Differential effects of N-methyl-D-aspartate receptor blockade on nociceptive somatic and visceral reflexes

OBJECTIVE: A Phase I study was conducted to determine the safety, toxicity, and maximum tolerated dose of preirradiation chemotherapy using carmustine (BCNU) and cisplatin in the treatment of high-grade gliomas. METHODS: Patients with newly diagnosed high-grade gliomas received BCNU and cisplatin after surgery, both before and during definitive radiation therapy. Preirradiation chemotherapy consisted of an administration of 40 mg/m2 BCNU on Days 1 through 3 and 30 mg/m2 cisplatin on Days 1 through 3 and 29 through 31 and repeated at 8 weeks to coincide with the start of radiation therapy. Postradiation chemotherapy consisted of an administration of 200 mg/m2 BCNU once every 8 weeks for four cycles. Radiation therapy consisted of 160-cGy fractions administered twice daily for 15 days, yielding a total dose of 4800 cGy. Dose escalation of BCNU was planned. If hematological toxicity was mild, the dose of cisplatin was to be held constant and BCNU dose escalated to 50 mg/m2 on Days 1 through 3. RESULTS: Eighteen patients were studied. The hematological toxicity was dose-limiting. Grade 3 or 4 leukopenia occurred in each of 10 patients (56%), and Grade 3 or 4 thrombocytopenia occurred in each of 9 patients (50%). Other toxicities included anorexia (94%), nausea (83%), emesis (33%), alopecia (94%), mild ototoxicity (50%), and, in one patient, death as a result of BCNU pulmonary toxicity. The median survival time was 14 months. Objective responses occurred in 45% of the patients evaluable for response. The maximum tolerated dose of this combination was 50 mg/m2 BCNU on Days 1 through 3 and 30 mg/m2 cisplatin on Days 1 through 3 and 29 through 31 before radiation and repeated in 8 weeks to coincide with the start of radiation. CONCLUSION: This schedule of the preirradiation administration of BCNU and cisplatin with accelerated hyper-fractionated radiation therapy for the treatment of high-grade gliomas provides a less toxic alternative to that of previous studies of preirradiation chemotherapy with these agents and merits further investigation.     

Phase II study of continuous infusion carmustine and cisplatin followed by cranial irradiation in adults with newly diagnosed high-grade astrocytoma

PURPOSE: To evaluate the activity and toxicity of carmustine (BCNU) and cisplatin administered as a 72-hour continuous intravenous infusion before radiation in adults with newly diagnosed high-grade astrocytomas. PATIENTS AND METHODS: Fifty-two patients with a Karnofsky performance status greater than 60 and no prior antineoplastic therapy entered this protocol. The median age of the patients was 55 years. Eighty-eight percent had glioblastoma multiforme and 12% had anaplastic astrocytomas. BCNU (40 mg/m2/d) and cisplatin (40 mg/m2/d) were administered concurrently as a 72-hour infusion every 3 to 4 weeks. Radiation was begun 4 weeks after the third cycle of chemotherapy or earlier for progressive disease. Responses required a > or = 50% reduction in contrast-enhancing volume. RESULTS: Forty patients (77%) completed three chemotherapy infusions, five (10%) received two infusions, and seven (13%) received only one. Fifty-one patients completed radiation. Seventeen (42%) patients with measurable disease had a partial response (PR) to chemotherapy, 23 (53%) had stable disease (SD), and two (4%) had progressive disease (PD) on chemotherapy. The median survival time for all patients was 13 months. Survival rates at 1, 2, 3, and 5 years were 62%, 19%, 12%, and 5%, respectively. Grade III to IV leukopenia occurred in 32% of patients; 63% received platelet transfusions and 58% required RBCs. Neutropenic fevers were rare and no intracranial hemorrhages or treatment-related deaths were noted. Nausea, vomiting, peripheral neuropathy, hearing loss, and thromboembolic events were relatively common. CONCLUSION: This chemotherapy regimen appears to have significant activity and may prolong survival in adults with newly diagnosed high-grade astrocytoma.     

