Abstracts/Lung Cancer 10 (1994) 395-430 421

(OC-34) by factor of 3.18 as a.wwd by the tetrazolium dye assay. The maximum sensitization of OC-34cells to adriamycinrequired prolonged pretreatment ( > 72 h) with calcitriol, although this pretreatment did not influence the intracellular uptake of ADM. The intracellular Ca” concentration was elevated in calcitriol-treated cells 5 h after adding ADM. We speculate that calcitriol increases sensitivity to ADM by potentiating disruption of intracellular calcium homeostasis.

Invivostudyofvinorelbine~atiom~tbeisplatin,Eflwrouradl or actinomycin D relative to a non-small-cell lung carcinoma (NSCLCN,-LJ Roussakis C. Pouchus YF, Gratas C, Riou D, Dimou P, Dabouis G et al. Rech. Subs. Marina Activite Biolog.. Uuiversitede Names, Faculte de Phatmacie, I rue Gaston Veil. BP 1024, 44035 Names-Cedex 01. Anti-cancer DN~ Des 1993:8:165-71.

Vinowlbine (Navelbine(R)) is a new antitumor agent chemically related to the Vinca alkaloid group, but differentiated by its in viva activity relative to non-small-cell lung carcinoma (NSCLC). Studies in the NSCLC-bearing nude mouse of vinorelhine associations with drugs currently used clinically in phase III (cisplatin, S-fluorouracil and actinomycin D) showed that such associations are ineffective or even of negative value and that it would be preferable to use vinorelbine alone in a single dose at the maximum tolerated concentration.

Prolonged, alternating chemotherapy for extensive small cell lung cancer: A Southwest Oncology Group study Livingston RB, Crowley JJ, Thompson T, Williamson SK, Meyers FJ, O’Rourke T et al. Southwest Oncology Group, Operations Ogice, 14980 Omicron Drive, San Antonio, TX 78245-3218. Cancer 1993;71:3509-13.

Badground. Etoposide may be schedule dependent in small cell lung cancer (SCLC), and some data suggest a benetit for incrd dose intensity in this disease. This study attempted to optimize dose intensity using an outpatient prognm that included prolonged, oral stoposide administration. Methook Cisplatin-etoposide (PE) and cyclophos- phamide,doxorubicin.andvi.ncristine(CAV)werealtematedatmonddy intervals in patients with extensive SCLC. PE was given as cisplatin 50 mg/m* on days 1 and 8 intravenousty (IV) and etoposide 50 mglm*lday for 14 days by mouth. CAV was administered as cyclophosphamide 60 mglm%ay for 21 days orally, doxorubicin 20 mglmzlweek for three doses, and vincristine 2 mg IV on day I only. At the end of 4 months, responding patients received an additional course of PE alternating with CAV, and whole-brain irradiation (3000 cGy in I5 fractions) was delivered to clinical complete responders (CR). Results. Among 61 eligible patients. 4achieved CR, and 1 I had a partial remission, by strict Southwest Oncology Group criteria. An additional 20 patients demon- strated greater than 50 46 tumor shrinkage on one disease assessment but did not have confuming measurements at a11 sites 4 weeks later. The overall response rate was 57 56, including the latter group. The toxicity was primarily hematologic, with three treatment-related deaths from nautropenic infection (5 sb). Grade 4 neutropenia ( < 500/I) occurred in nine patients (15%) and Grade 4 thrombocytopnia (< 255.0XJ11). in three (5 W). Analysis of the delivered dose intensity (in milligrams per square meter per week) as a function of that which was planned revealed a mean of 93 46 for a11 courses. Conclusions. Although substitution of prolonged oral etoposide in PE and oral cyclophosphamide in CAV proved to be feasible. t&se. results suggest no advantage over those from other reported series using these alternating regimens in which the agents are pulsed. Experience with alternating PE-CAV for extensive SCLC is reviewed.

