Northern California Oncology Group Research Articles

Phase III randomized study of radiotherapy plus procarbazine, lomustine, and vincristine with or without BUdR for treatment of anaplastic astrocytoma: final report of RTOG 9404

Purpose This study was an open-label, randomized Phase III trial in newly diagnosed patients with anaplastic glioma other than glioblastoma multiforme comparing external beam radiotherapy (EBRT) plus adjuvant procarbazine, cyclohexylchloroethylnitrosurea (lomustine), and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-h infusion each week of RT. Methods and materials Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible. A central pathology review was accomplished for most patients, but was not mandated before registration. The study had initially opened as a Northern California Oncology Group trial in 1991, becoming an Intergroup Radiation Therapy Oncology Group (RTOG), Southwestern Oncology Group and the North Central Cancer Treatment Group study in July 1994. A total accrual of 293 patients was planned for the sample size, using survival as the primary end point. The experimental arm (RT/BUdR + PCV) was to be compared with the control arm (RT + PCV) using a one-sided α = 0.05, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after enrollment completion. Results Between July 1994 and August 1996, 134 patients were randomized to EBRT + PCV (non-BUdR patients) and 134 to EBRT/BUdR + PCV (BUdR patients). The study was closed before the full-anticipated accrual on the basis of an interim analysis that predicted no survival benefit for the BUdR arm. Of the 268 patients, 41 and 37, respectively, were ineligible or canceled primarily on the basis of the central pathology review findings. Thus, 93 patients and 97 patients were eligible/analyzable in the non-BUdR and BUdR arms, respectively. Patient characteristics were well balanced in both arms, with most <50 years old and in the RTOG recursive partitioning analysis (RPA) Class I category. The minimal potential follow-up was 4.6 years. The median survival for non-BUdR patients was 4.1 years compared with 4.6 years for the BUdR patients ( p = 0.61). The 4-year overall survival rate was 51% in both arms. For RPA Class I patients (the best prognostic class), the median survival had not been reached for non-BUdR patients (4-year survival rate 61%) and was 5.6 years for BUdR patients (4-year survival rate 64%; p = 0.91). Each arm was also compared with the RTOG historical database for RPA Class I patients with no statistically significant difference found in overall survival (BUdR vs. historical, p = 0.31 and non-BUdR vs. historical, p = 0.48). Grade 4 toxicity occurred in 15 and 17 patients in the non-BUdR and BUdR arms, respectively, with one treatment-related death in the BUdR group. Conclusion No survival advantage was noted by adding BUdR to EBRT and PCV in this patient population

WEEKLY MITOMYCIN C FOLLOWED BY MONTHLY BACILLUS CALMETTE-GUERIN OR ALTERNATING MONTHLY INTERFERON-α2B AND BACILLUS CALMETTE-GUERIN FOR PROPHYLAXIS OF RECURRENT PAPILLARY SUPERFICIAL BLADDER CARCINOMA

We evaluated alternatives to bacillus Calmette-Guerin (BCG) monotherapy using a new combination of chemotherapy and immunotherapy for recurrent superficial bladder carcinoma. A total of 236 patients with frequently recurrent stage Ta or T1 bladder tumors were enrolled in our prospective, randomized, multicenter Finnbladder IV study. The initial mitomycin C instillation was instilled in all patients perioperatively after transurethral resection, followed by 4 weekly instillations of mitomycin C. Thereafter patients were randomized to receive monthly for up to 1 year BCG only or interferon-alpha2b and BCG alternating monthly. Primary end points were time to initial recurrence, recurrence rate (number of recurrences per patient-year) and recurrence index (number of recurrent tumors per patient-year). Of the 236 randomized patients 205 were eligible for study with a median overall followup of 30.7 months. Monthly BCG was superior to alternating monthly interferon-alpha and/or BCG with respect to time to initial recurrence (log rank test p <0.00001) as well as recurrence rate (0.4 versus 0.9, p <0.00001) and index (0.9 versus 3.0, p <0.00001). Side effects were limited. Monthly BCG given for up to 1 year preceded by perioperative and an additional 4 weekly mitomycin C instillations is a well tolerated mode of instillation therapy, providing excellent tumor control comparable to that of the best reported instillation regimens. No benefit was obtained by alternating interferon-alpha2b with BCG.

