Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors.

BACKGROUND: Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours. METHODS: Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m(-2) and CP 60-75 mg m(-2). Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m(-2), CP 60 mg m(-2)) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days. RESULTS: On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m(-2), 60 mg m(-2)); G 3 anorexia/fatigue/hypokalemia (1.2 mg m(-2), 60 mg m(-2)); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m(-2), 60 mg m(-2)). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m(-2), 60 mg m(-2)); G 4 mucositis (1.4 mg m(-2), 60 mg m(-2)); and G 3 hypokalemia (1.2 mg m(-2), 75 mg m(-2)). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m(-2) (days 1, 8) and CP 75 mg m(-2) (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers). CONCLUSIONS: On the 21-day cycle, eribulin mesylate 1.2 mg m(-2), administered on days 1 and 8, in combination with CP 75 mg m(-2), administered on day 1 is well tolerated and showed preliminary anticancer activity.

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar.

Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20-25 mg m(-2) intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m(-2) and escalated in an accelerated titration design to 25 mg m(-2). Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m(-2). The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10-73) ml h(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m(-2) in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.

Metabolic flare: indicator of hormone responsiveness in advanced breast cancer.

PURPOSE: The purpose of this study was to investigate whether positron emission tomography (PET) with the glucose analog [(18)F]fluorodeoxyglucose (FDG) and the estrogen analog 16 alpha-[(18)F]fluoroestradiol-17 beta (FES), performed before and after treatment with tamoxifen, could be used to detect hormone-induced changes in tumor metabolism (metabolic flare) and changes in available levels of estrogen receptor (ER). In addition, we investigated whether these PET findings would predict hormonally responsive breast cancer. PATIENTS AND METHODS: Forty women with biopsy-proved advanced ER-positive (ER(+)) breast cancer underwent PET with FDG and FES before and 7 to 10 days after initiation of tamoxifen therapy; 70 lesions were evaluated. Tumor FDG and FES uptake were assessed semiquantitatively by the standardized uptake value (SUV) method. The PET results were correlated with response to hormonal therapy. RESULTS: In the responders, the tumor FDG uptake increased after tamoxifen by 28.4% +/- 23.3% (mean +/- SD); only five of these patients had evidence of a clinical flare reaction. In nonresponders, there was no significant change in tumor FDG uptake from baseline (mean change, 10.1% +/- 16.2%; P =.0002 v responders). Lesions of responders had higher baseline FES uptake (SUV, 4.3 +/- 2.4) than those of nonresponders (SUV, 1.8 +/- 1.3; P =.0007). All patients had evidence of blockade of the tumor ERs 7 to 10 days after initiation of tamoxifen therapy; however, the degree of ER blockade was greater in the responders (mean percentage decrease, 54.8% +/- 14.2%) than in the nonresponders (mean percentage decrease, 19.4% +/- 17.3%; P =.0003). CONCLUSION: The functional status of tumor ERs can be characterized in vivo by PET with FDG and FES. The results of PET are predictive of responsiveness to tamoxifen therapy in patients with advanced ER(+) breast cancer.

Tubular breast cancer experience at Washington University: a review of the literature.

Our objective was to review the presentation and management of patients with tubular breast cancer treated at Barnes-Jewish Hospital and compare our findings with the available literature. Of 3908 cases of breast cancer treated at our institution between 1986 and 1995, the incidence of tubular breast cancer at Barnes-Jewish Hospital was 1.25%. We reviewed the breast cancer risks, initial presentation, treatment, and outcome of 39 women with 40 tubular breast cancers and compared our series with others in the literature. The mean patient age was 67 years, which is older than most other series. Twenty-nine of the 39 cancers (74%) were detected by screening mammography; the remainder presented with a palpable breast mass. The mean tumor size was 8 mm (range, 1-60 mm). Twenty-three of 25 tumors were ER+ (92%) and none had axillary nodal involvement. Bilateral breast cancer developed in 3 patients (8%). An additional 500 cases of tubular breast cancer have been described in the literature. When the component of the invasive tumor is > 75% tubular carcinoma, most patients present with early-stage disease that is ER+ in 47 of 56 tumors (84%). The natural history is indolent and metastases are rare. Bilateral breast cancer developed in 58 of the 540 cases (11%), 4 of which were tubular carcinomas. Local recurrences developed in 9 of 29 patients (31%) treated by excision alone. The role of tamoxifen has not been determined. Given the available data, the initial surgical staging and management of tubular carcinoma should be identical to other invasive histologies.

