Economic evaluation of sunitinib versus pazopanib and best supportive care for the treatment of metastatic renal cell carcinoma in Chile: cost-effectiveness analysis and a mixed treatment comparison.

Background: Sunitinib and Pazopanib are two metastatic renal cell carcinoma (MRCC) treatment alternatives, however the health system in Chile does not consider coverage for any. The cost-effectiveness versus relevant comparator was assessed to support evidence-based decision making. Methods: A four health states Markov model was built: first, second line treatments, BSC and death. Benefits were measured in QALYs, and efficacy estimates were obtained from an indirect treatment comparison. A 10-year time horizon and a 3% undifferentiated discount rate were considered. Deterministic and probabilistic sensitivity analyses were performed. Results: The costs of treating MRCC with Sunitinib were higher than Pazopanib and BSC. When comparing Sunitinib versus Pazopanib, the incremental benefit is small favoring Sunitinib (0.03 QALYs). The base case scenario shows an average ICER of PA versus BSC of US$62,327.11/QALY and of US$85,885/QALY for Sunitinib versus Pazopanib. The ICER was most sensitive to the OS relative to BSC, where evidence was associated to important bias. Conclusions: Sunitinib or Pazopanib can be considered cost-effective if a 3 GDP per-capita threshold is assumed. The decision between SU or PA is highly sensitive to the price of the drugs, rather than the outcomes. Therefore, the decision might be made based on cost-minimization exercise.

Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study.

AIMS: The appearance of peripheral neuropathy is the dose-limiting toxicity in many chemotherapy protocols, and glutamine has been proposed as a potentially neuroprotective agent in patients receiving paclitaxel. MATERIALS AND METHODS: In this non-randomised study, we assessed neurologic signs and symptoms, and changes in nerve-conduction studies in 46 consecutive patients given high-dose paclitaxel either with (n=17) or without (n=29) glutamine. Neurological assessments and electrodiagnostic studies were carried out at baseline and at least 2 weeks (median 32 days) after treatment. RESULTS: Patients who received glutamine developed significantly less weakness (P = 0.02), less loss of vibratory sensation (P = 0.04) and less toe numbness (P = 0.004) than controls. The per cent change in the compound motor action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes after paclitaxel treatment was lower in the glutamine group, but this finding was not statistically significant in these small groups. CONCLUSIONS: In this study, serial neurologic assessment of patient symptoms and signs seemed to be a better indicator of a possible glutamine effect than sensory- or motor-nerve-conduction studies. Prospective randomised trials are needed to clarify the effect of glutamine on paclitaxel and other types of chemotherapy-induced neuropathy.

Phase II trial of sequential high-dose chemotherapy with paclitaxel, melphalan and cyclophosphamide, thiotepa and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer.

A single high-dose cycle of chemotherapy can produce response rates in excess of 50%. However, disease-free survival (DFS) is 15-20% at 5 years. The single most important predictor of prolonged DFS is achieving a complete response (CR). Increasing the proportion of patients who achieve a complete response may improve disease-free survival. Women with metastatic breast cancer and at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and G-CSF. The first intensification was paclitaxel (825 mg/m(2)), the second melphalan (180 mg/m(2)) and the third consisted of cyclophosphamide 6000 mg/m(2) (1500 mg/m(2)/day x 4), thiotepa 500 mg/m(2) (125 mg/m(2)/day x 4) and carboplatin 800 mg/m(2) (200 mg/m(2)/day x 4) (CTCb). Sixty-one women were enrolled and 60 completed all three cycles. Following the paclitaxel infusion most patients developed a reversible, predominantly sensory polyneuropathy. Of the 30 patients with measurable disease, 12 converted to CR, nine converted to a PR*, and five had a further PR, giving an overall response rate of 87%. The toxic death rate was 5%. No patient progressed on study. Thirty percent are progression-free with a median follow-up of 31 months (range 1-43 months) and overall survival is 61%. Three sequential high-dose cycles of chemotherapy are feasible and resulted in a high response rate. The challenge continues to be maintenance of response and provides the opportunity to evaluate strategies for eliminating minimal residual disease.

Survey on the use of complementary and alternative medicine among patients with headache syndromes.

