Camptothecin and Taxane Regimens for Small-Cell Lung Cancer

ABSTRACT: For more than 2 decades, combination chemotherapy has beenthe standard treatment for patients with small-cell lung cancer. Despite highinitial response rates in both extensive- and limited-stage disease, long-termsurvival rates are only 10% to 20%. Camptothecins and taxanes are newer classesof agents that have shown significant activity against small-cell lung cancer.Their incorporation into chemotherapy regimens for small-cell lung cancer isbeing actively studied. In one randomized multicenter study, patients withadvanced small-cell lung cancer treated with irinotecan (CPT-11, Camptosar) andcisplatin had a better survival time than patients receiving standard therapy.The combination of taxanes and irinotecan holds promise as an active regimenthat may be tolerated better than cisplatin and irinotecan. [ONCOLOGY 16(Suppl9):33-38, 2002]

The Centers for Disease Control and Prevention recently reportedthat the annual mortality for lung cancer in the United States is 154,000.[1]Small-cell lung cancer accounts for approximately 15% of these tumors. Over thepast 2 decades, combination chemotherapy has become the standard of care forpatients who present with extensive disease. Regimens such as EP (etoposide,cisplatin [Platinol]), CAV (cyclophosphamide [Cytoxan, Neosar], doxorubicin [Adriamycin],vincristine), and EC (etoposide, carboplatin [Paraplatin]) can produce responserates as high as 80%. Nevertheless, for patients with extensive-stage disease,the median survival is just 7 to 11 months and few patients are alive 2 yearsfrom diagnosis. Even in limited-stage disease, combined modality treatment withconcurrent chemotherapy and radiation produces long-term survival in only 15% ofpatients.

As a result, evaluation of newer agents in treatment ofsmall-cell lung cancer is of critical importance. Newer agents that are activein small-cell lung cancer include irinotecan (CPT-11, Camptosar), docetaxel (Taxotere),gemcitabine (Gemzar), ifosfamide (Ifex), paclitaxel, topotecan (Hycamtin), andvinorelbine (Navelbine).[2] In this article, we will focus on progress in thedevelopment of camptothecin/taxane combinations in the management of small-celllung cancer.

Role of Camptothecin Derivatives inSmall-Cell Lung Cancer

The mechanism of action of camptothecin analogs involves theirinteraction with topoisomerase I. As a result, the DNA/topoisomerase complex isbound and normal DNA replication is disrupted, leading to double-stranded DNAbreaks and cell death. Semisynthetic compounds in this class include topotecanand irinotecan.

Irinotecan has shown activity against a broad range of animaland human malignancies, including lung cancer. In chemotherapy-naive small-celllung cancer patients, Negoro et al reported a 50% response rate to single-agentirinotecan in a small series.[3] In previously treated small-cell lung cancerpatients, response rates of 16% to 47% have been reported.[4] More recently, aJapan Clinical Oncology Group phase III trial of 152 extensive-stage small-celllung cancer patients showed superiority of irinotecan/cisplatin over etoposide/cisplatinin terms of median survival (411 vs 282 days, P = .0021), overall response rate(83% vs 68%), and 2-year survival rate (19% vs 7%).[5] Two North American phaseIII trials are under way to further define the role of irinotecan/cisplatincombinations in small-cell lung cancer.

Topotecan is the other approved semisynthetic camptothecin.Schiller et al treated 48 newly diagnosed extensive-stage patients withtopotecan at 2 mg/m²/d for 5 days every 3 weeks. The response rate was 40% andmedian survival was 10 months.[6] Pooled data of 168 patients with sensitiverelapse (defined as relapse occurring more than 3 months after previouschemotherapy) showed that 18% responded to topotecan with a median survival of30 weeks and a 1-year survival rate of 21%.[7] A randomized trial comparingtopotecan with CAV in patients with sensitive relapse demonstrated comparableresponse rates and survival times for the two regimens. In that study, topotecanwas more effective in controlling disease-related symptoms.[8] In a recentEastern Cooperative Oncology Group (ECOG) study of 223 patients withextensive-stage small-cell lung cancer, topotecan given after four cycles of EPimproved progression-free survival by 1.3 months when compared to observation.However, overall survival and quality of life were not statistically differentin the two arms.[9]

Role of Taxanes in Small-Cell Lung Cancer

The taxanes promote microtubular assembly but prevent theirdisassembly, thus interfering with normal tubulin polymerization and celldivision. Both the Pacific yew-derived paclitaxel and the semisyntheticcompound docetaxel show promise in the treatment of small-cell lung cancer.