Radiotherapy and concomitant weekly 1-hour infusion of paclitaxel in the treatment of head and neck cancer--results from a Phase I trial

PURPOSE: To define the maximum tolerated dose (MTD) by describing the dose-limiting toxicity (DLT) of weekly paclitaxel (PAC) given as a 1-h I.V. infusion in patients with head and neck cancer concomitant to irradiation. METHODS AND MATERIALS: Patients with unresectable or incompletely resected head and neck cancer were enrolled into a prospective, dose-escalating Phase I study. Toxicity was graded according to the WHO toxicity score. MTD dose was defined when two out of six patients developed DLT. The starting dose of PAC was 20 mg/m2 once weekly I.V. over 60 min, with a subsequent dose escalation of 10 mg/m2 in cohorts of three new patients. Radiation therapy was administered in three field technique over 6-7 weeks in 2.0 Gy/daily fractions for 5 consecutive days/week up to total doses of 60-70 Gy. RESULTS: From 1994-1996, 18 patients completing three dose levels were included into the study. Altogether, 101 courses of chemotherapy were evaluable for toxicity. On the second dose level (30 mg/m2) one of three patients experienced DLT with Grade IV mucositis. On the next dose level with 40 mg/m2 PAC weekly one patient experienced DLT being prolonged Grade III mucositis. From the following three patients required, two patients showed no DLT. The third patient showed mucositis of WHO Grade 4 and died from hemorrhage caused by a rupture of the a pharyngeal wall. Dose level 2 (30 mg/m2) was repeated and one of the three newly treated patients again suffered from mucositis WHO Grade 4. CONCLUSION: When PAC is given weekly as a 1-h infusion concomitant to radiotherapy, MTD is 30 mg/m2 with mucositis being DLT; hematological and further nonhematological toxicity is mild.     

Specificity of the BAX polymerase chain reaction system for detection of the foodborne pathogen Listeria monocytogenes

PURPOSE: The purpose of this study was to evaluate the toxicity and efficacy of twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes. METHODS AND MATERIALS: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and para-aortics at 4- to 6-h intervals, 5 days per week. The total external radiation doses were 24 to 48 Gy to the whole pelvis, 12 to 36 Gy parametrial boost, and 48 Gy to the para-aortics with an additional boost to a total dose of 54 to 58 Gy to the known metastatic para-aortic site. One or two intracavitary applications were performed to deliver a total minimum dose of 85 Gy to point A. Cisplatin (75 mg/m2, days 1 and 22) and 5-FU (1000 mg/m2/24 h x 4 days; days 1 and 22) were given for two or three cycles. RESULTS: Twenty-nine patients with clinical Stages I to IV carcinoma of the cervix with biopsy-proven para-aortic lymph nodes were enrolled in this study. Hyperfractionated external radiotherapy was completed in 86% (25 of 29). Brachytherapy was given in two applications to 48% (14 of 29), 31% (9 of 29) had one intracavitary application, 14% (4 of 29) had no brachytherapy, one had three applications, and one had five HDR applications. Radiotherapy was completed per protocol in 69%. Three courses of chemotherapy were given to 24% (7 of 29), 72% (21 of 29) received two courses, and one patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Radiotherapy toxicity was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. One Grade 5 toxicity occurred and the patient died from a myocardial infarction from chemotherapy and radiotherapy colitis during her course of therapy. The median follow-up time was 18.9 months. The overall survival estimates were 59% at 1 year and 47% at 2 years. The probability of local-regional failure was 38% at 1 year and 49% at 2 years. The probability of disease failure at any site was 45% at 1 year and 59% at 2 years. CONCLUSION: The results suggest that twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (31%, 9 of 29) of Grade 4 nonhematologic toxicity. One patient died from complications of therapy. Radiotherapy was completed per protocol in 69%. The survival estimates appear no better than standard fractionation radiotherapy without chemotherapy. Additional follow-up is necessary for long-term survival estimates.     

Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer

BACKGROUND: Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. PURPOSE: On the basis of these results, the Radiation Therapy Oncology Group (RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. METHODS: Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m2) on days 1 and 29 and 5 mg/m2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). RESULTS: Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy--46%, 11.4 months; chemotherapy plus radiotherapy--60%, 13.8 months; and hyperfractionated radiation therapy--51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P = .03). CONCLUSIONS: In "good-risk" patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage.     

