Treatment of small-cell lung cancer with an alternating chemotherapy regimen given at weekly intervals: a Southwest Oncology Group pilot study.

We designed an intensive, weekly treatment regimen for patients with small-cell lung cancer (SCLC) using six of the most active chemotherapeutic agents for this disease (doxorubicin [DOX], cyclophosphamide [CTX], vincristine [VCR], etoposide [VP-16], cisplatin [CDDP], and methotrexate [MTX]). The goal of this program was to gain rapid, repetitive exposure to multiple, active drugs. Treatment was administered weekly for a total of 16 weeks. Seventy-six SCLC patients (limited disease, 34; extensive disease, 42) were treated. The overall complete plus partial response rate was 82%. Complete response rates of 47% and 38% were observed in patients with limited (LD) and extensive disease (ED), respectively. The median survivals for patients with LD and ED were 16.6 and 11.4 months, respectively. Toxicities were tolerable and were primarily hematologic. Twenty-six patients had one or more transient life-threatening toxicities, but only one patient developed a fatal toxicity. Eighty-four percent of the patients received 80% or greater of the intended protocol dosages over the entire 16-week treatment period. We conclude that this intensive, short-duration treatment regimen is at least as good as other "standard" regimens, and we are encouraged aged by the complete response rate and median survival in patients with ED SCLC.

Extended administration of oral etoposide and oral cyclophosphamide for the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study.

PURPOSE: We designed an all-oral regimen of etoposide and cyclophosphamide for use in advanced non-small-cell lung cancer. PATIENTS AND METHODS: Eligible patients were chemotherapy-naive and had histologically confirmed assessable or measurable stage IV non-small-cell lung cancer. Patients received etoposide 50 mg/m2/d orally days 1 through 14 and cyclophosphamide 50 mg/m2/d orally days 1 through 14 every 28 days. Doses on later cycles were adjusted for myelosuppression. RESULTS: Sixty-six patients (64 eligible patients) received 192 cycles of oral extended etoposide/cyclophosphamide therapy (median, two cycles; range, zero to 15). Therapy was well tolerated with the mean dose per cycle being 104% of the originally scheduled dose. Two patients (3%) achieved a complete response and six (9%) achieved a partial response. Leukopenia, anemia, nausea/vomiting, and alopecia were the most common toxicities. Median survival was 6 months, and the 1-year survival rate was 25.6%, comparable to more intensive treatments. CONCLUSION: Oral extended etoposide/cyclophosphamide is a well-tolerated alternative for the treatment of stage IV non-small-cell lung cancer and can be used as a basis for the design of further outpatient regimens.

Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study.

PURPOSE: The Southwest Oncology Group (SWOG) conducted a randomized comparison of cisplatin plus fluorouracil (5-FU) and carboplatin plus 5-FU versus single-agent methotrexate (MTX) in patients with recurrent and metastatic squamous-cell carcinoma (SCC) of the head and neck. The primary objective was to compare separately the response rates of each combination regimen to standard weekly MTX. PATIENTS AND METHODS: Two hundred seventy-seven patients diagnosed with SCC of the head and neck were randomized to one of three treatments: (1) cisplatin 100 mg/m2 intravenously (IV) on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 21 days; (2) carboplatin 300 mg/m2 IV on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 28 days; and (3) MTX 40 mg/m2 IV given weekly. RESULTS: All three treatment regimens were well tolerated. However, both hematologic and nonhematologic toxicities were significantly greater with cisplatin plus 5-FU compared with MTX (P = .001). Toxicity from carboplatin plus 5-FU was intermediate compared with the other regimens. The complete and partial response rates were 32% for cisplatin plus 5-FU, 21% for carboplatin plus 5-FU, and 10% for MTX. The comparison of cisplatin plus 5-FU to MTX was statistically significant (P less than .001), and the comparison of carboplatin plus 5-FU to MTX was of borderline statistical significance (P = .05). Median response durations and median survival times were similar for all three treatment groups. Logistic regression models showed that only treatment assigned was associated significantly with response (P = .001). Cox proportional hazards models indicated that only performance status was associated significantly with survival (P less than .01). CONCLUSIONS: We conclude that combination chemotherapy resulted in improved response rates but was associated with an increased toxicity and no improvement in overall survival. Therefore, new treatments that may alter the course of disease in recurrent head and neck cancer patients still need to be identified.

Activity of esorubicin in recurrent malignant lymphoma: a Southwest Oncology Group study.

