Abstracts/Lung Cancer 13 (1995) 323-356 349

Paclitasel and crrboplatin in the treatment of &vanced non- small cell lung cmicer Langer CJ, Leighton J, M&leer C, Comis R O’Dwyer P, Ozols R. Department o/A4edicol Oncology, Fox Chose Cancer Center, Philadelphia, PA 19111. Semin Chico1 1995;22/3 Suppl6 (64-69)

Basedontbcsuperiorresponserates(21%to24%))ofpatientstreated with single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in Eastern Cooperative Oncology Group and M.D. Anderson Cancer Center trials in non-small cell lung cancer (NSCLC) and on the superior l-year survival rates of NSCLC patients treated with carboplatin in a randomized study of cisplatin combination and analogues, we initiated a phase II trial of paclitaxel/carboplatin in patients with stage IV or effusion-positive stage III NSCLC. Eligibility stipulated chemotherapy-naive patients with measurable disease, good performance status, and adequate hematologic, hcpatic, and renal flmtion. Previous radiotherapy w-a.5 restricted to 5 30% of marrow- bearing bone. Paclitaxel was initially given at I35 mg/mr over 24 hours followed by carboplatin dosed toa targeted ares under the concentration versus time curve (AUC) of 7.5, with treatment repeated at 3-week intervals for six cycles. Granulocyte colony-stimulating factor was introduced during the second and subsequent cycles, with the paclitaxel dose sequentially escalated in 40 mg/m’ increments to a maximum dose of 2 I5 mg/m2 in patients with less than grade 4 gmmdocytopenia and less than grade 3 thromhocyt~penia. of54 patients enrolkd, 30 currently are evaluable for response, 23 for toxicity. Myelosuppression has been the prmcipal toxicity, with grade 3 or 4 granuloqtolrenia occurring in 70% ofpatknts after the first cycle. After the introduction ofgmmdocyte colony-stimulating factor, gramdocytopenia decreased to 37% during the~cyclcandthenconsistentlyto2~~orlowaduringsubseguent cycles. Gnly 22% of cycles have been delayed for 1 week or more. Nentmpenic fever has occmred in five (5%) of 100 evahrable cycles. Other grade 3 or 4 toxicities include thromboqmpenia (13%), anemia (9%). fatigue (9%)). and hemorrhagic cystitis (1%). The paclitaxel dose wasboostedto2l5mg/mzinl2(76??)of17patientsbycycle3or4.At an AUC of 7.5, the median firstcycle carboplatin dose was 434 mg/m’ (range. 293 to 709 mg/m*). The objective response rate is SO%, with three complete, 12 partial, and five minor responses. We conclude that the paclitaxel/carboplatin combination is active in advanced NSCLC and, with AUC-based dosing of carboplatin, can be given at 3-week intervals. Although dose limiting at a paclitaxel dose of I35 mg/mr, granulaytopenia can be reduced substantially with granulccyte colony- stimulating factor, allowing sequential dose escalation of paclitaxel to I75 mum’ and 2 15 mg/m* in 70% of patients receiving three or more cycles.

New ttutment agents for advanced small cdl and non-small ceil bmg cmtcer Bumi PA Jr, Kelly K. University of Colorado Cancer Center: &XYBI~~, 4200E 9thAve. Denvec CO80262, SeminGncol l995;22:Suppl. 6:53- 63.

The am rate for lung cancer remains low (13%) primarily due to early Systemic spread and the inability to cure systemic disease. These facts have led to pessimism regarding the role of chemotherapy, especially in non-small cell lung cancers. However, recent random&d trials demonstmted that chemotherapy significantly prolongs smvival in advanced (stages IIIB and IV) and locally advamxd (stages IIIA and IIIB) non-small cell lung cancers. Paclitaxel (Taxol; Bristol-Myen Squibb Company, Princeton, NJ) is an active agent in both non-small and small cell lung cancers, producing objective response rates as high as MY other active agent Early combination studies show even higher response rates when paclitaxel is combined with cisplatin or carboplatin. UItlmately, rarxlomized trials will be needed to define the optimal use of paclitaxel amI other recently developed new agents in lung cancer.

