M. Andrew Burgess

Phase II Clinical Investigation of Gemcitabine in Advanced Soft Tissue Sarcomas and Window Evaluation of Dose Rate on Gemcitabine Triphosphate Accumulation

PURPOSE To evaluate the efficacy, toxicity, and optimal dose rate of gemcitabine in adult patients with advanced soft tissue sarcomas (STS) by comparing levels of gemcitabine triphosphate (GTP) in peripheral-blood mononuclear cells (PBMCs) of patients receiving two different dose rates. PATIENTS AND METHODS Fifty-six assessable patients with STS (17 gastrointestinal [GI] leiomyosarcomas and 39 other histologies) were treated on a two-arm phase II study. Gemcitabine was given at 1 g/m2 as a 30-minute infusion weekly for up to 7 weeks followed by 1 week of rest and reassessment of tumor. Subsequent cycles were given at 1 g/m2 weekly for 3 weeks followed by 1 week of rest. Nine patients underwent cellular pharmacologic studies at two different dose rates (1 g/m2 over a standard 30-minute infusion on week 1 and over pharmacologically based infusion of 150 minutes on week 2) to evaluate GTP levels in PBMCs. RESULTS Seven partial responses were noted among 39 patients, for an overall response rate of 18% (95% confidence interval, 7% to 29%). Median duration of response was 3.5 months (range, 2 to 13 months). Four of 10 patients with non-GI leiomyosarcomas achieved a partial response. No objective responses were noted in 17 patients with GI leiomyosarcomas. One patient had a mixed response. Median time to progression for all patients (both arms) was 3 months; median survival was 13.9 months. Treatment was generally well tolerated. Comparison of cellular pharmacology demonstrated a significant 1.4-fold increase in the concentration of GTP with the 150-minute infusion. CONCLUSION Given the limited therapeutic armamentarium for STS, the activity of gemcitabine is encouraging. Its potential for combination therapy in the salvage setting should be studied with pharmacologically guided fixed dose-rate infusion.

Results of Two Consecutive Trials of Dose-intensive Chemotherapy With Doxorubicin and Ifosfamide in Patients With Sarcomas

The authors evaluate the efficacy and feasibility of dose-intensive doxorubicin and ifosfamide combination chemotherapy in patients with sarcomas. From January 1995 to April 1996, 33 evaluable patients with either metastatic sarcoma or primary sarcomas with a high-risk for metastases (all except one was previously untreated with chemotherapy) were treated on two consecutive protocols. The median age was 45 years (range, 15-68 years). The first protocol included doxorubicin at 75 mg/m2 given as a 72-hour infusion on days 1 to 3 along with ifosfamide at 2 g/m2/d over 2 hours x 5, days 1 to 5 (protocol AI 75/10). Granulocyte colony-stimulating factor (G-CSF) was used only if indicated according to American Society of Clinical Oncology guidelines. The second protocol included doxorubicin at 90 mg/m2 as a 72-hour continuous infusion and ifosfamide at 2.5 g/m2/d for 4 days (protocol AI 90/10) with prophylactic G-CSF. A median of four cycles were administered (range, 1-6). Three patients achieved a pathologic complete response (CR) and 18 patients achieved a partial response (PR) for a response rate (RR) of 64% (95% confidence interval (CI), 45-80%). Response rate for the subset of patients with soft-tissue sarcomas was 66% (95% CI, 46-82%). Only three patients progressed on therapy. Febrile neutropenia was noted in 31% of cycles at AI 75/10 and in 56% of cycles at AI 90/10. One patient developed reversible grade 3 central nervous system (CNS) toxicity. There was one treatment-related death on AI 90/10 secondary to doxorubicin cardiac toxicity at a cumulative dose of 435 mg/m2. Dose-intensive doxorubicin plus ifosfamide is feasible in appropriately selected patients and appears to be a very active regimen in patients with sarcomas. The authors are currently testing this regimen with G-CSF and thrombopoietin.

Dose-escalating conformal thoracic radiation therapy with induction and concurrent carboplatin/paclitaxel in unresectable stage IIIA/B nonsmall cell lung carcinoma: A modified phase I/II trial

A modified Phase I/II trial was conducted evaluating the incorporation of three‐dimensional conformal radiation therapy into a strategy of sequential and concurrent carboplatin/paclitaxel in Stage III unresectable nonsmall cell lung carcinoma (NSCLC). The dose of thoracic conformal radiation therapy (TCRT) from 60 to 74 gray (Gy) was increased. Endpoints included response rate, toxicity, and survival.

