Autologous Bone Marrow Reinfusion Research Articles

Increasing Incidence of Late Second Malignancies After Conditioning With Cyclophosphamide and Total-Body Irradiation and Autologous Bone Marrow Transplantation for Non-Hodgkin’s Lymphoma

Although the risk of myelodysplastic syndrome (MDS) has been well-described following autologous bone marrow transplantation (ABMT), the risk of solid tumors has been poorly characterized. We report the incidence and outcome of solid tumors at 10-year follow-up in a large cohort of uniformly treated patients who underwent ABMT for non-Hodgkin's lymphoma (NHL). Between 1982 and 1997, 605 patients underwent ABMT for B-cell NHL, with uniform conditioning with cyclophosphamide and total-body irradiation followed by reinfusion of autologous bone marrow purged with anti-B-cell monoclonal antibodies. Current information on relapse of disease and second malignancies was obtained via an institutional review board-approved questionnaire sent to the referring oncologists. Forty-two solid tumors, six non-MDS hematologic malignancies, 39 nonmelanoma skin cancers, and 68 cases of MDS/acute myelogenous leukemia (AML) were observed at a median follow-up of 9.5 years. A cumulative incidence model using death as a competing risk found that the 10-year incidence of second malignancy is 21%, with 10.0% non-MDS malignancies. The projected incidence of all malignancies at 15 years is 29%. The principal risk factor for second malignancy is increased age at ABMT (P = .0002). In the entire cohort, 9.6% of patients have died of second malignancy. Lengthy follow-up demonstrates a significant incidence of second malignancies after ABMT for NHL. Although the incidence of MDS/AML starts to plateau, the incidence of solid tumors continues to rise. Second malignancies are responsible for a significant fraction of overall mortality following ABMT.

High-dose carmustine, thiotepa and etoposide followed by autologous bone marrow rescue for the treatment of high risk central nervous system tumors.

Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or non-biopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7-46.8). A total of 600 mg/m2 BCNU, 900 mg/m2 thiotepa and 1500 or 750 mg/m2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both newly diagnosed and recurrent CNS tumors.

Effects of peripheral stem cell or bone marrow reinfusion on peripheral serotonin metabolism.

Reinfusion of autologous hematopoietic peripheral blood stem cells (PBSC) or bone marrow is often accompanied by flushing, dyspnea, abdominal cramping, nausea and diarrhea. These symptoms and the observation that they can be prevented by ondansetron, a selective 5-HT3 receptor antagonist, led to the assumption that these side-effects are due to infusion of free serotonin during the reinfusion of PBSC or bone marrow. Twenty-five patients with solid tumors received, after myeloblative chemotherapy, a total of 30 reinfusions of PBSC and/or bone marrow. In 17 patients, serotonin levels in the bags containing the PBSC were measured. In all patients, platelet serotonin levels were determined before and 1 h post-reinfusion. In addition, before and 24 h after reinfusion urine was collected for determination of 5-hydroxyindole acetic acid (5-HIAA) and serotonin concentrations. Mean (+/- s.d.) total serotonin concentration in the bags was 2404 +/- 1555 nmol/l. Mean total volume reinfused was 471 +/- 185 ml. After reinfusion, the mean (+/- s.d.) levels of serotonin in platelets in patients increased from 3.2 +/- 1.4 nm/10(9) at baseline to 3.8 +/- 2.0 nm/10(9) (P = 0.02). Neither 24 h urinary 5-HIAA nor serotonin levels were affected. These results indicate that reinfusion of PBSC or bone marrow is accompanied by substantial infusion of free serotonin, which might explain the observed side-effects and justify the use of 5-HT3 receptor antagonists as pre- medication for this procedure.

Preparation of autologous bone marrow grafts for cryopreservation using the AS104 cell separator.