Graves'' ophthalmopathy and tobacco smoking

BACKGROUND: Despite standard treatment, surgery and/or radiotherapy, most patients with muscle invasive bladder carcinoma die early of distant metastasis. CMV chemotherapy has demonstrated a high response rate with moderate toxicity in advanced bladder carcinoma. In an attempt to eradicate undetectable metastatic disease and to avoid cystectomies, 36 patients were given up-front CMV. MATERIALS AND METHODS: The patients were 34 males and 2 females with a median age of 62 years (45-75); performance status 0-1 (WHO) in 34 patients; histology: 34 transitional carcinomas and 2 anaplastic carcinomas (grade II: 8, grade III: 28). Clinical staging was T2-3a: 19 patients, T3b: 14 patients and T4: 3 patients. Nineteen patients had complete trans-urethral resections (TUR) at diagnosis. The multimodal protocol started with 3 CMV courses (cisplatin 100 mg/m2 i.v. d 1, methotrexate 30 mg/m2 i.v. d 1, 8 and vinblastine 4 mg/m2 i.v. d 1, 8 every 3 weeks). Patients who yielded clinical complete responses (cCR) by cystoscopy, TUR biopsies and imaging techniques were given 3 additional courses. Cystectomy was performed in non-cCR patients and as salvage treatment. RESULTS: Following 3 CMV cycles, 29 patients (81%) responded (20 cCR and 9 cPR) and 7 (19%) did not (NR). Currently, with a median follow-up of 23.5 months (13-59), 13 have died and 23 are alive, 12 of whom retain their bladders. The projected overall survival is 51% at 4.5 years. Grade 3-4 hematological toxicity was presented in 8% of the cycles. No toxic deaths were observed. CONCLUSION: The CMV regimen, after TUR, produces a high response rate with tolerable toxicity. Bladders could be preserved in half of the CR patients.     

Drug resistance patterns among tuberculosis patients in Rome, 1990-1992

PURPOSE: A Phase II study to evaluate the effect of a five-drug regimen, VP-16, ifosfamide, cisplatin, vinblastine, and bleomycin (VIP/VB) on complete response rate, continuous disease-free survival, and toxicity in patients with advanced germ-cell tumor. PATIENTS AND METHODS: Twenty male patients with a histologic diagnosis of advanced-stage germ-cell cancer, previously untreated with chemotherapy, received the following: etoposide 75 mg/m2 i.v. days 1-5; ifosfamide (with mesna uroprotection) 1.2 g/m2 i.v. days 1-5; cisplatin 20 mg/m2 i.v. days 1-5; vinblastine 0.18 mg/kg i.v. day 1; bleomycin 30 units i.v. day 1; filgrastim 5 micrograms/kg days 7-16. Chemotherapy was given every 3 weeks (bleomycin weekly x 12) for four courses. RESULTS: All patients entered were evaluable for toxicity, response, and survival. Eleven of 20 (55%) achieved complete remissions with chemotherapy alone and an additional 5 (25%) were rendered disease-free with surgical resection of teratoma (3) or viable cancer (2). Two patients relapsed at 4 and 5 months from complete remission (CR). There was one treatment-related death, from bleomycin lung toxicity after thoracotomy. Thirteen patients (65%) are alive and continuously free of disease, with a median follow-up of 20 months and a minimal follow-up of 12 months. Hematologic toxicity was most common, with 16 patients (80%) having grade 3 or 4 leukopenia. CONCLUSIONS: VIP/VB appears to be a very active regimen in advanced disseminated germ-cell cancer. Hematological toxicity was severe but manageable.     

Mitomycin C, vinblastine, and carboplatin regimen in patients with nonsmall cell lung cancer. A phase II trial