Intracarotid infusion of cis‐diamminedichloroplatinum in the treatment of recurrent malignant brain tumors

Thirty‐five patients with malignant brain tumors (23 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation chemotherapy received cisplatin, 60 to 120 mg/m2, into the internal carotid artery by a transfemoral approach. Courses of therapy were repeated every 4 weeks. Therapeutic evaluation was performed monthly using the CT scan of the brain and clinical neurologic examination. Thirty patients were evaluable for response. Of 20 evaluable patients with primary malignant brain tumors, 6 responded to therapy and 5 had stable disease. The median time to tumor progression for responding patients was 33 weeks, for stable patients 16 weeks, and 13 weeks for all patients. Five of 10 evaluable patients with brain metastases responded to intracarotid cisplatin, and 2 patients had stable disease. The estimated median time to progression for responding patients was 30+ weeks and 12+ weeks for patients with stable disease. Side effects included seizures in 5 courses, mental agitation and motor restlessness in 1, and transient hemiparesis in 7. One patient may have had a drug‐related death, and one patient appeared to develop encephalopathy after treatment. Five patients had clinical deterioration in vision; in two patients it was bilateral. Intracarotid cisplatin has definite activity in patients with malignant primary brain tumors and in patients with brain metastases. The recommended starting dose for intracarotid cisplatin is 60 to 75 mg/m2. At this dose level side effects are uncommon, but includes the risk of neurologic and retinal toxicity.

The natural history of resectable metastatic melanoma (Stage IVA Melanoma)

One‐hundred‐two patients with malignant melanoma who had distant metastases surgically resected and were judged to be clinically free of disease (M. D. Anderson Stage IVA melanoma) were studied. The median survival for all the patients from time of diagnosis of stage IVA disease was 18 months. The site of the resected metastases did not appear to influence survival, being approximately the same for the brain (15 months), lung (16 months), intraabdominal (18 months), and skin and/or lymph nodes (23 months). The site of the resected metastases also did not influence the median disease‐free interval. Patients who had metastases resected from several organs at the same time had a median survival of 15 months, which was similar to that of patients with one resected site. Patients who were rendered Stage IVA on several occasions by surgical excisions had a median survival of 36 months. Thirty‐five patients received surgery only and 67 patients received adjuvant chemotherapy, immunotherapy, or combined chemoimmunotherapy after surgery. For the group treated with surgery only, the median disease‐free interval and survival from diagnosis of stage IVA disease were 6 months and 16 months, respectively, and for the adjuvant group 6 months and 21 months, respectively. Specifically, by the type of adjuvant therapy, the median disease‐free interval and survival from stage IVA for 23 patients receiving Corynebacterium parvum were 6.9 and 19 months; for 39 patients receiving BCG, eight months and 26 months; for 24 patients receiving BCG + DTIC, eight and 17.4 months; and for all 51 DTIC treated patients 6.3 and 17.8 months, respectively. Patients receiving BCG had a median survival superior to the surgery only group (P = 0.02). An increase in survival was seen predominantly in patients who achieved IVA status more than once and received BCG. Patients with recurrent soft‐tissue metastases appeared to benefit most from BCG in prolonging the disease‐free interval. Only 1/10 treated by surgery alone had a disease‐free interval longer than 1 year, compared with 9/16 who received BCG (P = 0.01). Stage IVA melanoma appears to be distinctly different in prognosis from Stage IVB melanoma and should be classified separately. Patients with recurrent soft‐tissue disease may benefit significantly from treatment with BCG.

Pilot study of vitaxin—an angiogenesis inhibitor—in patients with advanced leiomyosarcomas

