A phase II study of carboplatin and chronic high-dose tamoxifen in patients with recurrent malignant glioma

SummaryPurpose To determine the response rate, time to disease progression, survival, and toxicity of intravenous carboplatin and chronic oral high-dose tamoxifen in patients with recurrent malignant gliomas.Patients and methods Patients with histological confirmation of recurrent malignant gliomas were eligible for this multicenter phase II trial. Treatment consisted of 400 mg/m² carboplatin intravenously every 4 weeks and oral high dose chronic tamoxifen (80 mg bid in women and 100 mg bid in men).Results Twenty seven patients met the eligibility criteria and were evaluable for response. The histological subtypes were: 16 (59%) glioblastoma multiforme (GBM), malignant astrocytoma (5 patients), malignant mixed glioma (5 patients), and glioblastoma/gliosarcoma (1 patient). Twenty-two patients (82%) had an ECOG performance status of 0 or 1. No complete responses were observed, 4 patients (15%) achieved a partial response, and 14 patients (52%) had stable disease. Median time to progression was 3.65 months (95%CI 2.56, 4.83). Median overall survival was 14.09 months (95%CI 7.06, 19.91). One patient with a recurrent GBM had a sustained partial response and is progression free 81 months since starting treatment. Another patient with mixed malignant oligoastrocytoma also had a prolonged partial response (lasting 63 months) and is alive 84 months after treatment for recurrence. The most frequently reported grade 3 or 4 toxicities were fatigue (19%), nausea (11%) and anorexia (11%).Conclusions Carboplatin and high dose tamoxifen has similar response rates to other regimens for recurrent malignant gliomas and are probably equivalent to those found using tamoxifen as monotherapy. Long-lasting periods of disease free survival in some patients (particularly those with malignant mixed oligo astrocytomas) were found.     

The treatment of recurrent cerebral gliomas with all-trans-retinoic acid (tretinoin)

Malignant gliomas continue to be a significant sourceof mortality in young and middle aged adults.The introduction of new treatment strategies and multidisciplinaryapproaches has improved the outcome of patients withthese tumors only slightly. Because retinoic acid hasgrowth inhibitory activity against glioma and neuroblastoma cellsin cultures, we assessed the efficacy of all-trans-retinoicacid in the treatment of recurrent cerebral gliomas.Thirty-six patients with recurrent cerebral gliomas were enteredin the study and treated with 120 or150 mg/m²/day of all-trans-retinoic acid as a singleagent. The drug was given for 3 weeksfollowed with one week of rest. Two blocksof 4 weeks constituted one course of treatment.One (3%) of 34 evaluable patients had aminor response and 14 (41%) had stable disease.In the rest of the patients (56%), tumorscontinued to progress despite treatment. The median timeto progression of all evaluable patients was 8weeks, and for the responders was 17 weeks.The higher dose level (150 mg/m²) was associatedwith high incidence of headache, which responded todose reduction. The lower dose level was verywell tolerated, with mild, mainly dermatological toxicity.All-trans-retinoic acid as a single agent has nosignificant activity against recurrent cerebral gliomas.     

Thiotepa and etoposide treatment of recurrent malignant gliomas: phase I study

 Purpose: To determine: (1) the maximum tolerable dose (MTD) of thiotepa (TT) that can be administered with etoposide without stem cell support; (2) whether this regimen is active against recurrent malignant gliomas. Background: Although several chemotherapeutic agents show minor activity against recurrent brain tumors, there is no consensus about the most effective regimen. The alkylating agent TT has excellent central nervous system (CNS) penetration and is synergistic with the topoisomerase II inhibitor etoposide. Design/Methods: Fifteen patients with recurrent malignant gliomas (14 glioblastomas, 1 anaplastic astrocytoma) received intravenous etoposide 100 mg/m² on days 1, 2, and 3, and intravenous TT (40, 50, 60, or 70 mg/m²) on day 2. All had received irradiation, and eight BCNU. Chemotherapy was repeated every 3 – 4 weeks, with stepwise TT dose increments of 10 mg/m², provided toxicity was less than grade III. Results: The major toxicity was dose-limiting leukopenia. The MTD of TT in cycle 1 was 60 mg/m². All patients died of progressive disease and none died of chemotherapy-related complications. Conclusions: The MTD of TT in this regimen for recurrent malignant gliomas is 60 mg/m². Higher doses of TT would require colony-stimulating factors or stem cell support. Received: 14 March 1995 / Accepted: 5 September 1996     

Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas

COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m²/day and escalated by 25 mg/m²/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m²/day in the −EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. −EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m²/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.     