BACKGROUND: The mitomycin C, vinblastine, and cisplatin (MVP) combination is one of the most frequently used in the palliative setting, but it produces considerable toxicity. Carboplatin and cisplatin have different patterns of toxicity. The goal of this study was to evaluate a combination similar to MVP, using carboplatin instead of cisplatin to render it more feasible in an outpatient setting. METHODS: Inclusion criteria for this study included: inoperable patients or patients relapsing after previous surgery, with nonsmall cell lung carcinoma (NSCLC), a performance status (PS) > 50%, and no previous chemotherapy. The chemotherapy regimen included carboplatin, 300 mg/m2 on Day 1; mitomycin, 8 mg/m2 on Day 1; and vinblastine, 4 mg/m2 on Days 1, 8, and 15 (on Day 15 vinblastine was delivered only in the first cycle) (MVC) every 3 weeks for at least 3 cycles. RESULTS: From August 1991 until August 1994, 70 patients entered the trial. All were evaluable for toxicity and response. The median age was 62 years (range, 40-73 years). The male/female ratio was 60:10 (86%:14%); the ratio of Stage III to Stage IV disease was 26:44 (37%:63%); and the ratio of PS > 70 to < or = 70 was 49:21. A total of 296 cycles (median, 4 [range, 1-6 cycles] per patient) were delivered, 280 of 296 (95%) in an outpatient setting with only 4 patients requiring hospitalization for treatment delivery. Overall response rate (RR) was 38.6% (95% confidence interval [CI], 27-51%) (1 complete response, 1.5%; 26 partial responses, 37.1%). Median duration of response was 9.8 months (range, 2-27 months). In Stage III patients the RR was 42% and in Stage IV patients it was 34%. Overall median survival was 9.5 months (95% CI, 6.8-15.3 months). Survival at 1 year was 39% (standard error [SE] 3.6%) and was 11% at 2 years (SE 3.6%). In Stage III patients median survival was 13 months and the 1-year survival rate was 54% (SE 10%); Stage IV patients had a median survival of 7.4 months and a 1-year survival rate of 28% (SE 7%). Delivered dose intensity was: carboplatin, 71%; vinblastine, 60%; and mitomycin C, 77% of the planned dose intensity. The back calculation of carboplatin area under the curve (AUC) with Calvert's formula and with the Cockcroft-Gault glomerular filtration rate estimation, showed a median AUC value of 4 (range, 2-8). Using the more precise Chatelut formula, AUC was again 4 (range, 2-7). Hematologic toxicity was the major side effect; Grades 3 and 4 leukopenia were observed in 34% and 6% of patients, respectively, and Grades 3 and 4 thrombocytopenia in 25% and 4% of patients, respectively. Grade 2 infection occurred in 10% of patients, with only 1 case of sepsis; severe constipation and Grade 2 alopecia occurred in only 1 patient; and no case of higher than Grade 1 nephrotoxicity was observed. No pulmonary toxicity was observed. Compliance with treatment was good with only one patient refusal after the first cycle. CONCLUSIONS: Chemotherapy for advanced NSCLS is still controversial, because effectiveness in terms of RR and symptom control must be weighed against treatment toxicity and costs. From our study it appears that MVC is easy to deliver in an outpatient setting, and has good patient compliance, low toxicity profile, and promising RR and response duration. The substitution of carboplatin for cisplatin in regimens for advanced NSCLC should be considered.     

Escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin plus recombinant human granulocyte colony-stimulating factor in advanced urothelial carcinoma: an Eastern Cooperative Oncology Group trial

PURPOSE: This multicenter cooperative group phase I/II trial evaluated the toxicity and efficacy of escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) with recombinant human granulocyte colony-stimulating factor (rhG-CSF) in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: From November 1990 through October 1991, 35 patients with advanced urothelial cancer previously untreated with chemotherapy were treated with escalated dosages of M-VAC (M-VACII). In patients with prior pelvic radiotherapy, standard M-VAC (M-VACI) was administered plus rhG-CSF. For other patients, M-VACII dosages were methotrexate 40 mg/m2 (days 1, 15, and 22), vinblastine 4 mg/m2 (days 2, 15, and 22), doxorubicin 40 mg/m2 (day 2), and cisplatin 100 mg/m2 (day 2). In addition, rhG-CSF was administered at a dosage of 300 micrograms subcutaneously on days 4 to 11. Cycles were repeated every 4 weeks. For patients who tolerated the first course of therapy, subsequent escalation by 25% of all drugs was performed. RESULTS: Six complete responses and 15 partial responses were observed (60%; 95% confidence interval, 42% to 76%). The median duration of response was 4.6 months, and the median survival time was 9.4 months (range, 0.5 to 23.5+). Twenty-eight of 35 patients experienced grade 3 or 4 leukopenia, including 14 patients who developed fever associated with neutropenia. Eight (23%) early deaths were observed. CONCLUSION: This regimen (M-VACII) with escalated dosages of M-VAC was associated with significant toxicity and had no apparent benefit over M-VACI therapy with regard to complete response rate or survival. Further evaluation of the dose-intensity of the components of this regimen in this disease is likely to be of limited benefit to patients.     