Chemoradiotherapy with or without gram&y&macrophage colony- sthdhg factor in the tn8tment of knited-st8ge small- ceil lung cancer: A prospective phase III randomized study of the Southwest Oncology Group Bunn PA Jr, Cmwky J, Kelly K, Hazuka MB, Beasky K, Upchurch C et al. Southwest Oncology Gnwp, Operations Ogice. I4980 Omicmn 0,: San Antonio, TX 78245-3217. J Clin Oncol 1995;13:1632-41.

Purpose: This phase III randomized trial was designed to determine ifgranolocyte-maemphage colony-stimulating factor (GMCSF) reduces the hematologic toxicity and morbidity induced by chemoradiotherapy in limited- stage small-cell lung cancer (SCLC). Methods: This multicenter prospective trial randomized 230 patients to receive chemotherapy and radiotherapy (RT) with or without GM-CSF given an days 4 to 18 of each of six cycles. The primary end point was hematologic toxicity. Secondary end points included the following: nonhematologic toxicities; days of (1) fever, (2) antibiotics, (3) hospitalization, and (4) infection; number of tramfusions; drug doses delivered; and response rates and survival. Results: There was a statistically signiticant increase in the frequency and duration of life- threatening thrombocytopenia (P < ,001) in patients randomized to GM- CSF. GM- CSF patients had signitIcantly more toxic deaths (P < .Ol), more nonhematologic toxicities, more days in hospital, a higher incidence of intravenous (IV) antibiotic usage, and more tmnsfusions. Patients randomized to GMCSF had higher WBC and neutrophil nadirs p < .Ol), hut no signiBcant difference in the frequency of grade 4, leukopenia or neutropenia. Patients randomized to GM-CSF had a lower complete response rate (36% v 44%). but the diierences were not sign&ant (P = .29). There were no signi&ant differences in survival (median, I4 months on GM-CSF and I7 months on no GM- CSF; P = .l5). Conclusion: GM-CSF, as delivered in this study, should not be included with concurrent chemoradiotherapy treatment programs for limited- stage SCLC. The sirnultaneeus use of hematopoietic mlony- stimulating factors (CSFs) and chemoradiotherapy should be performed only in experimental settings. Chemoradiotherapy programs with cisplatinendetoposide([VP-l6]PE)andsimultaneouschestRTproduce grade 4 neutropenia andthrombocytopenia in a small-enough proportion of patients that prophylactic hematepoietic growth factors are clinically --

Phase II study of ifosfamide, carboplatin, and oral etoposide chemotherapy for extensive-disease smalkell lung cancer: An Eastern Cooperative Oncology Group pilot study Wolff AC, Ettinger DS, Net&erg D, Comis RL, RucLdtschel JC. Bonomi PD et al. Division of Hematology-Oncologv, Emory UniversiQ School of Medtcine, 1364 C&Ion Rd, NE Athnta, GA 30322. J Clin Oncol 1995;13:1615-22.

Purpose: A phase II study of ifosfatnide, carboplatin, and prolonged oral administration of etoposide (ICE) in patients with untreated extensive- disease (ED) small-cell lung cancer (SCLC) was conducted to assess toxidties, response, and median suwiwl. Patients andMetho& Between July 1990 and August 1992, 35 patients were treated. ICE doses were ifosthmide 5 g/m’ by 24-hour continuous intravenous (CIV) infusion with mesna on day 1, carboplatin 300 mg/m’ intravenously (IV) on day I, and etoposide 50 mg/m’ orally on days 1 to 21 every 4 weeks for up to six to eight cycles (schedule I). Because of severe hematologic toxicity in the first 18 patients, the last 17 patients rwxived tfosfamkk 3.75 mg/m’ Iv on day 1, carboplathi 300 mg/mr IV on day 1, and etoposide 50 mg omlly on days 1 to 14 (schedule II). Resuk Nine of IS Patients (50%) on schedule I had 13 episcdes of severe hematologic toxicity (one death), and only two (11%) received full doses on cycle 2. However, with schedule II, only four of 17 patients (24%) developed severe hematologic toxicity, and eight (47%) received full

