A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: impact on DNA methylation and lymphocyte populations.

BACKGROUND: Melanoma cell lines treated with decitabine show upregulation of cancer antigens, and interferon-α upregulates MHC Class I antigens in cancer cells, leading to enhanced T-cell recognition and T-cell mediated tumor apoptosis. We evaluated the synergy between the hypomethylating effects of decitabine and the immunomodulatory effects of interferon in a combination regimen administered to advanced melanoma patients in a phase 1 trial. METHODS: Patients with one prior systemic therapy were eligible. Using a modified 3 + 3 design, patients received escalating doses of decitabine and pegylated interferon α-2b (PEG-IFN) during every 28-day treatment cycle. Global DNA methylation was measured on days 1 and 5 of cycles 1 and 3. Cytokine profiling and quantification of T-cell subpopulations by FACS were performed at baseline and cycle 3. RESULTS: Seventeen patients were assigned to one of four dose levels. Decitabine 15 mg/m2/d + PEG-IFN 3 µg/kg was the maximum tolerated dose (MTD). Grade 3/4 cytopenias were seen across all dose levels: anemia (1), neutropenia (7), and thrombocytopenia (2). One patient remained progression-free for 37 weeks. The other 16 patients progressed at or before 12 weeks. Median overall survival was 39 weeks. Hypomethylation was seen at all dose levels. Due to treatment-induced lymphocytopenia, absolute changes in T-cell populations post-treatment were too small to be meaningfully interpreted. CONCLUSIONS: The response to this combination regimen was characterized by significant myelosuppression, particularly neutropenia. Although disappointing efficacy and slow accrual led to early closure of the trial, hypomethylation showed pharmacodynamic evidence of a therapeutic effect of decitabine at all dose levels.

Phase II trial of imatinib mesylate in patients with metastatic melanoma.

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Clinical evaluation of recombinant interferon alfa-2a (Roferon-A) in metastatic melanoma using two different schedules .

Based on the reports of activity of interferons against metastatic melanomas, we conducted a phase II study of recombinant interferon alfa-2a (Roferon-A, Hoffmann-La Roche, Nutley, NJ) in 66 patients with disseminated melanoma. All patients had excellent Eastern Cooperative Oncology Group (ECOG) performance status (0 to 1), and no evidence of brain metastases. Thirty patients had previously received chemotherapy and the remainder were untreated. The first 35 patients were treated on a daily schedule starting with a Roferon-A dose of 3 X 10(6) U/d and escalating to a maximum of 36 X 10(6) U/d over a period of 12 days. Because of excessive toxicity, the second group of 31 patients were treated on a fixed dose of 18 X 10(6) U/d [corrected] three times weekly (TIW). Among the 62 evaluable patients, five achieved an objective response for a response rate of 8% (95% confidence limits, 3% to 18%). Four patients had minor regressions and eight patients had stability of disease. The responses were evenly distributed between the two dose schedules. The major toxicity of interferon consisted of a constitutional syndrome of anorexia, fever, weight loss, and fatigue, which required a dose reduction in 75% of the patients on the daily schedule. Our data revealed a modest level of activity, which was not influenced by prior treatment or by the dose or schedule of interferon. Because of substantial toxicity with the daily schedule, we recommend a dose of 18 X 10(6) U/d [corrected] if interferon is used in the treatment of patients with melanoma.

Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: protection at the progenitor cell level.

