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Biomedical subjects

C L Shapiro

Publications and source records attributed to C L Shapiro.

At least 19 recordsLinked to original sources
PubMed2005

Phase I trial of liposomal encapsulated doxorubicin (Myocet; D-99) and weekly docetaxel in advanced breast cancer patients.

BACKGROUND: We conducted a phase I trial to determine the safety and maximum tolerated dose (MTD) of non-pegylated liposome-encapsulated doxorubicin (Myocet; D-99) administered with weekly docetaxel in metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: Twenty-one patients with no prior chemotherapy for MBC received D-99 (60 or 50 mg/m2) intravenously (i.v.) on day 1 and escalating doses of docetaxel (25, 30 and 35 mg/m2 i.v. on days 1 and 8 in cohorts of three to six patients. Treatment cycles were repeated every 21 days for a maximum of six cycles. RESULTS: The maximum tolerated dose (MTD) was 50 mg/m2 of D-99 in combination with 25 mg/m2 of weekly docetaxel. The most common grade 4 toxicity was neutropenia that occurred in 42 (41%) of treatment cycles, with 10 hospitalizations for febrile neutropenia. Serious protocol-defined cardiac events occurred in three (14%) patients, with two (10%; 95% confidence interval [CI] 1% to 30%) developing congestive heart failure (CHF) after a total cumulative anthracycline dose (adjuvant doxorubicin + D-99) of 540 mg/m2. CONCLUSIONS: D-99 in combination with weekly docetaxel, at the doses and schedule as administered in this trial, is not recommended for phase II testing. Additional trials, using different doses and schedules, are required to evaluate the potential side-effects and efficacy of D-99 and docetaxel.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer.

PURPOSE: We sought to evaluate the effects of chemotherapy-induced ovarian failure on bone loss and markers of skeletal turnover in a prospective longitudinal study of young women with breast cancer receiving adjuvant chemotherapy. PATIENTS AND METHODS: Forty-nine premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated within 4 weeks of starting chemotherapy (baseline), and 6 and 12 months after starting chemotherapy with dual-energy absorptiometry and markers of skeletal turnover osteocalcin and bone-specific alkaline phosphatase. Chemotherapy-induced ovarian failure was defined as a negative pregnancy test, greater than 3 months of amenorrhea, and a follicle-stimulating hormone > or = 30 MIU/mL at the 12-month evaluation. RESULTS: Among the 35 women who were defined as having ovarian failure, highly significant bone loss was observed in the lumbar spine by 6 months and increased further at 12 months. The median percentage decrease of bone mineral density in the spine from 0 to 6 months and 6 to 12 months was -4.0 (range, -10.4 to +1.0; P =.0001) and -3.7 (range, -10.1 to 9.2; P =.0001), respectively. In contrast, there were no significant decreases in bone mineral density in the 14 patients who retained ovarian function. Serum osteocalcin and bone specific alkaline phosphatase, markers of skeletal turnover, increased significantly in the women who developed ovarian failure. CONCLUSION: Chemotherapy-induced ovarian failure causes rapid and highly significant bone loss in the spine. This may have implications for long-term breast cancer survivors who may be at higher risk for osteopenia, and subsequently osteoporosis. Women with breast cancer who develop chemotherapy-induced ovarian failure should have their bone density monitored and treatments to attenuate bone loss should be evaluated.

Adult↗
PubMed2001

Prognostic significance of the number of bone scan abnormalities at the time of initial bone metastatic recurrence in breast carcinoma.

BACKGROUND: To gain insight into the factors that contribute to the more favorable prognosis associated with recurrence limited to bone in patients with breast carcinoma, the authors analyzed the number of sites of initial involvement identified on radionuclide bone scans in relation to long term outcome. METHODS: Records of 641 patients with clinical Stage I-III breast carcinoma that originally was diagnosed in 1974-1985 were reviewed. During follow-up, 295 patients (46%) experienced distant recurrence, including 116 with bone as the sole initial site of metastatic disease. Radionuclide bone scans identified the initial site(s) of recurrence in 113 of these latter 116 patients, and these studies were categorized by the number of skeletal lesions subsequently confirmed as metastases (1, 2, or > or = 3). Survival from time of recurrence and time of original diagnosis was analyzed using Kaplan-Meier methods, and factors associated with recurrence and mortality were examined using logistic and Cox regression. RESULTS: Median survival from time of recurrence was 35 months in the patients with bone-only metastases, compared with 11-26 months for all other sites of visceral recurrence exclusive of bone. Number of positive lymph nodes and estrogen receptor status were the only predictive variables for recurrence. Median survival from time of recurrence and time of original diagnosis for the 3 bone scan categories was: 1 lesion (n = 47), 53 and 86 months; 2 lesions (n = 22), 38 and 68 months; and > or = 3 lesions (n = 44), 22 and 58 months (P < 0.0001 and P < 0.005 for 1 and 2 lesions vs. > or = 3). In the "bone-only" group, the number of scan lesions was the strongest predictor of length of survival. CONCLUSIONS: Patients with breast carcinoma who experience a recurrence in bone at only one or two sites initially have a survival advantage over those with more extensive (> or = 3 sites) skeletal metastases and those with metastatic disease involving other visceral organs.