The ECOG performed a phase II study of single-agent paclitaxelin previously untreated extensive-stage small-cell lung cancer patients.Paclitaxel at 250 mg/m² infused over 24 hours produced a response rate of 34%,but 56% of patients had grade 4 leukopenia.[10] The North Central CancerTreatment Group used a similar paclitaxel schedule with the addition ofgranulocyte colony stimulating factor (G-CSF [Neupogen]) support and reported a53% response rate and a reduction to 14% in the rate of grade 4 leukopenia.[11]In a small trial involving pretreated patients with early relapses, paclitaxelwas associated with a 29% response rate.[12] When paclitaxel was combined withcisplatin, Nair et al reported impressive response rates of 71% to 89% inextensive-stage small-cell lung cancer patients.[13]

Docetaxel has also been studied for the treatment of small-celllung cancer. In a phase II trial of chemotherapy-naive small-cell lung cancerpatients conducted by the Southwest Oncology Group (SWOG), docetaxel at 100mg/m² produced a response rate of 25% and a median survival of 9 months.[14] TheEuropean Organization for Research and Treatment of Cancer (EORTC) reported aresponse rate of 25% with single-agent docetaxel at a dose of 60 mg/m² inpreviously treated patients.[15]

Combinations of Docetaxel and Irinotecan

In animal and human cell lines, the combination of taxanes andcamptothecins can be additive or synergistic, but results have been conflicting.Chou et al showed synergism between paclitaxel and topotecan in humanteratocarcinoma cell line,[16] but Kaufman et al actually showed antagonism whenthis combination was used in a human lung cancer cell line.[17] In vitro studiesof the combination of docetaxel and irinotecan showed notable activity in manymodels. There was the suggestion that their activity in combination may bedependent on dosing, sequencing, and cell type.

Couteau et al showed in a phase I study that when docetaxel wasgiven prior to irinotecan, no relevant drug interaction was detected and thepharmacokinetics were consistent with the behavior of each drug givenindividually.[18] Takeda et al gave the irinotecan prior to docetaxel andreported a mild increase in docetaxel clearance.[19] The bulk of evidencesuggests no clinically significant interaction between these two drugs withrespect to pharmacokinetics.[18-21]

In terms of dosing schedule, initial studies administered themedications on an every 3-week cycle. However, high rates of neutropenia andlate diarrhea were reported in such studies (see Table1). Couteau et alreported 85% with grade 4 leukopenia lasting a median of 5 days (and 22.5% withfebrile neutropenia).[18] Adjei et al reported 94% with grade 3/4 leukopenia and17% with febrile neutropenia.[22] Masuda et al reported grade 3 or 4 neutropeniain only 19% with only 6% having febrile neutropenia, but this study employedlower dose intensity. Most phase II trials of docetaxel/irinotecan also reportneutropenia as the most frequent toxicity.

When given with equivalent dose intensity, docetaxel on a weeklyschedule has a lower incidence of neutropenia compared to a 3-week schedule.Additionally, more frequent administration allows the option of withholdingdoses when neutrophil counts are borderline. Additionally, irinotecan displays amore favorable toxicity profile when given on a weekly basis. Major toxicitiesof irinotecan when given on an every-3-week schedule tend to be granulocytopenia,febrile neutropenia, and/or late diarrhea. When given on a weekly schedule,irinotecan has lower incidences of severe neutropenia and diarrhea. Thus givingdocetaxel/irinotecan combinations on a weekly schedule should be considered as ameans of increasing the safety of administration.

