Cisplatin and Thoracic Irradiation in Patients with Limited Small Cell Lung Cancer1

Vol. 9, 2085–2091, June 2003 Clinical Cancer Research 2085

A Phase I Study of Topotecan/Paclitaxel Alternating with Etoposide/ Cisplatin and Thoracic Irradiation in Patients with Limited Small Cell Lung Cancer1

Charles Lu, Ritsuko Komaki, Jin Soo Lee, and defined after accrual of 18 patients to four dose levels. Dong M. Shin, J. Lynn Palmer, Two of three patients developed grade 3 nonhematological Brenda J. Coldman, Katherine M. Pisters, toxicity (pneumonia) at the fourth dose level. Thus, the third dose level (topotecan 1.2 mg/m2, paclitaxel 160 mg/m2) was Jonathan M. Kurie, Frank V. Fossella, and defined as the MTD recommended for Phase II studies. One 2 Bonnie S. Glisson subject died suddenly on day 2 of cycle 1 without autopsy Departments of Thoracic/Head and Neck Medical Oncology [C. L., confirmation of the etiology. A second subject died during B. J. C., K. M. P., J. M. K., F. V. F., B. S. G.], Radiation Oncology cycle 3 due to thrombocytopenia, gastrointestinal bleeding, [R. K.], and Biostatistics [J. L. P.], The University of Texas M. D. and respiratory failure. Response rates after induction of Anderson Cancer Center, Houston, Texas 77030; The National Cancer Center Hospital, Kyonggi, Korea [J. S. L.]; and The topotecan and paclitaxel: 16 of 18 (88.8%) partial response, University of Pittsburgh Cancer Institute, Division of Hematology- 1 of 18 (5.5%) complete response. Response rates after Oncology, Pittsburgh, Pennsylvania 15213 [D. M. S] completion of therapy: 10 of 18 (55.5%) partial response, 7 of 18 (38.8%) complete response. Conclusions: Induction topotecan and paclitaxel before ABSTRACT chemoradiotherapy in patients with LD SCLC is feasible Purpose: Topotecan and paclitaxel are promising cyto- and results in expected toxicities. The outcome of a recently toxic drugs with novel mechanisms of action relative to other closed Cancer and Leukemia Group B Phase II study of chemotherapies used in the treatment of small cell lung similar design (CLB-39808) should help determine whether cancer (SCLC). In an effort to integrate paclitaxel and or not this approach warrants testing in a randomized topotecan into the treatment of limited disease (LD) SCLC, setting. we conducted a Phase I study of these agents administered as initial induction therapy. INTRODUCTION Experimental Design: Escalating doses of topotecan 2 2 In the United States, ϳ15–20% of lung cancers are small (0.8–1.4 mg/m d1–5) and paclitaxel (110–175 mg/m d1) cell carcinomas (1). One-third of patients with SCLC3 were administered i.v. every 21 days for two cycles to deter- have LD mine the maximum tolerated dose (MTD) in patients with (2), generally defined as a tumor that is confined to one hemith- LD SCLC. This was followed by two cycles of etoposide (120 orax and its surrounding regional lymph nodes (3). Meta-anal- 2 2 yses have demonstrated that a combination of chemotherapy and mg/m d1–3) and cisplatin (60 mg/m d1) with thoracic chest radiotherapy confers a survival advantage when compared radiotherapy. The first 5 subjects received 1.8 Gy once with chemotherapy alone (4, 5), and concurrent chemoradiation daily ؋ 25 fractions, while subsequent subjects received 1.5 in which radiotherapy is begun early in the induction phase of Gy twice daily ؋ 30 fractions. Two additional cycles of chemotherapy is the current standard of care for LD SCLC in chemotherapy (topotecan and paclitaxel, followed by etopo- the United States. The combination of cisplatin and etoposide side and cisplatin) were given. has become the favored first-line chemotherapy regimen for LD Results: Common toxicities included grade >3 neutro- SCLC (6). This combination regimen usually causes managea- penia in 67% of courses of topotecan and paclitaxel and ble myelosuppression and nonhematological toxicity, and when grade >2 esophagitis in 71% of patients. The MTD was it is administered with full-dose chest irradiation, it results in based on toxicity during the first two cycles of chemotherapy less toxicity than do other chemotherapy agents (7, 8). Despite receiving aggressive chemoradiotherapy delivered with curative intent, the majority of patients with LD SCLC dies secondary to high rates of both