Adult↗
PubMed2000

Smoking and alcohol use may be risk factors for poorer outcome in patients with clear cell renal carcinoma.

OBJECTIVES: To correlate the clinical outcomes of 148 patients with clear cell renal carcinoma treated at a single institution with a variety of other factors. METHODS: Cases were derived from a consecutive series of nephrectomy specimens obtained from 1980 to 1994. A retrospective review of clinical records was performed, with tobacco use, alcohol use, recurrence, and survival noted. RESULTS: The median age of the patients was 62 years. The median follow-up was 4.4 years. Of 148 patients, 82% had localized disease (MO), and 18% had suspected metastases (M1) at the time of nephrectomy. Of 121 patients without metastases at diagnosis, T classification was assessed for 117: 48 (41%) had T1 disease, 18 (15%) T2, 46 (39%) T3, and 5 (4%) T4. The Fuhrman grade was 1 or 2 in 51% of patients and 3 or 4 in 45%. Both clinical stage and grade were significantly associated with overall survival (P <0.0001 and P = 0.0028, respectively) and recurrence-free survival (P = 0.0002 and P = 0.0011, respectively). Smoking and alcohol use history was determined in 70% and 63% of patients, respectively. In patients with Stage M0, smokers had a significantly worse overall survival rate compared with nonsmokers (P = 0.039). Also, in patients with Stage M0, a trend toward a worse recurrence-free survival rate was noted in alcohol users compared with those who never used alcohol regularly (P = 0.06). CONCLUSIONS: The prognosis of clear cell renal carcinoma depends on the pathologic stage at diagnosis and the Fuhrman grade. Smoking is a known risk factor for developing renal cancer and may be associated with increased mortality from clear cell carcinoma in patients with Stage M0. Also, regular alcohol use may decrease the recurrence-free survival rate.

Adenocarcinoma, Clear Cell↗
PubMed2000

Improving discussion of surgical treatment options for patients with breast cancer: local medical opinion leaders versus audit and performance feedback.

We studied whether a hospital intervention utilizing medical opinion leaders and performance feedback reduced the proportion of women who reported that surgeons did not discuss options prior to surgery for early stage breast cancer. Opinion leaders provided clinical education to their peers using a variety of strategies and were selected for their ability to influence their peers. Performance feedback involved distributing performance reports that contained data on the outcomes of interest as well as on other treatment patterns. Twenty-eight hospitals in Minnesota were randomized to the intervention or to a control group that received performance feedback only. The proportion of patients at intervention hospitals who said that their surgeon did not discuss options decreased significantly (p < 0.001) from 33% to 17%, but a similar decrease was observed among control hospitals. Using medical opinion leaders to intervene in hospitals appeared as effective as performance feedback.

Adult↗
PubMed1999

Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulating factor in metastatic breast cancer. TLC D-99 Study Group.

