Adjuvant chemotherapy for completely resected stage III non-small-cell lung cancer: Results of a randomized prospective study

Abstracts/Lung

Cancer 11 (1994) 123-150

700 mg/mr over 14 days, all four patients experienced grade III or IV leukocytopenia, and two developed grade III stomatitis. No cumulative toxicity was observed. A steady concentration of etoposide was achieved 24 hours after the start of chemotherapy, and it was significantly correlated with surviving tractions of leukocytes (r = -64, P = .OOl) and platelets (r = -.68, P C .OOl). The leukocyte count at the termination of chemotherapy predicted the. nadii count (r = .93, P C .OOl). Conclusion: Stiy blood levelsof etoposide were maintained for prolongedperiods,during 14-daycontinuousinfusions.Leukocytopenia and stomatitis were dose&miting. Nadir counts and surviving fractions of leukocytes were predicted by the leokocyte count at the end of chemotherapy and the conceutmtion of etoposide, respectively. The recommendeddose for phase II trials is 600 mg/& over I4 days.

Combined treatment modalities Preoperative chemotherapy for locally advanced non-small cell lung cancer

Holmes EC, Ruckdeschel JC. Factor Building, UCLA School of Medicine, Los Angeles, CA 90024. Lung Cancer (Ireland) 1993;9 Suppl 2:S31-7. Recently, the field of preoperative chemotherapy for non-small cell lung cancer (NSCLC) has been the focus of Phase II trials. Extensive experience with preoperative therapy has been reported by such study groups as the Rush-Presbyterian group, Memorial Sloan-Kettering Cancer Center, the Dana Farber Institute, the University of Toronto, and the Lung Cancer Study Group. The studies by these and other investigative groups are reviewed here and, although all but one of the studies was flawed by the lack of a control arm, results are encouraging. Comparisonofdata fromthevarious studies isdifficult duetodiffemnces in preoperative staging, but it appears that 60- 75 % of patients may be expected to respond to one of a number of preoperative regimens, the majority of responders will be able to go on to surgical resection and about 10% of patients initially entered into a study are likely to attain histologic complete response, with correspondingly higher rates for those who undergo surgery. Toxicity rates are significant and survival data are not yet conclusive, however, and it is clear that a controlled trial is needed.

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(n = 11) progressed. Squamous histologic type was predictive of resectability, 18 of 20 patients having resectable squamous cell tumors (p c 0.05). Actuarial survivals at 1 and 2 years were 74% and 52%. respectively. ~npatientswithresectabletumorssurvivalsat 1 and 2year~ were 85 % and 67 % , respectively. For those with unresectable lesions, survivals were 43 96 and 14 % . Relapse- free survivals at 1 and 2 years for patients with resectable lesions were 70% and 42%, respectively. Relapses were local in 25 % (n = 4), at a distant site only in 50% (n = 8). combined local and distant in 25 % (n = 4). Distant relapse Occurred in the central nervous system only in 7 of 8 patients (88 %). Complete resectability was highly predictive of improved survival @ < 0.0002). Weight loss did not affect resectability but was associated with decreased survival (p < 0.003). Neoadjuvant chemotherapy appears to improve resectability and to pathologically downstage N2 non-small-ceil lung cancer from stage IIIA. Multiinstitutional randomized trials are needed to further demonstrate the efficacy of this approach.

Adjuvant chemotherapy for completely resected stage111nonsmall-cell lung cancer: Results of a randomized prospective study Ohta M, Tsuchiya R, Shimoyama M, Sawamura K, Mori T, Miyamwa N et al. National Kyushu Cancer Center, 3-l-l. Notame, Uinami-ku, Fukuoko 815, J Thorac Cardiovasc Surg 1993;106:703-8. Two hundred nine patients with completely resected stage III nonsmall- cell lung cancer were random&d to receive postoperative cisplatin and vindesine chemotherapy or no further treatment. Before randomization, patients were stratified by the histologic characteristics of their tumors (squamous versus nonsquamous cell carcinoma). Prognostic variables such as histology, performance status, extent of operation, and tumor and nodal status of the eligible patients in chemotherapy (n = 90) and control groups (n = 91) were equally distributed. There was no statistically significant difference in diseasefree and overall survival between the two groups. The 3-year diswaefree survivals of the chemotherapy and control groups were 37 46 and 42 96, respectively. The median survival times (S-year smvival) were 31 months (35 W) in the chemotherapy group and 37 months (41 W) in the control group. These was no different pattern in the first site of recurrence (local versus systemic) between the two groups. This study failed to demonstrate the therapeutic benefits of postoperative cisplatin and vindesine chemotherapy.