The objective was to determine headache patients' knowledge, prevalence of use and perceived effectiveness of complementary and alternative medicine. Seventy-three patients with headache syndromes attending a head and neck pain clinic were interviewed using a standardized questionnaire. Alternative medical therapies were used by 85% of surveyed patients for the relief of their head pain. In 60%, the therapies were perceived to have a benefit. Almost 100% of the patients were familiar with one or more of the presented alternative treatments. Eighty-eight per cent perceived at least one of the complementary treatments to be an effective remedy for headache pain. Exposure to and interest in alternative treatments are common among patients with headache syndromes, despite the lack of scientific evidence of benefit and assessments of risks for many of the treatments. Neurologists and general physicians should be aware of the increasing role of alternative medicine in the healthcare system. There is still an urgent need for objective, integrative and critical research with regard to complementary and alternative medicine.

Long-term quality of life and neuropsychologic functioning for patients with CNS germ-cell tumors: from the First International CNS Germ-Cell Tumor Study.

This study evaluated the quality of life and neuropsychologic functioning among patients enrolled between 1989 and 1993 in the First International CNS Germ-Cell Tumor Study. Quality-of-life questionnaires (Short Form-36 or Child Health Questionnaire) were completed on 43 patients at median follow-up of 6.1 years after diagnosis (range, 4.5-8.8 years), and intellectual and academic testing was performed on 22 patients. Psychosocial and physical functioning of patients aged 19 years and older at follow-up was within the average range, whereas the same functioning for patients aged 18 years and younger, as reported by their parents at follow-up, was low average and borderline, respectively. Overall psychosocial and physical health summary scores were positively correlated with age at diagnosis for both groups combined. Those who received CNS radiation therapy (n = 29) reported significantly worse physical health, but similar psychosocial health, compared with those treated without radiation. Neuropsychologic testing indicated full-scale and verbal IQ, reading, spelling, and math skills in the average range, and performance IQ in the low average range. Intelligence and math skills were positively correlated with age at diagnosis. Those with germinomas significantly outperformed those with nongerminomatous/ mixed tumors on all neuropsychological measures administered. Younger patients diagnosed with CNS germ-cell tumors are at increased risk for psychosocial and physical problems as well as neuropsychologic deficits. Exposure to irradiation adversely affects overall physical functioning, whereas tumor pathology appears to be a salient neurocognitive risk factor. Collaborative and randomized studies are required to further elucidate the late effects arising from factors such as age at diagnosis, tumor histology, level of irradiation therapy, and chemotherapy toxicity among these young and potentially curable patients.

Reduction of paclitaxel-induced peripheral neuropathy with glutamine.

PURPOSE: Dose-limiting toxicity of many newer chemotherapeutic agents is peripheral neuropathy. Prior attempts to reduce this side effect have been unsuccessful. We report on the possible successful reduction of peripheral neuropathy with glutamine administration after high-dose paclitaxel. EXPERIMENTAL DESIGN: Patients entered a high-dose chemotherapy protocol in which the first high-dose cycle was paclitaxel at 825 mg/m(2) given over 24 h. The first cohort of patients did not receive glutamine, and the second cohort of patients received glutamine at 10 g orally three times a day for 4 days starting 24 h after completion of paclitaxel. Neurological assessment was performed at baseline, and at least 2 weeks after paclitaxel, and consisted of a complete neurological exam and nerve conduction studies. RESULTS: There were paired pre- and post-paclitaxel evaluations on 33 patients who did not receive glutamine and 12 patients who did. The median interval between pre- and post-exams was 32 days. For patients who received glutamine, there was a statistically significant reduction in the severity of peripheral neuropathy as measured by development of moderate to severe dysesthesias and numbness in the fingers and toes (P < 0.05). The degree and incidence of motor weakness was reduced (56 versus 25%; P = 0.04) as well as deterioration in gait (85 versus 45%; P = 0.016) and interference with activities of daily living (85 versus 27%; P = 0.001). Moderate to severe paresthesias in the fingers and toes were also reduced (55 versus 42% and 64 versus 50%, respectively), although this value was not statistically significant. All of these toxicities were reversible over time. CONCLUSIONS: Glutamine may reduce the severity of peripheral neuropathy associated with high-dose paclitaxel; however, results from randomized, placebo-controlled clinical trials will be needed to fully assess its impact, if any. Trials are currently ongoing to assess its efficacy for standard-dose paclitaxel in breast cancer and other tumors for which peripheral neuropathy is the dose-limiting toxicity.