Treatment of recurrent malignant glioma with BCNU-fluosol and oxygen inhalation. A phase I-II study

Objectives: To evaluate the toxicity and response rate following BCNU with oxygen inhalation and escalatingdosages of fluosol administered to patients with radiographic progression of malignant glioma after definitivesurgery and radiotherapy. Method: This single arm, phase I-II multicenter trial, enrolled 99 patients withmalignant gliomas recurrent after definitive surgery and radiotherapy. All patients received a fixed dose(200 mg/m²) of BCNU along with 100% oxygen and fluosol, a perfluorochemical. Fluosol doses were escalat-edbetween patients (150, 275, 400 and 600 ml/m²). Treatment was repeated every 6 weeks for a maximum of 6cycles. Patients were assessed for toxicity at the time of infusion and sequentially thereafter. Response wasevaluated clinically and radiologically at least every 6 weeks. Results: Treatment was well tolerated. Dosereductions were required at least once in 18 patients, treatment delays were necessary at least once in 33patients. Grade 3-4 leukopenia occurred in 6 patients (12 events), grade 3-4 thrombocytopenia in 10 patients(25 events) and grade 3-4 liver enzymes elevations in 18 patients (31 events). Higher fluosol dosages did notproduce increases in toxicity or responses. Response or stabilization was seen in 57% (38% were stabiliza-tions)of the patients who entered the trial with progressive disease. The median time to progression was 45weeks, and median survival was 66 weeks for patients who had response or stabilization. For patients withglioblastoma response/stabilization was seen in 45% with a mean duration of 24 weeks, for patients withanaplastic astrocytoma response/stabilization was seen in 68% with a mean duration of 50 weeks. Conclusion:This treatment regimen is well tolerated. Our results suggest fluosol may enhance the effectiveness of BCNUfor the treatment of recurrent malignant gliomas. Future studies will be performed using fluosol at the dose of400 ml/m².     

A phase 1 study of vinblastine in combination with carboplatin for children with low-grade gliomas: a Children's Oncology Group phase 1 consortium study

Both carboplatin and vinblastine have demonstrated single-agent activity in children with low-grade gliomas. A phase 1 trial evaluating 2 different schedules of these 2 agents in combination was performed: (1) Schedule A = carboplatin (140 mg/m²) weekly × 3 + vinblastine (4.5 or 3.5 mg/m²) weekly × 6, every 6 weeks; (2) Schedule B = carboplatin (300, 400, or 500 mg/m²) on day 1 + vinblastine (4.0 mg/m²) weekly × 3, every 4 weeks. Twenty-six patients, median (range) age 4.4 (0.7–14.8) years, were enrolled. Four of 9 patients enrolled on Schedule A had recurrent grade 4 neutropenia, suggesting that this schedule was not feasible. Seventeen patients were enrolled on Schedule B. At the 500 mg/m² carboplatin dose level, 2 of 3 patients developed dose-limiting toxicity (elevated alkaline phosphatase, neutropenia). At the 400 mg/m² carboplatin dose level, none of the 6 patients had dose-limiting toxicity. Ten of 16 patients who received treatment on Schedule B completed the prescribed 12 courses. Of the 21 patients evaluable for response, central review confirmed 1 partial response and 6 minor responses. Eleven patients had stable disease (>3 months) and 3 developed progressive disease. Seven of 9 patients with visual pathway tumors and acute visual changes prior to enrollment had documented improvement. The recommended phase 2 dose and schedule is carboplatin, 400 mg/m²/dose on day 1, and vinblastine, 4 mg/m²/dose, weekly × 3, repeated every 4 weeks. Further study of this regimen in patients with low-grade glioma is warranted.     