PURPOSE: To estimate the toxicity and response rate of high-dose liposome-encapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company Inc, Princeton, NJ) in patients with advanced breast cancer. PATIENTS AND METHODS: Fifty-two breast cancer patients with bidimensionally measurable metastatic disease and no prior chemotherapy for metastatic disease received a 135 mg/m2 intravenous (i.v.) bolus of TLC D-99 with 5 microg/kg of granulocyte colony-stimulating factor via subcutaneous injection every 21 days. RESULTS: The median number of treatment cycles of TLC D-99 was three (range, one to 10 cycles), and the median total cumulative dose of TLC D-99 was 405 mg/m2 (range, 135 to 1,065 mg/m2). Grade IV neutropenia, thrombocytopenia, and mucositis were experienced by 48 (92%), 46 (88%), and 10 (19%) patients, respectively. Twenty (38%) of patients experienced cardiac toxicity: four (8%) experienced a decrease of 20% or more in left ventricular ejection fraction (LVEF) to a final value > or = 50%, nine (17%) experienced a decrease of 10% or more in LVEF to a final value less than 50%, and seven (13%) developed symptomatic congestive heart failure (CHF), including one patient who died of cardiomyopathy after receiving a total dose of 1,035 mg/m2. In a stepwise logistic regression model, the significant risk factors for the development of CHF were the cumulative dose of prior adjuvant doxorubicin (P = .007) and the total cumulative dose of TLC D-99 (P = .032). The overall response rate was 46% (95% confidence interval [CI], 32% to 61%) on an intent-to-treat basis. The median duration of response was 7.4 months (95% CI, 6.1 to 19.6 months) and the median progression-free survival was 6.1 months (95% CI, 5.4 to 7.5 months). CONCLUSION: There was no added therapeutic benefit to the dose escalation of TLC D-99 in this study. A high rate of cardiotoxicity was also observed, especially among patients who had received prior adjuvant doxorubicin. This was probably attributable to the dose and schedule of TLC D-99 used in this trial, as well as the patient's lifetime cumulative doxorubicin dose. Administration of high-dose TLC D-99 at 135 mg/m2 every 3 weeks by i.v. bolus infusion does not warrant further investigation.

Adult↗
PubMed1999

Monitoring therapeutic response in skeletal metastases using dual-energy x-ray absorptiometry: a prospective feasibility study in breast cancer patients.

Response to systemic therapy in breast cancer patients with lytic skeletal metastases manifests as a shift from increased bone resorption to new bone formation. We hypothesized that dual-energy x-ray absorptiometry (DXA) could be used to prospectively quantitate changes in bone mineral density (BMD) in metastatic skeletal lesions in breast cancer patients receiving systemic therapy. Nine metastatic breast cancer patients with one or more assessable lytic skeletal metastases receiving systemic therapy were prospectively evaluated with DXA, skeletal radiographs, computed tomography (CT), and radionuclide bone scans at baseline (t = 0 months, 2 months, and 6 months). The median (range) percentage change in BMD in skeletal lesions among patients responding to systemic therapy was 10.7% (0.1-21.85), 5.0% (-1.3-23.8), and 16.7% (-2.0-50.8) at 0-2, 2-6, and 0-6 months, respectively. Changes in BMD between 0-2, and 0-6 months were significant (Wilcoxin signed rank test; p = 0.013 and p = 0.017, respectively). The percentage change in BMD skeletal lesions between 0-2 and 2-6 months correlated with the changes imaged on skeletal x-rays (Spearman rank order correlation coefficient [Rs] = 0.511, p = 0.011) and CTs (Rs = 0.416, p = 0.046) but less so with bone scans (Rs = 0.293, p = 0.189). It is technically feasible to use DXA to prospectively monitor changes in lytic skeletal metastases in breast cancer patients receiving systemic therapy. The BMD of skeletal metastases increases in patients responding to treatment and was significantly correlated with the changes imaged on skeletal x-rays and CTs. Additional studies of DXA to evaluate response in skeletal metastasis are warranted.

Absorptiometry, Photon↗
PubMed1998

The quality of care for treatment of early stage breast carcinoma: is it consistent with national guidelines?

BACKGROUND: In response to the importance of early stage breast carcinoma as a public health concern and to the complexity of the clinical literature devoted to treatment of the disease, the National Institutes of Health has held a series of Consensus Development Conferences on the treatment of early stage breast carcinoma. The authors assessed compliance with standards of care for women treated in two states. METHODS: The authors identified patients diagnosed at 18 randomly selected hospitals (N = 1514) in Massachusetts and at 30 hospitals (N = 1061) in Minnesota. They collected data from medical records, patients, and their surgeons to assess compliance with four indicators of quality of care: radiation therapy after breast-conserving surgery, axillary lymph node dissection, chemotherapy for premenopausal women with positive lymph nodes, and hormonal therapy for postmenopausal women with positive lymph nodes and positive estrogen receptor status. RESULTS: Rates of compliance for 3 of the 4 standards of care were > 80% in both states. Only the rate for hormonal therapy for postmenopausal women was low (< 64%). However, the proportion of these women who received either chemotherapy or hormonal therapy was > 90% in both states. CONCLUSIONS: In the states studied, practice appears to be consistent with the results of national consensus conferences and clinical trials regarding the treatment of early stage breast carcinoma. For practices demonstrated to be associated definitively with better outcomes (for example, chemotherapy for premenopausal women with positive lymph nodes) or to be important with respect to prognosis (axillary lymph node dissection) high rates of compliance were observed.

