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Biomedical subjects

C Wheeler

Publications and source records attributed to C Wheeler.

At least 37 records · Page 2Linked to original sources
PubMed1994

High-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy: analysis by age.

The analysis was undertaken to determine if the time to progression and survival for women with breast cancer treated with high-dose chemotherapy after a conventional-dose induction therapy differs significantly for women younger and older than 40 years of age. All patients treated in phase II or III protocols of high-dose chemotherapy for breast cancer are included in this analysis. Women were treated on one of six protocols: four sequential phase II protocols for metastatic breast cancer involving cyclophosphamide at a dose of 6000 mg/m2, thiotepa at 500 mg/m2, and carboplatin at 800 mg/m2 (CTCb) chemotherapy; one phase II study of CTCb chemotherapy for stage III or inflammatory breast cancer; and a Cancer and Leukemia Group B phase III study of cyclophosphamide, carmustine, and cisplatin for women with more than 10 involved lymph nodes after primary therapy. Eligibility criteria for the patients with metastatic disease included histologically documented breast cancer, at least a partial response to conventional dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m2, and physiologic age of 18-55 years. Patients with inadequate renal, hepatic, pulmonary, and cardiac function or tumor involvement of marrow or central nervous system were excluded. Of 99 registered patients, three (3%) died of toxicity. There were no toxic deaths in protocols for stage II and III disease, and to date none of these patients have relapsed. Thus, there are no differences by age for these studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

The diagnosis of schizophrenia and its impact on the primary caregiver.

This qualitative study investigates how the diagnosis of schizophrenia in a young adult impacts on the primary caregiver in the family. In this study all participants were mothers who had sons recently diagnosed with schizophrenia. An extensive literature review revealed a lack of research in this area. The research methodology is described. Data analysis determined themes or patterns of experience amongst participants in this study. From this small study it was seen that the impact on the participants was intensely traumatic and far reaching. Six themes emerged: trauma/distress, fear, uncertainty, relief, disruption and powerlessness. The results have major implications for nurses and other health professionals working in the Mental Health field.

Adaptation, Psychological↗
PubMed1994

Reproducibility of a meal-based food frequency questionnaire. The influence of format and time interval between questionnaires.

OBJECTIVE: To compare the reproducibility and reported level of energy intake obtained using three versions of a meal-based food frequency questionnaire (FFQ) considering, firstly, the influence of FFQ format and, secondly, the influence of time interval between questionnaires. DESIGN: The study was conducted in two parts. In the first, subjects were randomly allocated to three groups (one for each FFQ) and sent, by mail, the same FFQ to complete on two separate occasions with a time interval of 4-6 weeks. In the second study, the reproducibility of one of the FFQs used in the initial study was compared, after an interval of 3 months, in a further group of people, matched as far as possible for gender, age and socio-economic status of area of residence. SUBJECTS: The study population was 651 supermarket shoppers from Geelong, a regional centre with a population of 150,000 situated in Victoria, Australia, who had previously responded to an in-store survey about meat purchasing patterns. Of the 651 shoppers, 144 women and nine men (38% of those eligible) in part I and 98 women and two men (45% of those eligible) in part II of the study satisfactorily completed a FFQ on both occasions. RESULTS: While there were few statistically significant differences in terms of mean nutrient intake and nutrient density between the three FFQ formats, all under-estimated energy intake relative to the minimum estimated energy requirements for a sedentary population. A significant decrease in reported intake of approximately 10% was also observed, regardless of FFQ format used, when the same questionnaire was completed a second time after an interval of 4-6 weeks. In contrast, when the time interval between questionnaires was increased to 3 months, there were few significant differences in intake between the first and second administrations. Moreover those changes in food intake which were significantly different after the longer interval were, in general, consistent with expected seasonal changes in food intake patterns. CONCLUSION: Under the conditions of our study differences in FFQ format appeared to have less effect on estimates of mean intake than the length of the time interval between questionnaires. Our results suggest that motivation to complete a FFQ is significantly diminished on the second occasion, when the interval between FFQs is only 4-6 weeks and to a lesser extent when it is 3 months. Researchers planning studies which aim to assess short-term changes in food intake by means of a FFQ, for example after an intervention programme, need to be aware of this effect and to determine its magnitude, by assessing the reproducibility of their FFQ over the relevant time-interval prior to the proposed intervention and by including an appropriate non-intervention comparison group in the design of their study if seasonal effects are likely to occur in the course of the study.

