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Cisplatin, Epirubicin, and Vindesine with Or Without Lonidamine in the Treatment of Inoperable Nonsmall Cell Lung Carcinoma a Multicenter Randomized Clinical Trial

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Cisplatin, Epirubicin, and Vindesine with Or Without Lonidamine in the Treatment of Inoperable Nonsmall Cell Lung Carcinoma a Multicenter Randomized Clinical Trial 63 Cisplatin, Epirubicin, and Vindesine with or without Lonidamine in the Treatment of Inoperable Nonsmall Cell Lung Carcinoma A Multicenter Randomized Clinical Trial Giovanni P. lanniello, M.D.' BACKGROUND. Lonidamine (LND) is an indazol-carboxylic acid derivative that se- Giuseppe De Cataldis, M.D? lectively inhibits the energy metabolism of neoplastic cells, and increases the per- Pasquale Cornella, M.D.~ meability of cell membranes. In vitro studies have demonstrated that LND can Michele Della Vittoria Scarpati, M.D! potentiate the oncolytic activity of cytotoxic drugs and is able to reverse the ac- Alfonso Maiorino, M.D! quired multidrug resistance of neoplastic cells. Some clinical trials have suggested Luigi Brancaccio, M.D." a synergism of LND with alkylating agents, cisplatin, and anthracyclines in various Riccardo Cioffi, M.D.~ solid tumors. Alessandra Lombardi, M.D.' METHODS. From June 1990 to June 1993, 158 previously untreated patients with Pietro Carnicelli, M.D* Stage IIIB and IV nonsmall cell lung cancer (NSCLC) were enrolled into a multicen- Vincenza Tinessa, M.D.' tric randomized trial to evaluate the addition of LND to a cisplatin-epirubicin- vindesine regimen. Eighty patients in the control arm (A) received cisplatin, 60 ' Departinent of Medical Oncology, G. Rurnrno mg/mz intravenously (i.v.); epirubicin, 60 mg/m2 i.v.; and vindesine, 3 mg/m2 i.v. Hospital, Benevento, Italy. (PEV), on Day 1 every 4 weeks, whereas 78 patients in the experimental arm (B) * First Piieumology Department, G. Da Procida received the same regimen with the addition of LND from 75 mg orally three times Hospital, Salerno, Italy. on Day 1 to 150 mg orally three times on Day 7+ until tumor progression occurred. Departinent of Medical Oncology, National Tu- RESULTS. The experimental treatment achieved a significantly higher proportion mor Institute, Naples, Italy. of major responses in comparison with the control regimen (43% vs. 24%; P = 0.02). The addition of LND apparently potentiated the activity of this cytotoxic Department of Medical Oncology, Second Uni- versity School of Medicine, Naples, Italy. treatment, particularly in patients with metastatic disease (overall response rate, 39% vs. 17%). The median time to progression (5 vs. 8 months; P = 0.0007) and Second Department of Thoracic Surgery, F. the median survival time (7.6 vs. 11 months; P = 0.0013) were also statistically Monaldi Hospital, Naples, Italy. improved in Arm B. The acute toxicity of the 2 treatments was low: only 6% of Third Pneumology Department, F. Monaldi patients in Arm A and 4% of patients in Arm B had to withdraw from treatment Hospital, Naples, Italy. due to Grade 4 World Health Organization toxicity. The main additional side effects ' Department of Pneumology, City Hospital, related to the administration of LND were epigastralgia, myalgia, asthenia, and Caserta, Italy. orchialgia. However, these symptoms were mild and controlled by the concomitant administration of low doses of steroids. CONCLUSIONS. The mild acute toxicity of the PEV regimen and the acceptable and Presented in part at the 19th Congress of the European Society of Medical Oncology, Lisbon, nonoverlapping additional side effects of LND render our experimental therapy Portugal, 1994; and at the 7th World Conference worthy of consideration for the management of NSCLC patients with poor perfor- on Lung Cancer, Colorado Springs, Colorado, mance status or low tolerance to more aggressive therapeutic approaches. Cancer 1994. 1996; 7663-9. 0 1996 American Cancer Society. The authors thank Dr. John Perchard for re- viewing the article. KEYWORDS nonsmall cell lung carcinoma, lonidamine, cisplatin-epirubicin-vinde- sine regimen, toxicity. Address for reprints: Giovanni P. lanniello, M.D., Department of Medical Oncology, G. Rummo Hos- ung cancer represents the leading cause of cancer deaths in men pital, Via dell' Angelo, 1; 82100 Benevento, Italy. Land women in Western countries.',* At present, the major contribu- Received December 4, 1995; revision received tion of histologic classification is the separation of small cell lung March 11, 1996; accepted March 11, 1996. cancer (SCLC) from the other types (squamous, large cell, and adeno- 0 1996 American Cancer Society 64 CANCER July 1,1996 / Volume 78 / Number 1 carcinoma) commonly termed nonsmall cell lung can- MATERIALS AND METHODS cer (NSCLC).NSCLC accounts for about 75-80% of all From June 1990 to June 1993, a series of 158 consecu- lung cancers and can be surgically resected in only 30- tive patients were enrolled in a multicentric random- 40% of patients with limited disea~e.~.