Adjuvant therapy with dibromodulcitol and BCNU increases survival of adults with malignant gliomas. EORTC Brain Tumor Group

OBJECTIVE: We tested adjuvant chemotherapy combining dibromodulcitol (DBD) and bischloroethylnitrosourea (BCNU) given postoperatively to adults with newly diagnosed supratentorial malignant gliomas. METHODS: We enrolled 269 patients, 255 of whom were eligible. After surgery, we treated all patients with radiation therapy, using a median dose of 60 Gy given in 30 fractions. After randomization, patients in the chemotherapy group also received (1) six weekly courses, administered during irradiation, of DBD 700 mg/m2 and (2) one to nine (median, four) courses, administered during the first year following radiation therapy, of DBD 1,000 mg/m2 on day 1 and BCNU 150 mg/m2 on day 2, with the course being repeated every 6 weeks. RESULTS: Patients treated with radiation therapy along with DBD plus BCNU (group 2) had significantly longer survival time (p = 0.044) and time to progression (p = 0.003) than did those treated with radiation therapy alone (group 1). The median survival time was 13.0 months for group 2 and 10.4 months for group 1; the median time to progression was 8.1 months for group 2 and 6.7 months for group 1. The percentage of patients alive at 18 and 24 months was 34% and 21% in group 2 compared with 21% and 12% in group 1. CONCLUSION: DBD plus BCNU is an effective adjuvant therapy for malignant glioma.     

术后辅助放化疗与单纯手术治疗在胃腺癌中的比较

Objective: Despite resection with curative intent, a majority of patients with gastric cancer will develop disease recurrence. Postoperative adjuvant chemo-radiotherapy increase the curability of surgery, prevent local recurrence and improve survival. Methods: Between December 2005 and February 2010, 33 patients were eligible for the study, 17 patients were randomly assigned for chemo-radiotherapy (GI) and 16 patients with surgery alone (GII). Patients in GI received chemotherapy (fluorouracil, 425 mg/m2/day, and leucovorin, 20 mg/m2/day, for 5 days) was initiated on day 1 and was followed by chemo-radiotherapy beginning 28 days after the start of the initial cycle of chemotherapy. Chemo-radiotherapy consisted of 4500 cGy of radiation at 180 cGy/day, five days/week for five weeks, with fluorouracil (400 mg/m2/day) and leucovorin (20 mg/m2/day) on the first four and the last four days of radiotherapy. One month after the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg/m2/day) plus leucovorin (20 mg/m2/day) were given one month apart. Results: Grade 3 gastrointestinal toxicity was more common (23.2%) while grade 3 hematological toxicity were (5.8%). Both 3-year survival (53%) and disease free survival (41%) rates were higher in GI than in GII in which they were 43.7% and 31% respectively. Relapse rate was higher in GII (56.3%) than in GI (35.3%). Conclusion: The present study revealed that chemo-radiotherapy after gastric resection in patients with gastric adenocarcinoma improves survival and relapse rates with manageable toxicities. However, studies with larger number of patients are recommended to confirm our results.     

Dynamic imaging of the normal pelvic floor

PURPOSE: To present tolerance and toxicity information on previously untreated high-risk early-stage and advanced-stage primary epithelial ovarian cancer patients treated with adjuvant 3-hour paclitaxel and carboplatin. PATIENTS AND METHODS: Consecutive patients with high-risk early-stage and advanced-stage epithelial ovarian cancer underwent maximal surgical debulking and/or staging. Paclitaxel (175 mg/m2) was infused over 3 hours followed by a 30-minute carboplatin infusion (area under the plasma concentration time curve = 7.0-7.5 mg/mL/min) for a planned six (q 21 day) courses. RESULTS: Twenty-two patients underwent 132 cycles and were evaluable for toxicity. Myelosuppression was dose-limiting. Grade 4 granulocytopenia occurred in 31% of the cycles. Grade 3 and 4 thrombocytopenia was uncommon (5%, 1%) and predictable. Delay in administration was necessary in 10 of 132 (7.6%) cycles (5 of 22 patients). Eight of these 10 delays were 7 days. Seventeen of 22 (77%) patients completed therapy without a delay. Non-hematologic toxicity was mild. A significant individual weight gain of 2.5 kg was noted. Among 19 patients with advanced disease, 16 had a complete clinical remission after six cycles of therapy. Nine patients with stage IIB-IV disease have undergone reassessment procedures (four pathologic complete responses, three microscopic positive, two macroscopic positive). Sixteen of 22 (77%) have no evidence of disease, four have no evidence of disease following a secondary therapy, one is under therapy with salvage chemotherapy, and one is dead of disease. Median follow-up is 14 months (range: 6-30 months). Comparatively, the mean carboplatin dose administered was 440 mg/m2 (95% CI, 428-486 mg/m2). CONCLUSION: Paclitaxel and carboplatin administered in this design are well tolerated, with predictable and acceptable hematologic and nonhematologic toxicity. Dose-limiting toxicity is granulocytopenia with relative platelet sparing. Outpatient administration is safe.     