Energy Intake↗
PubMed1994

High-dose ifosfamide/carboplatin/etoposide with autologous hematopoietic stem cell support: safety and future directions.

Agents with broad cytotoxic activity, steep linear log dose-response relationships, relative non-cross-resistance, and nonoverlapping nonhematologic toxicities can be combined to create new high-dose combination regimens. We have previously reported phase I dose-escalation studies of ifosfamide, carboplatin, and the combination of the two. Etoposide has reported synergism with these alkylators and produces mucositis as its dose-limiting toxicity. The current study was designed to define the maximum tolerated doses of high-dose combination ifosfamide/carboplatin/etoposide (ICE), with stem cell support for amelioration of hematologic toxicity. Forty-eight adults with advanced malignancy received ICE chemotherapy by 96-hour continuous infusion. Initially, etoposide was added to fixed-dose ifosfamide and carboplatin, then the maximum tolerated dose of etoposide was fixed while doses of the alkylators were individually escalated. Autologous marrow, with or without peripheral blood progenitor cells, was reinfused 3 days after completing chemotherapy. The maximum tolerated doses of ifosfamide, carboplatin, and etoposide were identified as 16 g/m2, 1.8 g/m2, and 1.2 g/m2, respectively. Mortality was 4%. Patients who had prior cisplatin exposure were at increased risk for renal toxicity. If serum creatinine levels (monitored twice daily) rose sharply during chemotherapy, ifosfamide and carboplatin were immediately stopped. Severe multiorgan toxicity developed in the few patients who experienced early renal toxicity. Early stopping enhanced the safety of this regimen. Interpatient differences in chemotherapy drug metabolism or reduced renal clearance may predispose individuals to severe toxicity by increasing overall drug exposure. It was concluded that the ICE regimen is well tolerated and warrants further exploration as treatment of patients with small cell lung cancer, ovarian and germ cell carcinomas, and lymphomas in phase II trials.

Adult↗
PubMed1993

Intensive combined modality therapy for limited-stage small-cell lung cancer.

BACKGROUND: Conventional-dose chemotherapy for small-cell lung cancer has resulted in high response rates but rarely in a cure. The addition of thoracic radiotherapy (chemoradiotherapy) has improved survival for patients having limited disease, resulting in a median survival of 14-18 months. Previous trials evaluating high-dose chemotherapy and autologous bone marrow transplantation have demonstrated enhanced complete response rates without documenting overall survival benefit. PURPOSE: The purpose of this phase II trial was to determine the disease-free and overall survival, toxic effects, and relapse patterns in patients with limited small-cell lung cancer who were in partial or complete response to first-line conventional-dose chemotherapy and then received intensive systemic combined modality therapy. METHODS: Adults with stage III small-cell lung cancer who had achieved at least a partial response to conventional-dose induction chemotherapy were treated with high-dose cyclophosphamide, cisplatin, and carmustine combined with autologous bone marrow transplantation. Cumulative doses of the three drugs were 5625, 165, and 480 mg/m2, respectively. After recovery, patients received thoracic radiotherapy (50-60 Gy in 25-30 fractions over 5-6 weeks) and cranial radiotherapy (30 Gy in 15 fractions during 3 weeks). RESULTS: Of 19 patients in the study, six had achieved complete response, eight had a greater than 90% reduction in tumor size, and five had a 50%-90% reduction in tumor size. After high-dose therapy, 15 of the 19 were in complete response. Overall, median time to treatment failure after high-dose therapy was 12 months. Overall survival was 73% (95% confidence interval [CI] = 42%-89%) at 1 year and 53% (95% CI = 22%-77%) at 2 years. Of the 14 patients in or near complete response before high-dose therapy, 10 remain disease free with no further chemotherapy a median of 15 (4-69+) months after therapy. Actuarial 2-year disease-free survival is 57% (95% CI = 20%-82%). One patient died of Candida sepsis. Morbidity was low, and most patients returned to full-time work. With the exception of herpes zoster, there were no complications more than 3 months after high-dose therapy. CONCLUSIONS: The majority of the patients in this study are experiencing prolonged and unmaintained disease-free survival. Our findings suggest that patients in or near complete response before high-dose therapy have the most favorable prognosis. IMPLICATIONS: A randomized comparison between this approach and conventional-dose therapy is planned to define the utility of dose intensification with autologous bone marrow transplantation in the treatment of patients with limited-stage small-cell lung cancer who are in or near complete response.