Adult↗
PubMed1998

Use of breast-conserving surgery for treatment of stage I and stage II breast cancer.

PURPOSE: To assess the use of breast-conserving surgery in two states reported to differ with respect to surgical treatment of breast cancer. METHODS: A retrospective cohort study based on data collected from medical records and patients was performed among 1,514 patients diagnosed with early-stage breast cancer in Massachusetts and 1,061 patients in Minnesota. Patients were identified at 18 randomly selected hospitals in Massachusetts and at 30 hospitals in Minnesota. The rate of breast-conserving surgery in both states and the correlates of breast-conserving surgery among women eligible for the procedure were determined. RESULTS: The rate of breast-conserving surgery in both states was much higher than previously reported. Among those eligible for the procedure, nearly 75% underwent breast-conserving surgery in Massachusetts and nearly half did so in Minnesota. Significantly (P < .003) more women who underwent mastectomy in Minnesota (27%) than in Massachusetts (15%) reported that their surgeon did not discuss breast-conserving surgery with them. Among women who underwent mastectomy and who reported being informed of both surgical alternatives, more women (P < .001) in Minnesota (74%) than in Massachusetts (62%) said they ultimately chose mastectomy because their surgeon recommended it. In Massachusetts, women treated at teaching hospitals were twice as likely as other women to undergo breast-conserving surgery. In Minnesota, women over age 70 and those who lived in rural areas were less likely than other women to undergo breast-conserving surgery. CONCLUSION: Although the rate of breast-conserving surgery in each state was higher than expected based on earlier reports, the rates differed considerably between states. Additional studies are needed to determine whether variation in practice between geographic areas is due to differences in patients' preferences and values or to surgeons' propensity for one type of surgery based on where they practice.

Aged↗
PubMed1998

Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients.

PURPOSE: To assess the cardiac effects of two different cumulative doses of adjuvant doxorubicin and radiation therapy (RT) in breast cancer patients. PATIENTS AND METHODS: Two hundred ninety-nine breast cancer patients were prospectively randomized to receive either five cycles (CA5) or 10 cycles (CA10) of adjuvant treatment with cyclophosphamide (500 mg/ m2) and doxorubicin (45 mg/m2) administered by intravenous bolus every 21 days. One hundred twenty-two of these patients also received RT. Estimates of the cardiac RT dose-volume were retrospectively categorized as low, moderate, or high. The risk of major cardiac events (congestive heart failure, acute myocardial infarction) was assessable in 276 patients (92%), with a median follow-up time of 6.0 years (range, 0.5 to 19.4). RESULTS: The estimated risk (95% confidence interval) of cardiac events per 100 patient-years was significantly higher for CA10 than for CA5 [1.7 (1.0 to 2.8) v 0.5 (0.1 to 1.2); P=.02]. The risk of cardiac events in CA5 patients, irrespective of the cardiac RT dose-volume, did not differ significantly from rates of cardiac events predicted for the general female population by the Framingham Heart Study. In CA10 patients, the incidence of cardiac events was significantly increased (relative risk ratio, 3.6; P < .00003) compared with the Framingham population, particularly in groups that also received moderate and high dose-volume cardiac RT. CONCLUSION: Conventional-dose adjuvant doxorubicin as delivered in the CA5 regimen by itself, or in combination with locoregional RT, was not associated with a significant increase in the risk of cardiac events. Higher doses of adjuvant doxorubicin (CA10) were associated with a threefold to fourfold increased risk of cardiac events. This appears to be especially true in patients treated with higher dose-volumes of cardiac RT. Larger studies with longer follow-up periods are needed to confirm these results.

Adult↗
PubMed1997

Repetitive cycles of cyclophosphamide, thiotepa, and carboplatin intensification with peripheral-blood progenitor cells and filgrastim in advanced breast cancer patients.