local and distant relapse, including brain Received 6/21/02; revised 10/24/02; accepted 1/23/03. metastases (9). To improve current therapies for this disease, The costs of publication of this article were defrayed in part by the new, effective systemic agents and refinements to current radio- payment of page charges. This article must therefore be hereby marked therapy techniques are clearly needed. advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by a grant from GlaxoSmithKline Oncology, and in part by Grant K12 CA088084 from the United States National Cancer Institute, Bethesda, MD. 2 To whom requests for reprints should be addressed, at The University 3 The abbreviations used are: SCLC, small cell lung cancer; LD, limited of Texas M. D. Anderson Cancer Center, Department of Thoracic/Head disease; ED, extensive disease; CALGB, Cancer and Leukemia Group and Neck Medical Oncology, 1515 Holcombe Boulevard, Box 432, B; MTD, maximum tolerated dose; CI, confidence interval; CR, com- Houston, TX 77030-4009. Phone: (713) 792-6363; Fax: (713) 796- plete response; DLT, dose-limiting toxicity; PR, partial response; PCI, 8655. prophylactic cranial irradiation.

Topotecan and paclitaxel are promising new cytotoxic treatment of LD SCLC, we conducted a Phase I study of these drugs with novel mechanisms of action relative to other chemo- agents administered as initial induction therapy followed by therapies used in the treatment of SCLC. Topotecan is a water- chest radiotherapy with concurrent cisplatin and etoposide, in soluble analogue of camptothecin, a plant alkaloid that has been addition to two additional cycles of chemotherapy. The main shown to inhibit the nuclear enzyme topoisomerase I, resulting objectives of this trial were to determine the MTD, toxicity in single-strand DNA breaks and cell death (10). A Phase II profile, and response rate of paclitaxel and topotecan when study in chemotherapy-naõ¬ve patients with ED SCLC demon- given as induction therapy in patients with LD SCLC. Other strated a 39% response rate (11), and a European Phase II trial secondary end points included the response rate to the entire in patients who had been treated previously with chemotherapy treatment regimen, duration of response, rate of progression-free demonstrated a response rate of 38% in chemotherapy-sensitive survival, and rate of overall survival. disease and 6% in refractory disease (12). Another Phase II study in patients with refractory disease reported an 11% response rate (13). A pivotal Phase III study in patients with PATIENTS AND METHODS recurrent disease compared single-agent topotecan to the com- Patients. Eligibility criteria included LD SCLC as doc- bination of cyclophosphamide, doxorubicin, and vincristine, umented by chest radiography; computed tomography of the yielding response rates of 24 and 18% (P ϭ 0.285) in the chest, brain, and abdomen; radionuclide bone scan; bone mar- experimental and control arms, respectively (14). In 1998, to- row aspiration and biopsy; and physical examination. Patients potecan received Food and Drug Administration approval for with N3 disease as manifested by ipsilateral supraclavicular or the treatment of SCLC after failure of first-line chemotherapy. contralateral mediastinal lymphadenopathy were eligible. Pa- Paclitaxel is another promising cytotoxic agent with a tients with contralateral hilar or contralateral supraclavicular different mechanism of action. Paclitaxel, a plant-derived prod- lymphadenopathy were excluded to limit the size of the irradi- uct, is a diterpene that exerts cytotoxic effects by promoting ation field and pulmonary toxicity. Patients with a pleural effu- microtubule assembly, which ultimately leads to disruption of sion visible on chest X-ray were excluded. Adequate organ mitosis and cell death (15). Two Phase II studies in chemother- function was required, including an absolute granulocyte apy-naõ¬ve ED SCLC reported encouraging single-agent re- count Ն 1,500/␮l, platelets Ն 150,000/␮l, total bilirubin Յ 1.5 sponse rates of 34% (16) and 53% (17). A Phase II trial of mg/dl, and serum creatinine Յ 1.5 mg/dl or creatinine clear- single-agent paclitaxel in disease that fails to respond to or ance Ն 40 ml/min. A performance status of Յ2 on the Zubrod relapses