Effect of tamoxifen on sexual functioning in patients with breast cancer.

PURPOSE: To define the incidence of sexual dysfunction in a population of women with breast cancer treated with tamoxifen. PATIENTS AND METHODS: Breast cancer patients with a performance status of 0 to 2 who had been treated with tamoxifen for 2 to 24 months completed the following measures: the Center for Epidemiologic Studies-Depression Scale, the Sexual History Form, and the Breast Cancer Prevention Trial Symptom Checklist. Forty-nine of the participants underwent gynecologic examinations with vaginal smears for determination of estrogen effect. RESULTS: Fifty-seven women were entered onto the trial. Sexual desire, arousal, and ability to achieve orgasm were comparable to norms established in participants in the Tamoxifen Prevention Trial (National Surgical Adjuvant Breast and Bowel Project P-01). Pain, burning, or discomfort with intercourse was reported in 54% of patients and did not correlate with age, surgical treatment of the primary cancer, or chemotherapy. Estrogen effect was seen on the vaginal smears of 34 of 49 participants and was more common in older patients (P = .054). The presence of estrogen effect correlated with negative reactions during sex (P = .02) and vaginal dryness or tightness (P = .046). CONCLUSION: Women treated with tamoxifen in the adjuvant setting experienced symptoms of sexual dysfunction. The individual contributions of chemotherapy and tamoxifen to sexual dysfunction warrant prospective study.

Positron emission tomographic assessment of "metabolic flare" to predict response of metastatic breast cancer to antiestrogen therapy.

We have investigated whether increased tumor uptake of fluorine-18 fluorodeoxyglucose (FDG) detected with positron emission tomography (PET) early after initiating tamoxifen therapy ("metabolic flare") predicts a hormonally responsive breast cancer. Eleven postmenopausal women with biopsy-proved estrogen receptor-positive (ER+) metastatic breast cancer were studied by PET with FDG and 16alpha[18F]fluoro-17beta-estradiol (FES) before and 7-10 days after initiation of tamoxifen therapy. FDG and FES uptake was evaluated semiquantitatively in 21 lesions. The PET results were correlated with follow-up evaluation, continued until the patient became unresponsive to hormone therapy (3-24 months). There were seven responders and four nonresponders based on clinical follow-up. None of the responders had a clinical flare reaction, but all demonstrated metabolic flare, with a mean +/- standard deviation increase in tumor standardized uptake value (SUV) for FDG of 1.4+/-0. 7. No evidence for flare was noted in the nonresponders (change in SUV for FDG -0.1+/-0.4; P = 0.008 vs. responders). The degree of ER blockade by tamoxifen was greater in responders (mean decrease in SUV 2.7+/-1.7) than in nonresponders (mean decrease 0.8+/-0.5) (P = 0.04). The lesions of responders had higher baseline SUVs for FES than did those of three of four nonresponders (>/=2.2 vs

Assessment of knowledge about cancer pain management by physicians in training.