Paclitaxel in combination chemotherapy with radiotherapy in patients with unresectable stage III non-small-cell lung cancer

PURPOSE: The addition of combination chemotherapy to standard radiation therapy has improved treatment for locally unresectable non-small-cell lung cancer. In this phase II study, we evaluated the toxicity and efficacy of a novel chemotherapy regimen that included paclitaxel, cisplatin, and etoposide plus concurrent radiation therapy in this group of patients. PATIENTS AND METHODS: Thirty-three patients with previously untreated, unresectable stage III non-small-cell lung cancer (stage IIIA, 11 patients; stage IIIB, 22 patients) initially received two courses of chemotherapy, which included paclitaxel 135 mg/m2 by 1-hour infusion on day 1, cisplatin 60 mg/m/ intravenously (i.v.) on day 2, and etoposide 100 mg/m2 i.v. on days 1, 2 and 3. On week 6, radiation therapy (60 Gy in 30 fractions) was initiated in conjunction with two additional courses of chemotherapy: paclitaxel 135 mg/m2 i.v. by 1-hour infusion on day 1, cisplatin 5 mg/m2 i.v. on days 2- to 10, and etoposide 25 mg/m2 on days 1 to 10. RESULTS: This combined modality program was feasible and well tolerated by most patients. During the two courses of induction chemotherapy, grade 3 or 4 myelosuppression occurred in only six patients (18%). Esophagitis was common during combined modality therapy (grade 3, 10 patients; grade 4 five patients). Forty-two percent of patients had partial response after two courses of induction therapy, and 82% of patients had an objective response at completion of therapy. Twelve patients (36%) had a complete response. Nineteen patients remain progression-free at a median of 8 months; the median survival time has not been reached. CONCLUSION: This paclitaxel-containing combined modality therapy is feasible and highly active in patients with inoperable stage III lung cancer. Esophagitis is the most common severe toxicity with this program. Further studies with paclitaxel-containing combination regimens in patients with stage III non-small-cell lung cancer are indicated.     

A pilot study of nedaplatin and etoposide for recurrent gynecological malignancies

Nedaplatin is a new analogue of cisplatin with similar efficacy but less renal toxicity. We assessed the efficacy and toxicity of nedaplatin and etoposide for recurrent gynecological malignancies. Eight patients were treated with 100 mg/m2 of nedaplatin (day 1) and 70 mg/m2 of etoposide (days 1, 3, and 5 ) every 4 weeks. A total of 17 courses was given. Grade 3/4 leucopenia and thrombocytopenia occurred, but was manageable. The response rate was 37.5% (partial response n=3; no change n=4; progressive disease n=1). In conclusion, a phase II study of this regimen for recurrent gynecological malignancies is warranted.     

Combined antineoplastic and antiretroviral therapy for patients with Hodgkin's disease and human immunodeficiency virus infection. A prospective study of 17 patients. The Italian Cooperative Group on AIDS and Tumors (GICAT)