GEMCITABINE PLUS CISPLATIN FOR ADVANCED TRANSITIONAL CELL CARCINOMA OF THE URINARY TRACT: A PHASE II MULTICENTER TRIAL

We determined the activity and toxicity of gemcitabine plus cisplatin in patients with inoperable or metastatic transitional cell carcinoma of the urinary tract. A total of 54 patients with transitional cell carcinoma, measurable disease and Eastern Cooperative Oncology Group performance status 2 or greater were enrolled in this multicenter phase II trial. Previous adjuvant or neoadjuvant therapy for locally advanced disease was acceptable if it had been completed more than 1 year before study entry. Every 4 weeks patients received 1,000 mg./m.2 gemcitabine intravenously on days 1, 8 and 15, and 70 mg./m.2 cisplatin intravenously on day 2. All patients were evaluable for response and toxicity. Notably only 7 of the 54 patients (13%) previously received chemotherapy in an adjuvant or neoadjuvant setting. Overall we observed 26 objective responses (48%), of which 15% were complete. Median time to progression was 23 weeks and median survival was 54 weeks. Treatment was well tolerated. The main toxicities were leukopenia (grade 3 in 28% and grade 4 in 11% of patients), anemia (grade 3 in 34% and grade 4 in 6%) and thrombocytopenia (grade 3 in 14% and grade 4 in 6%). Other relevant side effects were nausea and vomiting in 20% of cases, fever in 24%, alopecia in 22%, renal failure in 7.4% and mucositis in 2%. Combined cisplatin plus gemcitabine is highly active in advanced transitional cell carcinoma of the urinary tract with manageable toxicity. The response rate, time to treatment failure and overall survival appeared to be comparable to those achieved with combined methotrexate, vinblastine, doxorubicin and cisplatin. Conversely toxicity appeared lower. Evaluation of this regimen in randomized studies with methotrexate, vinblastine, doxorubicin and cisplatin is strongly suggested.

A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404

Purpose: This study was an open label, randomized Phase 3 trial in newly diagnosed patients with anaplastic glioma comparing radiotherapy plus adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherapy. Methods and Materials: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished, but was not mandated prior to registration. The study had initially opened as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor progression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after completion of enrollment. Results: As of July 1996, 281 patients had been randomized; 53 (20%) were ineligible, primarily based upon central pathology review, and another 39 cases were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In February 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BUdR plus PCV respectively (one-sided, p = 0.96). The conditional power analysis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in the two arms seem to be due to early deaths in the BUdR arm, not related to toxicity of the treatment. Conclusions: Despite encouraging Phase 2 results with BUdR, it is unlikely that a survival benefit will be seen. A final study analysis will not be done for at least 3 more years.

Influence of bromodeoxyuridine radiosensitization on malignant glioma patient survival: A retrospective comparison of survival data from the Northern California Oncology Group (NCOG) and Radiation Therapy Oncology Group trials (RTOG) for glioblastoma multiforme and anaplastic astrocytoma

