S, et al: A late phase II study of CPT-11on uterine cervical cancer and ovarian cancer. Research groups of CPT-11 ingynecologic cancers. Gan To Kagaku Ryoho 18:1681-1689, 1991.
27. Takeuchi S, Takamizawa H, Takeda Y, et al: An early phase II study ofCPT-11 in gynecologic cancers. Research group of CPT-11 in gynecologic cancers.Gan To Kagaku Ryoho 18:579-584, 1991.
28. Sugiyama T, Yakushiji M, Noda K, et al: Phase II study of irinotecan andcisplatin as first-line chemotherapy in advanced or recurrent cervical cancer.Oncology 58:31-37, 2000.
29. Sugiyama T, Hasuo Y, Nishida T, et al: Impact on survival followingsuccessful neoadjuvant chemotherapy and radical surgery for stage IIb bulky andstage IIIb cervical cancer. Gynecol Oncol 81:330-331, 2001.