A phase II trial of esorubicin (4' deoxydoxorubicin) was conducted by the Southwest Oncology Group in 88 assessable patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) at the time of first relapse. Esorubicin was administered at two dose levels: 25 mg/m2 for patients at risk for excessive myelosuppression, and at 30 mg/m2 for all others at 21-day intervals. Overall, 33 of 88 patients (38%) responded to treatment including three complete remissions (CRs; 3%) and 30 partial remissions (PRs; 34%), with the median duration of response lasting 6.2 months. Response rates did not differ significantly by histologic subtype: 31% of 26 patients with favorable NHL, 33% of 43 patients with unfavorable NHL, and 58% of 19 patients with HD. Twelve of 33 responding patients (36%) had relatively durable remissions lasting from 1 to more than 4 years. Leukopenia (less than 3,000 cells per microliter) was seen in 65 of 88 patients (74%) and was severe (less than 1,000 cells per microliter) in 20 of 88 patients (23%). Clinical signs or symptoms of congestive heart failure were not seen and the ejection fraction (EF) fell 10% to 20% in three patients. Esorubicin is an active agent in patients with NHL or HD at the time of first relapse.

An evaluation of prostate-specific antigen as a screening test for prostate cancer.

Prostate cancer is the second leading cause of cancer death in men. Recently, there has been increased interest in the use of prostate-specific antigen (PSA) as a screening test for prostate cancer. The PSA test offers the benefit of a reproducible, objective value that is independent of the examiner's skill; however, it does not seem to be effective alone as a screening test for prostate cancer. Additionally, the efficacy of treatment for prostate cancer with radiation therapy or radical prostatectomy remains to be demonstrated. Thus, further studies demonstrating an improved mortality in prostate cancer with PSA screening need to be performed before universal screening with PSA can be recommended. Meanwhile, education of the patient regarding the risks, benefits, and costs of PSA screening and subsequent treatment should be addressed before performing a PSA test.

Methotrexate cerebrospinal fluid pharmacokinetics in a patient with lymphoma treated with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone.

The role of "moderate-dose" systemic methotrexate in preventing central nervous system lymphomatous relapse is unknown. Certain patients with diffuse non-Hodgkin's histologic subtypes have an increased risk of relapse in the central nervous system, and it would be helpful to know if intravenous "moderate-dose" methotrexate might treat or possibly protect the meninges from involvement. In part, the rationale behind the recent regimen of methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), and dexamethasone (m-BACOD) is to protect the central nervous system, and the empiric proof of this protection awaits the follow-up results of trials currently underway. In the meantime, the systemic and cerebrospinal fluid pharmacokinetics of moderate-dose intravenous methotrexate were studied in one patient whose histologic subtype places him at high risk for central nervous system involvement. Although the central nervous system levels of methotrexate in this patient never reached 1 X 10(-6) M, the levels exceeded 1 X 10(-7) M for at least 24 hours. The implications of peak dose versus sustained exposure to a lower dose of methotrexate are discussed.

The role of laminin-1 in the modulation of radiation damage in endothelial cells and differentiation.

Microvascular dysfunction due to endothelial damage is often associated with the ionizing radiation used during cancer therapy. This radiation-induced capillary injury is a major factor in the inhibition of new vessel growth (angiogenesis) and in disease states such as radiation-induced pneumonitis and nephropathy. Many studies have examined the effects of radiation on endothelial cell function; however, little is known regarding the role the basement membrane plays in radiation-induced endothelial cell damage and angiogenesis. Therefore, we examined the effects of gamma radiation on aortic explants, and in vitro on three endothelial cell types (of artery, vein and capillary origin) irradiated with or without the basement membrane glycoprotein laminin-1. As expected, irradiation inhibited angiogenic sprouting of the aortic explants, endothelial cell proliferation, attachment, migration and differentiation in vitro in a dose-dependent manner. However, the effect of radiation on several of these processes in angiogenesis was reduced when the cells were irradiated on laminin-1. To further evaluate the effects of radiation on endothelial cells, we examined the expression of the vascular endothelial cell growth factor (VEGF) kinase domain region receptor in endothelial cells irradiated in the presence and absence of laminin-1. In endothelial cells irradiated on laminin-1, KDR expression increased 2.5-fold over control levels. Therefore, although radiation has a dose-dependent inhibitory effect on processes associated with angiogenesis in vitro, the presence of the basement membrane glycoprotein laminin-1 during irradiation decreases these effects.

Treatment of non-small-cell lung cancer with vinblastine and very high-dose cisplatin. A Southwest Oncology Group study.