350 Abstracts/Lung Gmcer 13 (1995) 323-356

doses on cycle 2. objective responses were observed in 29 of 35 patients (83%) (schedule I, 16 of 18 patients [89%]; schedule II, 13 of 17 patients [76%]). There wereeight (23%) complete responses (CRs) and 21(60%) partial XS~WS (PRS). The median survival duration was 8.3 months, and I- and 2-year survival rates were 37% and 14% respectively. Conclusion: ICE with oral etoposide has comparable activity with other regimens in ED SCLC. However, the 2-year survival rate may be higher and ICE with the. lower doses of schedule II could be given safely with acceptable toxicity. Further studies of ICE compared with standard two- drug regimens are warranted.

A random&d trial of two cisplatin-containing chemotherapy regimens in patients with Stage III-B and IV non-small cell lung cancer Erkisi M, Domn F, Burgut R, Kocabas A. Department of Medical Oncology Cuknmva Universityh4edicaISchoo1, Balcal I, Adana. Lung Cancer (Ireland) 1995;12:23746.

Seventy-four newly diagnosed patients with histologically proven Stage III-B and IV non-small cell lung cancer were randomized to re- ceive either cisplatin: 20 m@mz x day x 5, ifosfamide: 1.8 g/m’ x day x 5, mesna: 1.2 g/m2 x day x 5, etoposide: 100 mg/m’ x day x 5 (ICE) or cisplatin: 20 g/m2 x day x 5 and etoposide: 100 mg/mr x day x 5. Re- sponse rates were 59% in the ICE and 40% in the CE arm with a sig- niticant advantage in response duration and overall survival in the ICE receiving patients (P = 0.03, P = 0.0008). As we used granulocyte colony stimulating factor (G-CSF) very frequently, myelotoxicity remained substantial but acceptable.

Paclituel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: A phase II toxicity, response, and survival analysis Langer CJ, Leighton JC, Comis RL, O’Dwyer PJ, McAleer CA, Bonjo CA et al. Deparbnent ofMedical Oncology Fox Chase Cancer Center: Philadelphia, PA 19111. J Clin Dncol 1995;13:1860-70.

Purpose: To determine the activity and toxicity of combination paclitaxel(24 hours) and carhoplatin in advanced non-smallcell lung cancer (NSCLC). Patients ImdMetkocir: Eligibility required measurable disease (stage IV or stage BIB with mahgnant pleural effusion), Eastern Cooperative Oncology Group (ECGG) performance status 0 or 1, absolute neutrophil count 2,OOO/iL, platelet count 100,OOOAL serum creatinine concentration % 1.5 mg/dL, and bilirubin level % 2 mg/dL. Paclitaxel was initially administered at a dose of 135 mg/m*/d, followed by carboplatin on day 2 at a targeted area under the concentration-time curve (AUC) of 7.5 using the Calvert formula. Gramdocyte colony- stimulating factor (G-CSF) 5 ig/kg subcutaneously (SC) on days 3 to 17 was introduced during the second and subsequent cycles. In patients who sustained less than grade 4 myelosuppression, the paclitaxel dose was sequentially escalated 40 mg/m’ per cycle to a maximum of 215 mg/mz. Treatment was repeated at 3-week intervals for six cycles. Results: From June 1993 through February 1994, 54 patients were enrolled; 53 are assessable for toxicity and response. The median age was 62 years (range, 34 to 84). Sixty-nine percent were male, 65% had adenocarcinoma, and 93% had stage IV disease. ‘Bvo hundred sixty- eight cycles were administered; 32 patients (59%) completed aR six cycles. ‘Bventy- five unanticipated hospitalizations occurred during treatment (9.3% of cycles) in 20 patients (37%). Myelosuppression was the principal toxicity; grade 3 or 4 gramdocytopenia occmred in 57% of patients after the first cycle, but decreased to 35% during the second cycle alter introduction of G- CSF and consistently remained % 22% during subsequent cycles. Seven episodes of neutmpenic fever occurred, all during the first cycle. Grade 3 or 4 thrombocytopenia and anemia