Purpose : To examine the effect treatment using Bromodeoxyuridine (BrdU) during radiation therapy on malignant glioma patient survival by comparing historical survival data from several large clinical trials. Methods : A retrospective analysis of patient survival by comparing historical survival data from several large clinical trials. 79-18, and 83-02 and the Northern California Oncology Group (NCOG) study 6G-82-1 was conducted. Patient data was supplied by both groups, and analyzed by the RTOG. Pretreatment characteristics including age, extent of surgery, Karnofsky Perfomance Status (KPS), and histopathology were collected; the only treatment variable evaluated was the the use of BrdU during radiation therapy. Radiation dose, dose-fractionation schedule, use of chemotherapy, and/or type of chemotherapy was not controlled for in the analyses. Univariate and multivariate analyses were conducted to examine the potential treatment effect of BrdU on patient survival. Results : Data from 334 patients treated with BrdU on NCOG 6G-82-1 and 1743 patients treated without BrdU on 3 RTOG studies was received. Patients were excluded from the review if confirmation of eligibility could not be obtained, if the patient was ineligible for the study they entered, if central pathology review was not done, or if radiotherapy data was not available. Patients treated according to the RTOG studies had to start radiatherapy within 4 weeks of surgery; no such restriction existed for the NCOC studies. To ensure comparability between the studies, patients from the NCOG studies who began treatment longer than 40 days from surgery were also excluded. The final data set included 296 cases from the NCOG studies (89%) and 1478 cases from the RTOG studies (85%). For patients with glioblastoma multiforme (GBM) the medial survival was 9.8 months in the RTOG studies and 13.0 months in the NCOG trial ( p < 0.0001). For patients with AA the medial was 35.1 months for the RTOG studies and 42.8 30 years of age, across the extent of surgery, and for GBM patients. A proportional hazards regression model that included treatment, histopathology, KPS, age, and extent of surgery demonstrated that treatment with BrdU was included in the best model only for the GBM group of patients (risk ratio 0.83). Conclusions : Because of the heterogeneity of the treatment groups, including potentially important differences in pathology reviewers assessment of nonglioblastoma cases, differences in radiation dose and schedules, and chemotherapy during reviewers assessment of nonglioblstoma cases, differences in radiation dose and schedules, and chemotherapy during or after radiation, these analyses cannot provide the definite answer as to whether BrdU given during radiation therapy improves survival in patients with malignant glioma. There does appear to be a favorable treatment effect seen in patients with GBM, with a lesser effect in patients with AA.

Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost

Purpose : To study patterns of recurrence in patients with focal primary glioblastoma treated on Northern California Oncology Group protocol 6G-82-2 including surgery, focal external beam radiotherapy (59.4–60 Gy) with oral hydroxyurea followed by temporary brain implant with high-activity iodine-125 sources (50 Gy), and six cycles of chemotherapy with procarbazine, lomustine, and vincristine. Methods and Materials : Serial brain imaging scans were available for review in 25 of 34 patients with glioblastoma who underwent brain implant boost. Of 381 scans performed between the date of diagnosis and the date of death or last follow-up, 362 (95%) were re-reviewed. Disease progression was scored as local (within 2 cm of the implant site), separate within the brain parenchyma (⩾ 2 cm from the implant site), subependymal, or systemic. Both initial and subsequent failures were scored. Results : Three patients are 5-year survivors, without evidence of disease, at 267, 292, and 308 weeks. Of the 22 initial sites of failure, 17 (77%) were local, three (14%) were separate brain lesions (one of which was due in retrospect to multicentric disease at diagnosis), one (5%) subependymal, and one (5%) systemic. Five patients with local failure later had other sites of failure, including a separate brain lesion in 1, subependymal spread in 3, and both in 1. One patient with separate brain failure later had local progression and then subependymal spread. Conclusion : Although there was a significant risk of separate brain lesions or subependymal spread over time, local tumor progression was the predominant pattern of failure.