PURPOSE: The purpose of this study was to optimize the dose, schedule, and timing of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) administration that would best abrogate myelosuppression in patients with sarcoma. PATIENTS AND METHODS: Sarcoma patients who had experienced severe myelosuppression after chemotherapy with Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co, Evansville, IN), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dacarbazine ([CyADIC], cycle 1) were eligible. GM-CSF was administered during a 14-day period until 1 week before cycle 2 of CyADIC and was resumed 2 days after cycle 2 completion. The schedule subsequently was modified to allow the earlier administration of GM-CSF in which CyADIC was compressed from 5 days to 3 days, and GM-CSF was administered immediately after the discontinuation of CyADIC in cycle 2. To understand better the impact of GM-CSF on bone marrow stem cells, the proliferative status of bone marrow progenitors was examined during treatment. To evaluate the effects of GM-CSF on effector cells, select functions of mature myeloid cells were also examined. RESULTS: In the seven patients who were treated on the initial schedule, GM-CSF enhanced the rate of neutrophil recovery; however, severe neutropenia was not abrogated, By using the modified schedule in 17 patients, GM-CSF significantly reduced both the degree and the duration of neutropenia and myeloid (neutrophils, eosinophils, and monocytes) leukopenia. The mean neutrophil and mature myeloid nadir counts were 100/mm3 and 280/mm3 in cycle 1 and 290/mm3 and 1,540/mm3 in cycle 2 (P less than .01 and P less than .001). The duration of severe neutropenia (neutrophil count less than 500/mm3) and myeloid leukopenia (myeloid leukocyte count less than 1,000/mm3) were reduced from 6.2 and 6.8 days in cycle 1 to 2.8 and 1.4 days in cycle 2 (P less than .001). While 16 of 17 patients experienced severe myeloid leukopenia (less than 500/mm3) in cycle 1, only two of 17 experienced severe myeloid leukopenia in cycle 2 (P less than .001). Overall, severe neutropenia was abrogated in seven patients, which made them eligible for dose-escalation of Adriamycin. The fraction of cycling progenitors increased threefold on GM-CSF and decreased dramatically below the baseline within 1 day of GM-CSF discontinuation. CONCLUSIONS: The modified schedule improved the beneficial effects of GM-CSF by enhancing myeloprotection and permitting dose-intensification of chemotherapy. The increased myeloid mass and quiescent progenitors at the initiation of chemotherapy suggest that GM-CSF might allow further chemotherapy dose-rate intensification by shortening the interval between courses.

Effects of PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein, on chemotherapy-induced multilineage myelosuppression in patients with sarcoma.

PURPOSE: To evaluate the clinical safety and ability of PIXY321, a novel fusion protein of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), to ameliorate chemotherapy-induced multilineage myelosuppression. PATIENTS AND METHODS: PIXY321 was administered by subcutaneous injection twice daily (25 to 1,000 micrograms/m2/d) over 14 days to 24 chemotherapy-naive patients with sarcoma in a phase I/II study. Three weeks from the initiation of PIXY321, the first cycle of chemotherapy with cyclophosphamide, doxorubicin, and dacarbazine (DTIC) (CyADIC) was administered over 3 days. Four weeks later, a second cycle of CyADIC was administered, followed by 14 days of PIXY321. RESULTS: Treatment with PIXY321 was well tolerated. Local skin reactions and constitutional symptoms were the main side effects. The dose-limiting toxicity was not encountered; however, headache and fatigue were more frequent at the highest dose (1,000 micrograms/m2). PIXY321 before chemotherapy elicited a modest increase in the WBC count (consisting mainly of mature neutrophils), platelets, and corrected reticulocyte counts (all P < .001). Following chemotherapy, PIXY321 at effective doses (500 to 1,000 micrograms/m2/d), significantly reduced both the degree (mean nadir, 70 v 310/microL; P = .016) and duration (mean days < 500/microL, 6.6 v 3.9 days; P = .002) of neutropenia. Cumulative thrombocytopenia was not observed during the first two cycles of CyADIC (mean nadir platelet count, 103 v 95 x 10(3)/microL, in cycles no. 1 and 2, respectively; P = NS). Compared with our historic control data, the mean nadir platelet count in cycle no. 2 was significantly higher after PIXY321 (1.7-fold, P < .05) than with CyADIC alone or with GM-CSF support. There was a suggestion for a dose response, since the mean percentage change in nadir platelet values from cycle no. 1 to cycle no. 2 increased with the PIXY321 dose (P < .02), with the peak effect observed at 750 micrograms/m2/d. CONCLUSION: These results suggest a potential clinical role for PIXY321 in attenuating the cumulative multilineage hematopoietic toxicity of chemotherapy.

Prognostic factors for survival of patients treated systemically for disseminated melanoma.