Actuarial Analysis↗
PubMed1993

The use of G-CSF or GM-CSF mobilized peripheral blood progenitor cells (PBPC) alone or to augment marrow as hematologic support of single or multiple cycle high-dose chemotherapy.

High dose chemotherapy with autologous bone marrow support (ABMT) can achieve prolonged relapse-free survival in relapsed lymphomas, leukemias, and certain solid tumors. The principal morbidity and mortality relate to the infectious complications that occur during the 3-4 week aplasia until the marrow autograft recovers. Progenitor cells can be mobilized into the peripheral blood compartment by hematopoietic growth factors, used alone or after chemotherapy. We describe four trials using cytokine-mobilized peripheral blood progenitor cells (PBPC). In the first trial, PBPC collected after GM-CSF administration were used to augment marrow. Reconstitution of trilineage marrow function occurred promptly, resulting in short hospital stays and fewer platelet transfusions. In a second study, GM-CSF/chemotherapy-mobilized PBPC were used as the sole hematopoietic support during high dose chemotherapy. Granulocyte and platelet reconstitution was rapid. Time to hematopoietic recovery, transfusion requirements, and duration of hospital stay were all significantly improved for the patients receiving PBPC compared with similar patients receiving marrow alone. While most patients experienced prompt hematopoietic recovery they showed sluggish platelet engraftment. The next two trials built on the observation that a few PBPC alone could support both granulocyte and platelet recovery and were designed to test the feasibility of sequential high-dose therapies. In one trial, PBPC given with and without marrow made it possible to deliver two sequential cycles of high-dose therapy. The second trial utilized PBPC plus cytokines to deliver four cycles of dose-intensive chemotherapy at doses that could not be given with cytokine support alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

High-dose chemotherapy with autologous stem cell support for breast cancer: a review of the Dana-Farber Cancer Institute/Beth Israel Hospital experience.

The overall median survival of women with advanced or high-risk primary breast cancer has not changed with conventional chemotherapy. Regimens employing high-dose chemotherapy with autologous stem cell support (ABMT) have been developed with the hope of optimizing tumor response and increasing survival. Early phase I studies in women with advanced refractory disease achieved high response rates of short duration. Second generation studies combined an induction phase followed by one high-dose intensification at time of maximum tumor response. The Dana-Farber Cancer Institute/Beth Israel Hospitals have developed the high-dose intensification regimen of cyclophosphamide, thiotepa, and carboplatin (CTCb) for use in women with metastatic and high-risk stage IIIB/inflammatory breast cancer. To date, approximately 19% of women with metastatic disease remain progression free using this approach, with median length of follow-up approaching 40 months. Although the median duration of follow-up for the stage IIIB women is much shorter (approximately 12 months), greater than 90% of these women are thus far disease free. With the advent of hematologic support, such as blood stem cells and colony-stimulating factors, the morbidity, mortality, and costs associated with this treatment have been substantially reduced, allowing for two or more cycles of high-dose intensification to be employed, to exploit the potential of dose-intensity to optimize response.