At the Yale Cancer Center, we have conducted a phase I studyevaluating weekly docetaxel/irinotecan. We originally delivered the medicationsweekly for 4 weeks on an every-6-week cycle, but due to frequent treatmentdelays at day 21 due to neutropenia, we amended the dosing guidelines. We foundthat the combination was better tolerated when docetaxel at 35 mg/m² andirinotecan at 60 mg/m² were given on days 1 and 8 of an every-3-week cycle. In44 patients studied, preliminary data show grade 3 or 4 neutropenia in 25% andonly 1 patient had dose-limiting febrile neutropenia (2.3%). Diarrhea became thedose-limiting toxicity, but first-cycle grade 3 or 4 diarrhea was only presentin 11.3%. Font et al, Vernejoux et al, and Seneviratne et al also reportedreduced complications of neutropenia in weekly docetaxel/irinotecan regimens andvarious gastrointestinal toxicities then became dose-limitingtoxicities.[21,23,24] Thus, weekly combinations appear to allow saferadministration of docetaxel/irinotecan.

Phase II studies of docetaxel/irinotecan have been reported atleast in abstract form for non-small-cell lung cancer, ovarian cancer, gastriccancer, pancreatic cancer, and mesothelioma.[25-29] Unfortunately, progress inthe evaluation of small-cell lung cancer has been slower. Possible reasonsinclude lower incidence of small-cell lung cancer patients compared to non-small-celllung cancer, and preferential enrollment in standard regimen or other clinicaltrials (such as phase III studies of cisplatin/irinotecan). Nevertheless,studies of this promising combination should be pursued for patients withextensive disease.

Combinations of Paclitaxel and Irinotecan

Several phase I studies have also been performed evaluating thecombination of paclitaxel and irinotecan (see Table2).[30-34] Most studies haveachieved similar dose intensity and use some variant of a weekly dosingschedule. The dose-limiting toxicity is commonly related to severe neutropenia.Interestingly, an early report by DeMario et al of paclitaxel dosed at 80 mg/m²followed by irinotecan at 30 mg/m² given weekly for 3 weeks on an every-4-weekcycle was complicated by prolonged grade 4 lymphopenia in 4 of 4 patients,lasting a mean duration of 12.8 days.[30] Two patients (50%) developed fungalsepsis in the first cycle and their protocol required paclitaxel dose reduction.Two Japanese pharmacokinetic analyses of phase I trials show that paclitaxelincreases the AUC (area under the concentration-time curve) of irinotecan andits metabolites (such as
SN-38).[31,32]

Rushing et al performed a phase I/II trial evaluating weeklypaclitaxel/irinotecan specifically in treating small-cell lung cancer.[33] Theywere able to escalate doses to a recommended dose of paclitaxel at 50 mg/m² andirinotecan at 60 mg/m² weekly for 3 weeks on an every 4-week cycle. However, outof 19 enrolled patients, grade 4 toxicities included sudden demise due to acutepulmonary embolus, septic shock in the setting of neutropenia, thrombocytopenia,and dehydration without diarrhea or vomiting. Out of seven patients evaluablefor response, three (43%) had complete response and five had at least partialresponse (71%). A phase II study was initiated and results are pending; however,it was designed to administer paclitaxel/irinotecan immediately after inductiontherapy with etoposide/platinum, so it will be difficult to ascertain thecontribution of the paclitaxel/irinotecan portion to the observed outcomes.

Other Combinations of Taxanes and Camptothecins

Several studies have investigated docetaxel and topotecan in avariety of solid tumors.[35-37] Pharmacokinetic analyses have shown thattopotecan significantly reduced docetaxel clearance and led to increasedneutropenia.[38] Glisson et al performed a phase I study which resulted in arecommendable dose of docetaxel 75 mg/m² on day 1 and topotecan 1.4 mg/m² ondays 1 to 3 on a 21-day cycle with G-CSF support. They found one partialresponse in a small-cell lung cancer patient and plan a phase II study of theirregimen.[37]

The two-drug combination of paclitaxel and topotecan has beenstudied since the mid-1990s. Lilenbaum et al reported that G-CSF allowed themaximum tolerated dose of paclitaxel to be increased from 80 to 230 mg/m² whengiven with a fixed dose of topotecan of 1.0 mg/m² for 5 days every 21 days.[39]In a phase I trial of 17 untreated small-cell lung cancer patients, Schnell etal recommended a dose of paclitaxel at 135 mg/m² on day 1 along with topotecanat 1.5 mg/m² on days 1 to 3 without G-CSF support.[40] The Cancer and LeukemiaGroup B (CALGB) enrolled 36 extensive-stage small-cell lung cancer patients in aphase II study of paclitaxel at 175 mg/m² on day 1, topotecan at 1 mg/m² on days1 to 5, and G-CSF. They reported a median survival of 9.4 months and a 1-yearsurvival of 26.5%. These results were similar to those achieved with thestandard regimens.[41]