Phase II study of homoharringtonine in patients with recurrent primary malignant central nervous system tumors

A phase 11 trial of Homoharringtonine (HHT) was performed in 15 patients with recurrent or progressive malignant glioma. The drug was administered at a initial dose of 4 mg/m²/day by continuous 5 day intravenous infusion (3 mg/m²/day x 5 days for heavily pretreated patients). Courses were repeated every 3–4 weeks upon recovery from toxicity. No objective antitumor regressions occurred. Two patients had no change in their CT brain scans for 2–3 months and one patient had stable disease for 6 months. Toxicity was tolerable and included myelosuppression and occasionally mild hypotension. Chemosensitivity testing with HHT and several other chemotherapy drugs was performed in glioma cell lines, including cell lines derived from these patients. The results suggest that HHT is an inactive drug in malignant glioma using this dose schedule.     

A phase I clinical trial of low-dose interferon-α-2A, thalidomide plus gemcitabine and capecitabine for patients with progressive metastatic renal cell carcinoma

Background We have conducted a phase I trial to determine the maximum tolerated dose of gemcitabine in combination with interferon, thalidomide and capecitabine. Methods Patients received oral capecitabine 1,000 mg/m² per day, divided in 2 daily doses, 2 weeks on, 1 week off; subcutaneous interferon-α 1 mIU twice a day without an interruption; daily oral thalidomide 200 mg/day for the first 7 days, then escalated to 400 mg/day without an interruption. Gemcitabine was given by intravenous administration over 30 min on day 1, week 1 and day 8, week 2. Initial dose level of gemcitabine was 400 mg/m². The dose of gemcitabine was the phase I variable. One cycle was 3 weeks. Results and discussion We treated 12 patients, 6 patients were entered at a dose level of 0 (gemcitabine 400 mg/m²) and 6 patients entered at a dose level-1 (gemcitabine 200 mg/m²). Eight of 12 patients completed at least 12 weeks of therapy. Three partial responses and two stable disease were observed. The remaining patients had progressive disease. Non-hematologic toxicity was either grade 1 or 2. Hematologic toxicity at dose level 0 consisted of 3 patients with grade 3/4 neutropenia, and 1 patient with grade 3 thrombocytopenia. At dose level-1 grade 1/2 neutropenia was observed. Conclusions The completion of our phase I experience determined our maximum tolerated dose to be dose level-1. The phase II trial is currently being proposed for patients with rapidly growing clear cell, other histologies that may contain sarcomatoid elements or collecting duct tumor.     

Dose-intensive,Time-compressed Procarbazine,CCNU, Vincristine (PCV) with Peripheral Blood Stem Cell Support and Concurrent Radiation in Patients with Newly Diagnosed High-grade Gliomas

The dose intensity of the PCV regimen can be doubled using peripheral blood stem cell (PBSC) support. This study sought to determine the feasibility of giving dose-intensive PCV concurrently with radiation therapy. Twelve patients, age 3.2–22.7 years, median 7.5 years, with newly diagnosed high grade gliomas were enrolled. Diagnoses included diffuse intrinsic brainstem gliomas (BSG) (n=6), glioblastoma (n=4), anaplastic astrocytoma (n=2). PBSCs were harvested prior to chemotherapy with G-CSF priming. Chemotherapy consisted of CCNU 130 mg/m² and vincristine 1.5 mg/m² on day 0, and procarbazine 150 mg/m² on days 1–7. PBSCs were reinfused on day 9 of each course. Four courses of chemotherapy were administered every 28 days or when blood counts recovered. The first course was administered the week prior to RT, the second course began on week 3 of RT and the third and fourth course were given after RT. Hematologic toxicity was mild and the majority of courses were given on schedule. Five of six patients with diffuse BSG showed clinical improvement and three showed a radiographic response; however, only one remains alive 12+ months from diagnosis. All four patients with non-brainstem large-volume tumors showed clinical deterioration and radiographic progression during or shortly after RT. MRI scans showed massive edema and enhancement. Median time to radiographic progression was five months. Median overall survival was 11 months. We conclude that dose-intensive, time-compressed PCV given concurrently with large-volume RT appears to result in unacceptable toxicity in patients with large residual tumors.     