Cisplatirreyclophosphrunidemitomyeinannbi~donchrmo~py with supportive care vea-5~3 supportive care alone for treatment of metastatic non- smakell lung cancer Cartei G, Cartei F, Cantone A. Caasarano D. Genco G, TobaIdin A et al. Divisione di Oncoiogia Medica, Centro di Prevenzione dei Tumori, USL7, 33100 Udine. J Nat1 Cancer Inst 1993;85:794-800.

Background: Patientswith TNM stage IV non-smaIl-celI lung cancer have short survival times. Previous controlled studies comparing chemothcrapyandsupportivecamforthe treatmentofthis typeofcancer have not given consistent results, have inchtded patients with different disease stages, and have rarely reported drug dose intensity. Purpose: The prmnt trial was designed to assess the safety and the effect on survival of supportive care alone versus chemotherapy with cisplatin, cyclophosphnmide,andmimmycincombin~withappropriatesupportive care in patients with stage IV non- smaII-cell lung cancer. Methods: Patients (n = 102) with stage IV non-small- cell lung cancer were mndomly assigned to one of two treatment regimens. The combined modality group (52 patients) received supportive care along with cisplatin (75 mgi&), cyclophosphamide (400 mg13). and mitomycin (10 mglmf) given intravenously at 3-week intervals. The supportive care group (50 patients) received supportive care alone. Randomization was stratttied on the basis of histology (squamous versus nonsquamous cell carcinoma), performance status (Kamofsky), and weight loss (during the 6 months precediig randomization). The two groups were well matched for age and sex. Survival analysis was performed after the last patient died. Results: The median number of chemotherapy cycles was 3.5 per patient. Mean weekly delivered doses of drugs were as follows: cisplatin, 22.1 mgid; cyclophosphamide. 118 mgiai; and mitomycin. 2.9 mg/&. Toxic effects due to chemotherapy were generally mild, but peripheral neuropathy and hematologic and renal toxic effects were observed. In the supportive care group. mean survival was 6. I months (median, 4.0 months); six patients livedat least 12 months and two lived at least I8 months. In the combined modality group, mean survival was Il.3 months (median, 8.5 months); 20patients lived at least 12 months. I3 lived at least 18 months, and tive lived at 1-t 24 months. Difference insurvival wasstatistically s&icant(P< .OOOl). Survival wasdirectly related to initial performance status in both groups (PC .Ol) and was significantly (P < .Ol) longer for patients with squamous cell carcinoma than for those with nonsquamous cell carcinoma. Conclusions: The combination of supportive care and cisplatin-cyclophospbamide- mitomycin therapy offers a survival advantage over supportive care aIoneinpatientswithadvancednon-smalI-cellIungcancer. Implications: Metastatic non-smalI_celI lung cancer, generally considered to be unresponsive or marginally responsive to chemotherapy, can be treated with chemotherapy, with an expectation of prolonging patient survival. Although the results of the present study are encouraging, clinical research should continue to be directed toward developing more effective treatments for this disease.

Evaluation of cisplntin intensity in metastatic non-small-cell lung cancer: A phase IU study of the Southwest Oncology Group Gandara DR. Crowley J. Livingston RB, Perez EA. Taylor CW, Weiss G et al. Operations Once. Southwest Oncology Group (SWOG8738). 5’430 Fredericksburg Rd. San Antonio, 1x 78229-6197. J Clin Oncol 1993: 11:873-E.