One other study evaluated a sequential dose-dense schedule inthis combination. Felip et al gave paclitaxel at 250 mg/m² on day 1 every 14days for three cycles, followed by topotecan at 2.5 mg/m² on days 1 to 5 on anevery-14-day cycle for three additional cycles. G-CSF was administered with eachcycle. They reported an overall response rate of 73% (16 partial responses, 3complete responses; 26 evaluable patients) and median survival of 10.5 months.In terms of toxicity, febrile neutropenia occurred in 19% (one toxic death[5%]), and only during the topotecan portion of therapy.[42]

Paclitaxel combined with topotecan and carboplatin in athree-drug regimen (PCT) has also been studied in the management of small-celllung cancer. The combination of the three has overlapping toxicity in terms ofmyelosuppression that has limited the dosages of each drug that can be given. Arecent phase II study by Hainsworth et al used the PCT combination as first-linetherapy for 46 patients with limited-stage small-cell lung cancer and 59patients with extensive-stage small-cell lung cancer.[43] They gave paclitaxelat 135 mg/m² on day 1, carboplatin at an AUC of 5 on day 1, and topotecan at0.75 mg/m² on days 1 to 3 of a 21-day cycle. Limited-stage patients alsoreceived concurrent lung irradiation (to 45 Gy). Those with partial responses orstable disease after four cycles (82%) were then treated with an oral etoposideregimen (50 mg alternating with 100 mg/d for 10 days on a 21-day cycle) forthree additional courses.

They reported impressive response rates of 88% forextensive-stage and 93% for limited-stage patients. The median survival forextensive-stage small-cell lung cancer patients was 8.3 months and forlimited-stage patients it was 17.2 months. The protocol was tolerated fairlywell by patients with good ECOG performance status (0/1), with the main toxicitybeing neutropenia (grade 3/4 in 45%) and thrombocytopenia (grade 3/4 in 20%).However, in the cohort of poorer performance status patients (ECOG 2), excessivetoxicity was noted, with 5 of 12 patients (43%) suffering treatment-relateddeaths. The authors concluded that this PCT regimen did not appear to offerimprovement in efficacy over standard EP regimens, but had greater morbidity.

The SWOG 9914 study also investigated the PCT combination asfront-line therapy for extensive-stage small-cell lung cancer.[44] Theyadministered paclitaxel at 175 mg/m² on day 4, carboplatin at an AUC of 5 on day4, and topotecan at 1.0 mg/m² on days 1 to 4 every 21 days for six cycles. Theyenrolled 82 patients with ECOG performance status of 0 to 2, and have reported amedian time to progression of 7 months, median survival of 12 months, and 1-yearsurvival rate of 50%. Toxic deaths occurred in 7% of evaluable patients andcommon grade 3/4 toxicities included neutropenia (48%), thrombocytopenia (44%),anemia (15%), and nausea (12%). Given its promising survival data and acceptabletoxicity profile, phase III trials are warranted. However, concerns about thehematologic morbidity of these regimens persist. One possibility in managing therestrictions of neutropenia is peripheral blood stem-cell support (PBSC).Schilder et al have explored higher-dose PCT with PBSC in the phase I setting,and shown an acceptable toxicity profile.[45] A phase II trial evaluating thisregimen as front-line therapy for small-cell lung cancer is under way.

Conclusion

The current management of small-cell lung cancer remainsfrustrating. For many years clinical research failed to demonstrate a convincingadvance beyond the results obtained with four to six cycles of cisplatin andetoposide. The recent Japanese Clinical Oncology Group study, if confirmed,provides hope that cytotoxic chemotherapy can be designed that will improvesurvival in this highly chemotherapy-sensitive disease. Taxanes andcamptothecins in combination have shown promise in early trials and should befurther studied in the future.

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