shortly after treatment with cyclophosphamide, doxo- scale, no previous chemotherapy or radiotherapy, no recent rubicin, and etoposide therapy yielded an impressive 29% re- history of other malignancies (excluding nonmelanoma skin sponse rate (18). Recent studies examining the effectiveness of cancer or carcinoma in situ of the uterine cervix), and written paclitaxel-based chemotherapy combinations in SCLC have informed consent were also required. The treating radiation demonstrated high response rates (19, 20). The preliminary oncologist was required to certify that the tumor could be results of a large randomized trial (CALGB 9732) comparing encompassed by irradiation fields that would not “significantly” the use of cisplatin and etoposide with or without paclitaxel in compromise pulmonary function. The institutional review board untreated patients with ED SCLC failed to demonstrate a sur- at The University of Texas M. D. Anderson Cancer Center vival advantage, however (21). approved the protocol. All subjects were accrued and treated at During the design phase of this study, other investigators The University of Texas M. D. Anderson Cancer Center. were examining the combination of paclitaxel and topotecan in Therapy. This trial was a Phase I study of two cycles ED SCLC. A CALGB Phase I study in patients with advanced (cycles 1 and 2) of topotecan and paclitaxel administered as cancer yielded recommended Phase II doses, given in cycles initial induction therapy in patients with LD SCLC. Patients every 21 days, of 230 mg/m2 paclitaxel on day 1 and 1 mg/m2 received two subsequent cycles (cycles 3 and 4) of cisplatin and topotecan on days 1Ð5 with filgrastim support and 80 mg/m2 etoposide with concurrent thoracic radiotherapy, which was then paclitaxel on day 1 and 1 mg/m2 topotecan on days 1Ð5 without followed by an additional cycle (cycle 5) of topotecan and filgrastim (22). A subsequent CALGB Phase II study in ED paclitaxel and a final cycle (cycle 6) of cisplatin and etoposide. SCLC used this dosing schedule with filgrastim, resulting in an Chemotherapy cycles were administered every 21 days. The unexpected number of treatment-related deaths (23). Patient dose levels for topotecan and paclitaxel are summarized in accrual was suspended and later restarted with a reduced dose of Table 1. Paclitaxel was administered i.v. for 3 h on day 1 of 175 mg/m2 paclitaxel on day 1 (24). Another Phase II study in cycles 1, 2, and 5. Premedications for paclitaxel consisted of ED SCLC untreated previously studied the effectiveness of 135 20 mg of i.v. dexamethasone, 300 mg of i.v. cimetidine, and mg/m2 paclitaxel on day 5 and 1.25 mg/m2 topotecan on days 50 mg of i.v. diphenhydramine administered 30 min before 1Ð5 every 28 days with filgrastim support. The first 3 patients treatment. Topotecan was administered i.v. for 30 min on days enrolled in the study developed grade 4 myelosuppression that 1Ð5 of cycles 1, 2, and 5. The dose levels for cisplatin and led to sepsis and death in one case and resulted in a reduction of etoposide are summarized in Table 1. Etoposide was given i.v. the topotecan dose to 1 mg/m2 on days 1Ð5 for all subsequent for2hondays 1Ð3 of cycles 3, 4, and 6. Cisplatin was given i.v. patients (25). In light of these data, we reasoned that in patients on day 1 of cycles 3, 4, and 6 after administration of etoposide. untreated previously with LD SCLC, an initial dose level of 0.8 Patients received 2.5 liters of i.v. hydration on the days of mg/m2 topotecan on days 1Ð5 and 110 mg/m2 paclitaxel on day cisplatin therapy. Carboplatin area under the curve six was 1 without filgrastim would be appropriate. substituted for cisplatin in patients with a creatinine clearance In an effort to integrate paclitaxel and topotecan into the Ն40 and Յ60 ml/min. A complete blood count with differential