Purpose: To test the concept that cisplatin dose-intensity is important in the treatment of non-smalI-z:slI lung cancer (NSCLC). the Southwest Oncology Group (SWGG) performed a randomized trial comparing standard-dose cisplatin (SDCP) 50 mg/lrI days I and 8 on a 28-day cycle for eight cycles, high-dose cisplatin (HDCP) 100 mgln? days 1 and 8 for four cycles, and higbdose cisplatin plus mitomycin (HDCP-M) 8

422 Abstracts/Lung Cancer 10 (1994) 395-430

mg/m’ day 1. To isolate the effects of dose-intensity versus total dose, the planned cumulative cisplatin dose was 800 mg/nl in each arm. fnrietus and Merhods: Between July 1988 and April 1990, 356 patients were rtnrolled and 323 were eligible and assessable. All patients had metastauc, measurable disease. were chemotherapy-naive, and had a performance status (PS) of 0 to 2. Results: Confirmed complete plus partial response tates were SDCP, 12%; HDCP, 14%: and HDCP-M, 27% (P < .05). Complete responses were uncommon (HDCP. 3%; HDCP-M. 4%) and were observed only in the high-dose arms. Progressive disease occurred more frequently in the SDCP arm (57 46) compared with HDCP (38 %) or HDCP-M (34%) (P < .05). However, there were no significant differences in mediao survival times (SDCP, 6.9 months; HDCP, 5.3 months; HDCP-M, 7.2 months; P = 53). The mean delivered dose-intensity for clsplatio was significantly greater in the high-dose arms: HDCP 41 mglm’lwk and HDCP-M 39 mgim’lwk, versus SDCP 23 mglm’lwk (P = .05). The high-dose arms resulted in an mcreased incidence of ototoxiciry. em&s, and myelosuppression. but similar degm of renal toxicity and oeuropathy compared with SDCP. Conclusion: This study does not confirm evidence of a steep clinical dose-response curve for cisplatm in NSCLC at the cisplauo dose-intensities achieved. The addition of mitomycin increases the response rate, but does not improve survival. Continued evaluation of new agents m thts disease IS warranted.

Cisplatin, S-fluorouracil, and etoposide for advanced non-small cell lung cancer Lynch TJ Jr. Kass F, Kalish LA, Elias AD. Strauss G, Shulman LN et al. Hematology-Oncology Unit. Massachuserts General Hospital, Fruit Street. Boston. MA 02114. Cancer 1993:71:2953-7.

Background. Cisplatin and atoposide combination chemotherapy is the most commonly used regimen for advanced non-small cell lung cancer (NSCLC). S- Fluorouracil(5-FU) IS an agent with little intrinsic activity against NSCLC. However, there is increasing evidence that 5- FU is synergistic with cisplatin and vice versa. In an effort to improve on the traditional chemotherapeutic approach to NSCLC, a treatment regimen consisting of cisplatio. 5-FU, and etoposide (PFE) was developed. Methook. Thirty-five patieocs with advanced NSCLC were treated with the PFE regunen (cisplatin 25/m&&/d and 5-FU loo0 mg/ ml/d by continuous inlits1ooandetoposide60 mg/mz/d, each for4days). Tba cycles were repeated every 28 days. Resufrs. The patients received a mean of 2.8 cycles of PFE. Ten patients had a partial response to chemotherapy for an overall response rate of 28.6%. The median survival was 7.0 months. Toxicities included myocardial infarction (2 of 35), congestive heart failure (2 of 35). fatal pulmonary embolus (1 of 35). and a cerebrovascular accident ( 1 of 35). Toe incidence of Grade 4 oeutropenia (5.7%) and thrombocytopoia (8.5%) was acceptable. Conclurionr. The response rate, duration of response, and survival in this group of 35 patients treated with PFE was similar to that reported for cisplatm and etoposide. The increased cardiovascular toxicity may be the result of the infused 5-FU.

The case for mitomycin in non-small cell lung cancer Spain RC, Hortobadyi GN. Division of Oncology, St. Luke’s Hospital. 1311 Shake Boulevard. Cleveland. 01144104. Oncology (Switzerland) 1993:5O:Suppl. 1:35-52.