Leiomyosarcomas comprise one of the common histologic subsets of a rare and heterogenous group of tumors called soft tissue sarcomas. Leiomyosarcomas have a variable biologic behavior depending on their site of origin. Tumors originating in the gastrointestinal (GI) tract belong to a broader class of tumors called GI stromal tumors and are refractory to standard chemotherapeutic agents such as doxorubicin and ifosfamide. Those originating outside the GI tract, especially the ones arising from the uterus, conversely are indeed sensitive to these standard chemotherapeutic agents. Unfortunately, the options for salvage chemotherapy after failure of initial therapy with standard agents are very limited, and therefore newer strategies need to be investigated aggressively. Angiogenesis is critical for the growth and development of tumor. It is a complicated process initiated by the expression of several proteases and growth factors acting as angiogenic molecules. The migration of endothelial cells is dependent on their adhesion to extracellular matrix proteins, such as vitronectin, through a variety of cell adhesion receptors known as integrins. The role of the integrin avb3 in the angiogenic process has been established. Blocking neoangiogenesis by inhibiting the anb3 integrin therefore can result in antitumor activity. We tested Vitaxin, a humanized monoclonal antibody targeted against the endothelial cell anb3 integrin in a group of patients with advanced leiomyosarcomas with an intent to test feasibility and safety and to better estimate the antitumor activity that was observed in one patient with liver metastases from a leiomyosarcoma in the Phase I study of Vitaxin performed at the Sidney Kimmel Cancer Center in San Diego, California. Vitaxin was administered intravenously as an outpatient at a fixed dose of 0.25 mg/kg over 9

Surgical management, DNA content, and patient survival in adrenal cortical carcinoma

BACKGROUND Surgical resection is the only potentially curative treatment for adrenal cortical carcinoma, yet the value of extended resection, palliative resection, and tumor DNA analysis remains unclear. METHODS The records of 23 patients with adrenal cortical carcinoma who underwent primary surgical resection at our institution were retrospectively reviewed. Flow cytometric DNA analysis was performed on primary tumor tissue from 14 patients. RESULTS Sixteen of 23 patients underwent complete resection. For these 16 patients the median follow-up was 43 months, the actuarial median survival was 46 months, and the actuarial 5-year survival rate was 46%. The seven patients who underwent incomplete resection all died of disease with a median survival of 8.5 months. Isolated local recurrence as the first site of failure occurred in two patients. Only completeness of resection (p = 0.004) and stage at presentation (p = 0.006) were significant prognostic indicators. None of the following predicted a poor prognosis in patients who underwent complete resection: (1) need for extended resection, (2) presence of renal vein or inferior vena cava tumor thrombus, or (3) tumor aneuploidy (14 of 14 tumors were aneuploid). CONCLUSIONS Long-term survival is possible in patients with adrenal cortical carcinoma if complete, margin-negative tumor resection can be achieved. Isolated local recurrence is uncommon after complete resection. Because adrenal cortical carcinomas are consistently aneuploid, tumor DNA content is not a useful prognostic factor.

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.

Protected environment–Prophylactic antibiotic program for malignant sarcomas: Randomized trial during remission induction chemotherapy

Fifty‐one evaluable patients with malignant sarcomas were randomly allocated to receive three courses of remission induction chemotherapy with cyclophosphamide, vincristine, Adriamycin, and dimethyl triazeno imidazole carboxamide (CYVADIC) on the protected environment‐prophylactic antibiotic (PEPA) program24 or as controls.27 The complete remission rate was 33% for the PEPA group and 15% for the control group (P = 0.22). The response rates (complete plus partial) were 71% and 67%, respectively. The durations of response were similar for both groups of patients, but the PEPA patients survived substantially longer (median, 84 weeks vs. 58 weeks). The frequency of infection was significantly lower among the PEPA patients, and the doses of CYVADIC could be escalated more often among these patients. Dosage escalation was associated with a higher complete remission rate and lower fatality rate.

The value of adriamycin in the treatment of diffuse malignant pleural mesothelioma

Thirty‐six patients with diffuse malignant pleural mesothelioma were seen over a period of 15 years. The median age was 60 years (range, 21 to 75 years), and the male to female ratio was 2.3 to 1. The most common symptoms were chest pain and shortness of breath and all patients presented with pleural effusion on chest x‐ray. The diagnosis was established by tissue biopsy in all cases. The median survival time for all patients was 12.5 months. Twenty‐one patients were treated with an adriamycin‐containing regimen and in this group, the median survival time from histological diagnosis was 14 months. In contrast, the median survival time for the 15 patients, who did not receive adriamycin, was 6 months (p = 0.009). The median survival time from the initiation of chemotherapy was 9 months for the adriamycin group and 2 months for patients treated with other types of chemotherapy (p = 0.001). Adriamycin appears to be of benefit in the treatment of diffuse malignant pleural mesothelioma. Cancer 42:1692–1696, 1978.