Table 1 Dose levels Table 2 Patient characteristics (n ϭ 18) Cycles 1, 2, and 5 Age, years Median 67 Dose level Ϫ11234 Range 42Ð73 No. of subjects 3384 Sex Topotecan (mg/m2 d1Ð5) 0.65 0.8 1.0 1.2 1.4 F6 Paclitaxel (mg/m2 over 3 h d1) 90 110 135 160 175 M12 Zubrod performance status Cycles 3, 4, and 6 118 Dose level Ϫ2 Ϫ10 Etoposide (mg/m2 d1Ð3) 80 100 120 Cisplatin (mg/m2 d1) 50 60 60 margins. Ipsilateral supraclavicular irradiation was performed for adenopathy in that region, when necessary for primary tumor coverage (primary tumor in the upper lobe with upper mediastinal node involvement), or for cases of bulky (Ͼ5 cm) pre or and platelet counts was obtained weekly and immediately before paratracheal adenopathy. Contralateral hilar or contralateral su- each cycle began. Serum chemistry assays (electrolytes, blood praclavicular treatment was not allowed. Dosage to the spinal urea nitrogen, creatinine, total bilirubin, aminotransferases, al- cord was limited to a total of 35 Gy. kaline phosphatase, and lactate dehydrogenase) were performed PCI was offered to all patients who achieved a CR after before each cycle began. Prophylactic ciprofloxacin, 500 mg completion of all therapy. Treatment consisted of 10 daily p.o. twice a day on days 6Ð15, was administered in every 2.5-Gy fractions for a total dose of 25 Gy. chemotherapy cycle. Study Design. This trial was a Phase I dose escalation Acute toxicity was scored with the National Cancer Insti- study of topotecan and paclitaxel given as initial induction tute Common Toxicity Criteria. Chemotherapy cycles were held therapy to patients with LD SCLC. The primary objective was until patients recovered an absolute granulocyte count Ն to determine the MTD in this setting and characterize the 1,200/ml and platelet count Ն 100,000/ml and the patient’s toxicity. A secondary objective was to assess response to induc- nonhematological toxicity had been reduced to grade 1 or grade tion topotecan and paclitaxel and to the entire treatment regi- Յ2 for patients with esophagitis. Patients with decreased creat- men. Patients were accrued in cohorts of three beginning at dose inine clearance received carboplatin instead of cisplatin as de- level 1 as defined in Table 1. Each cohort was followed for a scribed previously. Filgrastim was administered for the treat- minimum of 3 weeks before any additional patients were ac- ment of neutropenic fever or prolonged grade 4 neutropenia (Ͼ7 crued. DLT was defined as febrile neutropenia, grade 4 neutro- days) and was given prophylactically with subsequent cycles. penia of Ͼ7 days’ duration, grade 4 thrombocytopenia, or grade Filgrastim was not administered during thoracic radiotherapy. Ն3 nonhematological toxicity. If none of the 3 patients treated Doses of all chemotherapeutic drugs were reduced one dose at a dose level experienced DLT in the first cycle, the subse- level (Table 1) for patients with grade 4 thrombocytopenia, in quent cohort was treated at the next higher dose level. If 1 of 3 addition to prolonged grade 4 neutropenia or febrile neutrope- patients experienced DLT at a dose level, an additional 3 pa- nia, despite the use of prophylactic filgrastim. An exception was tients were entered at that dose level. If 1 of 6 patients experi- made in cycle 3, in which full doses of cisplatin and etoposide enced DLT at a dose level, the subsequent cohort was accrued were used with concurrent thoracic radiotherapy even if these at the next higher dose level. If more than one of three or more toxicities occurred during cycle 2 with topotecan and paclitaxel. than 2 of 6 patients experienced DLT, the subsequent cohort was During thoracic radiotherapy, cisplatin and etoposide (cycle 4) treated at the next lower dose level. The MTD was defined as were not given until esophagitis had been reduced to grade Յ2, the dose level that produced DLT in 2 of 6 patients or that level and one dose level reduction (Table 1) was required if grade 4 immediately below the one that produced DLT in Ͼ2of6orϾ1 esophagitis developed. Grade 3 nonhematological toxicity re- of 3 patients. quired a dose reduction of one level, and grade 4 toxicity Responses to treatment were assessed with chest radiogra- resulted in treatment discontinuation. Intrapatient dose escala- phy after each cycle of chemotherapy and with chest computed tion was permitted for chemotherapy cycles 2 and 5 (topotecan tomography after cycle 2 (to document response to topotecan and paclitaxel) in the absence of hematological toxicity greater and paclitaxel) and cycle 6 (to document final treatment re- than grade 2 and nonhematological toxicity greater than grade 1. sponse). A designation of CR or PR, no change, or progressive Thoracic radiotherapy