Suggestions of a dose-response effect for cisplatin in non-small-cell lung cancer have contributed to the development of very high-dose cisplatin regimens (200 mg/m2 per cycle). We treated 53 eligible patients with metastatic or recurrent non-small-cell lung cancer with a combination of 100 mg/m2 cisplatin and 4 mg/m2 vinblastine, each given on days 1 and 8 of a 28-day cycle. We observed no complete response and 4 partial responses (8%). Median survival was 6 months. Toxicities of grade III or greater included leukopenia (11 cases), nausea/vomiting (6 cases), thrombocytopenia (2 cases), anemia (2 cases), and elevation of transaminase (1 case). Neurotoxicity has been reported to be a major problem in several other very high-dose cisplatin regimens. The low level of neurotoxicity observed in this study may be attributable to the median cumulative cisplatin dose of less than 600 mg/m2. This vinblastine/very high-dose cisplatin regimen showed minor activity against non-small-cell lung cancer. The level of activity did not surpass that of standard-dose (100 mg/m2 per cycle) cisplatin-containing regimens.

Phase I trial of aggressive weekly chemotherapy in small-cell carcinoma of the lung.

We have treated 10 patients with small-cell carcinoma of the lung with an aggressive weekly chemotherapy regimen. Treatment consisted of cyclophosphamide and doxorubicin (Adriamycin) on day 1, methotrexate on day 8, followed by leucovorin on days 9, 10, and 11 cis-platinum on day 15, VP-16 on days 15, 16, and 17, vincristine on days 1, 8, 15, and 22, and trimethoprim/sulfa twice daily. Cycles were repeated every 28 days. The primary toxicity was hematologic. One treatment-related death occurred. All other patients tolerated treatment without irreversible toxicity. There have been three complete responses and seven partial responses. This very active regimen is tolerated with acceptable toxicity even in patients with poor performance status.

Phase II evaluation of low-dose continuous 5-fluorouracil and weekly cisplatin in advanced adenocarcinoma of the stomach. A Southwest Oncology Group study.

We have conducted a Phase II trial in patients with metastatic gastric cancer utilizing low-dose continuous infusion 5-fluorouracil (5FU) and weekly cisplatin (CDDP). The 5FU was administered at a dose of 200 mg/m2 per day by 24-hour continuous infusion via a permanent central venous catheter. The CDDP was administered at a dose of 20 mg/m2/week for the first 8 weeks, then every other week thereafter. Patients were evaluated for response every 8 weeks. There were 2 complete and 2 partial responses out of 39 eligible and evaluable patients for an overall response rate of 10% (95% CI = 3-24%). The primary toxicities were nausea, hyponatremia, and anemia. Overall, treatment was well tolerated. We conclude that, although the treatment is relatively well tolerated, the regimen has minimal activity in this disease and does not deserve further study.

Phase II evaluation of ifosfamide/mesna in metastatic prostate cancer. A Southwest Oncology Group study.

The combination of ifosfamide and mesna was evaluated in a phase II trial in the treatment of metastatic prostate cancer. Two separate groups of patients were to be evaluated: patients with no prior hormonal therapy and hormonally refractory patients. Patients were treated with ifosfamide 1.5 g/M2, and mesna at 30% of the ifosfamide dose was administered immediately before and 4 and 8 h after ifosfamide treatment. Both drugs were given i.v. daily for 5 days every 21 days. Response was assessed every 6 weeks. Of 29 eligible and evaluable patients with hormonally refractory disease, there were two partial responders for a response rate of 7% (95% confidence interval, of 0.1-23%). Of nine eligible patients with no prior hormone treatment, there was one partial response, for a response rate of 11% (95% confidence interval, 0.3-48%). Unfortunately, the target accrual goal for this arm of the study was never achieved. The most common toxicities were myelosuppression and neurologic toxicity. These drugs do not warrant further evaluation in the disease.

A pilot study of the physician acceptance of tele-oncology.

During the winter of 1993, medical oncologists from an urban, university-based hospital provided oncology care to rural patients using interactive video clinics (tele-oncology). In order to assess physician satisfaction with this form of outreach, surveys were performed after the video encounters, as well as after a limited number of subsequent clinical encounters on site. Various aspects of satisfaction were evaluated. Although the sample was small (a total of 41 clinical encounters and 3 oncologists), the results suggested that there was a reasonable level of physician satisfaction with, and confidence in, the use of video to replace some on-site oncology consultations. A definitive study of tele-oncology for providing care to rural cancer patients therefore appears to be warranted.

Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741.