PURPOSE: The current American Joint Commission on Cancer (AJCC) staging system distinguishes between soft tissue and visceral metastases in advanced (stage IV) melanoma. We sought to verify these staging criteria and to identify prognostic variables that could be used to evaluate the impact of systemic therapy on long-term survival during the prior decade. PATIENTS AND METHODS: We conducted a retrospective study of patients with advanced cutaneous melanoma enrolled in clinical trials between 1979 and 1989 at The University of Texas M.D. Anderson Cancer Center. Pretreatment age, sex, number of organs with metastases, serum levels of lactate dehydrogenase (LDH) and albumin, and period of enrollment were analyzed using a Cox proportional hazards model of survival. RESULTS: In univariate and multivariate analyses that involved 318 stage IV patients, normal serum levels of LDH and albumin, soft tissue and/or single visceral organ metastases (especially lung), female sex, and enrollment late in the decade were independent positive predictors for survival. In multivariate analyses, the current AJCC criteria did not significantly predict outcome. Systemic treatment response did not bias these results, and only 4% of patients had a complete response. Patients who lived more than 2 years (11%) had a mix of favorable prognostic characteristics and a high frequency of systemic or surgically induced complete response. CONCLUSION: This study supports the use of stratification parameters that reflect the favorable prognostic impact of soft tissue or single visceral organ metastases and normal serum levels of LDH and albumin at time of enrollment in advanced melanoma trials. Improved survival over the prior decade probably reflects advances in diagnostic and palliative interventions.

Long-term outcome of patients with American Joint Committee on Cancer stage IIB extremity soft tissue sarcomas.

PURPOSE: It has been suggested that patients with small (< 5 cm), high-grade extremity soft tissue sarcomas (STS) have an excellent overall prognosis and, consequently, may not require adjuvant therapies. PATIENTS AND METHODS: A comprehensive review of all patients with extremity STS treated at a tertiary care cancer hospital over a 9-year period (January 1984 to December 1992) was performed. Prognostic factors, treatment data, and long-term outcome were evaluated in the subset of 111 patients with American Joint Committee on Cancer stage IIB (G3/4, T1a/b) disease. RESULTS: The median tumor size was 3.0 cm (range, 0.6 to 4.9 cm), and 55 tumors (50%) were deep in location. All patients underwent surgical resection; 68 (61%) received pre- or postoperative radiotherapy, and 32 (29%) received doxorubicin-based chemotherapy. The median follow-up was 76 months. Forty patients (36%) experienced 59 recurrences. First recurrences occurred at local, regional, and distant sites in 21, five, and 14 patients, respectively. The 5-year actuarial local recurrence-free, distant recurrence-free, disease-free, and overall survival rates were 82%, 83%, 68%, and 83%, respectively. The presence of a microscopically positive surgical margin was an independent adverse prognostic factor for both local recurrence (relative risk [RR] = 3.75; 95% confidence interval [CI], 1.25 to 11.25; P =.02) and disease-free survival (RR = 2.57; 95% CI, 1.33 to 4.98; P =.005). CONCLUSION: Event-free outcome for this subset of patients with high-grade STS does not seem as favorable as previously reported by other investigators. Patients who undergo maximal surgical resection with microscopically positive margins represent a subset of T1 STS patients who warrant consideration for adjuvant therapies.

Phase II study of recombinant interleukin 1alpha and etoposide in patients with relapsed osteosarcoma.

A Phase II trial using interleukin 1alpha (IL-1alpha) and etoposide for patients with relapsed osteosarcoma (OS) was undertaken to assess the feasibility and tolerability of combination therapy with biotherapy and chemotherapy. Nine patients with histologically proven relapsed OS were treated with IL-1alpha immediately followed by etoposide daily for 5 days every 3 weeks. Surgical resection of lung metastasis or peripheral tumor was performed after two or three cycles. We observed three partial responses; disease was stable in another case. One case could not be evaluated. The side effects associated with combination therapy were as predicted from known side effects of the individual agents; however, more profound neutropenia was observed. Four patients exhibited clinical signs of capillary leak syndrome, i.e., hypotension, edema, and weight gain. The etiology of the capillary leak was unclear, because serum IL-1alpha, IL-2, tumor necrosis factor, and nitric oxide levels could not be used to predict which patients would develop capillary leak. Histological analysis of tumor specimens obtained after two or more courses of therapy showed changes consistent with a response to a biological response modifier: peripheral fibrosis surrounded the metastasis with infiltration of chronic and acute inflammatory cells. Because the response of relapsed OS to any type of salvage regimen has been poor, we interpret the clinical response of this therapy as good. However, the significant side effects associated with this therapy must also be taken into consideration before deciding to use this combination therapy. It is unfortunate that the study was stopped early due to halted production of IL-1alpha. If this agent is again manufactured for clinical use, we conclude that additional evaluation in patients with relapsed OS is warranted.