was begun within 24 h of day 1, disease was made on the basis of standard WHO criteria (27). cycle 3, of chemotherapy (cisplatin and etoposide). The first 5 Survival time was measured from the 1st day of treatment until patients accrued received 25 daily fractions of 1.8 Gy for 5 the date of death and calculated by the Kaplan-Meier method weeks (total dose, 45 Gy). Radiotherapy was amended after (28). Progression-free survival was measured from the 1st day results from a large Phase III intergroup study demonstrated a of treatment to the date on which disease progression was survival advantage with twice daily irradiation (26). Subsequent documented. On completion of protocol therapy, patients were patients received 30 1.5-Gy fractions twice daily for 3 weeks, seen in the clinic every 3 months for 1 year and subsequently for a total dose of 45 Gy. The target volume included the every 6 months. Clinical evaluations included history, physical primary tumor plus regional hilar, mediastinal, and, in some examination, chest X-ray, and a complete blood count with cases, ipsilateral supraclavicular lymph nodes, with 1Ð2-cm differential, platelet count, and serum chemistry assays.

Table 3 Summary of hematological toxicity by dose level A. Topotecan and paclitaxel (cycles 1, 2, and 5) No. of patientsa Neutropenia Thrombocytopenia Anemia Dose level No. of courses Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 1 4/7 2/2 2/3 0/0 0/0 0/0 0/0 2 7/12 3/4 6/6 3/4 0/0 2/2 0/0 3 9/23 1/1 8/18 0/0 0/0 0/0 0/0 4 3/6 1/1 3/5 0/0 0/0 1/1 0/0 B. Cisplatin and etoposide (cycles 3, 4, and 6) No. of patientsa Neutropenia Thrombocytopenia Anemia Dose level No. of courses Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Ϫ1 3/4 1/1 1/1 0/0 0/0 0/0 0/0 0 16/40 6/7 10/12 3/3 2/2 3/3 1/1 a One patient developed grade 4 thrombocytopenia during cycle 3 (chemoradiation) associated with gastrointestinal bleeding and death.

RESULTS Table 4 Summary of Nonhematological Toxicity grades 2Ð4 Patients. Between March 1997 and May 1999, 18 pa- Toxicity Grade No. of patients/no. of courses tients were entered into this study. Their characteristics are Arthralgia 2 3/4 listed in Table 2. Their median age was 67 years, and 12 (67%) Esophagitis 2 10/15 were men. All patients had a Zubrod performance status of 1. 3 2/2 Patients were accrued at four dose levels. One patient treated at Nausea/Vomiting 2 5/7 dose level 4 died suddenly on day 2 of the first cycle; the patient 3 2/2 4 1/1 had acute dyspnea, chest pain, and, shortly thereafter, cardiac Fatigue 2 4/6 arrest. Although either a pulmonary embolism or a myocardial 3 3/5 infarction was the suspected cause of death, a postmortem 4 1/1 examination was not performed, precluding any definitive diag- Infection 2 3/7 nosis. This early death precluded any formal radiological as- 3 3/3 sessment of response to therapy. The patient was categorized as a nonresponder and included in both response and survival analyses. The remaining 17 patients received a total of 92 cycles of chemotherapy, with all 17 patients receiving at least two of courses, possibly influenced by the use of prophylactic cip- cycles and 14 patients receiving the full six cycles. rofloxacin. Grade Ն3 thrombocytopenia and anemia occurred in Determination of MTD. A determination of MTD was 8 and 6% of courses, respectively. made on the basis of the occurrence of DLT during the first two Similar hematological toxicity data for all 44 courses of cycles of topotecan and paclitaxel. Of the first 6 patients en- cisplatin and etoposide (cycles 2, 3, and 6) are summarized in rolled at dose levels 1 and 2, none developed DLT during the Table 3. Grades 3 and 4 neutropenia occurred in 18 and 30% of first two cycles. One of the 8 patients treated at dose level 3 courses, respectively, with two cases (5%) of neutropenic fever. developed DLT (febrile neutropenia). A total of 4 patients were Grade Ն3 thrombocytopenia and anemia occurred in 11 and 9% entered at dose level 4. As described previously, 1 patient of courses, respectively. One patient received chemotherapy suffered an early sudden death on day 2 of cycle 1, and an cycles 1 and 2 (topotecan and paclitaxel, dose level 2) and additional replacement subject was enrolled at the same dose subsequently developed