This survey assessed the knowledge of physicians in training about the pharmacology of opioid analgesics and the benefits of palliative radiation therapy in the management of cancer pain. Eighty-one trainees at the Washington University Medical Center completed a questionnaire that addressed the palliative care of a hypothetical patient with metastatic non-small cell lung cancer. The questions addressed were 1) opioid selection, 2) conversion of parenteral to oral morphine, 3) management of opioid toxicities, 4) opioid addiction, and 5) efficacy of radiation therapy. The results demonstrated that few physicians in training were familiar with the stepwise progression of analgesic selection outlined in the World Health Organization (WHO) guidelines. When asked to convert a parenteral dose of morphine to an equivalent dose of a controlled-release preparation, 75% calculated a dose that was less than one-third the correct dose; only four (5%) calculated the dose correctly. Trainees were familiar with the management of opioid toxicities. They were unfamiliar with the palliative benefits of radiation therapy. Although 41% recognized that complete relief of pain could be achieved in 50%-60% of patients, most (70%) predicted that maximum pain relief would be seen within the first month, and 98% predicted maximum benefit by 12 weeks. Although cancer pain management has been highlighted in the lay and medical literature, physicians in training still demonstrate deficiencies in their knowledge about the pharmacology and bioequivalency of the opioid and the benefits of radiation therapy. Published guidelines for the management of cancer pain need to be disseminated to all medical personnel caring for patients with cancer.

Results of a trial with topotecan dose escalation and concurrent thoracic radiation therapy for locally advanced, inoperable nonsmall cell lung cancer.

PURPOSE: To conduct a dose escalation clinical study with topotecan and concurrent standard dose thoracic irradiation to assess its feasibility and toxicity in the treatment of patients with locally advanced, inoperable nonsmall cell lung cancer (NSCLCA). METHODS AND MATERIALS: Between April 1993 and August 1994, 12 patients with inoperable, loco-regionally advanced NSCLCA were entered in a prospective dose escalation trial and assigned to receive concurrent thoracic radiotherapy and topotecan. Patients received thoracic irradiation to a total tumor dose of 60 Gy in 30 fractions. Initial fields were to encompass the gross disease plus the mediastinum. Topotecan was delivered by bolus injection days 1 through 5, and days 22 through 26, beginning on the same day as the radiation therapy. The initial dose level was 0.5 mg/m2. Two additional dose levels of 0.75 mg/m2 and 1.0 mg/m2 were tested. RESULTS: Six patients were accessioned to the 0.5 mg/m2 dose level, three patients to the 0.75 mg/m2 dose level, and three patients to the 1.0 mg/m2 dose level. At the 0.5 mg/m2 dose level, zero of six patients had > or = Grade 4 hematologic toxicity. One of the six had Grade 3 esophagitis. At the 0.75 mg/m2 dose level, two of three patients had > or = Grade 3 nonhematologic toxicity including anorexia, fatigue, nausea, vomiting, and weakness; zero patients experienced > or = Grade 4 hematologic toxicity. At the 1.0 mg/m2 dose level one of three patients had > or = Grade 3 esophagitis, and two of three patients experienced Grade 4 neutropenia. With a follow-up of 12 to 24 months, two patients are alive and free of disease, three patients are alive with disease (two with distant metastasis, one with local disease and distant metastasis), and the remaining seven patients are dead of disease. CONCLUSIONS: The combination of topotecan and thoracic radiotherapy for nonsmall lung cancer, in the manner given by this protocol, could be safely given at a dose level of only 0.5 mg/m2 days 1 to 5 and 22 to 26 with 60 Gy of external beam radiotherapy. Higher doses of topotecan were associated with high hematologic and gastrointestinal toxicity. Distant metastasis was the primary pattern of failure.

Positron emission tomography with 2-[18F]Fluoro-2-deoxy-D-glucose and 16alpha-[18F]fluoro-17beta-estradiol in breast cancer: correlation with estrogen receptor status and response to systemic therapy.