Active immunotherapy with ultraviolet B-irradiated autologous whole melanoma cells plus DETOX in patients with metastatic melanoma.

Our objective was to determine the clinical activity, toxicity, and immunological effects of active immunotherapy using UVB-irradiated (UVR) autologous tumor (AT) cells plus adjuvant DETOX in metastatic melanoma patients. Eligibility included nonanergic patients fully recovered after resection of 5 or more grams of metastatic melanoma. Treatment consisted of intradermal injections of 10(7) UVR-AT plus 0.25 ml of DETOX every 2 weeks x 6, then monthly. Peripheral blood mononuclear cells (PBMCs) were harvested for cytotoxicity assays, and skin testing was performed for delayed-type hypersensitivity (DTH) determinations before the first, fourth, seventh, and subsequent treatments. Forty-two patients were treated, 18 in the adjuvant setting and 24 with measurable disease. Among the latter group, there were two durable responses in soft-tissue sites and in a bone metastasis. Treatment was well tolerated. Thirty-five patients were assessable for immunological parameters; 10 of these patients, including the 2 responders, demonstrated early induction of PBMC cytotoxicity against AT cells that persisted up to 10 months on treatment before falling to background levels. In five of seven patients, the fall-off heralded progressive disease. Late induction of a weak DTH reaction to AT cells was observed in eight patients. Active immunotherapy with UVR-AT + DETOX had modest but definite clinical activity in advanced melanoma. The induction of both PBMC cytotoxicity and DTH reactivity to AT cells supported a specific systemic immune effect of treatment, although the former more closely followed disease course in this study.

Leiomyosarcoma of renal vein.

Leiomyosarcomas arising from the renal vein are rare tumors: only 13 cases are found in the literature. We report a case in a sixty-one-year-old woman who presented with back pain and hematuria. She underwent resection of the tumor and an ipsilateral nephrectomy. The tumor recurred locally, and the patient died thirty months after diagnosis. Review of the cases reported in the literature reveals the aggressive nature of these tumors and the need for a combined therapeutic approach.

Mechanism of the anti-tumour effect of biochemotherapy in melanoma: preliminary results.

During the conduct of a biochemotherapy trial in which cisplatin, vinblastine and dacarbazine (CVD) were administered concurrently with interleukin-2 (IL-2) plus interferon-alpha 2a (IFN-alpha 2a) (biochemotherapy) in advanced melanoma, we performed a series of laboratory studies in an attempt to understand better the mechanism of anti-tumour effect of the regimen. We initially hypothesized that CVD enhanced the anti-tumour effect of the biotherapy. However, in the first 10 patients studied, of whom eight were responders, we observed no lymphokine-associated killer cell (LAK) and minimal natural killer (NK) cell activities. This prompted us to change our initial hypothesis. Based on the work of others which showed a marked synergism between IL-1 alpha and cisplatin, apparently mediated by H2O2 derived from tumour-infiltrating macrophages, we reasoned that the biotherapy could enhance the cytotoxicity of the CVD regimen. To evaluate macrophage function, we measured serum neopterin levels in eight responders and seven non-responders. An increase of six or more times above baseline levels was observed in seven out of eight responders but in only two of seven non-responders (P = 0.041). We also examined the level of DNA inter-strand cross-link in peripheral blood mononuclear cells in four responders and four responders, as a means to evaluate the DNA repair process. A DNA cross-link index > or = 0.75 was observed in all four responders but only in one non-responder (P = 0.14). Our preliminary results suggest that concurrent biochemotherapy may exert its predominant anti-tumour effect by direct cytotoxicity and that macrophages may be involved in this process.

Myxoid malignant fibrous histiocytoma: experience with chemotherapy.