PURPOSE: As an alternative to single-cycle cyclophosphamide, thiotepa, and carboplatin (CTCb) intensification, we evaluated the feasibility of administering one-quarter dose CTCb for four cycles with peripheral-blood progenitor-cell (PBPC) and filgrastim (granulocyte colony-stimulating factor [G-CSF]) in advanced-stage breast cancer patients. PATIENTS AND METHODS: From June 1992 to August 1993, 20 stage IIIB (n = 7) and IV (n = 13) breast cancer patients received 78 cycles of induction with doxorubicin 90 mg/m2 by intravenous (IV) bolus with G-CSF 5 microg/kg/d by subcutaneous injection (SC) repeated every 14 to 21 days for four cycles. PBPC were collected by 2-hour single-blood volume leukapheresis on 2 consecutive days at the time of hematologic recovery from each cycle of doxorubicin. Eighteen patients received 61 cycles of intensification with cyclophosphamide 1,500 mg/m2, thiotepa 125 mg/m2, and carboplatin 200 mg/m2 by IV continuous infusion with G-CSF 10 microg/kg/d SC and PBPC support repeated every 21 to 42 days for four cycles. RESULTS: Twelve of 20 patients (60%) completed all four planned cycles of doxorubicin induction followed by four cycles of one-quarter dose CTCb intensification. Statistically significantly decreases in the yield of mononuclear cells (MNC) (median slope per day, -0.032; P = .03), granulocyte-macrophage colony-forming unit (CFU-GM) (median slope per day, -0.57; P = .0008), and burst-forming unit-erythroid (BFU-E) (median slope per day, -1.18; P = .006) were observed over the course of the eight leukaphereses. Of 18 patients who began CTCb, 12 (67%) completed four cycles. Six patients were removed from study during intensification: two for progressive disease (PD), one refused further treatment, and three for dose-limiting hematologic toxicity. A fourth patient fulfilled the criteria for dose-limiting hematologic toxicity after cycle 4. The toxicity of the multiple cycle CTCb intensification regimen consisted of grade IV leukopenia, grade IV thrombocytopenia, and febrile neutropenia in 100%, 100%, and 26% of cycles, respectively. The median duration of each CTCb cycle was 24 days (range, 18 to 63), and the median duration of an absolute neutrophil count (ANC) < or = 500/microL and platelet count < or = 20,000/microL during each cycle was 6 days (range, 2 to 15) and 4 days (range, 0 to 38), respectively. CONCLUSION: It is feasible to administer repetitive cycles of one-quarter dose CTCb intensification with PBPC and G-CSF. Additional studies are required to determine whether multiple cycles of CTCb intensification might offer a therapeutic advantage over a single high-dose cycle.

Adult↗
PubMed1997

Modulation of vinblastine resistance in metastatic renal cell carcinoma with cyclosporine A or tamoxifen: a cancer and leukemia group B study.

Multidrug resistance mediated by P-glycoprotein may be an important cause of chemotherapy failure. Renal cell carcinoma is a disease known to demonstrate a high degree of intrinsic chemotherapy drug resistance, and this has been shown to be related to intrinsic overexpression of P-glycoprotein. Cyclosporine A and tamoxifen have been shown to reverse multidrug resistance in renal cell carcinoma cell lines in vitro. Phase I studies have defined appropriate doses of cyclosporine A and tamoxifen that can be combined with continuous-infusion vinblastine and safely achieve serum levels associated in vitro with resistance reversal. A randomized Phase II study was carried out by the Cancer and Leukemia Group B to evaluate the potential of high doses of cyclosporine A or tamoxifen to modulate clinical vinblastine resistance in patients with advanced renal cell carcinoma. Patients were treated initially with continuous-infusion vinblastine alone (1.2 mg/m2/day for 4 days or 1.5 mg/m2/day for 5 days); patients with stable or progressive disease were then treated with the same vinblastine regimen, combined with a high-dose regimen of either cyclosporine A (12.5 mg/kg/day for 5 days) or tamoxifen (400 mg/m2 as a loading dose and 300 mg/m2/day for 13 days). Sixty-three patients were randomized to each arm. Eighty patients on both arms were evaluable for response to vinblastine alone; of these, only one patient achieved a partial response. Thirty-three patients went on to be treated with vinblastine and high-dose cyclosporine A. No responses were observed, although four patients with progressive disease on prior vinblastine achieved stabilization of disease after cyclosporine A was added. Addition of cyclosporine resulted in more leukopenia (5% versus 25%) and in transient hyperbilirubinemia (24%) and neurocortical changes (11%). No significant azotemia was observed. Thirty-five patients received high-dose tamoxifen with continuous-infusion vinblastine. One complete remission was seen in a patient who had stable disease only with prior vinblastine alone; no other responses were observed. Leukopenia was not more severe with the addition of tamoxifen to vinblastine, nor was hyperbilirubinemia observed. However, 9% of patients developed transient ataxia with or without neurocortical changes as a result of high-dose tamoxifen therapy, and 11% developed phlebitis. We conclude that advanced renal cell carcinoma is a highly chemoresistant tumor, that continuous-infusion vinblastine has no appreciable activity in the therapy of this disease, and that addition of high doses of cyclosporine A or tamoxifen was not able to modulate this resistance in these patients. Suggestions regarding study design for future drug resistance modulation trials were made based on the design and conduct of this study.