Phase II trial of temozolomide in children with recurrent high-grade glioma

SummaryPurpose The objective of the study was to evaluate the efficacy and toxicity of Temozolomide (TMZ) administered for 5 consecutive days in three daily dosing in children with recurrent or refractory high-grade glioma.Patients and methods Twenty-four patients with a median age of 10.5 years were enrolled onto this open-label, multicenter, phase II study. The patients were previously treated with surgical resection (17 of 24), radiotherapy (19 of 24) and chemotherapy (18 of 24). Therapy was administered orally three times a day for 5 consecutive days at the dose of 200 mg/m²/d×5 for chemotherapy naive patients. In patients heavily pretreated with chemotherapy the starting dose was of 150 mg/m²/d×5.Results A total of 95 cycles were administered. The median progression free-survival (PFS) was 3 months for the entire group while disease stabilization was obtained in 7 patients (29.1%), all with supratentorial tumors. No CR or PR was observed. TMZ treatment showed a limited toxicity. Thrombocytopenia was the most common hematological adverse effect.Our data suggest a marginal activity of TMZ in children with recurrent high-grade glioma.     

Intravenous recombinant interferon beta in patients with recurrent malignant gliomas: a phase I/II study.

A multicenter phase I/II trial of a human recombinant interferon beta (Betaseron; Triton Biosciences, Alameda, CA) was conducted in patients with recurrent glioblastoma and anaplastic astrocytoma in six centers between 1986 and 1988. Betaseron was given intravenously three times per week, starting at 90 x 10(6) IU per dose and escalating by 90 x 10(6) IU every 2 weeks up to a maximum dose of 540 x 10(6) per treatment. All patients had failed prior radiotherapy, and most had failed one or more courses of chemotherapy. Of the 72 patients entered into the protocol, 65 were considered assessable. Of 65 patients, 41 had glioblastoma, and 24 had anaplastic astrocytoma. Of the 65 assessable patients, 15 (23%) had an objective response (R), and 18 (28%) had stable disease (S), with a combined R and S rate of 51%. The Kaplan-Meier median time to progression was 24 weeks for the responders, 10 weeks for the nonresponders, and 23 weeks for the whole group. These results suggest that Betaseron has definite activity in recurrent gliomas, with an R + S rate of 51%. The maximum-tolerated dose (MTD) is between 180 and 360 x 10(6) IU, with neurotoxicity being the most troublesome toxicity at higher doses. Two patients died of treatment-related complication. Since most responders showed responses at the 180 x 10(6 IU dose range, further studies using a lower dose of Betaseron aimed at decreasing toxicity and allowing chronic maintenance therapy are merited.     

Atypical and malignant meningiomas: an outcome report of seventeen cases

Interferons alpha and beta have been reported to cause tumor regression in a small proportion of patients with recurrent glioma. Eflornithine, an irreversible inhibitor of ornithine decarboxylase, reduces cellular polyamine levels and has also been reported to cause tumor regression in patients with recurrent anaplastic astrocytoma and glioblastoma multiforme. In vitro evidence suggests that interferon and eflornithine are synergistic. In this phase II trial, we investigated the combination of recombinant alpha interferon (36 × 10⁶ units/m² subcutaneously days 3 to 7) and eflornithine (2.25 g/m² QID PO days 1 to 7) repeated every 28 days. All 29 patients entered in the study were evaluable for toxicity and efficacy. Toxicity consisted primarily of fever, chills, myalgia, weakness and fatigue as well as cortical dysfunction including somnolence, confusion, and exacerbation of underlying neurologic deficits. One patient died from cerebral herniation attributable to interferon. None of the patients experienced objective tumor regression. Seven patients (24%) were stable for more than six months, but the disease stability could also be explained by indolent underlying disease or inability to distinguish recurrent tumor from delayed radiation effects. Intermittent high-dose recombinant interferon alpha plus eflornithine demonstrated no definite antitumor effects in this trial.     