We evaluated the AS104 cell separator (Fresenius AG, Bad Homburg, Germany) for ex vivo processing of bone marrow (BM) grafts of 43 patients suffering from germ cell cancer (GCC, n = 22), acute lymphocytic leukemia (ALL, n = 13) and malignant lymphoma (ML, n = 8). Recoveries of total nucleated cells (TNC), mononuclear cells (MNC) and colony-forming units granulocyte-macrophage (CFU-GM) were determined in the BM concentrates prepared for cryopreservation. Hematopoietic reconstitution was analyzed in patients who underwent autologous transplantation following high-dose radio-/chemotherapy (HDRCT). Processing of the BM suspension with a median volume of 1,013 ml (range: 422-1,574) resulted in 156 ml (80-186) within 50-120 min (median: 90). In the BM concentrates, medians of 28.6% TNC (10.6-69.6), 37.9% MNC (22.3-86.4), and 52.4% CFU-GM (20.8-96.4) were recovered. Twenty-six patients underwent HDRCT with reinfusion of autologous BM and were evaluable for engraftment. They received a median of 0.8 x 10(8) MNC/kg (0.3-1.6 x 10(8)) and 2.2 x 10(4) CFU-GM/kg (0.6-12.8 x 10(4) for hematopoietic rescue. Engraftment with neutrophils > 500/microliter occurred in a median time of 12 days (8-33) in all patients. We conclude that ex vivo processing of autologous BM with median recovery rates of 37.9% for MNC, and 52.4% for CFU-GM, results in a cell population that can rescue patients from HDRCT. The described technique is convenient, time-efficient, and provides reliable results in preparing BM autografts for cryopreservation.

Acute cholecystitis after autologous bone marrow transplantation for acute myeloid leukemia

We investigated the incidence of acute cholecystitis in patients with acute myeloid leukemia (AML) undergoing autologous bone marrow transplantation in complete remission. Thirty-five consecutive acute myeloid leukemia patients were given oral busulfan 4 mg/kg/day for 4 days and IV cyclophosphamide 50 mg/kg/day for 4 days followed by reinfusion of autologous bone marrow purged with 4-hydroperoxycyclophosphamide. Five of 35 patients developed clinical evidence of acute cholecystitis, manifested by fever, nausea, vomiting, right-upper-quadrant pain, and abdominal guarding, within 18 days after autologous bone marrow infusion. Ultrasonography and CT scans of the abdomen supported the diagnosis of cholecystitis. Three patients underwent cholecystectomy, while two patients were treated medically; all recovered uneventfully. A review of 338 consecutive bone marrow transplant patients who underwent marrow transplantation for a variety of diseases and were treated with other high-dose cytotoxic regimens during the same time period revealed significantly fewer cases of cholecystitis, i.e. two, (p < 0.0001). Five of 35 AML patients undergoing autologous bone marrow transplant using busulfan, cyclophosphamide, and purged bone marrow developed evidence of acute cholecystitis. These findings suggest that the busulfan/cyclophosphamide preparative regimen may be associated with acute cholecystitis. The true incidence of this injury and its pathogenesis remain to be elucidated.

Intensive chemotherapy with autologous bone marrow transfusion as primary treatment in women with breast cancer and more than five involved axillary lymph nodes