Myxoid malignant fibrous histiocytoma (MFH) is an intermediate grade tumor with a definite metastatic potential but a relatively indolent natural history compared to the pleiomorphic variant of MFH. Little is known about its sensitivity to chemotherapy. We reviewed our experience with chemotherapy in myxoid MFH between 1986 and 1992. The patient population was identified through a search of the database maintained by the Departments of Melanoma-Sarcoma Medical Oncology and Pathology: 55 patients with histologically confirmed diagnosis of myxoid MFH were identified. Chemotherapy was administered to 18 of these patients (10 females, 8 males). The median age was 65 (range: 30-76). Ten patients had an extremity primary, seven had a trunk or retroperitoneal primary, and one patient had head and neck as the site of primary tumor. The median size of the primary tumor was 11 cm (range: 5-23 cm) in maximum dimension. Seven patients received chemotherapy in the neoadjuvant setting, eight received it for recurrent or metastatic disease, and three received it postoperatively after complete resection of the tumor. All patients received doxorubicin and dacarbazine with or without cyclophosphamide. Of the 15 patients evaluable for response, 4 achieved an objective response (one CR, 3 PRs, RR = 27%) to a median of 3 cycles (range: 1-7 cycles). At the time of last follow-up, eight patients are alive with no evidence of disease, two patients are alive with disease, and eight patients have expired. The median follow-up is 51 months (range: 26-216 months) from diagnosis. The relatively small sample precludes any definitive conclusions; however, it seems that doxorubicin- and dacarbazine-based chemotherapy has modest activity in myxoid MFH.

Extraskeletal myxoid chondrosarcoma. Long-term experience with chemotherapy.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare low-grade soft tissue sarcoma that has been reported to have an indolent nature history, and relatively good prognosis. The majority of primary tumors are located in the extremities and they tend to be bulky at presentation. Studies with long-term follow-up have revealed the development of distant metastases in virtually all patients, eventually resulting in death. We reviewed our experience with EMC over the last three decades. The patient population was identified through a search of the database maintained by the Departments of Patient Studies, Pathology, and Melanoma-Sarcoma Medical Oncology. Eleven patients with histologically confirmed diagnosis of EMC were identified. The median age was 59 (37-81 years), and there were nine males and two females. Nine patients had an extremity location and the remaining two had a chest wall and abdominal wall primary, respectively. The median size of the primary tumor was 10 cm (range: 4-17 cm) in maximum dimension. Ten of the eleven patients received chemotherapy, mainly with doxorubicin- and dacarbazine-based regimens. One patient is currently on beta-interferon. No objective responses were noted, to a median of 4 (2-6) cycles of chemotherapy. Three patients were treated with ifosfamide as a second-line chemotherapy without any benefit. Three patients have expired, two patients are alive with no evidence of disease, and six patients are alive with disease. The median follow-up is 5 years (range: 1.33-17 years) from diagnosis. Although small numbers preclude adequate assessment, there is no evidence of efficacy of standard soft-tissue sarcoma chemotherapy in patients with EMC.

Osteosarcoma chemotherapy effect: a prognostic factor.

Chemotherapy has become a routine part of the treatment of osteosarcoma. However, the precise role of preoperative chemotherapy remains in question. Between 1979 and 1982, a group of 40 patients were treated by multimodality therapy consisting of preoperative chemotherapy (intra-arterial cis-platinum and systemic adriamycin), surgery, and postoperative chemotherapy. Survival in this group is 64%, while continuous disease-free survival is 58%. Although age, sex, tumor size, site, and classification were found to be prognostic factors, histologic evidence of response to preoperative chemotherapy, measured as percent tumor necrosis, was found to be the most significant prognostic factor. When continuous disease-free survival was calculated as a function of tumor necrosis it was 91% in patients with greater than or equal to 90% tumor necrosis, while it was 14% in patients with less than 90% tumor necrosis. At initial presentation, 7% of patients were judged limb-salvage candidates. But due to the local effects of preoperative chemotherapy, 60% ultimately underwent limb-salvage surgery. Preoperative arteriograms were a reliable means of monitoring response to chemotherapy and served as an indicator of residual viable tumor. Using arteriogram directed planes of section, postchemotherapy, specimens were "mapped" and analyzed for chemotherapy effect. When present, residual viable tumor was preferentially found at the interface of tumor and normal anatomic structures; "sanctuary sites." It is necessary that standard methods for analyzing postchemotherapy specimens be developed; a technique is described.

Pharmacokinetic/pharmacodynamic analysis of adjuvant pegylated interferon α-2b in patients with resected high-risk melanoma.