We assessed the value of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and 16alpha-[18F]fluoro-17beta-estradiol (FES) in women with breast cancer for predicting response to systemic therapy. Results of FES-PET were correlated with estrogen receptor (ER) status. Forty-three women with locally advanced or metastatic breast cancer underwent FDG-PET and FES-PET prior to institution of systemic therapy. All patients had measurable disease and had tumors submitted for ER determination. Cancers were considered functionally hormone sensitive if the standardized uptake value of the lesion on FES-PET was >/=1.0 (FES+) and hormone resistant if the standardized uptake value was <1.0 (FES-). Information obtained by FES-PET was compared with the results of ER assays. The tumor response to chemotherapy and hormonal therapy was correlated with intensity of uptake by both FDG-PET and FES-PET. The ER status of the breast cancers was negative (ER-) in 20 patients, positive (ER+) in 21 patients, and unknown in 2 patients. All 20 of the ER- tumors were also FES-. However, of the 21 ER+ tumors, 16 were FES+ and 5 were FES-. Thirty patients were treated initially with chemotherapy, and 21 (70%) demonstrated objective responses. We were unable to correlate the response to chemotherapy with information obtained by FDG-PET or FES-PET. Thirteen patients were treated with hormone therapy, and 8 (61%) responded to that therapy. Only 1 of the 5 patients whose tumors were ER+ but FES- received hormone therapy, and this treatment resulted in disease stabilization only. Multiple sites of disease were assessed by FES-PET in 17 patients with metastatic breast cancer. Functional hormone sensitivity, defined by FES-PET, was concordant with multiple lesions in 13 (76%). Ten patients with locally advanced breast cancer developed recurrent disease. The initial site of recurrence was the breast in 5 patients. Of the 5 patients with systemic recurrence, 4 had disease detected at the site of recurrence on the pretreatment FDG-PET study but not detected on pretreatment computed tomography. In our experience, FDG-PET imaging is more sensitive than conventional imaging methods, including computed tomography, in staging women with breast cancer. When compared with the in vitro assay of ER status, FES-PET has an apparent sensitivity of 76% and specificity of 100%. Our finding of a subset of patients who have tumors that are ER+ and FES- suggests that the functional assessment of hormone sensitivity by PET imaging can identify patients with ER+ disease whose tumors are likely to be hormone refractory.

Positron tomographic assessment of estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor assays.

UNLABELLED: The purpose of this study was to assess the results of PET with 16 alpha-[18F]fluoro-17 beta-estradiol (FES) and [18F]fluoro-2-deoxy-D-glucose (FDG) to validate the concordance between tumor estrogen-receptor (ER) status as determined by FES-PET and in vitro assays and to assess the relationship between tumor metabolic activity determined by FDG-PET and tumor ER status, both of which may provide information about tumor aggressiveness and prognosis. METHODS: We studied 32 patients with primary breast masses and 21 patients with clinical or radiological evidence of recurrent/metastatic breast carcinoma. A diagnosis of breast carcinoma was subsequently proven in 43 patients (24 primary, 15 metastatic and 4 recurrent tumors). In vitro assessment of ER status was available for 40 malignant lesions (23 primary and 17 metastatic/recurrent). The patients underwent PET with both FES and FDG, and the uptake of each tracer within each lesion was evaluated qualitatively as well as semiquantitatively using the standardized-uptake-value (SUV) method. RESULTS: We found good overall agreement (88%) between in vitro ER assays and FES-PET. This degree of agreement is similar to that observed between replicate in vitro assays (with discordances due to interlaboratory, interassay and specimen variability). We were, however, unable to demonstrate any significant relationship between tumor FDG uptake and ER status or between tumor FDG and tumor FES uptake in these patients. CONCLUSION: These results indicate that in vitro ER assays and/or FES-PET provide unique direct information about breast cancer ER status that cannot be obtained indirectly by FDG-PET.

Factors influencing cosmetic results after conservation therapy for breast cancer.