A phase II study of intravenous carboplatin for the treatment of recurrent gliomas

Summary Thirty-two patients with recurrent glioma who had previously received radiation therapy and chemotherapy with nitrosoureas were treated with intravenous carboplatin every 3 weeks, starting at a dose of 350 mg/m², with a dose escalation of 25 mg/m² every 6 weeks until a level 4 hematologic toxicity was reached. Of the 28 patients who could be evaluated for a response, 50% demonstrated a response or had stabilization of their disease after two infusions of carboplatin. Their median time to tumor progression and median duration of survival were 19 weeks and 38 weeks. Thrombocytopenia was the major toxicity and was severe in one-third of the patients. No neurologic or renal toxicities were noted. Carboplatin has demonstrated activity against recurrent gliomas in patients who have already had extensive chemotherapy. Increasing the dose of carboplatin may improve the rate of response and the duration of progression-free survival in patients with recurrent glioma.     

Systemic sagopilone (ZK-EPO) treatment of patients with recurrent malignant gliomas

It has been demonstrated that sagopilone (ZK-EPO) has antitumor activity in human orthotopic glioma models in vitro and in vivo. The objective of this study was to evaluate the safety and efficacy of ZK-EPO in patients with pretreated, recurrent malignant gliomas. Fifteen patients with recurrent malignant gliomas who had received prior surgery, radiotherapy, and ≥2 lines of alkylating chemotherapy were recruited. ZK-EPO (16 mg/m²) was administered iv for 3 h every 21 days. The primary end point was six months progression-free survival (PFS-6); secondary end points were safety, toxicity, response rate, and median time to progression (TTP). Magnetic resonance imaging (MRI) evaluations were performed every two cycles and toxicity was evaluated at each cycle using common terminology criteria for adverse events (CTCAE 3.0). A median of four cycles was administered. The median TTP was 13 weeks. PFS-6 was achieved in five patients (33%), three with glioblastoma multiforme and two with anaplastic astrocytoma. The most common treatment-related adverse event was neuropathy, which occurred in 6/15 patients. ZK-EPO had an acceptable safety profile and clinically relevant activity in patients with pretreated, recurrent malignant gliomas.     

A phase II study of thalidomide and irinotecan for treatment of glioblastoma multiforme

Purpose Irinotecan is a cytotoxic agent with activity against gliomas. Thalidomide, an antiangiogenic agent, may play a role in the treatment of glioblastoma multiforme (GBM). To evaluate the combination of thalidomide and irinotecan, we conducted a phase II trial in adults with newly-diagnosed or recurrent GBM. Patients and methods Thalidomide was given at a dose of 100 mg/day, followed by dose escalation every 2 weeks by 100 mg/day to a target of 400 mg/day. Irinotecan was administered on day 1 of each 3 week cycle. Irinotecan dose was 700 mg/m² for patients taking enzyme-inducing anticonvulsants and 350 mg/m² for all others. The primary endpoint was tumor response, assessed by MRI. Secondary endpoints were toxicity, progression-free survival, and overall survival. Results Twenty-six patients with a median age of 55 years were enrolled, with fourteen evaluable for the primary outcome, although all patients were included for secondary endpoints. One patient (7%) exhibited a partial response after twelve cycles, and eleven patients (79%) had stable disease. The intention to treat group with recurrent disease included 16 patients who had a 6-month PFS of 19% (95% CI: 4–46%) and with newly-diagnosed disease included 10 patients who had a 6-month PFS of 40% (95% CI: 12–74%). Gastrointestinal (GI) toxicity was mild, but six patients (23%) experienced a venous thromboembolic complication. Two patients had Grade 4 treatment-related serious adverse events that required hospitalization. There were no treatment-related deaths. Conclusion The combination of irinotecan and thalidomide has limited activity against GBM. Mild GI toxicity was observed, but venous thromboembolic complications were common. Presented in part at the 8th Annual SNO Meeting in Keystone, CO, November 13–16, 2003.     

5-Fluorouracil and Recombinant Alpha Interferon-2a in the Treatment of Advanced Colorectal Carcinoma: a Dose Optimization Study

Summary

A dose optimization study was carried out with the aim of identifying the maximally tolerated dose of recombinant alpha interferon – 2a (raIFN-2a) in combination with 5-fluorouracil (5FU). 5FU was given at the dose of 750 mg/m² over a 4-hour infusion on day 1 – – > 5 followed by 750 mg/m² weekly i.v. bolus. Recombinant aIFN-2a was started at 3 × 10⁶ IU subcutaneously three times/week. 12 patients with advanced colorectal carcinoma were included in the study. 10 patients had previously received chemotherapy for advanced disease.