Patients with breast cancer and a high number of involved axillary lymph nodes have a poor prognosis, despite adjuvant chemotherapy. The 5-year disease-free survival (DFS) in this group amounts to 30–40% and the 10-year DFS is only 15–20%. Therefore, new treatment modalities are being sought for this group of patients. The aim of the present study was the evaluation of the efficacy of high-dose chemotherapy combined with autologous bone marrow support. 24 patients with a primary breast cancer with more than five involved axillary lymph nodes received, after surgery, six courses of induction chemotherapy followed by ablative chemotherapy and reinfusion of autologous bone marrow. All patients were premenopausal or less than 2 years postmenopausal. Induction chemotherapy consisted of methotrexate (MTX) 1.5 g/m 2 intravenous (i.v.) and 5-fluorouracil (5-FU) 1.5 g/m 2 i.v. on day 1, prednisone 40 mg/m 2 orally on days 2–14, doxorubicin 50 mg/m 2 i.v. and vincristine 1 mg/m 2 i.v. on day 14. Courses were repeated six times every 4 weeks. 10 patients received cyclophosphamide 7 g/m 2 i.v. and etoposide 1.5 g/m 2 i.v. as intensive regimen, in 14 patients this comprised mitoxantrone 50 mg/m 2 i.v. and thiotepa 800 mg/m 2 i.v. Reinfusion of autologous marrow followed on day 7. Finally, patients received locoregional radiotherapy for extranodal disease and tamoxifen 40 mg daily orally over a period of 2 years. The median age of patients was 42 years, range 29–54. The median number of involved nodes was 10. During induction therapy, fever requiring i.v. antibiotics occurred in 4% of 144 courses, 14% of patients suffered from mucositis WHO grade 2–3, and the other patients had mucositis grade 1. During the ablative chemotherapy, 1 patient died, 6 developed septicaemia, 5 showed mucositis grade 3–4 and the other patients had mucositis grade 1 or 2. In the follow-up, 1 patient died from acute cardiac failure. Reversible radiation-induced pneumonitis occurred in 7 out of 14 irradiated patients; symptoms started directly following radiotherapy and lasted for several weeks, but disappeared in due course. During follow-up, 2 patients with six and > 10 positive nodes, respectively, have relapsed after 18 and 36 months, both in the cyclophosphamide/etoposide regimen. Median observation is 3 years, disease-free survival at 5 years is predicted to be 84%. Intensive treatment in these patients with high numbers of involved axillary lymph nodes is a toxic regimen, but may improve the chance of surviving free of disease.

Randomized Trial of High Dose Chemotherapy With Autologous Bone Marrow Support as Adjuvant Therapy for High-Risk, Multi-Node Positive Malignant Melanoma

Chemotherapy adjuvant to surgery in metastatic melanoma has been evaluated in only a few prospective randomized trials. In the treatment of metastatic melanoma, dacarbazine has response rates of 15%-25% and in several studies, when combined with other alkylating agents, has yielded even higher response rates. Among the highest response rates are those achieved by using high-dose chemotherapy regimens combined with autologous bone marrow support (transplantation). We conducted a prospective randomized clinical trial to test the efficacy of high-dose alkylating agents in combination with autologous bone marrow support given as adjuvant therapy for high-risk stage II (World Health Organization) melanoma. Thirty-nine patients with metastases involving five or more lymph nodes were randomly assigned to one of two treatment arms within 8 weeks of lymphadenectomy: immediate treatment or observation only. The immediate-treatment arm consisted of 19 patients who, immediately after random assignment, received high-dose chemotherapy with alkylating agents, followed 3 days later by reinfusion of autologous bone marrow. The observation arm consisted of 20 patients who were observed until relapse (confirmed by biopsy) and were then treated with the identical high-dose alkylating agent chemotherapy followed by reinfusion of autologous bone marrow. Bone marrow was harvested from the patients under general anesthesia 1-2 weeks prior to chemotherapy and was cryopreserved. Chemotherapy consisted of intravenous administration of cyclophosphamide (1875 mg/m2 as a 1-hour infusion daily for 3 days), cisplatin (55 mg/m2 per day by continuous infusion over the same 72-hour period), and carmustine (BCNU) (600 mg/m2) given immediately after cisplatin on the 4th day as a 2-hour infusion. The total doses of the three drugs were 5625, 165, and 600 mg/m2, respectively. All patients received medical evaluations every 6-12 weeks over the study period. Kaplan-Meier estimates were used to determine the time to disease progression on the basis of intent to treat. There was no statistically significant difference in overall survival or in time to disease progression between the two treatment arms. However, the median time to progression was 16 weeks in the observation arm and 35 weeks in the immediate-treatment arm. Immediate adjuvant high-dose chemotherapy with alkylating agents followed by autologous bone marrow support more than doubled the time to disease progression compared with observation alone, though the difference was not statistically significant. No differences in overall survival were noted.