Multimodality therapy of patients with stage WA, NZ nonsmall-cell lung cancer: Impact of preoperative chemotherapy on reaectahility and downstaging

Carboplatin, etoposide, and radiotherapy, followed by surgery, for the treatment of marginally resectable non-small cell lung cancer

Kim DH, Lynch TJ, Mentxer SJ, Lee TH, Strauss GM, Elias AD et al. Division of lhoracic Surgery, Brigham and Women’s Hospital, 75 Fran&d., Boston, MAO2115. JThoracCardiovascSurg 1993;106:6%702. To assess the effect of neoadjuvant platinum-based chemotherapy on resectability, stageofdiseaseatresection, andpattemsofrecurrenceand survival in patients with IIIA, N2 non-small-cell lung cancer, we examined the first 60 patients treated with neoadjuvant chemotherapy followed by attempted resection in our institution. Of 67 patients identified, 7 patients were ineligible because of comorbidities, 3 patientsreliisedchemotherapy, and 1 consented butdiedbeforetreatment. Fifty-six received neoadjuvant chemotherapy. Complications of chemotherapy were minor, with no deaths. Fifty-four patients had thoracotomy; 75 % (n = 42) had complete resection and 25 % (n = 14) had unresectable lesions. One postoperative death occurred (2%). Pathologic review of specimens and nodal groups revealed that 41% (n = 23) were downstaged, 39 96 (n = 22) remained stage IIIA, and 19 %

Deutsch MA, Leopoldt KA, Crawford J, Wolfe W, Foster W, Blackwell S et al. Department of Medicine, Duke University Medical Center, Durham. NC 27710. Gxncer Treat Rev 1993;19 Suppl C:53-62. The present study was undertaken in order to determine the feasibility and efficacy of induction chemotherapy with carboplatin and etoposide, followed by weekly carboplatin and full-course radiotherapy as pre-operative therapy for marginally resectable non-smell cell lung cancer (NSCLC). Twenty-eight patients with good Eastern Cooperative Oncology Group (ECGG) performance status ratings and stage IIIA NSCLC received induction chemotherapy with carboplatin (dose computed with the Egorin formula, days 1 and 29) and etoposide (100 mg/mr/day, days I through 3 and 29 through 31). This was followed by 100 mglmr weekly carboplatin given over 6 weeks, concurrently with 60 Gy radiotherapy. Patients with either responsive or stable disease underwent thoracotomy 4 weeks at?er the completion of combinedmodality therapy. All 29 patients received the first chemotherapy cycle (average carboplatin dose, 407 mg/m$ range, 195 to 586 mglmr).

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Cancer II (1994)

World Health Organization (WHO) grade 3/4 neutropenia and thrombocytopeninwereobservedin53md34kofpatients,~tively. There were three.febrile neutropenic episodes, but no septic deaths. Five patieats(l8%)requireddosereductionspriortothesecondchemot cycle, but the dose intensity of carboplatin was maintained (average dose, 390 mglm’; range, 195 to 586 mg/m’). In all, 82% of patients received tidldose radiotherapy, and 73 96 received at least five of six planned concurrent weekly carboplatin doses. Carboplatin doses were most frequently delayed for thrombocytopenia and/or leukopenia. Carboplatin did not increase the incidence of radiation-induced esophagitis. Only three patients required interruption of radiotherapy, for esophagitis (two patients) and persistent thrombocytopenia (one patient). The response rate to preoperative therapy was 64%. In this study, we demonstrated the ability to deliver escalated doses of carboplatin with standard-dose etoposide as induction chemotherapy with reasonable myelotoxicity. The combmed-modality therapy was well tolerated, and the addition of we&y carboplatin did not result in increased radiation-related toxicity. This neoadjuvant regimen is active in the treatment of locally advanced NSCLC, and compares favorably to other cisplatin-based regimens.

Other treatment modalities IR-192, low dose rate endobronchinl brachytherapy treatment of malignant airway obstruction

in the

Raju PI, Roy T, McDonald RD, Harrison BR, Crim C, Hyers TM et al. Blair Oncdogy Associates,Building .!?.501 Howard Ave., Altoona. PA 16601. hatJ Radiat Oncol Biol Phys 1993;27:677- 80. Purpose: To assess the value of lowdose-rate endobronchial brachytberapy in thetreattmnt of malignant airway obstruction. MAhads and Materials: Between September 1986 and April 1989, 39 patients with malignant airway obstruction had 49 catheter placements for an afterloading, low-dose-rate Ir-192 endobronchial brachytherapy. A flexible fiberoptic bronchoscope with fluoroscopic guidance was used for positioning. Thirty-eight of 39 (97%) patients completed the prescribed treatments. Ninety-seven percent had received previous external radiation in doses ranging from 36-60 Gy. One patient had metastatic renal cell carcinoma; the remainder had recurrent lung cancer. Endobronchial laser treatments were given to three patients 23 weeks prior to endobronchial brachytherapy. All patients were followed until death. The median dose delivered in 48 of the 49 placements was 20 Gy at 1 cm. Resuh: Follow-up bronchoscopy was performedin28(72%)of39patients.Ofthese, 13(46%)hadacomplete response, 12 (43%) had a partial response, and 3 (17%) had a minor response. Dyspnea improved in 30 of 37 patients (82%); hemoptysis in 17 of 19 patients (89%); cough in 31 of 39 patients (79%); and postobstructive pneumonia in 21 of 23 patients (92%). The median survival for the entire group was 5 months (range 1-31 months). Conclusion: This technique is simple, well-tolerated and offered significant palliation.