Phase I study of high-dose cisplatin, ifosfamide, and etoposide

To test the feasibility of a regimen of high-dose cisplatin, ifosfamide, and etoposide (VP-16; VIPP regimen), we registered 15 patients with advanced non-small-cell lung cancer in a phase I trial of the Northern California Oncology Group. One cycle of treatment consisted of high-dose cisplatin given at 100 mg/m2 i.v. on days 1 and 8, VP-16 given at 60-75 mg/m2 i.v. on days 1-3, plus ifosfamide given at 1.0-1.2 g/m2 i.v. on days 1-3; cycles were repeated every 28 days. There were 13 men and 2 women; the median age was 59 years (range, 47-72 years). The median Karnofsky performance status (KPS) was 90 (range, 70-100). All patients were assessable for toxicity and response. The median number of cycles delivered per patient was two (range, one to four). Hematologic toxicity was dose-limiting and required de-escalation of the ifosfamide and VP-16 doses. Ten patients developed a white blood count of < 1000/mm3 and seven patients developed a platelet count of < 50,000/mm3. The duration of cytopenia increased progressively with each subsequent cycle of therapy. Two patients required antibiotics for neutropenic fever with documented infections (pneumonia, bacteremia). Seven patients received red blood cell transfusions for a hemoglobin level of < 8 gm/dl. Grade III or IV non-hematologic toxicities were uncommon and involved one patient each with grade 3 ototoxicity and grade 3 neurotoxicity. Five patients developed laboratory evidence of renal salt wasting. The overall response rate was 33% (5/15) with a complete response being achieved by two patients (13%) and a partial response being attained by three (20%). The overall median survival was 44 weeks. We conclude that although this regimen demonstrated activity, hematologic toxicity limited its use in the palliative treatment of non-small-cell lung cancer. Using hemopoietic growth-factor support to permit dose escalation, this schedule of VIPP may be of interest in a number of different chemotherapy-sensitive tumor types.

Is a surgical resection leaving positive margins of benefit to the patient with locally advanced squamous cell carcinoma of the head and neck: A comparative study using the intergroup study 0034 and the radiation therapy oncology group head and neck database

Purpose : The purpose of this study was to determine whether or not for patients with squamous cell carcinomas of the head and neck, a surgical resection leaving positive margins followed by postoperative adjuvant therapy improves the outcome compared to a matched group of patients treated with definitive radiotherapy alone. Methods and Materials : From January 1985 through January 1990 a consortium of national cooperative groups (Radiation Therapy Oncology Group, Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, Northern California Oncology Group, Southeast Group, and Southwest Oncology Group) conducted a phase III clinical trial testing the efficacy of adjuvant chemotherapy for patients with resectable, squamous cell carcinomas of the head and neck. One hundred and nine patients were excluded from this study due to positive surgical margins. These patients have been followed prospectively with regards to local/regional tumor control, development of distant metastases, and survival. The postoperative treatment of these patients was not specified by the protocol but the majority of patients received postoperative radiotherapy ± chemotherapy. These patients were compared with a matched group of patients from the Radiation Therapy Oncology Group head and neck database of patients treated with definitive radiotherapy alone using a standard fractionation schema. Matching parameters included primary tumor site, T-stage, N-stage, Karnofsky performance status, and age. Results : Actuarial curves are presented for local/regional control and survival. At 4 years the local/regional control rate is 44% for the positive margin patients compared to 24% for the patients from the data base ( p = 0.007). However, there is no significant difference between the survival curves ( p = 0.76) with respective median survivals being 18.1 months vs. 17.9 months and 4-year survivals being 29% vs. 25%. Conclusion : While an incomplete excision followed by postoperative therapy does not seem to improve survival compared to treatment with radiotherapy alone, it appears to yield significantly better local/regional control. This would argue for its applicability in selected palliative settings. A follow-up, Phase III trial for patients with advanced tumors may be warranted to test traditional resectability criteria.

Consolidation hemibody radiotherapy following induction combination chemotherapy in high-tumor-burden multiple myeloma.

Curative therapy for multiple myeloma continues to be an elusive goal. This report discusses the Northern California Oncology Group (NCOG) phase I and II trial in high-tumor-burden disease that used a strategy that consisted of induction chemotherapy (vincristine, melphalan, cyclophosphamide, and prednisone [VMCP]) for eight cycles followed by sequential hemibody radiation therapy (RT) and subsequent chemotherapy for an additional eight cycles. Seventy-two previously untreated stage III myeloma patients were entered onto the study. Sixty-nine received induction chemotherapy, 40 received induction chemotherapy and hemibody RT, and 23 received induction chemotherapy, hemibody RT, and consolidative chemotherapy. Twenty-two complete responses (CRs) were obtained by induction chemotherapy, with four additional CRs after RT and consolidative chemotherapy. Nineteen patients developed grade 4 hematologic toxicity primarily after upper hemibody RT. Eight of these developed long-standing neutropenia or thrombocytopenia. Median survival of the group was 134 weeks, which was not significantly different from other approaches. Hemibody RT can be combined with chemotherapy as induction therapy and can be safely administered in a community setting. However, as administered here no survival advantage was demonstrated.

Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: Report of intergroup study 0034

To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region, a randomized clinical trial was conducted under the auspices of the Head and Neck Intergroup (Radiation Therapy Oncology Group, Southwest Oncology Group, Eastern Oncology Group, Cancer and Leukemia Group B, Northern California Oncology Group, and Southeast Group). Eligible patients had completely resected tumors of the oral cavity, oropharynx, hypopharynx, or larynx. They were then randomized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy (CT/RT) or postoperative radiotherapy alone (RT). Patients were categorized as having either “low-risk” or “high-risk” treatment volumes depending on whether the surgical margin was ≥ 5 mm, there was extracapsular nodal extension, and/or there was carcinoma-in-situ at the surgical margins. Radiation doses of 50–54 Gy were given to “low-risk” volumes and 60 Gy were given to “high-risk” volumes. A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis. The 4-year actuarial survival rate was 44% on the RT arm and 48% on the CT/RT arm ( p = n. s.). Disease-free survival at 4 years was 38% on the RT arm compared to 46% on the CT/RT arm ( p = n. s.). At 4 years the local/regional failure rate was 29% vs. 26% for the RT and Cr/RT arms, respectively ( p = n. s.). The incidence of first failure in the neck nodes was 10% on the RT arm compared to 5% on the CT/RT arm ( p = 0.03 without adjusting for multiple testing) and the overall incidence of distant metastases was 23% on the RT arm compared to 15% on the CT/RT arm ( p = 0.03). Treatment related toxicity is discussed in detail, but, in general, the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy. Implications for future clinical trials are discussed.

Highly anaplastic astrocytoma: A review of 357 patients treated between 1977 and 1989

Between May 1977 and August 1989, 357 patients (199 male, 158 female; median age 40 years) with highly anaplastic astrocytomas other than glioblastoma multiforme were treated according to any of several protocols used in studies by the University of California, San Francisco, and the Northern California Oncology Group. The data evaluated were age, Karnofsky Performance Score, survival, time to tumor progression, therapy, and the effect of treatment at the time of progression. The records of 219 patients were taken from the University of California database, and those of the other 138 were taken from the Northern California Oncology Group computer files. Their median Karnofsky Performance Score was 90% (range 40–100%), the overall median survival was projected as 170.9 weeks, and the median time to first tumor progression was 127.3 weeks. The median survival time measured after the first progression was 41.3 weeks. Age and Karnofsky Performance Score had a significant influence on survival and on time to the first tumor progression, whereas extent of surgery and the use of interstitial brachytherapy in the initial therapy did not. We conclude that these patients can expect a median survival of over 3 years, that young age and high Karnofsky Performance Score have a positive influence on survival, and that salvage therapies can extend survival after the onset of tumor progression for nearly a year. Although it did not lengthen survival when used in initial therapy, interstitial brachytherapy used at the time of tumor progression was associated with increased survival.

High-dose cisplatin and mitomycin C in advanced non-small cell lung cancer: A phase II study of the Northern California Oncology Group : Gandara DR, Perez EA, Wold H, Caggiano V, Malec M, Ahn DK et al. University of California Service, VA Medical Center, 150 Muir Road, Martinez, CA 94553. Cancer Chemother Pharmacol 1990;27:243-7

High-dose cisplatin and mitomycin C in advanced non-small cell lung cancer: A phase II study of the Northern California Oncology Group : Gandara DR, Perez EA, Wold H, Caggiano V, Malec M, Ahn DK et al. University of California Service, VA Medical Center, 150 Muir Road, Martinez, CA 94553. Cancer Chemother Pharmacol 1990;27:243-7

Rapidly alternating radiotherapy and high dose cisplatin chemotherapy in stage IIIB non-small cell lung cancer: Results of a phase I/II study