Anti-Ri-associated paraneoplastic opsoclonus-ataxia syndrome in a man with transitional cell carcinoma.

BACKGROUND: There are several case reports describing paraneoplastic syndromes in patients with various forms of bladder carcinoma. Current immunologic analyses have enabled the identification of the antineuronal autoantibodies associated with specific syndromes. METHODS: A patient with a history of bladder carcinoma presented with opsoclonus and myoclonus. RESULTS: Workup confirmed the presence of anti-Ri antibodies in the patient's serum and cerebrospinal fluid. The target Ri antigen was found to be expressed by the tumor. CONCLUSIONS: To the authors' knowledge, there are few reports in the literature describing the long-term clinical follow-up and postmortem evaluation in a patient with this form of paraneoplastic syndrome. More important, the authors believe the current study represents the first time that the presence of anti-Ri antibodies has been noted in a paraneoplastic syndrome associated with transitional cell carcinoma of the bladder.

The pharmacokinetics and pharmacodynamics of high-dose paclitaxel monotherapy (825 mg/m2 continuous infusion over 24 h) with hematopoietic support in women with metastatic breast cancer.

PURPOSE: We evaluated the pharmacokinetics and pharmacodynamics of high-dose paclitaxel (HDP) monotherapy (825 mg/m2 continuous infusion over 24 h) with peripheral blood progenitor cell (PBPC) and G-CSF support in 17 women with metastatic breast cancer. METHODS: Pharmacokinetic and pharmacodynamic data were collected in 17 women entered in a phase II trial of sequential HDP, and high-dose melphalan and cyclophosphamide/thiotepa/carboplatin. RESULTS: The maximal plasma concentration (Cmax), area under the plasma concentration time curve (AUC), apparent clearance (Clapp), duration of plasma concentration above 0.05 microM (t > 0.05 microM) for paclitaxel were (means SD): 9.11 +/- 7.45 microM, 145 +/- 88 microM x h, 8.06 +/- 2.90 l/h per m2 and 82.4 +/- 31.2 h, respectively. There was a significant correlation between the plasma paclitaxel concentration at 1 h (r2 = 0.87), 12 h (r2 = 0.85) and 23 h (r2 =0.92) and the AUC (P < 0.0001). Duration of neutropenia was brief (median 3 days, range 0-5 days) and neutrophil recovery occurred earlier (median 6 days, range 0-7 days) than could be attributed to infused PBPC. Median nadir count for platelets was 66 x 10(9)/l (range 13-160 x 10(9)/l). Pharmacodynamic analysis showed no correlation between pharmacokinetic parameters (Cmax, AUC, t > 0.05 microM) and time to neutropenic nadir, duration of neutropenia, platelet count nadir and grades of neuropathy or mucositis. In ten patients in whom detailed neurologic and nerve conduction studies were performed, linear regression analysis showed a significant correlation between pre- and post-HDP treatment total neuropathy scores (r2 = 0.46, P = 0.03). CONCLUSIONS: HDP (825 mg/m2 continuous infusion over 24 h) did not appear to be myeloablative. The degree of neurotoxicity subsequent to HDP was associated with the degree of baseline neuropathy but was not predictable from pharmacokinetic parameters.

Chemotherapy for intramedullary spinal cord tumors.

Intramedullary tumors are rare, accounting for only about 4% of all CNS neoplasms. Although surgery represents the most effective treatment, recurrence may occur. As a large proportion of intramedullary malignancies occur in children, who are more sensitive to the deleterious effects of irradiation, chemotherapy assumes an important role. This article describes the most common intramedullary tumors and the role of chemotherapy.

Bilateral facial nerve palsy secondary to the administration of high-dose paclitaxel.

Bilateral facial nerve palsy is an uncommon occurrence. We describe a case of bilateral facial nerve palsy secondary to a single cycle of high-dose paclitaxel therapy (825 mg/m2), in a woman with breast cancer. Prior to her high-dose therapy, she had a residual grade 2 peripheral neuropathy following treatment with ten cycles of standard-dose paclitaxel (total dose 3200 mg). The features of the peripheral neuropathy due to standard-dose paclitaxel, which can be both motor and sensory, are well described. Cumulative paclitaxel dose is considered a risk factor for development of the neuropathy. Although facial nerve palsy secondary to paclitaxel is not previously reported, other cranial nerve toxicity has been described. Consistent with reports of the reversibility of paclitaxel-induced peripheral neuropathy, the facial nerve palsies in our patient resolved over 23 months. Ongoing studies of high-dose paclitaxel warrant close attention to its cumulative neurotoxic effects, particularly in patients previously treated with neurotoxic chemotherapy.