Induction chemotherapy and intensification with autologous bone marrow reinfusion in patients with locally advanced and disseminated breast cancer.

In 56 patients with disseminated or locally advanced breast cancer it was attempted to reach a state of no evidence of disease by a remission induction regime containing prednisone, 5-fluorouracil, methotrexate, doxorubicin and vincristine. If successful, patients received an intensification regimen consisting of cyclophosphamide (7 g/m2) and etoposide (1.5 g/m2) with autologous bone marrow reinfusion. The complete remission rate of the induction regimen was 52% and the partial remission rate 42%. 32 patients received the intensification regimen. Two toxic deaths occurred. The median time to disease progression in the group with disseminated disease was 15 months. After a median observation of 4 years, 11 out of 19 patients with locally advanced breast cancer were free of disease. It is concluded that this approach may lead to prolonged disease-free survival in patients with locally advanced breast cancer, but does not influence the survival in disseminated disease.

Adjuvant chemotherapy with autologous bone marrow reinfusion in patients with prognostically unfavourable breast cancer

Adjuvant chemotherapy with autologous bone marrow reinfusion in patients with prognostically unfavourable breast cancer

Recombinant human interleukin 3 in clinical oncology.

Interleukin 3 (IL-3) is a multipotent hematopoietic growth factor which became available as a recombinant (rh) growth factor for use in the clinic a few years ago. In dose-finding studies, this hematopoietic growth factor has been evaluated without and after standard chemotherapy. Stimulatory effects on leukocytes, neutrophils, eosinophils, monocytes, reticulocytes and platelets were observed in some studies. Chemotherapy postponement due to insufficient bone marrow recovery was less frequent when IL-3 was administered. There are some clinical studies available in which rhIL-3 is combined with rh granulocyte-macrophage colony-stimulating factor (GM-CSF). The results do not clearly suggest superiority of these combinations over rhGM-CSF alone, but this may be partly due to the time scheduling of the growth factors. Administration s.c. is not inferior to i.v. Side effects mainly consist of flu-like symptoms and headache. The role of rhIL-3 after high-dose chemotherapy and autologous bone marrow reinfusion is still questionable. The addition of rhIL-3 to rhGM-CSF both administered after chemotherapy may allow a very high yield of peripheral stem cells suitable for bone marrow reconstitution after high-dose chemotherapy. rhIL-3 can stimulate leukemia tumor cell proliferation in vitro as well as proliferation of solid tumor cell lines. It is not yet clear in which way rhIL-3 combined with chemotherapy will effect tumor response and patient survival. It is too early to define the exact place of rhIL-3 in oncology. Additional studies with rhIL-3 alone and in combination with other growth factors are needed.

High-dose carmustine and autologous bone marrow reinfusion in the treatment of refractory or relapsed small cell lung carcinoma : Rushing DA, Friedenberg WR, Baldauf MC, Broste S, Gehlsen JA, Kriesel DH et al. Marshfield Clinic, 1000 North Oak Avenue, Marshfield, WI 54449. Cancer 1991;68:720–4

High-dose carmustine and autologous bone marrow reinfusion in the treatment of refractory or relapsed small cell lung carcinoma : Rushing DA, Friedenberg WR, Baldauf MC, Broste S, Gehlsen JA, Kriesel DH et al. Marshfield Clinic, 1000 North Oak Avenue, Marshfield, WI 54449. Cancer 1991;68:720–4

High-Dose Cyclophosphamide, Etoposide and BCNU with Non-Cryopreserved Autologous Bone Marrow Transplantation for Poor Prognosis Malignant Lymphoma