Reviews ‘Patient-like’ nude- and SCID-mouse models of human lung and pleural cancer (review) Astoul P, Wang X, Hoffman RM. AntiCancer Inc., 5325 Metro Street, San Diego, CA 92110. Int J Gncol 1993;3:713-8. Lung cancer is one of the leading causes of cancer-related adult deaths in the world, and its incidence is rising. Patients with malignant

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pleural effusionsate considered to be in malignant disease or in the tern&al stage. For both, the lack of efficacy of nonsurgical tmatment moda&s is related to the lack of suitable animal models for new drug discovery. Models based on athymic nude mice have heen used for human cancer research. However, S.C. or i.m. xenografts usually do not metastasize, or do so at low frequencies. Conversely, human tumor cells orthotopically implanted in the corresponding organs of nude mica resultin much higher metastatic rates. By avoiding disruption of tumor integrity, we have found that orthotopic implantation of histologically-intact patient specimens leads to models better reflecting the original behavior of human cancer than models constructed by orthotopic injectionof cell suspensions. With the development of a novel thoracotomy procedure, we have constructed ‘patient-like’ models of lung cancer (SCLC and NSCLC) with regional spread and distant metastases mimicking the clinical features of these diseases. Moreover, by implantation of histologically-intact human tumor tissue in the parietal or visceral pleura of nude mice, we were able to construct models of early- and advanced- pleural cancer, respectively. Indeed, symptoms and survival of pleural- implanted mice closely resembletheclinicPlsiR~~~ga~~y~i~fi~t~ff~~ in survival between parietal- and visceral-pleural implanted mice, the I~tar~ingmPdvanced-stPgeaocer.‘Ihussuchmodsls,~fl~g clinical features, should be of great value in the development of new drugs and tmatment strategies.

Current perspectives in the treatment of small cell lung cancer Turrisi AT III, Aisner J, Johnson D, Comis R. UH B2C490, Box 0010, 15lXl E Medical Center Driw, Ann Arbor, MI 48109. Lung Cancer (Ireland) 1993;9 Suppl l:S109-22. Neither chemotherapy nor radiotherapy alone is adequate to treat bothbulkylocaldisesseandthePlmostuniverssldistsntmicrometastases of small cell lung cancer (SCLC). Despite improved overall and 2-year survival rates associated with combiig the two treatment modalities, however, their potential for toxic interaction demands careful consideration. The specific toxicity profile of the chemotherapeutic agent used must be calculated and balanced with the radiotherapy dose, fractionation, volume, and timing with chemotherapy to give thepatient the maximum benefit and the least amount of risk. Results of clinical trials indicate that fractionation of the radiation dose takes advantage of the fact that fractionation causes less damage to and allows for repair of normal tissue, whereas the tumor cells ofSCLC arekilled exponentially by even small radiation doses per traction. Further evaluation of radiation volume is needed to answerquestions on the risk- benefit ratio of normal lung exposure versus complete coverage of areas of potential metastasis, and to determine whether dose of volume is the more critical factor for lung toxicity. Finally, the timing of radiotherapy also must be studied further. Early radiotherapy offers the potential for killing small cells before they migrate, but attempts to compensate for such early exposure may lead to subtherapeutic doses of chemotherapy and, thus, to lower response rates.

Treatment of elderly patients with small cell lung cancer KeaneM, Camey DN. Marer Misertconhe Hospital, E&es Stree?, Dublin 7. Lung Cancer (Ireland) 1993;9 Suppl l:S91-8. The changing face of our population during the next 25 years will have a major impact on the practice of clinical oncology. At present, in the United States, 13 96 of the population is 65 years of age or older; however, by the year 2020 approximately 22 96 (1 in 5) will be 65 years or older. The incidence of cancer increases dramatically with advancing age, and more than 55 I of all cancers currently are observed in persons 65 years of age or older. Moreover, results of cancer treatment during the past 20 years have shown a significant decrease in cancer mortality