PURPOSE: Host, tumor, and treatment-related factors influencing cosmetic outcome are analyzed for patients receiving breast conservation treatment. METHODS AND MATERIALS: Four-hundred and fifty-eight patients with evaluable records for cosmesis evaluation, a subset of 701 patients treated for invasive breast cancer with conservation technique between 1969 and 1990, were prospectively analyzed. In 243 patients, cosmetic evaluation was not adequately recorded. Cosmesis evaluation was carried out from 3.7 months to 22.3 years, median of 4.4 years. By pathologic stage, tumors were 62% T1N0, 14% T1N1, 15%, T2N0, and 9% T2N1. The majority of patients were treated with 4-6 MV photons. Cosmetic evaluation was rated by both patient and physician every 4-6 months. A logistic regression analysis was completed using a stepwise logistic regression. P-values of 0.05 or less were considered significant. Excellent cosmetic scores were used in all statistical analyses unless otherwise specified. RESULTS: At most recent follow-up, 87% of patients and 81% of physicians scored their cosmetic outcome as excellent or good. Eighty-two percent of physician and patient evaluations agreed with excellent-good vs. fair-poor rating categories. Analysis demonstrated a lower proportion of excellent cosmetic scores when related to patient age > 60 years (p = 0.001), postmenopausal status (p = 0.02), black race (p = 0.0034), and T2 tumor size (p = 0.05). Surgical factors of importance were: volume of resection > 100 cm3 (p = 0.0001), scar orientation compliance with the National Surgical Adjuvant Breast Project (NSABP) guidelines (p = 0.0034), and > 20 cm2 skin resected (p = 0.0452). Extent of axillary surgery did not significantly affect breast cosmesis. Radiation factors affecting cosmesis included treatment volume (tangential breast fields only vs. three or more fields) (p = 0.034), whole breast dose in excess of 50 Gy (p = 0.0243), and total dose to tumor site > 65 Gy (p = 0.06), as well as optimum dose distribution with compensating filters (p = 0.002). Daily fraction size of 1.8 Gy vs. 2.0 Gy, boost vs. no boost, type of boost (brachytherapy vs. electrons), total radiation dose, and use of bolus were not significant factors. Use of concomitant chemotherapy with irradiation impaired excellent cosmetic outcome (p = 0.02). Use of sequential chemotherapy or adjuvant tamoxifen did not appear to diminish excellent cosmetic outcomes (p = 0.31). Logistic regression for excellent cosmetic outcome analysis was completed for age, tumor size, menopausal status, race, type of surgery, volume of breast tissue resected, scar orientations, whole breast radiation dose, total radiation dose, number of radiation fields treated, and use of adjuvant chemotherapy. Significant independent factors for excellent cosmetic outcome were: volume of tissue resected (p = 0.0001), type of surgery (p = 0.0001), breast radiation dose (p = 0.005), race (p = 0.002), and age (p = 0.007). CONCLUSIONS: Satisfactory cosmesis was recorded in 81% of patients. Impaired cosmetic results are more likely with improper orientation of tylectomy and axillary incisions, larger volume of breast resection, radiation dose to the entire breast in excess of 50.0 Gy, and concurrent administration of chemotherapy. Careful selection of treatment procedures for specific patients/tumors and refinement in surgical/irradiation techniques will enhance the cosmetic results in breast conservation therapy.

Management of locally advanced carcinoma of the breast. I. Noninflammatory.

BACKGROUND: The treatment of patients with locally advanced noninflammatory breast cancer has evolved substantially over the past 30 years. From 1968 to 1989, 281 women were treated at Mallinckrodt Radiation Oncology Center with four different treatment methods. Median follow-up was 6.2 years (range 3-22 years); no patient was lost to follow-up. METHODS: Retrospective review of records and analysis of data on a computer file were carried out. Thirty-five patients were treated with irradiation alone, 33 with irradiation and adjuvant chemotherapy, 81 with mastectomy and irradiation, and 132 with mastectomy, irradiation, and chemotherapy (triple-modality). RESULTS: Actuarial 5- and 10-year disease free survival (DFS) rates were 45% and 36%, respectively, with triple-modality therapy, 31% and 10% with irradiation and chemotherapy, 32% and 19% with irradiation and mastectomy, and 19% and 11% with irradiation alone. Cause specific survival (CSS) paralleled DFS in the four groups. Locoregional tumor control at 5 years was 91% for irradiation, mastectomy, and chemotherapy, 80% for irradiation and mastectomy, 54% for irradiation and chemotherapy, and 31% for irradiation alone. Systemic therapy and/or irradiation given before mastectomy yielded better locoregional tumor control, DFS, and CSS (not statistically significant). No difference in results was noted with radical, modified radical, or total mastectomy. In the triple-modality group, no chest wall failures occurred with chest wall doses greater than 5040 cGy. Grade 2 or higher treatment sequelae were noted in 10-42% of patients, depending on treatment modality. CONCLUSIONS: Triple-modality therapy yielded improved locoregional tumor control, DFS, and CSS compared with other modalities. Patients treated with surgery had better locoregional tumor control than those who received irradiation alone or in combination with chemotherapy, but the impact on DFS and CSS was less impressive. Additional clinical trials are needed to define further the role and optimal use of the various therapeutic modalities in the management of locally advanced breast cancer.