Severe fatigue, most likely attributable to rIFN, was the dose – limiting toxicity. The dosage of raIFN-2a could not be further escalated above 12 × 10₆ IU. At this dose level all patients required dose reduction due to fatigue, fever, myalgia and severe reduction of performance status.     

Neurotoxicity of combination chemotherapy with procarbazine,CCNU and vincristine (PCV) for recurrent glioma

In cerebral glioma combination chemotherapy with procabazine, CCNU and vincristine (PCV) is used as adjuvant therapy in cases of recurrence. Standard PCV is usually well tolerated, but intensive PCV (CCNU 130 mg/m² on day 1, procarbazine 75 mg/m² on day 8–21, vincristine 1.4 mg/m² on day 8 and 29; 6 courses every 6 weeks) is less well tolerated. We observed central neurotoxic side effects (focal neurological deficit, cognitive disturbances, slowing of EEG background activity, atrophy on cerebral MR) in combination with hematological and hepatic toxicity in four of 26 PCV treated patients with recurrent glioma. Prolonged myelosuppression and/or ongoing (partial reversible in two patients) neurological deficit still influence daily life in three of four patients months after discontinuation of chemotherapy. Despite the fact that all four patients used anticonvulsants and have been treated with radiotherapy in the past, we have the strong impression that central neurotoxic side effects are related to intensive PCV therapy. We advocate to use the standard PCV regimen in patients with recurrent glioma, because of this potential toxicity and the lack of evidence that intensive PCV leads to better tumor control than standard PCV in cerebral glioma.     

Escalating doses of interferon alpha-2A with cisplatin and concomitant radiotherapy: a phase I study

In this phase I study, we added escalating doses of interferon-alpha2A (IFN) to cisplatin and twice-daily radiotherapy based on the following rationale. Radiation enhancement has been shown for both interferon and cisplatin; in addition, potentiation of the cytotoxic activity of cisplatin by interferon has been demonstrated. A total of 48 patients with advanced solid tumors were treated with radiotherapy in 2 daily fractions of 125 cGy plus cisplatin at 8–10 mg/m² per day delivered on 3 different schedules (continuous infusion, daily short-term infusion, and single short-term infusion of 50 mg/m²). IFN was injected s.c. 2h preceding the first daily fraction of radiation. IFN doses ranged from 0 to 5.0×10⁶ U/m² per day. All therapy was given over 5 days of every other week until completion of the radiotherapy. Treatment at all dose levels was well tolerated during cycles 1 and 2, with no instance of acute grade 3 or 4 toxicity being noted. However, cumulative myelosuppression in patients receiving more than two treatment cycles was seen at all dose levels and was attributed to the repeated administration of cisplatin. Alteration of the cisplatin schedule did not allow for further dose escalation of cisplatin. Our recommended doses are cisplatin given at 8 mg/m² per day as a continuous infusion with IFN at 5.0×10⁶ U/m² per day. Among 24 patients with non-small-cell lung cancer, 2 had a complete response, 9 had a partial response, and 7 had stable disease. We conclude that this concomitant cisplatin-IFN-radiotherapy regimen is feasible. Activity was seen in non-small-cell lung cancer, and further studies of this regimen in that disease appear indicated.     

A phase I trial of concomitant chemoradiotherapy with cisplatin dose intensification and granulocyte-colony stimulating factor support for advanced malignancies of the chest