~The remaining ized study performed in 6 medical oncology or pneu- patients, with locally advanced or metastatic disease mology departments in the same geographic area of (Stages IIIB and IV), are considered unresectable. For southern Italy. Baseline eligibility criteria included a these patients, the role of chemotherapy has not yet histologically or cytologically proven diagnosis of been well defined and it is still in debate, especially NSCLC (with the exclusion of part oat cell mixed his- considering the low survival rates obtained at 5 years, t~logy)~'of Stage IIIB or IV, according to the TNM ranging from 10- to 15%.3f5-8Among the more than cla~sification;~~bidimensionally measurable indicator 50 cytotoxic agents fully evaluated in Phase 11 single lesions not previously treated with chemotherapy; age agent trials, only a few (cisplatin, mitomycin C, ifos- 5 75 years; Eastern Cooperative Oncology Group famide, Vinca alkaloid derivatives, and high dose epi- (ECOG) performance status (PS) 5 2; life expectancy rubicin) are able to induce objective response rates 5 3 months; hemoglobin level of 2 11 g/dL, leukocyte of about 15-20%.' Combination regimens containing count of 2 4000/mm3, platelet count of 2 100,000/ cisplatin in association with vinka alkaloids or etopo- mm3; and normal liver and renal function tests. A his- side, with or without a third drug such as mitomycin C, tory of prior malignant neoplasm, recent myocardial yielded objective responses ranging from 25-50%.l0-l3 infarction, or the presence of severe cardiac arrhyth- Recently, Souquet et al.14 have reviewed 7 randomized mia, serious concomitant medical illness, or brain me- clinical trials performed in 700 patients with Stage IIIB tastases were considered exclusion criteria. Patients and IV NSCLC comparing combination chemothera- who had received previous surgical or radiation treat- pies (4 of which included cisplatin) versus best sup- ment were included in the study provided that the portive therapy. From this meta-analysis, a slight sur- recurrent disease was pathologically documented and vival advantage during the first 6 months of treatment at least 4 weeks had elapsed since previous treatment was found in patients treated with chemotherapy. was completed. All patients gave their informed con- However, the quality of life is not always fully evalu- sent to participate in this trial, which was approved by the Ethical Committee for Biomedical Research of ated in these patient^.'^ the National Tumor Institute of Naples. Lonidamine (LND) is an indazol-3-carboxylic acid Patients were stratified for participating center, derivative that has been found to interfere selectively stage of disease (IIIB vs. IV), and PS (0-1 vs. 21, and with the energy metabolism of neoplastic cells as it randomly allocated to receive either cisplatin, 60 mg/ inhibits mitochondria1 hexokinase, which is normally m2 intravenously (i.v.1, epirubicin, 60 mg/m' i.v.; and absent in differentiated cells.16 Furthermore, it can vindesine, 3 mg/m' i.v. (PEV) on Day 1 every 28 days modify the lipid structure of cell membranes, increas- for a maximum of 6 courses (PEV - Arm A), or the ing their permeabi1ity.l6-l8In preclinical in vitro and same regimen as above plus LND orally 3 times a day in vivo studies, LND increased the killing of cells in- at a total dose of 225 mg (75 mg + 75 mg + 75 mg) duced by radiation, hyperthermia, and several anti- on Days 1 and 2; 300 mg (150 mg + 75 mg + 75 mg) neoplastic drugs, such as cyclophosphamide, melpha- on Days 3 and 4;375 mg (150 mg + 150 mg + 75 mg) Ian, carmustine, teniposide, mitomycin C, cisplatin, on Days 5 and 6; and 450 mg (150 mg + 150 mg + doxorubicin, and epir~bicin.'~-'~ 150 mg) from Day 7 onward (PEV + LND - Arm B). LND can be orally administered to humans, is rap- Prehydration with 2 liters of saline solution to induce idly absorbed by the gastrointestinal tract, and its forced diuresis was administered in all patients, and plasma level has a half-life of about 12 hours. It is the prophylactic antiemetic treatment was the same manufactured as 150-mg tablets. The specific side ef- in both treatment arms. Low doses of steroids were fects of LND are asthenia, myalgia, epigastralgia, or- administered to patients reporting myalgia or testicu- chialgia in men, conjunctivitis, and photophobia, lar pain possibly related to LND administration. Dose which are usually mild and disappear after discontinu- reductions or treatment delays were made on the basis ation of the drugzgIt does not produce myelotoxicity, of evaluated toxicities (according to the World Health cardiotoxicity, or nephrotoxicity and thus has no over- Organization (WHO) scoring system)34 before each lapping toxicity with other cytotoxic chemotherapy course. In cases of incomplete bone Based on the above findings, we decided to evaluate marrow recovery, dosages of drugs were reduced as the potentiating effect of LND on a combination of follows: 50% of the planned dose of epirubicin and cisplatin, epirubicin, and vindesine that showed vindesine, and 75% of the planned dose of cisplatin promising results in a previous Phase 11 trial con- were given in the presence of a leukocyte count ducted by our group.31 of 3000-3900/mm3 or a platelet count of 75,000- PEV c LND in Advanced NSCLC/lanniello et al.
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