Germ cell tumors of the CNS in children: recent advances in therapy.

Primary germ cell tumors of the central nervous system are rare neoplasms, accounting for no more than 2% of all malignancies in children and young people under 20 in the Western hemisphere. They have unique features related to age at diagnosis and sites of origin, as well as race and gender predilection. Prognosis has been clearly shown to be strongly related to pathological classification as either pure germinoma or nongerminomatous germ cell tumor, although many of these lesions are comprised of mixed elements. The presence of serum or cerebrospinal fluid tumor marker elevation has been an essential determinant of response to treatment. Because of the deleterious effects of irradiation on the immature nervous system, investigators have used chemotherapeutic strategies that either reduce or eliminate radiation therapy. In this article, we review the most recent advances in therapy for CNS germ cell tumors in the pediatric population and highlight the importance of cooperative trials in this setting.

Supratentorial ependymomas in adult patients.

OBJECTIVE: Ependymomas arise from different areas in the neuraxis and have variable outcomes that depend on tumor location and patient age at the time of presentation. The predictive value of histology for these tumors is unresolved. We report a series of adult patients with supratentorial ependymomas to characterize the roles of surgery, histology, ploidy, and proliferation index in tumor control. METHODS: Fourteen of the 23 supratentorial ependymomas were in the region of the third ventricle and the remainder were located in the hemispheres. Resections were gross total in 12 patients, subtotal in 8, and biopsy in 3. A single pathologist reviewed all slides and quantitated the deoxyribonucleic acid. The mean follow-up duration was 95 months (+/-75 mo). RESULTS: All of the malignant ependymomas were hemispheric (n = 4). Mortality occurred only in patients with third ventricular tumors; two patients died as a result of surgical complications and three as a result of tumor progression. Kaplan-Meier estimates of 5- and 10-year survival rates were 100% for hemispheric and 72.5% for third ventricular tumors (62.5% including the two perioperative deaths). The median time to recurrence was 53 months, with a 10-year progression-free survival rate of 27%. Univariate analysis revealed that recurrence was associated with malignant histology, including mitoses, cellularity, and aneuploidy. For nonmalignant ependymomas, recurrence was associated with subtotal resection and metastases. S-phase fraction did not correlate with recurrence. Only malignant histology correlated with recurrence on multivariate analysis. CONCLUSION: Although the numbers are too small to draw any definite conclusions, treatment of ependymomas that arise in the supratentorial compartment in adult patients results in excellent outcomes despite frequent recurrences. Association with the third ventricle and metastases seem to have a negative impact on survival, whereas malignant histology, subtotal resection, and metastases may be predictors of recurrence.

Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders.

The identification of antineuronal antibodies has facilitated the diagnosis of paraneoplastic neurological disorders and the early detection of the associated tumours. It has also led to the cloning of possibly important neuron-specific proteins. In this study we wanted to identify novel antineuronal antibodies in the sera of patients with paraneoplastic neurological disorders and to clone the corresponding antigens. Serological studies of 1705 sera from patients with suspected paraneoplastic neurological disorders resulted in the identification of four patients with antibodies that reacted with 37 and 40 kDa neuronal proteins (anti-Ma antibodies). Three patients had brainstem and cerebellar dysfunction, and one had dysphagia and motor weakness. Autopsy of two patients showed loss of Purkinje cells, Bergmann gliosis and deep cerebellar white matter inflammatory infiltrates. Extensive neuronal degeneration, gliosis and infiltrates mainly composed of CD8+ T cells were also found in the brainstem of one patient. In normal human and rat tissues, the anti-Ma antibodies reacted exclusively with neurons and with testicular germ cells; the reaction was mainly with subnuclear elements (including the nucleoli) and to a lesser degree the cytoplasm. Anti-Ma antibodies also reacted with the cancers (breast, colon and parotid) available from three anti-Ma patients, but not with 66 other tumours of varying histological types. Preincubation of tissues with any of the anti-Ma sera abrogated the reactivity of the other anti-Ma immunoglobulins. Probing of a human complementary DNA library with anti-Ma serum resulted in the cloning of a gene that encodes a novel 37 kDa protein (Mal). Recombinant Mal was specifically recognized by the four anti-Ma sera but not by 337 control sera, including those from 52 normal individuals, 179 cancer patients without paraneoplastic neurological symptoms, 96 patients with paraneoplastic syndromes and 10 patients with non-cancer-related neurological disorders. The expression of Mal mRNA is highly restricted to the brain and testis. Subsequent analysis suggested that Mal is likely to be a phosphoprotein. Our study demonstrates that some patients with paraneoplastic neurological disorders develop antibodies against Mal, a new member of an expanding family of 'brain/testis' proteins.