Adenocarcinoma↗
PubMed1993

Primary Ki-1 anaplastic large-cell lymphoma in adults: clinical characteristics and therapeutic outcome.

PURPOSE: A study was undertaken to improve our understanding of the clinicopathologic features and therapeutic outcome for adults with primary Ki-1 anaplastic large-cell lymphoma (ALCL). PATIENTS AND METHODS: A retrospective review of records of 31 adult patients with primary Ki-1 ALCL was performed. The analysis included stage and distribution of disease, tumor-cell phenotype, response to initial and salvage therapy, and disease-free and overall survival. RESULTS: The median age of patients was 44 years (range, 16 to 86). Forty-eight percent of patients tested had lymphomas of T-cell phenotype, 30% lymphomas of B-cell phenotype, and 22% of non-T-, non-B-cell phenotype. Twenty-nine percent of patients had stages I and II disease, 65% demonstrated extranodal involvement, and 32% had skin involvement at presentation. Most patients received intensive chemotherapy and 48% achieved a sustained complete remission (CR), with an additional 17% of patients treated successfully with salvage therapy. Stage was highly predictive of achieving a sustained CR, but bulk disease and B symptoms did not predict for relapse after initial therapy or survival. Of seven patients who underwent autologous bone marrow transplantation (ABMT), three remain disease-free 9 to 42 months after transplant. CONCLUSION: Patients with Ki-1 ALCL have a high frequency of advanced-stage disease and extranodal involvement and are more likely to have tumors of T-cell phenotype than patients with large-cell lymphoma. However, response to standard lymphoma chemotherapy is similar to other patients with large-cell lymphoma, with a high remission rate in early-stage disease. Patients with advanced-stage disease have a poor remission duration and may require more intensive therapy, as may also be the case with large-cell lymphoma.

Adolescent↗
PubMed1993

Prognostic factors for treatment outcome in autotransplantation of intermediate-grade and high-grade non-Hodgkin's lymphoma with cyclophosphamide, carmustine, and etoposide.

PURPOSE: We examined a consecutive series of 78 patients with non-Hodgkin's lymphoma treated on prospective protocols with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (CBV) plus autotransplantation to determine prognostic factors for time to treatment failure. PATIENTS AND METHODS: Patients with relapsed, refractory, or poor-risk intermediate- and high-grade non-Hodgkin's lymphoma were treated with CBV with autologous marrow or peripheral-blood progenitor cell support. Patient characteristics before transplantation were examined in univariate analyses by the log-rank test and simultaneously in a Cox proportional hazards regression analysis. A best-predictive model was determined from those variables significant (P < .10) in the univariate test. RESULTS: In univariate analysis, intermediate-grade and immunoblastic lymphoma, responsiveness to pretransplant salvage chemotherapy, and transplantation after primary therapy (first complete response [CR] or partial response [PR]) were associated with prolonged time to treatment failure. In proportional hazards multiple regression analysis, intermediate-grade and immunoblastic histology, responsive disease, and autotransplantation in first CR or PR were positive prognostic factors, and these characteristics are the basis of the best-predictive model for prolonged time to failure. Actuarial 3-year failure-free survival of patients with stable or responding disease at autotransplant was 54%. CONCLUSION: CBV is an effective conditioning regimen in intermediate-grade and immunoblastic non-Hodgkin's lymphoma. Patients with these histologies transplanted while responding to primary therapy, or those with stable disease or disease responding to salvage therapy at the time of autotransplant, are most likely to benefit. Patients with lymphoblastic lymphoma or diffuse undifferentiated lymphoma did poorly with CBV and should be offered alternative therapy.

Adolescent↗
PubMed1993

Large-cell and immunoblastic lymphoma of the mediastinum: prognostic features and treatment outcome in 57 patients.