20 patients with poor prognosis malignant lymphoma (Hodgkin's disease 8, high grade non-Hodgkin's lymphoma 12) were treated with high-dose cyclophosphamide (120 mg/kg), etoposide (2100 mg/m2) and BCNU (400mg/m2) followed by reinfusion of autologous non-frozen bone marrow, which had been stored for 72 hours at 4°C. All evaluable patients (19/20) had a full haematopoietic reconstitution. Median time to achieve neutrophils > 500 μl was 26 days (range 15–39) and median time to achieve an unsupported platelet count >20000/μl was 29 days (range 12–55). During a median follow-up of 10.5 months (range 2–36) 2 of 8 patients with Hodgkin's disease and 3/12 patients with non-Hodgkin's lymphoma relapsed after a median of 4.5 months (range 1–6). The projected event-free survival at 24 months was 61% and 70% for patients with non-Hodgkin's lymphoma and Hodgkin's disease respectively. We conclude that high-dose chemotherapy with non-frozen autologous bone marrow transplantation is safe in terms of haematopoietic reconst...

Myeloablative chemoradiotherapy and autologous bone marrow infusions for treatment of neuroblastoma: factors influencing engraftment

Bone marrow harvested from cancer patients for autologous bone marrow reinfusion (ABMR) after myeloablative treatment may be injured, in both its proliferating and stromal cell pools, by either previous treatment or manipulation at the time of harvest. We have examined the relative effects of seven covariates on hematologic recovery after ABMR in children with neuroblastoma (NBL) using univariate and step-up analysis. We measured recovery by times to achieve (1) white blood cell counts greater than 1,000/microL; (2) absolute neutrophil counts greater than 500/microL; and (3) platelet counts greater than 20,000/microL without transfusion. In univariate analysis, recovery was significantly associated with the amount of prior chemotherapy and the interval between last chemotherapy and marrow harvest. Patient sex, the number of granulocyte-macrophage colonies infused, harvest-to-freeze interval, and use of purging were marginally associated. After adjusting for potential confounders in a multivariate model, the amounts of chemotherapy and granulocyte-macrophage colonies infused were independently significant predictors of time to total white blood cell count recovery; chemotherapy courses and chemo-to-harvest interval were predictors of neutrophil count recovery; and sex, use of purging, and harvest-to-freeze interval were marginal predictors of platelet recovery. The speed of hematologic recovery after ABMR seems to depend mainly on pre-existing factors and marginally on manipulation of the marrow after harvest. These factors may affect both proliferating and stromal cell pools.

Myeloablative Chemoradiotherapy and Autologous Bone Marrow Infusions for Treatment of Neuroblastoma: Factors Influencing Engraftment

Abstract Bone marrow harvested from cancer patients for autologous bone marrow reinfusion (ABMR) after myeloablative treatment may be injured, in both its proliferating and stromal cell pools, by either previous treatment or manipulation at the time of harvest. We have examined the relative effects of seven covariates on hematologic recovery after ABMR in children with neuroblastoma (NBL) using univariate and step-up analysis. We measured recovery by times to achieve (1) white blood cell counts greater than 1,000/microL; (2) absolute neutrophil counts greater than 500/microL; and (3) platelet counts greater than 20,000/microL without transfusion. In univariate analysis, recovery was significantly associated with the amount of prior chemotherapy and the interval between last chemotherapy and marrow harvest. Patient sex, the number of granulocyte-macrophage colonies infused, harvest-to-freeze interval, and use of purging were marginally associated. After adjusting for potential confounders in a multivariate model, the amounts of chemotherapy and granulocyte-macrophage colonies infused were independently significant predictors of time to total white blood cell count recovery; chemotherapy courses and chemo-to-harvest interval were predictors of neutrophil count recovery; and sex, use of purging, and harvest-to-freeze interval were marginal predictors of platelet recovery. The speed of hematologic recovery after ABMR seems to depend mainly on pre-existing factors and marginally on manipulation of the marrow after harvest. These factors may affect both proliferating and stromal cell pools.