BACKGROUND: The optimal therapeutic approach for patients with Hodgkin's disease (HD) and human immunodeficiency virus (HIV) infection is unknown. In an attempt to improve the results obtained with standard chemotherapy and to decrease the occurrence of opportunistic infections (OI) during chemotherapy and follow-up observed in a previous experience, the authors designed a prospective combined antineoplastic and antiretroviral approach. METHODS: Between March 1989 and March 1992, 17 consecutive previously untreated patients (median age, 30 years) with HD and HIV infection were enrolled. They had Stage III and IV or Stage I and II disease with adverse prognostic factors. The median CD4+ cell count was 184/microliters. Patients were stratified in two groups and treated accordingly. Group A was made up of patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of less than 3 and without OI. These patients received epirubicin 70 mg/m2 intravenously on day 1, bleomycin 10 mg/m2 IV on day 1, and vinblastine 6 mg/m2 IV on day 1 (regimen EBV). Group B was made up of patients with PS of 3 or greater or previous OI who had received a 50% reduced dose of epirubicin and vinblastine and a full dose of bleomycin. Courses were repeated every 21 days for six cycles. Zidovudine was given at the dose of 500 mg/day from the beginning of chemotherapy in Group B and after the third cycle in Group A. RESULTS: Overall, 14 of 17 (82%) patients had an objective response and 9 of 17 (53%) achieved a complete remission (CR) of disease for a median duration of 20 months. Toxicity was moderate with Grade 3-4 leukopenia in eight patients and Grade 3 thrombocytopenia in one patient. Thirteen of 17 patients received zidovudine as planned with a median duration of 9 months. Only one patient had OI during or after chemotherapy (median follow-up, 11 months). No worsening of HIV markers during the combined therapy was seen, with the median CD4+ cell count before and after therapy being 184/microliters and 203/microliters, respectively. The median survival time was 11 months, with an actuarial survival rate of 48% at 36 months. The median survival time for the nine patients with CR has not been reached at the time of this analysis. CONCLUSIONS: These results revealed the feasibility and the activity of the combination of EBV regimen and zidovudine. Objective response rate seems similar to those previously observed in patients receiving standard chemotherapy, but only one patient had OI, and this compares favorably with the 16 OI observed in 28 patients treated with standard chemotherapy (6% versus 57%) in the authors' previous experience. Thus, it seems that the addition of antiretroviral therapy to the EBV regimen decreased the occurrence of OI during chemotherapy or follow-up.     

Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: radiation therapy oncology group protocol 91-06

PURPOSE: Patients with locally advanced inoperable non-small-cell lung cancer (NSCLC) have a poor clinical outcome. We conducted a prospective study to evaluate the merit of chemotherapy administered concurrently with hyperfractionated thoracic radiation therapy. PATIENTS AND METHODS: Seventy-nine patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of concurrent chemoradiation therapy. Treatment consisted of two cycles of oral etoposide 100 mg/d (50 mg/d if body-surface area [BSA] < 1.70 m2), intravenous cisplatin 50 mg/m2 on days 1 and 8, and hyperfractionated radiation therapy 5 days per week (1.2 Gy twice daily > 6 hours apart; total 69.6 Gy). RESULTS: Seventy-six assessable patients with a Karnofsky performance status > or = 60 and adequate organ function who had received no prior therapy were evaluated for clinical outcome and toxic effects. After a minimum follow-up duration of 21 months, the 1- and 2-year survival rates and the median survival duration were 67%, 35%, and 18.9 months overall; they were 70%, 42%, and 21.1 months for patients with weight loss of < or = 5%. Toxicity was significant; 57% developed grade 4 hematologic toxicity, 53% grade 3 or 4 esophagitis, and 25% grade 3 or 4 lung toxicity. However, only 6.6% of patients had grade 4 or lethal nonhematologic toxicity, which included three treatment-related deaths (two of pneumonitis and one of renal failure). CONCLUSION: Concurrent chemoradiation therapy with oral etoposide and cisplatin plus hyperfractionated radiation therapy is feasible. The survival outcome from this regimen compares favorably with that of other chemoradiation trials and even of multimodality trials that have included surgery.     

Concurrent cisplatin, prolonged oral etoposide, and vincristine plus chest and brain irradiation for limited small cell lung cancer: a phase II study of the Southwest Oncology Group (SWOG-9229)

PURPOSE: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. METHODS AND MATERIALS: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m2 (days 1-14, 29-42, and 57-70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. RESULTS: Among 56 eligible patients, 93% had SWOG performance status 0-1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimum follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3). CONCLUSION: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.     

Mineral waters: instead of soap or better than soap?