The activity of mitomycin in non-small cell lung cancer (NSCLC) has beem well documented in both single-institution pilot and muiti- institution random&d trials. Despite the inclusion of patients ineligible for current trials of newer single agents due to poor performance status, prior umdiatioo to indicator lesions, orpriorchamotberapy, mitomycin emerges from such prior studies as the most consistently active single

agent currently available for NSCLC. While randotnizcxl trials in stage IV disease demonstrate an improved response rate with mitomycin and cisplatin in comparison with cisplatin alone (p = 0.03). and with mitomycin, viodesine, and cisplatin in comparison with vindesine and cisplatin alone (p = 0.003). the potential with mitomycio is most apparent with weekly bolus or infused vindesine/vinblastine, and higher-dose cisplatiu (MVP) in neoadjuvant approaches to stage III disease. Indeed. four trials ofoeoadjuvant MVP m predominantly stage IIIA (bulky N2) disease produced a consistent 1 g-month median and 26- 33 56 3-year survival, which is to be compared with 8 months and 6 56, respectively, with traditional thoracic inadiatioo alone. Nonetheless, priorusc:ofmitomycinwithoutguidelin~forcumulativedose,sch~ulz, or guidelines for use in combined-modality therapy has produced widespread frustration stemming not only from frequent sntioeoplastic effect, but also from frequent toxicity. The several related syndromesof mitomycio-associated thrombotic microangiopathy, ranging from hamolytic-uremic syndrome to pulmonary injury, appear avoidable through limiting the cumulative mttomycin dose to a maximum of 30 mg/m$ scheduling mitomycin at not less than J- to 6-week intervals. perioprativa use of corticosteroids and low inspired oxygen; and close patient follow-up. W&ile daxamethasone preceding mitomycin reduces the frequency and severity of mitomycin-associated lung injury (p = 0.0005). daxamethasooc premedicatmoalso reduces the response rate of MVP in NSCLC (p < 0.025).

Mitomycin, ifosfamide, and cisplatin in non-small cell lung cancer Cullen MH. Queen Elizabeth Hospital. Edgbaston, Birmingham El5 27X. Oncology (Switzerland) 1993:5O:Suppl. 1:31-1.

Mitomycia. ifosfamide, and cisplatin have demonstrated the best single-agent activity thus far in patients with non-smalt ceil lung cancer (NSCLC), the most common malignant disease in the western world. For this reason, we initiated a phase II study. giving these three agents in combination (designated MIC) to 74 patients with inoperable NSCLC. Sixty-stx pauents were evaluable for response. of whom 30 (45%) demonstrated a partial response and 7 ( 11 W) a complete response. These results, along with those obtained in two other phase II trials of MIC in NSCLC. prompted us to begin a large-scale, multicenter, phase III study of MIC in patients with inoperable limited-stage NSCLC. In this oogomg study, patients have been randomized to receive treatment with .MIC and radiotherapy or radiotherapy alone. We hope. to resolve the issue of whether a survival advantage is conferred on NSCLC patients treated with radiotherapy in combination with this promising chemotherapeutic regimen.

Experience with mitomycin in the treatment of non-small ceil lung cancer Folmao RS. Deparzmenr of Medicine. Section of Oncology, Bridgepoti Hospital, Bridgepon. CT Oncology (Switzerland) 1993:5O:SuppI. 1:24-30.

Mitomycin has proven to be among the most active drugs available for the single-agent treatment of non-small cell lung cancer (NSCLC). In combination with vioca alkaloids and cisplatin. mitomycin cart produce response rates greater than or equal to 50% in properly selected patients. In our experience, such responses were achieved using moderate doses (7 or 8 mg/m’) of mitomycin, which also resulted in fewer hematologic and other toxicities. Delivery of MVP (mitomycin/vinca alkaloidlcisplarm) to 150 patients with stages III and IV NSCLC during thelast decadeshowedmaximal respon~wasachievdaftertwoorthrrz cycirsoftherapy. A comparativeanalysisofresultsreported using MVP regimens suggests that high response rates are associated with greater do~-intenslveuseofcisplatinaodIrs~rdose-inteosivellseofrmtomycin.