grade 4 thrombocytopenia after cycle 3 level. Among the remaining 3 patients treated at dose level 4, 2 (cisplatin and etoposide). This patient was hospitalized with required hospitalization for nonneutropenic pneumonia at the gastrointestinal bleeding and subsequently died of respiratory end of cycle 2 or the beginning of cycle 3. Both patients failure. received thoracic radiotherapy, but further chemotherapy was The frequency of the common grades 2Ð4 nonhematologi- not feasible. Because 2 of 3 patients treated at dose level 4 cal toxicities is summarized in Table 4. Grade Ն2 esophagitis, developed DLT (grade 3 infection), dose level 3 (1.2 mg/m2 nausea/vomiting, and fatigue occurred in 71, 47, and 47% of topotecan i.v. on days 1Ð5, 160 mg/m2 paclitaxel i.v. day 1) was patients, respectively. Grade 1 sensory neuropathy was observed defined as the MTD for future Phase II testing. in 11 (65%) patients. As expected, grade 2 arthralgia was Toxicity. Dose escalation or reduction and myelosup- reported solely during cycles that included paclitaxel, and the pressive toxicity for all 48 courses of topotecan and paclitaxel majority of grade 2 or higher esophagitis occurred during con- (cycles 1, 2, and 5) are summarized in Table 3. As expected, current chemoradiotherapy. Among the12 patients who received neutropenia was the most common toxic effect, with grades 3 twice daily radiation, 2 patients developed grade 3 esophagitis, and 4 neutropenia occurring in 17 and 67% of the total courses, whereas no episodes of grade 3 esophagitis occurred among the respectively. Febrile neutropenia, however, occurred in only 2% 5 patients treated with once daily radiation. The only episode of

grade 4 nausea and vomiting occurred with the receipt of cis- used 135 mg/m2 paclitaxel (24-h infusion) on day 1 and 1 platin and etoposide. mg/m2 topotecan on days 1Ð5 every 21 days with filgrastim Response. Response was considered a secondary end support and reported a 60% response rate among 28 evalu- point of this trial. As described previously, 17 patients received able patients. Tweedy et al. (30) reported a response rate of at least two cycles of topotecan and paclitaxel, and all 18 100% in 15 patients treated with the same regimen as the subjects were included in the calculation of response rates. The patients in the study by Jacobs et al., except paclitaxel was subject who suffered an early death during cycle 1 was catego- administered as a 3-h infusion. The smallest of these studies rized as a nonresponder. Sixteen completed thoracic radiother- included 14 patients who were treated with 135 mg/m2 pa- apy, and 14 completed both radiotherapy and six cycles of clitaxel on day 5 and 1 mg/m2 topotecan on days 1Ð5 with chemotherapy. After two cycles, PR and CR rates were 88.8 and filgrastim support with a response rate of 71% (31). Although 5.5%, respectively, for an overall response rate of 94.4% (95% preliminary, these data are consistent with our findings that CI, 72.7Ð99.9%). After all six cycles, PR and CR rates were indicate that this combination regimen is highly active in the 55.5 and 38.8%, respectively, for an overall response rate of treatment of SCLC. 94.4% (95% CI, 72.7Ð99.9%). Eleven patients subsequently The MTDs of topotecan and paclitaxel as defined in this received PCI. The median period between completion of therapy study appear reasonable in the context of the standard doses of and PCI was 44 days (range: 26Ð91 days). these agents. The topotecan dose of 1.2 mg/m2 i.v. on days 1Ð5 Survival and Patterns of Recurrence. The survival rate every 21 days is 80% of the single-agent dose approved for the was not an end point in this Phase I trial, but the data were 2 calculated and reported. Six patients were alive at the time of second-line treatment of relapsed SCLC (1.5 mg/m i.v. on days analysis, with a median follow-up time of 39 months. Five of 1Ð5 every 21 days). In fact, a recent analysis of data pooled from these patients have no evidence of recurrent disease. Local and several multicenter second-line SCLC trials suggests that dose 2 distant recurrences have occurred in 5 and 8 subjects, respec- reductions to 1.25 mg/m /day after the first cycle of topotecan tively, with 2 individuals experiencing both local and distant are not