Alternating radiotherapy and chemotherapy increases tumor cure rates in some animal models with reduced normal tissue damage compared to sequential use of these modalities. To test this concept in non-small cell lung cancer, 23 patients with predominantly Stage IIIB disease were treated on a Northern California Oncology Group pilot study of alternating radiotherapy and high dose cisplatin. Radiotherapy consisted of 6000 cGy delivered in three separate 10-day courses of 200 cGy/fraction/day during weeks 1 and 2, 5 and 6, and 9 and 10. High dose cisplatin, 100 mg/m2 in 3% saline, was administered on weeks 3 and 4, 7 and 8, 11 and 12, and 15 and 16. The response rate in 22 eligible patients is 73% ( 16 22 ) with four complete responses and 12 partial responses. Feasibility of this approach is demonstrated by 20 22 patients completing radiotherapy and a median of 2.5 courses of chemotherapy administered. Median survival time is 14.2 months (range 2–40+ months). One- and 2-year survival rates are 64% ( 14 22 ) and 41% ( 9 22 ), respectively. Hematologic, renal, and radiation-related toxicities were significant but manageable. We conclude that rapid alternation of radiotherapy and a high dose intensity cisplatin regimen is feasible in Stage IIIB non-small cell lung cancer, with a high response rate and acceptable toxicity. The long-term impact on local control and survival remains unclear, although preliminary survival data are encouraging in this poor prognosis population. Further studies of this concept are warranted.

Phase I study of high dose cisplatin, ifosfamide and VP-16 (VIPP) in advanced non-small cell lung cancer (NSCLC): Perez EA, Sowray PC, Fory LW, Gandara DR. Northern California Oncology Group, Belmont, CA and UC Davis/ VAMC Martinez. CA 94553

Phase I study of high dose cisplatin, ifosfamide and VP-16 (VIPP) in advanced non-small cell lung cancer (NSCLC): Perez EA, Sowray PC, Fory LW, Gandara DR. Northern California Oncology Group, Belmont, CA and UC Davis/ VAMC Martinez. CA 94553

Rapidly alternating radiotherapy and high dose cisplatin in stage III Non-Small Cell Lung Cancer (NSCLC): Results of a pilot study: DR Gandara, FH Valone, EA Perez, AB Deisseroth, M Roach, DK Ahn, T Phillips. Northern California Oncology Group (NCOG)

Rapidly alternating radiotherapy and high dose cisplatin in stage III Non-Small Cell Lung Cancer (NSCLC): Results of a pilot study: DR Gandara, FH Valone, EA Perez, AB Deisseroth, M Roach, DK Ahn, T Phillips. Northern California Oncology Group (NCOG)

Rapidly alternating radiotherapy and high dose cisplatin in stage III non-small cell lung cancer (NSCLC): Results of phase I–II study : DR Gandara, FH Valone, EA Perez, AB Deisseroth, M Roach, DK Ahn, T Phillips. Northern California Oncology Group (NCOG)

Rapidly alternating radiotherapy and high dose cisplatin in stage III non-small cell lung cancer (NSCLC): Results of phase I–II study : DR Gandara, FH Valone, EA Perez, AB Deisseroth, M Roach, DK Ahn, T Phillips. Northern California Oncology Group (NCOG)

A Phase II Trial of Carbetimer for the Treatment of Colorectal Cancer

Carbetimer (carboxyimamidate) was administered at a dose of 6,500 mg/m2/day intravenously for 5 consecutive days to 14 patients with measurable metastatic or recurrent colorectal cancer in a single institution phase II study of the Northern California Oncology Group. A total of 38 cycles of therapy were administered; nine patients completed at least three cycles of treatment. No partial or complete responses were observed. One patient did have a greater than 50% response in the liver while developing new retroperitoneal lymphadenopathy and is considered a nonresponder. Carbetimer was well tolerated with elevations of calcium from 10.2 to 12.5 mg/dl in nine patients, prolongation of prothrombin time and partial thromboplastin time in 14 patients, proteinuria in 10 patients, dizziness in six patients, nausea in two patients, and venous pain during infusion in three patients. Myelosuppression was not observed. Carbetimer at this dose and schedule is inactive in the treatment of colorectal cancer.