High-dose carmustine and autologous bone marrow reinfusion in the treatment of refractory or relapsed small cell lung carcinoma.

Fourteen patients with small cell carcinoma of the lung in relapse or with disease refractory to chemotherapy were treated with carmustine (BCNU) at doses of 600 to 1000 mg/m2 intravenously followed by autologous bone marrow transplantation. All patients previously were treated with cyclophosphamide, doxorubicin, vincristine, and etoposide. Seven of the 14 patients responded to the high-dose BCNU (50% response with 95% confidence limits ranging from 23% to 77%). Three patients had a complete response, and four had a partial response. Regrowth of tumor occurred within 60 days of treatment in the responding patients. Death occurred in six patients before the recovery of the platelet count to 50,000 cells/microliters. Although the response rate was high, the toxicity was excessive. In the dosage range of 600 to 1000 mg/m2 in heavily pretreated patients, BCNU is not recommended, but additional investigation may be warranted in patients with central nervous system metastases who previously were treated with radiation therapy.

Treatment of metastatic breast cancer

Relapse of breast cancer connotes a dire prognosis. However, long-term survival with remissions and disease exacerbation are possible using conservative treatment strategies and often sequential hormonal manipulations. Hormonal therapy is the mainstay of metastatic breast cancer treatment for patients with hormonally sensitive tumors; cytotoxic chemotherapy, for patients with hormonally independent tumors. High-dose chemotherapy with autologous bone marrow reinfusion is currently under investigation.

Intensive combination chemotherapy and autologous bone marrow transplantation leads to the reappearance of philadelphia chromosome-negative cells in chronic myelogenous leukemia

Fifteen patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who were ineligible for allogeneic bone marrow transplantation (BMT) or alpha-interferon therapy were included in this study. Eight patients were in the first late chronic phase, five were in the second chronic phase, one was in the accelerated phase, and one was in the blastic phase. Autologous bone marrow cells (median, 2.5 x 10(8) nucleated cells/kg) were stored at a median of 30 months after diagnosis. Patients were treated with cyclophosphamide (1.5 g/m2 daily for 4 days), carmustine (BCNU) (300 mg/m2), and etoposide (VP-16) (250 mg/m2 daily for 3 days) (CBV), followed by reinfusion of autologous bone marrow. Hematopoietic recovery was rapid, and toxicity was mild to moderate in 14 patients. One patient died of cytomegalovirus pneumonitis. Eight of 15 patients showed Ph suppression to less than 90% Ph-positive metaphases after autologous BMT. Major cytogenetic responses (Ph suppression to less than 35% Ph-positive metaphases) developed in four patients. Cytogenetic responses were observed in 4 of 11 patients infused with 100% Ph-positive marrows, and in all 4 patients infused with Ph-mosaic marrows (mixture of diploid and Ph-positive cells). Better results were observed when autologous BMT was performed in the chronic phase compared with the advanced phases. The major cytogenetic responses have lasted for 3, 4, 12, and 15+ months, whereas minor cytogenetic responses lasted for only a short time (less than 2 months). Three of seven patients (43%) in the chronic phase with previous resistance to alpha-interferon therapy became sensitive to alpha-interferon therapy after autologous BMT. The authors concluded that intensive chemotherapy followed by autologous BMT produced cytogenetic remissions in patients with Ph-positive CML and reinduced disease sensitivity to alpha-interferon therapy in patients previously resistant to it. This is particularly useful when treatment is given during the chronic phase and stem cells are collected at a time of previous cytogenetic remission.

Myeloablative therapy with autologous bone marrow transplantation as consolidation of remission in patients with follicular lymphoma

A study has been in progress since June 1985 to evaluate the use of myeloablative therapy (cyclophosphamide [60 mg/kg × 21 and total body irradiation [200 cGy × 6]) followed by reinfusion of autologous bone marrow in patients in second or subsequent remission of B-cell non-Hodgkin’s lymphoma. The marrow mononuclear cell fraction is being treated in vitro with three cycles of the monoclonal antibody anti-CD20 (anti-B1, Coulter Immunology) and baby rabbit complement (Pel-Freez).