associated with decreased efficacy (32). Although the 2 recurrences. Median survival time for all 18 patients was 15.1 paclitaxel dose of 160 mg/m i.v. for3his64%ofthedose used (lower 95% CI, 10.7) months with a median progression-free in the original Phase II trials documenting single-agent activity survival time of 11.5 (lower 95% CI, 8.4) months (upper 95% CI in SCLC (250 mg/m2 for 24 h; Refs. 16 and 17), lower doses of not estimable in either case because of censored values at upper paclitaxel (175Ð225 mg/m2) are commonly used in combination ranges). Two- and 4-year survival rates were 39% (95% CI ϭ chemotherapy regimens for other solid tumors, such as non- 22Ð69%) and 31% (95% CI ϭ 15Ð64%), respectively. small cell lung and head and neck cancers (33, 34). One might argue that the paclitaxel doses used in this study were not optimal and that higher doses with filgrastim support would DISCUSSION have resulted in improved outcomes. There are no randomized Paclitaxel and topotecan are representative of an increas- studies in patients with SCLC that directly address this question, ing number of recently developed cytotoxic agents with dif- although sequential Phase II trials suggest a possible dose re- ferent mechanisms of activity against SCLC. In theory, the sponse effect with paclitaxel at doses of 135 mg/m2 versus 200 incorporation of these agents into first-line chemotherapy mg/m2 when administered with carboplatin and etoposide (35). with cisplatin and etoposide may be effective against resist- Randomized trials in patients with other solid tumors, such as ant subclones and improve patient outcome. To investigate those with recurrent ovarian and head and neck cancers, how- the use of topotecan and paclitaxel in the initial treatment of ever, have not shown a dose response relationship or increased LD SCLC, we conducted this Phase I study examining the use of these agents together before treatment with standard survival benefit for higher doses of paclitaxel (36, 37). chemotherapy concurrent with thoracic irradiation. As antic- In summary, we have demonstrated the feasibility of using ipated, neutropenia was the primary toxic effect. During the topotecan and paclitaxel before chemoradiotherapy in patients first two cycles, grade 4 neutropenia developed in 13 of 17 with LD SCLC. We defined an MTD for Phase II studies and (76%) patients, although there was only 1 case of febrile observed expected hematological and nonhematological toxici- neutropenia. We found the treatment regimen to be feasible ties. By the time we had completed accrual to this study, a Phase and highly active, with a 94.4% (95% CI, 72.7Ð99.9%) II CALGB trial (CLB-39808) with a similar treatment plan for response rate after two cycles of topotecan and paclitaxel. patients with LD SCLC had opened and was accruing patients. Our data support our Phase II dose recommendation of 1.2 In this trial, patients received two cycles of topotecan and mg/m2 topotecan i.v. on days 1Ð5 and 160 mg/m2 paclitaxel paclitaxel given with growth factor support before receiving i.v. on day 1 with ciprofloxacin prophylaxis. three cycles of carboplatin and etoposide with concurrent tho- We are unaware of any published manuscripts that report racic irradiation. We therefore decided not to pursue Phase II the use of this chemotherapy regimen in patients with SCLC. continuation of our trial. The CALBG trial has recently closed However, several groups have recently published preliminary after accruing of 75 patients, and efficacy results are awaited results in limited abstract form, including Phase II studies in with interest. Preliminary toxicity analyses did not demonstrate patients with untreated ED SCLC. A CALGB trial (29) used any obvious increase in adverse events associated with chemo- 175 mg/m2 paclitaxel on day 1 and 1 mg/m2 topotecan on radiotherapy (38). Final response and survival data from this days 1Ð5 every 21 days with filgrastim support and yielded a trial should help determine whether or not this approach war- 68% response rate in 34 evaluable patients. Jacobs et al. (25) rants testing in a randomized setting.

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Charles Lu, Ritsuko Komaki, Jin Soo Lee, et al.

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