Chemotherapy in the management of malignant gastrointestinal disease.

Malignancies arising from the gastrointestinal tract represent a diversity of histologies and natural history. The role of chemotherapy in the multidisciplinary approach to these malignancies is reviewed in this article.

A phase II randomized study comparing sequential and combined intraarterial cisplatin and radiation therapy in primary brain tumors. A Southwest Oncology Group study.

The Southwest Oncology Group conducted a trial of intra-arterial cisplatin (150 mg intravenously every 21 days for 2 doses) administered concomitant with or before radiation therapy. Because of technical difficulties cannulating the artery, 27 of 33 eligible patients were able to receive the cisplatin by arterial injection. Five patients died before completion of the study, and 11 patients in each treatment arm were evaluable for response. Three patients (27%) had an objective tumor regression in each treatment arm. Thromboembolic problems complicated 8 of 57 (14%) chemotherapeutic courses. The median survival for the 33 eligible patients was comparable for both groups: 10.8 months in the concomitant treatment arm and 9.6 months with sequential therapy. Problems related to drug administration and toxicity made it impossible to determine the role of intraarterial cisplatin in the initial management of primary high-grade gliomas.

A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck.

PURPOSE: To determine whether combination chemotherapy is superior to single agents for recurrent/metastatic head and neck cancer, we compared the efficacy and toxicity of cisplatin (CP) and fluorouracil (5-FU), alone and in combination in a phase III trial. PATIENTS AND METHODS: Two hundred forty-nine patients with recurrent head and neck cancer were randomized to one of three treatments: CP (100 mg/m2) and 5-FU (1 g/m2 x 4), CP, or 5-FU every 3 weeks. RESULTS: The overall response rate to the combination (32%) was superior to that of CP (17%) or 5-FU (13%) (P = .035). Response was associated with good performance status (PS) but not with primary site, site of recurrence, histology, prior irradiation, or relative dose intensity. Median time to progression was less than 2.5 months, and there was no significant difference in median survival (5.7 months) among the groups. By multivariate analysis, patients with better PS and poorly differentiated tumors had superior survival. Hematologic toxicity and alopecia were worse in the combination arm. CONCLUSION: Although the response rate to the combination of CP plus 5-FU was superior to that achieved with single agents, survival did not improve.

High-dose cisplatin for metastatic soft tissue sarcoma.

Between August 1984 and January 1987, the Southwest Oncology Group (SWOG) registered 46 patients with metastatic sarcomas on SWOG 8465, a Phase II trial of high-dose cisplatin in patients with metastatic soft tissue sarcoma. Six patients were ineligible for the following reasons: poor performance status (two patients); ineligible diagnosis (three patients, two with Ewing's sarcoma of bone and one with metastatic chondrosarcoma); and evaluable but nonmeasurable disease (one patient with bone-only disease). Of the 40 fully evaluable patients, 34 had received prior chemotherapy; treatment was with cisplatin (40 mg/m2/d for 5 consecutive days). Cisplatin was mixed in 250 ml of 3% NaCl and hydrated with a normal saline solution at a rate of 250 ml/h, beginning 12 hours before the first dose of cisplatin was specified. The second treatment was given 3 weeks after the first, with all subsequent treatments given every 4 weeks. After three cycles of treatment, responding patients were treated at a cisplatin dose of 20 mg/m2/d for 5 consecutive days. Leukopenia was of Grade 3 or 4 in seven patients, whereas thrombopenia was of Grade 3 or 4 in eight patients. More severe myelosuppression was produced in patients who had received prior radiotherapy. A single case of reversible Grade 4 nephrotoxicity was produced; neurotoxicity was observed in 11 cases, but was of Grade 3 in only 2 cases. Of the 40 evaluable cases, six showed partial responses or no responses, for a major response rate of 15%. High-dose cisplatin has minor activity and major toxicity in the treatment of metastatic soft tissue sarcomas, and should be considered investigational.