Prolonged oral etoposide is an active regimen in small and nonsmall cell carcinoma of the lung, carcinomas of the breast and ovary, germ cell tumors, and in lymphoma. A Phase II trial was conducted by the Gynecologic Oncology Group to determine its activity in endometrial carcinoma. Twenty-six patients with advanced or recurrent endometrial carcinoma were entered into study; one patient was ineligible because of an incorrect cell type. The remaining eligible patients were treated with etoposide at a starting dose of 50 mg/m2/day (30 mg/m2/day with prior radiotherapy) for 21 days. Based on hematologic toxicity, a dose escalation to a maximum dose of 60 mg/m2/day was prescribed. Twenty-two patients were evaluable for response and 25 were evaluable for toxicity. Fourteen had received prior radiotherapy and 24 had received prior chemotherapy. A median of two courses were given (range, 1-10). Grade 3 or 4 leukopenia occurring in 52% was the most common complication (grade 3, 36%; grade 4, 16%). Grade 4 thrombocytopenia occurred in 16% of patients. There were no objective responses including four patients with serous papillary carcinoma. This regimen is not significantly active as second-line therapy in endometrial carcinoma.     

Treatment of small cell carcinoma of the lung using methyl-CCNU (NSC-95441) combined with cyclophosphamide (NSC-26271) and vincristine (NSC-67574) in a 3-week schedule

Twenty-six patients with small cell carcinoma of the lung were treated with a combination of methyl-CCNU (75 mg/m2 orally), cyclophosphamide (750 mg/m2iv), and vincristine (1.4 mg/m2iv) once every 3 weeks and followed for 2-56 weeks (mean, 24 weeks). An average of seven treatments were given per patient. Myelotoxicity was mild to moderate with no white blood cell count (wbc) less than 1000 cells/mm3 and no platelet count less than 25,000 cells/mm3. Six patients (23%) had a wbc of 1000-2000 cells/mm3 and two (8%) had a platelet count of 25,000-75,000 cells/mm3. Sixty-eight persons of the projected dose of methyl-CCNU was given. Fourteen of 22 patients with measurable disease (54%) responded. Of 14 patients who had received no prior treatment 64% responded with a median survival duration of 40 weeks. Complete responses occurred only in patients without prior radiation therapy or chemotherapy. We conclude that methyl-CCNU may be given with an acceptable level of toxicity in an every 3-week schedule and that the combination of cyclophosphamide, methyl-CCNU, and vincristine warrants further evaluation in the treatment of small cell carcinoma of the lung.     

Short-course induction chemoradiotherapy with paclitaxel for stage III non-small-cell lung cancer

BACKGROUND: This study assessed toxicity, tumor response, disease control, and survival after short-course induction chemoradiotherapy and surgical resection in patients with stage III non-small-cell lung carcinoma. METHODS: Forty-five patients with stage III non-small-cell lung carcinoma received 12-day induction therapy of a 96-hour continuous infusion of cisplatin (20 mg/m2 per day), 24-hour infusion of paclitaxel (175 mg/m2), and concurrent accelerated fractionation radiation therapy (1.5 Gy twice daily) to a dose of 30 Gy. Surgical resection was scheduled for 4 weeks later. Postoperatively, a second identical course of chemotherapy and concurrent radiation therapy (30 to 33 Gy) was given. RESULTS: Induction toxicity resulted in hospitalization of 18 (40%) patients for neutropenic fever. No induction deaths occurred. Of 40 (89%) patients who underwent thoracotomy, resection for cure was possible in 32 (71%) patients. Pathologic response was noted in 21 (47%) patients, and 14 (31%) were downstaged to mediastinal node negative (stage 0, I, or II). At a median follow-up of 19 months, 24 patients were alive, 10 with recurrent disease. Of 21 deaths, 16 were from recurrent disease, three were from treatment, and two were unrelated. Recurrent disease was distant in 21 patients, distant and locoregional in 2, and locoregional in 3. The Kaplan-Meier projected 24-month survival is 49%. Projected 24-month survival is 61% for stage IIIA, 17% for stage IIIB (p = 0.035); 84% for pathologic responders, 22% for nonresponders (p<0.001); 83% for downstaged patients (stage 0, I, or II), 33% for those not downstaged (p = 0.005); and 63% for resectable patients, 14% for unresectable patients (p = 0.007). CONCLUSIONS: We conclude that short-course neoadjuvant therapy with paclitaxel (1) has manageable toxicity and a low treatment mortality, (2) results in good tumor response and downstaging, (3) provides excellent locoregional control with most recurrences being distant, and (4) has improved the median survival compared with historical controls. Survival was better in stage IIIA patients, resectable patients, pathologic responders, and patients downstaged to mediastinal node negative disease (stage 0, I, or II).