A phase I study of high-dose BCNU, etoposide and escalating-dose thiotepa (BTE) with hematopoietic progenitor cell support in adults with recurrent and high-risk brain tumors.

This phase I dose-escalation study was performed to determine the tolerability of three-drug combination high-dose BCNU (B) (450 mg/m2), escalating-dose thiotepa (500-800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days in 22 adults with malignant primary brain tumors. Patients received G-CSF and hematopoeitic support with peripheral blood progenitor cells (PBPC) (n = 18) or both PBPC and marrow (n = 4). The maximum tolerated dose of thiotepa with acceptable toxicity was determined as 800 mg/m2. The 100-day mortality rate was 9% (2/22). Grade III/IV toxicities included mucositis (71%), diarrhea (29%), nausea/vomiting (19%), and hepatic toxicity (14%). Neurological toxicities occurred in 24% and included seizures (two patients) and encephalopathy (three patients). Encephalopathy was transient in two patients and progressive in one patient. All patients had neutropenic fever. Median time to engraftment with absolute neutrophil count (ANC) >0.5 x 10(9)/l was 10 days (range 8-30 days). Platelet engraftment >20 x 10(9)/l occurred after 11 days (range 9-65 days). In the eighteen patients supported solely with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho = -0.78, p = 0.001) and platelet engraftment (rho = -0.76, p = 0.002). Overall, 11% of evaluable patients (2/18) had a complete response to BTE. Median time to tumor progression (TTP) was 9 months, with an overall median survival of 17 months. BCNU (450 mg/m2), thiotepa (800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days is a tolerable combination HDC regimen, the efficacy of which warrants further investigation in adults with optimally resected chemoresponsive brain tumors.

High-dose thiotepa and etoposide-based regimens with autologous hematopoietic support for high-risk or recurrent CNS tumors in children and adults.

The prognosis in patients with primary brain tumors treated with surgery, radiotherapy and conventional chemotherapy remains poor. To improve outcome, combination high-dose chemotherapy (HDC) has been explored in children, but rarely in adults. This study was performed to determine the tolerability of three-drug combination high-dose thiotepa (T) and etoposide (E)-based regimens in pediatric and adult patients with high-risk or recurrent primary brain tumors. Thirty-one patients (13 children and 18 adults) with brain tumors were treated with high-dose chemotherapy: 19 with BCNU (B) and TE (BTE regimen), and 12 with carboplatin (C) and TE (CTE regimen). Patients received growth factors and hematopoietic support with marrow (n = 15), peripheral blood progenitor cells (PBPC) (n = 11) or both (n = 5). The 100 day toxic mortality rate was 3% (1/31). Grade III/IV toxicities included mucositis (58%), hepatitis (39%) and diarrhea (42%). Five patients had seizures and two had transient encephalopathy (23%). All patients had neutropenic fever and all pediatric patients required hyperalimentation. Median time to engraftment with absolute neutrophil count (ANC) >0.5 x 10(9)/l was 11 days (range 8-37 days). Time to ANC engraftment was significantly longer (P = 0.0001) in patients receiving marrow (median 14 days, range 10-37) than for PBPC (median 9.5 days, range 8-10). Platelet engraftment >50 x 10(9)/l was 24 days (range 14-53 days) in children. In adults, platelet engraftment >20 x 10(9)/l was 12 days (range 9-65 days). In 11 patients supported with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho = -0.87, P = 0.009) and platelet engraftment (rho = -0.85, P = 0.005), with CD34+ dose predicting time to engraftment following HDC. Overall, 30% of evaluable patients (7/24) had a complete response (CR) (n = 3) or partial response (PR) (n = 4). Median time to tumor progression (TTP) was 7 months, with an overall median survival of 12 months. These TE-based BCNU or carboplatin three-drug combination HDC regimens are safe and tolerable with promising response rates in both children and older adults.