Preliminary results of concurrent radiotherapy and chemotherapy in advanced cervical carcinoma: A phase I–II prospective intergroup NCOG-RTOG study

Thirty-eight patients with advanced carcinoma of the cervix were prospectively treated with a concurrent combination of radiotherapy (RT) and chemotherapy (CT) using the drugs 5-fluorouracil (5FU), mitomycin C and cis-platinum as part of a Northern California Oncology Group (NCOG) and Radiation Therapy Oncology Group (RTOG) intergroup study. RT consisted of 36.00 Gy to the pelvis in 4 weeks followed by a 9.00-Gy parametrial boost. This was followed by two intracavitary applications for a total of 4000 mg hr of radium equivalent when possible. 5FU (1000 mg/m 2/24 hr for 96 hr by iv infusion) and mitomycin C (10 mg/m 2/iv bolus) were given during the second week of external RT. 5FU (dose as above) and cis-platinum (75 mg/m 2/iv over 6 hr) were given during the first intracavitary application. Of 36 patients evaluable for toxicity, 11% had grade 3 nonhematological toxicity and 11% had reversible grade 4 hematological toxicity. There were no toxic deaths. A complete response rate of 62.5% was obtained overall (median survival not reached). This study suggests that this particular combination of RT and CT in advanced cervical carcinoma is effective and well tolerated.

Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarrazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report

Data from Northern California Oncology Group protocol 6G61, which was closed in February 1983, were reanalyzed in December 1988. The protocol called for a randomized trial that compared the effects of following 60 Gy radiation/oral hydroxyurea treatment with either carmustine (BCNU) or the combination of procarbazine, lomustine (CCNU), and vincristine (PCV) for two histologic strata: glioblastoma multiforme and other anaplastic gliomas. PCV produced longer survival and time to tumor progression than BCNU for both histologic groups, although the difference was statistically significant only for the anaplastic gliomas. With PCV treatment, time to progression and survival doubled for anaplastic glioma patients in the 50th and 25th percentiles.

High-dose cisplatin and mitomycin C in advanced non-small cell lung cancer: a phase II study of the Northern California Oncology Group

To investigate chemotherapeutic dose intensity in advanced non-small-cell lung cancer (NSCLC), we evaluated a pharmacokinetically designed schedule of high-dose cisplatin (200 mg/m2 per 28-day cycle) plus mitomycin C. Between March 1987 and March 1989, 62 patients were registered for a phase II study of the Northern California Oncology Group (NCOG). The treatment schedule consisted of cisplatin in hypertonic saline given on a divided days 1 and 8 schedule (100 mg/m2 on each day) plus mitomycin C given at a dose of 8 mg/m2 on day 1 of each cycle. In 61 patients evaluable for response analysis, the overall response rate was 39% (24/61), with a complete response being achieved in 6% (4/61) of cases and a partial response, in 33% (20/61). The response according to reviewed histologic subtype included squamous, 53% of patients (10/19); large cell, 31% (4/13); and adenocarcinoma, 34% (10/29). The median survival for all patients was 29.3 weeks. The mean cisplatin and mitomycin C delivered dose intensities in this study were 45 mg/m2 per week (90% of the projected dose) and 1.5 mg/m2 per week (75%). The toxicity of this combination regimen in the 62 enrolled patients was significant but manageable. Leukopenia (WBC, less than 1,000/mm3) and thrombocytopenia (platelets, less than 25,000/mm3) occurred in 3% and 8% of patients treated, respectively. Dose-limiting renal toxicity and clinically significant ototoxicity developed in 8 patients each (13%), and a peripheral sensory neuropathy was observed in 17 cases (27%). Whether this type of dose-intensive therapy results in an improved therapeutic index in NSCLC is currently being evaluated in a randomized comparative trial versus standard-dose cisplatin therapy.