occurted in 47%and 33%of patients, respectively. Eight patients (15%) required platelet transfusions and 16 (30%) required packed RBC support. Neuropathy, myalgias/arthralgias, and thrombocytopenia, although generally mild, were cumulative. The paclitaxel dose was boosted to 2 15 mg/rnl in 70% of patients who received thtee or more cycles. At an AUC of 7.5, the median first-cycle catboplatin dose was 424 rnglml (range, 273 to 709 mg/m*). The objective response rate was 62% with five (9%) complete responses and 28 (53%) partial responses, The median progression-free survival time was 28 weeks and the median survival time 53 weeks. The l-year survival rate is 54%. Conciusion: The paclitaxel- catboplatin combination is active in advanced NSCLC and may enhance survival; it merits further investigation in phase III trials.

Radiotherapy The evolution of Radiation Therapy Oncology Group @TOG) protocols for nonsmall cell lung cancer Byhardt RW. Deparmtent of Radiation Oncology, Medical ColIege of UGconsin, 8700 Ff! Wisconsin Ave., Milwaukee, WI 53226. Int J Radiat Oncol Biol Phys 1995;32:1513-25.

Over the past 2 decades, the Radiation Therapy Oncology Group (RTOG) haa played a significant role in clarifying the role of radiation therapy (IIT) in the treatment of nonsmall cell hmg cancer (NSCLC). RTOG lung cancer research has evolved over this time period through a systematic succession of investigations. For unresectable NSCLC, the dependence of local tumor control and survival on total dose of standard fractionation RT, as well as pretreatment performance characteristics, was demonstrated in initial RTGG trials. Subsequently, further radiation dose intensification was tested using altered fractionation RT to total doses up to 32% higher than stamkud RT to 60 Gy, given as either hyperfractionation or accelerated fractionation, while attempting to retain acceptable normal tissue toxicity. These higher doses required rethinking of established P.T techniques and limitations, as well as careid surveillance of acute and late toxicity. A survival advantage was shown for hyperfractionation to 69.6 Gy, in favorable performance patients, compared to 60 Gy. Further testing of high dose standard RT will use three- dimensional, conformal techniques to minimize toxicity. RTOG further extended the theme of treatment intensification for mmzecmble NSCLC by cvahrating combined chemotherapy (CT) and RT. Improved local control and survival was shown for induction CT followed by standard RT to 60 Gy, compared to standard RT (60 Gy) and altered fractionation RT (69.6 Gy). The intent of current studies is to optimize dose and scheduling of combined CT and standard RI’, as well as combined CT and altered fractionation PT. Noncytotoxic RT adjuvants, such as hypoxic cell sensitizers, nonspecific immune stimulants, and biologic response modifiers have also been studied. Resectable NSCLC has also been an RTDG focus, with studies of preoperative and postoperative RT, CT, and CT/RT, including the prognostic value of serum and tissue factors. RTGG studies have yielded incremental improvements in treatment outcome for NSCLC, better understanding of the disease dynamics, and a strong foundation for future investigations.

Long term results of a Phase I/II study of aggressive chemotherapy and sequential upper and lower hemibody radiation for patients with extensive stage small cdl lung cancer Bonner JA, Eagan RT, Liengswangwong V Frytak S, Shaw EG, Evans RG et al. ,44q Clinic, 200 First Sheet SrC: Rocheste,: MN 55905 Cancer 1995;76:406-12.

Background. A Phase I/II study of an aggressive six-drug chemotherapy regimen followed by the use of sequential hemibody