Phase I trial of sequential high-dose chemotherapy with escalating dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer.

A single high-dose cycle of chemotherapy with stem cell support can produce disease-free survival of 15-20% for at least 3 years in women with responding stage IV breast cancer. North American Autologous Bone Marrow Transplant Registry data suggest that a complete response (CR) is the single most important prognostic factor associated with prolonged disease-free survival. Therefore, if sequential high-dose chemotherapy can increase the CR rate, then perhaps an increased proportion of patients will remain disease free. Women with at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and granulocyte colony-stimulating factor. The first intensification was a dose escalation of paclitaxel (400-825 mg/ m2), the second intensification was melphalan (180 mg/m2), and the third intensification consisted of 6000 mg/m2 cyclophosphamide (1500 mg/m2/day), 500 mg/m2 thiotepa (125 mg/m2/day), and 800 mg/m2 carboplatin (200 mg/m2/day; CTCb). Thirty-six women were enrolled and 31 completed all three cycles. After the paclitaxel infusion most patients developed reversible predominantly sensory neuropathy. Of the 19 patients with measurable disease, 6 converted to CR, 7 converted to a PR* (the complete resolution of all soft tissue or visceral disease with sclerosis of prior lytic bone lesions), and 2 had a further PR for an overall response rate of 79%. Two patients had no further response and disease in two patients progressed, and thus they were taken off the study before CTCb. Seventy-eight percent are progression-free at a median follow-up of 14 months (range, 3-24+). Three sequential cycles of high-dose chemotherapy are feasible and were administered in this study with no mortality. Single agent paclitaxel at doses up to 825 mg/m2 were well tolerated with moderate reversible toxicity.

Advances in brain tumor chemosensitivity.

Despite advances in surgery and radiation, most malignant central nervous system tumours recur. Chemotherapy has assumed an important role in treatment, particularly for responsive tumors such as primary central nervous system lymphoma and oligodendrogliomas. The design of sound chemotherapeutic trials for brain tumors requires an understanding of drug resistance. Drug sensitivity may be improved in a variety of ways: through the use of agents at higher than conventional doses or in new treatment schedules, through the use of localized resistance to modulators, and even through genetic manipulation of malignant cells. As treatment with chemotherapy for central nervous system tumors becomes more successful, new measurements of tumor response may need to be developed to replace or complement standard criteria.

Phase I trial of retroviral-mediated transfer of the human MDR1 gene as marrow chemoprotection in patients undergoing high-dose chemotherapy and autologous stem-cell transplantation.

PURPOSE: Normal bone marrow cells have little or no expression of the MDR p-glycoprotein product and, therefore, are particularly susceptible to killing by MDR-sensitive drugs, such as vinca alkaloids, anthracyclines, podophyllins, and paclitaxel and its congeners. Here we report the results of a phase I clinical trial that tested the safety and efficacy of transfer of the human multiple drug resistance (MDR1, MDR) gene into hematopoietic stem cells and progenitors in bone marrow as a means of providing resistance of these cells to the toxic effects of cancer chemotherapy. PATIENTS AND METHODS: Up to one third of the harvested cells of patients who were undergoing autologous bone marrow transplantation as part of a high-dose chemotherapy treatment for advanced cancer were transduced with an MDR cDNA-containing retrovirus; these transduced cells were reinfused together with unmanipulated cells after chemotherapy. RESULTS: High-level MDR transduction of erythroid burst-forming unit (BFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) derived from transduced CD34+ cells was shown posttransduction and prereinfusion. However, only two of the five patients showed evidence of MDR transduction of their marrow at a low level at 10 weeks and 3 weeks, respectively, posttransplantation. The cytokine-stimulated transduced cells may be out-competed in repopulation by unmanipulated normal cells that are reinfused concomitantly. The MDR retroviral supernatant that was used was shown to be free of replication-competent retrovirus (RCR) before use, and all tests of patients' samples posttransplantation were negative for RCR. In addition, no adverse events with respect to marrow engraftment or other problems related to marrow transplantation were encountered. CONCLUSION: These results indicate the feasibility and safety of bone marrow gene therapy with a potentially therapeutic gene, the MDR gene.