Concomitant chemoradiotherapy with cisplatin and combination chemotherapy in the neoadjuvant setting have both shown promising results.Purpose: To identify a locally and systemically active concomitant chemoradiotherapy regimen incorporating high-dose cisplatin, interferon alfa-2a (IFN), fluorouracil (5-FU), hydroxyurea (HU) and radiotherapy.Methods: Phase I cohort design establishing the maximal tolerated dose (MTD) of cisplatin with and without granulocyte colony stimulating factor (GCSF). For the first six dose levels, a 4-week cycle consisted of escalating doses of cisplatin during weeks 1 and 2, IFN (week 1), and 5-FU and HU (week 2) with single daily radiation fractions of 200 cGy during days 1–5 of weeks 1–3 and no treatment in week 4. When dose-limiting neutropenia was encountered, GCSF was added during weeks 1, 3, and 4. Finally, to decrease esophagitis, the radiotherapy schedule was altered to 150 cGy twice daily during weeks 1 and 2, followed by a 2-week break (level 7).Results: Forty-nine patients with refractory chest malignancies were treated. The MTD of this regimen without GCSF was cisplatin 50 mg/m² in weeks 1 and 2, IFN 5 million Units (MU)/m² per day on days 1–5 in week 1, 5-FU 800 mg/m² per day for 5 days by continuous infusion, and HU 500 mg every 12 h for 11 doses during week 2. The addition of GCSF during weeks 1, 3, and 4 allowed for escalation of cisplatin to 100 mg/m² during weeks 1 and 2, with a decreased dose of IFN at 2.5 MU/m² per day to avoid renal toxicity. Dose-limiting toxicity (DLT) included severe neutropenia, thrombocytopenia, and esophagitis in 5 of 13 patients. Increased thrombocytopenia in patients receiving GCSF was not observed. During hyperfractionated radiotherapy (level 7) chemotherapy doses were as above except for a reduction of 5-FU to 600 mg/m² per day. While severe esophagitis was reduced, grade 4 thrombocytopenia became more prevalent and was seen in 6 of 7 patients. In-field tumor responses were observed in 17 of 28 evaluated patients with non-small-cell lung cancer. The median times to progression and survival were 4 and 6 months, respectively. When only patients with all known disease confined to the radiotherapy field were considered the corresponding times were 6 and 15 months, respectively. Most treatment failures occurred outside of the irradiated field.Conclusions: (1) This intensive multimodality regimen can be given with aggressive supportive care incorporating GCSF. The recommended phase II doses for a 4-week cycle are cisplatin 50 mg/m² week 1, and 100 mg/m² week 2, IFN 2.5 MU, HU 500 mg every 12 h×11 and 5-FU 800 mg/m² per day with single fraction radiotherapy during weeks 1–3 and GCSF during weeks 1, 3, and 4. (2) GCSF can be safely administered and provides effective support of neutrophils when administered simultaneously with IFN, cisplatin, and chest radiotherapy. (3) There is synergistic renal toxicity when high doses of IFN and cisplatin are given together. (4) Hyperfractionated radiotherapy decreases the severity of esophagitis but increases thrombocytopenia. (5) Although highly toxic, response rates, time to progression and survival figures with this regimen are encouraging and support its investigation in the phase II setting.Presented at the International Association for the Study of Lung Cancer Workshop on Non-Small Cell Lung Cancer, Bruges, Belgium, August, 1993     

Vinorelbine and epirubicin in metastatic breast cancer. A dose finding study

The aim of the study was to define the maximum tolerated dose (MTD) of vinorelbine given as one or two weekly doses in combination with epirubicin 60 mg/m² every third week. The MTD was defined as the dose resulting in a WHO grade III or IV leucopenia exceeding 50% of patients. Patients were treated in groups of 10 at escalating doses of vinorelbine. The number of patients at the final dose level was expanded to 20. The dose of epirubicin was kept constant at 60 mg/m² every third week. At dose level 1,15 mg/m² vinorelbine was given on day 1 at level 2,20 mg/m² was given on day 1 and at level 3,20 mg/m² was given on days 1 and 8. The MTD was reached at dose level 3. WHO haematological toxicity grade IV occurred in 0, 10 and 45% and grade III at 60, 30 and 30% of patients at dose levels 1, 2 and 3, respectively. Despite the common occurrence of grade IV haematological toxicity, only two serious infections were noted. Non-haematological toxicity of vinorelbine included neurotoxicity, manifesting as muscle weakness, constipation and paresthesias in the majority of patients. Neurotoxicity was usually mild and did not require treatment discontinuation. Phlebitis at the injection site was troublesome in many patients. Alopecia and nausea, probably due to epirubicin, occurred in most patients. The response rates were 22% (95% CI (confidence interval) 3–60%), 40% (12–74%) and 60% (36–81%) at levels 1,2 and 3, respectively (nonsignificant).