PURPOSE: High-dose pegylated interferon α-2b (peginterferon α-2b) significantly decreased disease recurrence in patients with resected stage III melanoma in a clinical study. We investigated the pharmacokinetics (PK) and safety of high-dose peginterferon α-2b in patients with high-risk melanoma. METHODS: For PK analysis, 32 patients received peginterferon α-2b 6 µg/(kg week) subcutaneously for 8 weeks (induction) then 3 µg/(kg week) for 4 weeks (maintenance). PK profiles were determined at weeks 1, 8, and 12. Exposure-response relationships between peginterferon α-2b and absolute neutrophil count (ANC) and alanine aminotransferase (ALT) level were also studied. RESULTS: Peginterferon α-2b was well-absorbed following SC administration, with a median T (max) of 24 h. Mean half-life estimates ranged from 43 to 51 h. The accumulation factor was 1.69 after induction therapy. PK parameters showed moderate interpatient variability. PK profiles were described by a one-compartmental model with first-order absorption and first-order elimination. Toxicity was profiled and was acceptable; observed side effects were similar to those previously described. Dose reduction produced proportional decreases in exposure and predictable effects on ANC in an Imax model; however, a PK/pharmacodynamic (PK/PD) relationship between peginterferon α-2b and ALT could not be established with high precision. CONCLUSIONS: Peginterferon α-2b was well-absorbed and sustained exposure to peginterferon α-2b was achieved with the doses tested. These data confirm and extend previous PK observations of peginterferon α-2b in melanoma and solid tumors. Our PK/PD model of exposure and ANC effect provides useful information for prediction of peginterferon α-2b-related hematologic toxicity.

Phase II Study of Paclitaxel in Patients With Soft Tissue Sarcomas.

Purpose. Patients with soft tissue sarcoma (STS) who have previously received standard chemotherapy including adriamycin (doxorubicin), ifosfamide, cyclophosphamide and DTIC (dacarbazine) have very limited therapeutic options. It is important to identify new drugs with some activity in this disease and we therefore undertook this trial to determine the antitumor activity of paclitaxel (Taxol).Methods. We conducted a phase II study of paclitaxel in patients with STS who had received prior standard chemotherapy. Paclitaxel was administered at a starting dose of 200 mg m(-2) as a 24-h infusion with STS premedication, every 21 days or upon hematologic recovery (absolute granulocyte count (AGC) >/= 1500/mul, platelets >/= 100 000/mul). Neupogen was not used routinely. The study was conducted based on a two-stage design proposed by Simon. Responses were assessed radiographically using standard criteria.Results. Nineteen eligible patients were treated in the first stage of the study. The median age was 50 years (range 20-68 years), and there were nine females and 10 males with Zubrod performance status of 1 or 2. One patient achieved a minor response. Median AGC nadir was 0.1/mul on day 12 with absolute neutropenia lasting 5 days. Median platelet nadir was 171 000/mul on day 9. There were no grade 3/4 non-hematologic toxicities and no deaths related to treatment.Discussion. Paclitaxel, at this dose and schedule, is well tolerated but inactive in this patient population.

A phase I trial of weekly lomustine in patients with advanced cancer.

BACKGROUND: Lomustine is a commercially available chloroethyl nitrosourea compound whose antitumor activity in vitro and in animal tumor models exceeds its activity in humans. Part of the poor clinical performance of this drug may be explained by dose-limiting subjective toxicity observed with the standard schedule of one oral dose of approximately 130 mg/m2 every 6-8 weeks. METHODS: Twenty patients were enrolled in a Phase I clinical trial of weekly oral lomustine. The first dose level was 24 mg/m2, with subsequent dose increases in increments of 6 mg/m2. Intrapatient dose escalations were allowed if there were no toxic reactions noted after 12 weekly doses. RESULTS: The dose-limiting toxic effect was the development of thrombocytopenia in 35% of patients (6 of 17) treated at 30 mg/m2 after a median of 12 weekly doses (range, 5-20 weeks), whereas in 18% of patients (3 of 17), neutropenia developed after a median of 12 weeks (range, 9-22 weeks). Grade 3 or Grade 4 hematologic toxicity developed in three of three patients whose doses were escalated to 36 mg/m2/week after showing no evidence of toxicity for 12-16 weeks at 30 mg/m2/week. Partial remission was observed in two patients with malignant melanoma, and stable disease was observed in two patients with hypernephroma. Nausea, vomiting, and malaise were not significant complications of treatment. CONCLUSION: Lomustine can be administered at a dose of 30 mg/m2/week for 12+ weeks to patients with cancer who have received previous treatment with minimal toxicity while retaining antitumor activity.