Adult↗
PubMed1995

Treatment of metastatic breast cancer: present and future prospects.

Patients with recurrent breast cancer can be divided into three categories: those with locoregional recurrence, those with distant nonvisceral recurrence, and those with visceral recurrence. Survival from time of first relapse is clearly dependent on these categories. Selection of therapeutic modality should be based on considerations of site recurrence, symptomatology, anticipated response to therapy, and expected toxicities related to the therapy. Chemotherapy is appropriate for patients who are either unlikely to respond to hormone therapy, quite symptomatic, clearly hormone refractory, or have rapidly progressive visceral disease. Previously untreated patients are likely to respond to chemotherapy, with no clear-cut marker or clinical category associated with increased or decreased likelihood of benefit. Studies are ongoing to identify markers for response to chemotherapy, with recent investigations focusing on HER-2/neu expression. Standard combination chemotherapeutic regimens, consisting of either cyclophosphamide/methotrexate/5-fluorouracil (CMF) or cyclophosphamide/doxorubicin/5-fluorouracil (CAF), are associated with response rates in untreated patients of 35% to 80% and in previously treated patients of 10% to 40%. Although CAF probably has a slightly higher response rate than CMF, the toxicity of CAF is substantially higher. Newer agents are effective in both previously untreated and treated patients with breast cancer. These include paclitaxel, docetaxel, vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France), and amonafide. Furthermore, modulation of previously existing agents, designed to overcome resistance, has been tested. Only leucovorin/5-fluorouracil has apparent clinical benefit. A number of novel approaches are being designed or are currently being used in clinical trials. These include differentiating agents, anti-angiogenesis factors, antitumor antigen-based therapy, growth factor receptor/ligand therapy, and gene therapy.

Antineoplastic Agents↗
PubMed1995

Central venous access catheters.

Indwelling central venous access catheters were first introduced into clinical practice about 20 years ago. Today these catheters are an indispensable part of the treatment provided to adult and pediatric oncology patients. This article discusses the indications and major complications of central venous catheters.

Adult↗
PubMed1995

Dose escalation of N,N',N"-triethylenethiophosphoramide combined with pentoxifylline for advanced breast cancer.

Pentoxifylline potentiates the cytotoxicity of alkylating agents in preclinical models. In this study we sought to define the maximum tolerated dose (MTD) of N,N',N"-triethylenethiophosphoramide (thioTEPA) with pentoxifylline, and to estimate the antitumor response to this combination in previously treated breast cancer patients. Thirty-five previously treated advanced breast cancer patients received 70 cycles (median, 2 cycles/patient; range, 1-6) of 1600 mg of oral sustained release pentoxifylline every 8 h for 4 doses in combination with escalating doses of i.v. bolus thioTEPA 40-65 mg/m2 administered 3 h after the second dose of pentoxifylline. Thrombocytopenia was dose limiting at 65 mg/m2 of thioTEPA, and the MTD was defined as 60 mg/m2. Among 25 patients treated at the MTD, leukopenia was grade 2 in 9 patients (36%), grade 3 in 4 patients (16%), and grade 4 in 2 patients (8%); thrombocytopenia was grade 2 in 3 patients (12%), grade 3 in 4 patients (16%), and grade 4 in 3 patients (12%). No other thioTEPA-related toxicity was observed. Plasma concentrations of thioTEPA, TEPA, and pentoxifylline were measured in 6 patients. The median (range) area under the plasma concentration versus time curve for thioTEPA was 29.4 microM/h (26. 2-40.5) and for TEPA was 16.3 microM/h (9.2-21.7 microM-h). The median (range) maximal plasma concentration of pentoxifylline and major metabolites I, IV, and V were 1.2 microgram/ml (0.2-7.8), 4.0 microgram/ml (0.5-16.4), 0.4 (range 0.1-0.8), and 2.9 (1.1-5.5), respectively. No objective responses were observed among 21 evaluable patients treated at the MTD (95% confidence interval, 0-15%). The combination of pentoxifylline and thioTEPA is well tolerated but not active in previously treated advanced breast cancer patients. Further clinical trials using commercially available oral sustained release pentoxifylline as a modulator of alkylating agents are not warranted.

Administration, Oral↗