High dose combination chemotherapy with ifosfamide, cyclophosphamide or cisplatin, mitomycin C and mustine with autologous bone marrow support in advanced non-small cell lung cancer. A phase I/II study

Twenty-three patients with advanced NSCLC were treated with high dose chemotherapy using four agents and autologous bone marrow reinfusion. Ten patients received two bolus doses of cyclophosphamide (maximum tolerated total dose 10 G m-2), ifosfamide as a 24 h infusion (11 G m-2) followed by mitomycin C (70 mg m-2) as a subsequent 24 h infusion and mustine as two boluses (total dose 30 mg m-2). Another 13 patients received the same agents except cisplatin was substituted for cyclophosphamide, two doses (total dose 100 mg m-2) being given in a 24 h period. The median time of recovery to greater than or equal to 20,000 platelets was 21 days and of neutropaenia greater than or equal to 500 was 12-15 days. Unusual non-haematological toxicity e.g. cardiomyopathy, colitis, veno occlusive disease was not noted, all patients being given regular selenium and other trace elements. Three patients died in the first 2 weeks. There were five complete responses (22%) and 12 partial responses (52%) with four patients (2CR, 2PR) still alive at 27, 48, 73 and 82 weeks. The patient's Karnofsky performance in the cisplatin regimen improved over pretreatment values when compared a month after the end of treatment. The high dose regimen was associated with a high (74%) response rate, but with an overall median survival of only 6 months. The regimen has no advantage over conventional doses with the same agents in patients with metastatic NSCLC.

Phase I Trial of High-Dose Etoposide, High-Dose Cisplatin, and Reinfusion of Autologous Bone Marrow for Lung Cancer

We undertook a phase I trial using fixed-dose cisplatin, escalating doses of etoposide, and reinfusion of previously obtained autologous bone marrow in 29 relapsed or refractory small cell and non-small-cell lung cancer patients. Median age was 59 years (range of 38-68 years). Three patients had small-cell and 26 patients had non-small-cell lung cancer. Patients received i.v. cisplatin 200 mg/m2 over 5 days and i.v. etoposide 600 mg/m2/day for 3 days (total of 1,800 mg/m2) that was escalated to 800, 1,000, 1,200, 1,400, and 1,600 mg/m2/day for 3 days (total of 2,400-4,800 mg/m2). Cryopreserved autologous bone marrow was thawed and reinfused through a central venous catheter the second day after the completion of chemotherapy. Toxicities included nausea, vomiting, alopecia, high-tone hearing loss, mucositis, diarrhea, renal insufficiency, metabolic acidosis, and severe myelosuppression. The duration of neutropenia (less than 500 neutrophils/microliter) ranged from 5 to 22 days (median of 11 days) and the duration of severe thrombocytopenia (platelets of less than 20,000/microliters untransfused) ranged from 2 to 19 days (median of 9 days). Reversible renal insufficiency (peak serum creatinines of 6.7, 6.6, 4.3, and 3.5 mg/dl) occurred in four patients who completed the therapy. In three patients, death occurred within 4 weeks of chemotherapy and marrow reinfusion. Three complete and 12 partial remissions (range of 1+(-)22+ months, median of 3 months) were observed. No response was noted in eight patients and tumor progression within 1 month of transplant occurred in two patients. The maximally tolerated dose of etoposide was 1,400 mg/m2/day (total of 4,200 mg/m2), since two of three patients developed life-threatening diarrhea at the 1,600 mg/m2/day (total of 4,800 mg/m2) dose. The encouraging antitumor effects of this regimen suggest that this approach may be useful therapy for lung cancer and other tumors sensitive to VP-16 and cisplatin.