PURPOSE: A retrospective study was performed to define clinical characteristics and therapeutic outcome for patients with large-cell and immunoblastic lymphoma of the mediastinum. PATIENTS AND METHODS: Fifty-seven patients who presented with primary, mediastinal large-cell and immunoblastic lymphoma were retrospectively studied to determine initial sites of disease, radiologic characteristics, treatment, outcome, and factors that have prognostic significance for progression-free and overall survival. RESULTS: Fifty-six of the 57 patients had disease that was confined to sites above the diaphragm. Bulky disease and extensive intrathoracic infiltration were common in these patients. All patients were treated with intensive chemotherapy regimens, and 44% of patients received chest irradiation. The overall 5-year survival by Kaplan-Meier estimation was 50% with a freedom-from-relapse rate of 45%. Predictors of disease relapse after chemotherapy included the presence of a pleural effusion (P = .015), a number of involved extranodal sites (P < .01), and a lactic dehydrogenase (LDH) ratio > 3.0 (LDH value/upper limit of assay; P = .04) as well as an incomplete treatment response as evidenced by residual mass on chest radiograph (P = .02) or persistent gallium 67 avidity (P = .01) after chemotherapy. Predictors of decreased survival included the presence of pleural effusion (P = .001), the number of involved extranodal sites (P = .022), and a positive posttreatment 67Ga scan (P = .027). CONCLUSION: Patients with primary mediastinal large-cell and immunoblastic lymphoma have an approximate 50% chance of surviving disease-free after initial therapy. The presence of pleural effusion at presentation was associated with an extremely poor outcome. Bulk disease per se was a negative predictive factor only in patients without pleural effusions when compared with patients who did not have bulk disease. In addition, all patients with involvement of two or more extranodal sites relapsed when treated with standard chemotherapy.

Actuarial Analysis↗
PubMed1993

High-dose combined alkylating agent therapy with autologous stem cell support and chest radiotherapy for limited small-cell lung cancer.

Although initially responsive to chemotherapy, patients with small-cell lung cancer (SCLC) almost invariably suffer relapse. Recurrent SCLC responds poorly to treatment. Previous trials using high-dose chemotherapy with bone marrow support have commonly used single agents or combined alkylating agents without chest radiotherapy. Among patients with limited disease receiving dose-intensive chemotherapy, locoregional relapse remained the predominant site of first failure. Recent phase II trials using intensive locoregional therapy (aggressive concurrent chemoradiotherapy) have resulted in promising survival. Our trial used combined alkylating agents with autologous marrow support and chest radiotherapy in patients with limited disease in response to conventional-dose induction chemotherapy. Of 19 patients treated, the actuarial survival was 56% with a median follow-up of 18 months following high-dose therapy. Patients who achieved complete or near-complete response prior to high-dose therapy enjoyed the best prognosis. Continued evaluation of intensive systemic and local therapy for SCLC is indicated.

Alkylating Agents↗
PubMed1992

Mobilization of peripheral blood progenitor cells by chemotherapy and granulocyte-macrophage colony-stimulating factor for hematologic support after high-dose intensification for breast cancer.