Weekly fluorouracil and high-dose leucovorin: efficacy and treatment of cutaneous toxicity.

Intensive therapy with 5-fluorouracil (FU) and leucovorin (LV) has proved to be effective in the treatment of advanced colorectal cancer. The toxicity of this regimen has not been systematically evaluated. In the present study, 52 patients with advanced colorectal and refractory cancers received sequential 2-month cycles of weekly FU and high-dose LV and were monitored for toxicity as well as response in 103 cycles. Of 24 evaluable patients with colorectal cancer, 1 complete and 9 partial responses were seen (42%); 4 of 10 patients who had been refractory to conventional FU treatment responded to the FU/LV regimen. One partial response was observed among six patients with gastric carcinoma, and three minor responses were seen in five women with refractory breast cancer. A total of 24 patients (46%) completed the first cycle on schedule, although 7 subjects required a reduction in the dose of FU. The majority of patients required treatment breaks because of toxicity. Gastrointestinal toxicity proved to be dose-limiting on this schedule, necessitating FU dose modification and treatment of both diarrhea in 15 subjects and acute abdominal pain in 7 cases. No patient required a further treatment delay of FU dose adjustment. Myelosuppression was an uncommon complication on this regimen. Cutaneous toxicity was also prominent in this series of patients, with the hand-foot syndrome developing in 14 cases (27%); 11 subjects who developed this complication were treated with pyridoxine (150 mg daily), and all experienced improvement in their symptoms within 1 week. Partial and complete responses were observed in 41% of evaluable patients with colorectal cancer and in one of six evaluable patients with gastric carcinoma. We conclude that FU and high-dose LV can safely be given on a weekly basis, although acute gastrointestinal and cutaneous toxicity are common.

High-dose cisplatin in disseminated melanoma: a comparison of two schedules.

A total of 38 patients with metastatic melanoma received monthly chemotherapy with cisplatin at a dose of 200 mg/m2, per cycle; 14 received 20 mg/m2 cisplatin i.v. on days 1-5 and 24 were given 100 mg/m2 i.v. on days 1 and 8. Objective responses were seen in 2/14 treated on days 1-5 and in 5 of 22 evaluable subjects receiving cisplatin on days 1 and 8, for an overall response rate of 22%. The median survival of all patients was 6 months, with no significant difference observed between the two schedules. Severe neurotoxicity and myelosuppression were more common in patients treated on days 1-5. Two patients treated in this manner were bedridden due to neurotoxicity and four developed grade 4 leukopenia after the first cycle of chemotherapy. Only one patient treated with the divided-dose schedule became leukopenic during the first cycle, and none of the patients were debilitated by neurotoxicity. Thrombocytopenia was statistically more severe. Nausea and vomiting, fatigue, ototoxicity, and paresthesia were seen with equal frequency. Very high doses of cisplatin can be delivered with acceptable toxicity using a divided-dose schedule. As the response rate on this schedule appeared to be comparable with that achieved on the more toxic consecutive 5-day schedule, the former deserves to be tested in diseases known to show a dose response to cisplatin. However, in melanoma, administration of 200 mg/m2 per course did not appear to be associated with a markedly improved response rate, compared with cisplatin alone at "standard" doses.

Transcatheter therapy for malignant neoplasms.

Interventional radiology has developed into a subspecialty with application in the treatment and palliation of patients with advanced malignant diseases. A directed catheter delivers high concentrations of chemotherapy directly into the tumor bed. Embolic particles may be injected to stop hemorrhage or to occlude the blood supply of a cancer, resulting in pain relief or tumor shrinkage. These techniques can be incorporated into a multidisciplinary approach to cancer.