BACKGROUND: Fluorouracil (5-FU), oxaliplatin and irinotecan combinations improve time to tumor progression (TTP), objective response and overall survival (OS) in patients with metastatic colorectal cancer (MCRC). Here we identify and describe patients treated on Intergroup study N9741 who initially had inoperable MCRC, but who obtained sufficient chemotherapeutic benefit to allow removal of their metastatic disease. PATIENTS AND METHODS: Patient research records in study arms (A) irinotecan/5-FU/leucovorin (LV) (IFL, n = 264), (F) oxaliplatin/5-FU/LV (FOLFOX4, n = 267) and (G) oxaliplatin/irinotecan (IROX, n = 265) were reviewed. TTP and median OS were calculated. RESULTS: Twenty-four (3.3%) of 795 randomized patients underwent curative metastatic disease resection [hepatectomy, 16; radiofrequency-ablation (RFA), six; lung resection, two]. Twenty-two out of 24 (92%) resected patients received an oxaliplatin-based regimen (FOLFOX4, 11; IROX, 11). Seven patients (29.2%) remain disease-free; relapses occurred mainly in the resected organ. Median OS in resected patients is 42.4 months, and median TTP is 18.4 months. All six patients treated with RFA have recurred. Four out of five (80%) patients who received chemotherapy following resection are disease-free. CONCLUSIONS: Resection of metastatic disease after chemotherapy is possible in a small but important subset of patients with MCRC, particularly after receiving an oxaliplatin-based chemotherapy regimen, with encouraging OS and TTP observed in these highly selected patients.

Phase I evaluation of spirogermanium and 5-fluorouracil in colorectal carcinoma.

We have conducted a phase I study to evaluate the toxicity and tolerance of a 5 day continuous infusion of spirogermanium and 5-fluorouracil, (5-FU). The 5-FU was administered via a peripheral vein at 1000 mg/M2/day for 5 days by continuous infusion. Simultaneously, spirogermanium was administered via an indwelling central venous catheter by continuous infusion for 5 days starting at 50 mg/M2/day and escalating to 250 mg/M2/day. Sixteen patients received a total of 54.5 courses of therapy. The most common and severe toxicity was neurotoxicity. Mild to moderate gastrointestinal toxicity also occurred. No significant hematologic toxicity occurred. Two partial responses occurred lasting 11 and 20.5 months, both at the 100 mg/M2/day level of spirogermanium. The recommended phase II dosages are 5-FU 1000 mg/M2/day and spirogermanium 200 mg/M2/day by 5 day continuous infusion with escalation of the spirogermanium in selected individuals. Patients on long term therapy should have close neurologic evaluation and follow up. Consideration should also be given to evaluating a group of patients at the 100 mg/M2/day level of spirogermanium due to the responses seen at this level.

Phase II trial of 6-thioguanine administered as 120 hour continuous infusion for refractory or recurrent small cell lung cancer. A Southwest Oncology Group study.

Nineteen eligible patients with recurrent small cell lung cancer were treated with a 120 hour continuous infusion of 6-thioguanine at a starting dose of 35 mg/m2/day. There were no responses in these 19 patients. Toxicity was acceptable with the primary toxicity being hematologic. Based on this trial, 6-thioguanine is not felt to have significant antitumor activity in this patient population.

Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study.

BACKGROUND: A previous Southwest Oncology Group study demonstrated a 30% response rate with the combination of cisplatin and mitotane in the treatment of patients with metastatic adrenocortical carcinoma. Several case reports suggested that the combination of etoposide and cisplatin may be an active regimen in this disease. Because of these reports of potential activity, the authors conducted a Phase II trial evaluating the combination of etoposide and cisplatin. Due to the lack of data regarding the objective response rates to mitotane, the authors planned to evaluate the response rate to mitotane after disease progression on etoposide and cisplatin in patients with no prior mitotane therapy. METHODS: Patients with advanced, unresectable, or metastatic adrenocortical carcinoma with objectively measurable disease or biochemical abnormalities received cisplatin, 50 mg/m(2), intravenously on Days 1 and 2, and etoposide, 100 mg/m(2), on Days 1, 2, and 3. Cycles were repeated every 21 days. At the time of disease progression, patients who had not previously received mitotane received 1000 mg orally 4 times a day along with cortisone acetate and fludrocortisone acetate. RESULTS: Of the 47 patients entered onto the study, 45 were eligible. Nine patients had received mitotane previously and 36 had not. Objective responses were noted in 11% of patients (5 of 45 patients) (95% confidence interval, 3.7-24%). The median survival was 10 months. The most common toxic effects were hematologic, gastrointestinal, and neurologic. Only 16 patients with no prior mitotane therapy went on to receive mitotane at the time of disease progression. An objective response was noted in 13% of patients (2 of 16 patients). The most common toxic effects were edema and gastrointestinal effects. CONCLUSIONS: The current study demonstrates that the combination of cisplatin and etoposide has minimal activity in advanced and metastatic adrenocortical carcinoma and other treatment strategies are warranted.