High-dose therapy with autologous marrow support results in durable complete remissions in selected patients with relapsed lymphoma and leukemia who cannot be cured with conventional dose therapy. However, substantial morbidity and mortality result from the 3- to 6-week period of marrow aplasia until the reinfused marrow recovers adequate hematopoietic function. Hematopoietic growth factors, particularly used after chemotherapy, can increase the number of peripheral blood progenitor cells (PBPCs) present in systemic circulation. The reinfusion of PBPCs with marrow has recently been reported to reduce the time to recovery of adequate marrow function. This study was designed to determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF)-mobilized PBPCs alone (without marrow) would result in rapid and reliable hematopoietic reconstitution. Sixteen patients with metastatic breast cancer were treated with four cycles of doxorubicin, 5-fluorouracil, and methotrexate (AFM induction). Patients responding after the first two cycles were administered GM-CSF after the third and fourth cycles to recruit PBPCs for collection by two leukapheresis per cycle. These PBPCs were reinfused as the sole source of hematopoietic support after high doses of cyclophosphamide, thiotepa, and carboplatin. No marrow or hematopoietic cytokines were used after progenitor cell reinfusion. Granulocytes greater than or equal to 500/microL was observed on a median of day 14 (range, 8 to 57). Transfusion independence of platelets greater than or equal to 20,000/microL occurred on a median day of 12 (range, 8 to 134). However, three patients required the use of a reserve marrow for slow platelet engraftment. In retrospect, these patients were characterized by poor baseline bone marrow cellularity and poor platelet recovery after AFM induction therapy. When compared with 29 historical control patients who had received the same high-dose intensification chemotherapy using autologous marrow support, time to engraftment, antibiotic days, transfusion requirements, and lengths of hospital stay were all significantly improved for the patients receiving PBPCs. Thus, autologous PBPCs can be efficiently collected during mobilization by chemotherapy and GM-CSF and are an attractive alternative to marrow for hematopoietic support after high-dose therapy. The enhanced speed of recovery may reduce the morbidity, mortality, and cost of high-dose treatment. Furthermore, PBPC support may enhance the effectiveness of high-dose therapy by facilitating multiple courses of therapy.

Adolescent↗
PubMed1992

A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy.

PURPOSE: The study was designed to determine the duration of complete response (CR) for patients with unresectable or metastatic breast cancer treated with high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) while responding to conventional-dose therapy. METHODS: Eligibility criteria included histologically documented metastatic or unresectable breast cancer, at least a partial response (PR) to conventional-dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m3, and physiologic age between 18 and 55 years. Patients with inadequate renal, hepatic, pulmonary, and/or cardiac function or tumor involvement of marrow or CNS were excluded. Cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 were given by continuous infusion over 4 days. After recovery, sites of prior bulk disease were to be radiated or resected if feasible. RESULTS: Of 29 registered patients, one died of toxicity (3%; hemorrhage). CRs and PRs continued a median of 16 and 5 months after transplant, respectively (26 and 9 months from initiation of chemotherapy for metastatic disease). Of 10 patients transplanted in CR, four have not progressed at 17 to 31 months after transplantation (25 to 43 months after beginning standard-dose therapy). One of four patients with uptake on bone scan as their only sites of residual disease before transplant and one of three who converted from PR to CR with transplant have not progressed at 27 and 29 months, respectively, after transplant. CONCLUSIONS: CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable.

Adult↗
PubMed1992

Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response.

BACKGROUND: Cyclophosphamide, which forms the nucleus for virtually all preparative regimens for autologous bone marrow transplantation (ABMT), is an alkylating agent of which cytotoxicity is not directly caused by the parent compound but by its biologically active metabolites. Its nonmyelosuppressive toxicity in the ABMT setting is cardiomyopathy. We attempted to determine any correlation between plasma levels of total cyclophosphamide and the subsequent development of cardiac dysfunction. PATIENTS AND METHODS: Analyses of plasma levels and the derivation of plasma concentration-time curves (area under the curve [AUC]) were performed in 19 women with metastatic breast carcinoma, who received a continuous 96-hour infusion of cyclophosphamide, thiotepa, and carboplatin (CTCb) with ABMT. The assay for total cyclophosphamide measures the inactive parent compound; reliable assays of the active metabolites of cyclophosphamide are not yet available. RESULTS: Six of 19 women developed moderate, but transient, congestive heart failure (CHF) as assessed by clinical and radiologic criteria. These patients had a significantly lower AUC of total cyclophosphamide (median, 2,888 mumol/L/h) than patients who did not develop CHF (median, 6,121 mumol/L/h) (P less than .002). Median duration of tumor response in these patients was also more durable; at least 22 months in patients with lower AUCs versus a median of 5.25 months in those with higher AUCs (P = .008). CONCLUSION: These pharmacokinetic data support the premise that enhancement of cyclophosphamide activation may lead to both greater tumor cytotoxicity and increased but reversible end-organ toxicity. Early analysis of pharmacokinetic data may allow modulation of cyclophosphamide administration in an attempt to enhance therapeutic efficacy.