Treatment of hepatic metastases in ocular melanoma. Embolization of the hepatic artery with polyvinyl sponge and cisplatin.

Patients with ocular melanoma have a high incidence of hepatic metastases, which primarily determine their length of survival. In an attempt to control the neoplastic disease in the liver, embolization of the hepatic artery with a combination of polyvinyl sponge (Ivalon) and a suspension of cisplatin was performed in two patients with hepatic metastases from ocular melanoma. Dramatic regression of the hepatic metastases, lasting 19 and six months, occurred in these two patients after one or two such treatments. Our preliminary, albeit successful, experience with this therapeutic approach suggests that it may offer relatively prolonged periods of remission and warrants further investigation.

Myxoid liposarcoma. Experience with chemotherapy.

BACKGROUND: Myxoid liposarcoma (ML) is the most common type of liposarcoma. It has been classified as an intermediate grade tumor with a definite metastatic potential but a relatively indolent natural history. Little is known about its sensitivity to chemotherapy. METHOD: The authors reviewed their experience with chemotherapy in ML from 1986 to 1992. The patient population was identified through a search of the database maintained by the Department of Melanoma-Sarcoma Medical Oncology of the M.D. Anderson Cancer Center. RESULTS: Forty-four patients each with a histologically confirmed diagnosis of ML were identified. Twenty-one were treated with chemotherapy. The median age was 45 years (31-69 years); there were 14 men and 7 women. The ML in 19 patients was in the lower extremity, one in the head and neck, and one pelvic. The median size of the primary tumor was 15 cm (range, 7-48 cm) in maximum dimension. Of the 18 patients who received doxorubicin- and dacarbazine-based chemotherapy as a frontline regimen [median of 3 (2-9) cycles] and were evaluable for response, 8 (1 completed response, 7 partial responses) achieved an objective response (44%, 95% confidence interval 21-67%). Two of the remaining three patients who were also treated with a similar regimen were not evaluable for response (one received chemotherapy postoperatively, and the other received concomitant radiation and doxorubicin), and the third patient received ifosfamide as frontline chemotherapy because of a significant cardiac history. Seven patients received chemotherapy in the neoadjuvant setting, 13 for recurrent or metastatic disease, and 1 postoperatively after complete tumor resection. At the last follow-up, 10 patients were alive with no evidence of disease, 3 were alive with disease, and 8 had died. The median follow-up was 51 months (range, 6-199 months) from diagnosis. CONCLUSION: The authors conclude that doxorubicin- and dacarbazine-based chemotherapy is effective in the treatment of ML.

Phase II study of paclitaxel in patients with previously treated osteosarcoma and its variants.

BACKGROUND: Patients with osteosarcoma and its variants who did not respond to standard chemotherapy including doxorubicin, ifosfamide, cisplatin, and high dose methotrexate were treated with paclitaxel so that its therapeutic activity in these patients could be determined. METHODS: We conducted a Phase II study of paclitaxel in patients with conventional osteosarcoma (10), malignant fibrous histiocytoma of the bone (3) and dedifferentiated chondrosarcoma (2) whose disease had progressed after prior standard chemotherapy including doxorubicin, cisplatin, ifosfamide, and high dose methotrexate. Paclitaxel was administered at a starting dose of 175 mg/m2 as a 24-hour infusion with standard premedication every 21 days or upon hematologic recovery (absolute granulocyte count [AGC] > 1500/microliters, platelets > 100,000/microliters). Neupogen was not used routinely. The study was conducted based on a two-stage design. A total of 17 patients were entered into the protocol. Two were ineligible since they had Ewing's sarcoma. Responses were assessed radiographically and pathologically when feasible, using standard criteria. RESULTS: Fifteen eligible patients were treated in the first stage of the study. Median age of the patients was 31 years (range, 19-61 yrs). There were 8 females and 7 males with a Zubrod performance status of 0 or 1. One patient achieved a mixed response and 14 developed progressive disease. Median AGC nadir was 0.3, on Day 13, lasting 5 days. Median platelet nadir was 134, on Day 8. There were no Grade III or IV nonhematologic toxicities and no deaths related to treatment. CONCLUSIONS: Paclitaxel, at this dose and schedule, is well tolerated but inactive in this patient population.