Phase II trial and cost analysis of fazarabine in advanced non-small cell carcinoma of the lung: a Southwest Oncology Group study.

BACKGROUND: Fazarabine is a novel nucleoside with broad spectrum pre-clinical activity and was chosen for study in patients with incurable non-small cell carcinoma of the lung. The expenses associated with investigational treatment have been assumed to be more than what would occur with conventional therapy, however, data are limited. METHODS: Twenty-three patients with metastatic non-small cell lung cancer were treated with fazarabine. Fazarabine was administered as a 72 hour continuous infusion at 2.0 mg/M2/hour. A cost analysis of treatment was calculated for patients treated in Springfield, MO. RESULTS: There were no responses (0%, 95% confidence interval = 0-15%) and median survival was 8 months. An analysis of the cost of treatment in the 4 patients treated in Springfield, MO, was compared to the costs of treatment with 4 cycles of cisplatinum and etoposide. There were no significant differences in costs for patients treated with the investigational agent as compared with conventional chemotherapy. CONCLUSIONS: Fazarabine has no demonstrable activity in patients with metastatic non-small cell carcinoma of the lung. Treatment with this agent in an investigational setting was no more expensive than treatment with conventional chemotherapy.

Phase II evaluation of didemnin B in hormonally refractory metastatic prostate cancer. A Southwest Oncology Group study.

Didemnin B, a dipsipeptide isolated from the Caribbean tunicate Trididemnum with antitumor and antiviral activity was evaluated in a phase II trial in the treatment of metastatic, hormonally refractory adenocarcinoma of the prostate. Thirteen patients were treated with didemnin B at 3.5 mg/m2 and 20 patients were treated at 6.3 mg/m2 intravenously every 28 days. Response was assessed every 8 weeks. Of 32 evaluable patients there was one partial response for an overall response rate of 3% (95% confidence interval of 0.1-16%). The most common toxicities were nausea, vomiting, and diarrhea. Serious cardiac and pulmonary toxicities were also noted. This drug does not appear to warrant further evaluation in this disease as a single agent.

Prolonged, alternating chemotherapy for extensive small cell lung cancer. A Southwest oncology Group study.

BACKGROUND: Etoposide may be schedule dependent in small cell lung cancer (SCLC), and some data suggest a benefit for increased dose intensity in this disease. This study attempted to optimize dose intensity using an outpatient program that included prolonged, oral etoposide administration. METHODS: Cisplatin-etoposide (PE) and cyclophosphamide, doxorubicin, and vincristine (CAV) were alternated at monthly intervals in patients with extensive SCLC. PE was given as cisplatin 50 mg/m2 on days 1 and 8 intravenously (i.v.) and etoposide 50 mg/m2/day for 14 days by mouth. CAV was administered as cyclophosphamide 60 mg/m2/day for 21 days orally, doxorubicin 20 mg/m2/week for three doses, and vincristine 2 mg i.v. on day 1 only. At the end of 4 months, responding patients received an additional course of PE alternating with CAV, and whole-brain irradiation (3000 cGy in 15 fractions) was delivered to clinical complete responders (CR). RESULTS: Among 61 eligible patients, 4 achieved CR, and 11 had a partial remission, by strict Southwest Oncology Group criteria. An additional 20 patients demonstrated greater than 50% tumor shrinkage on one disease assessment but did not have confirming measurements at all sites 4 weeks later. The overall response rate was 57%, including the latter group. The toxicity was primarily hematologic, with three treatment-related deaths from neutropenic infection (5%). Grade 4 neutropenia (< 500/microliters) occurred in nine patients (15%) and Grade 4 thrombocytopenia (< 25,000/microliters), in three (5%). Analysis of the delivered dose intensity (in milligrams per square meter per week) as a function of that which was planned revealed a mean of 93% for all courses. CONCLUSIONS: Although substitution of prolonged oral etoposide in PE and oral cyclophosphamide in CAV proved to be feasible, these results suggest no advantage over those from other reported series using these alternating regimens in which the agents are pulsed. Experience with alternating PE-CAV for extensive SCLC is reviewed.