Adult↗
PubMed1991

Escalating doses of carboplatin with high-dose ifosfamide using autologous bone marrow as support: a phase I study.

In this phase I study, 16 adult cancer patients were treated with concurrent 4-day continuous infusions of ifosfamide at 12 g/m2 and escalating doses of carboplatin (400-1600 mg/m2) to determine the major non-haematological dose-limiting toxicity of the combination. Mesna was given by continuous infusion over 5 days for uroprotection (total dose per course = 15 g/m2). Autologous bone marrow support, which was mandated for subsequent dose levels once granulocytes remained below 500/microliters for more than 14 days in at least 2 patients entered at a given dose level, was used at dose levels above 400 mg/m2 carboplatin. Renal toxicity became dose-limiting at the maximum tolerated dose level of 1600 mg/m2 carboplatin. Temporary creatinine elevations above 2 mg/dl (median peak 2.6 mg/dl) were observed in 3 and irreversible renal toxicity occurred in 1 (peak creatinine 6.9 mg/dl, chronic creatinine 5-6 mg/dl) of the 5 patients entered at this dose level. Severe confusion and lethargy associated with rising creatinine developed in 2 patients. Two complete and four partial responses were documented in 14 heavily pretreated evaluable patients. The complete responses continue at 14+ and 20+ months in a patient with germ cell carcinoma and Ewing's sarcoma, respectively. Carboplatin appears to contribute to the renal toxicity of ifosfamide. Nevertheless, the combination of carboplatin and ifosfamide at 80% and 75% of the single-agent maximal tolerated doses respectively produced acceptable non-haematological toxicity. Further studies in the treatment of sarcoma, germ cell, ovarian and lung carcinomas with this combination are warranted.

Adult↗
PubMed1991

GM-CSF potentiated peripheral blood progenitor cell (PBPC) collection with or without bone marrow as hematologic support of high-dose chemotherapy: two protocols.

High-dose chemotherapy with autologous bone marrow support (ABMS) achieves prolonged relapse-free survival in relapsed lymphomas and leukemias and has provided durable complete responses in certain solid tumors. The principal morbidity and mortality result from the infectious and bleeding complications during the 3-4 week aplasia until the bone marrow autograft can recover. Hematopoietic growth factors, alone or used after chemotherapy, increase the number of circulating progenitor cells in the peripheral blood compartment. In one trial, 12 patients with solid tumors were treated with high-dose chemotherapy and supported with both bone marrow and peripheral blood progenitor cells (PBPC) collected after GM-CSF administration. Reconstitution of bone marrow function occurred quickly (ANC greater than 500/microliters by day 17; platelet-transfusion independence by day 16), resulting in short hospital stays (median, 28 days). In a second study, 12 patients with metastatic breast cancer responding to induction chemotherapy (doxorubicin, 5-fluorouracil, and methotrexate) were given GM-CSF during induction to collect PBPCs during leukocyte recovery. These PBPCs were used as the sole hematopoietic support during high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin. Granulocyte and platelet reconstitution were extremely rapid (median, 14 and 12 days, respectively). When compared with 29 patients undergoing the same intensification therapy using ABMT as sole support, time to hematopoietic recovery, transfusion requirements, and duration of hospital stay were all significantly improved for the patients receiving PBPC. PBPC with or without marrow may enhance the safety, tolerance, and cost of high-dose therapy. Moreover, PBPC may render multiple course combination, high-dose therapy feasible.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

A phase I study of high-dose ifosfamide and escalating doses of carboplatin with autologous bone marrow support.

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.

Adult↗