High-dose cyclophosphamide, thio-TEPA, etoposide with autologous bone marrow transplantation for refractory cancers

We studied high-dose chemotherapy with autologous bone marrow transplantation (ABMT) for 10 patients with malignant lymphoma or breast cancer refractory to conventional chemotherapy. Conditioning regimen was consisted of cyclophosphamide 60 mg/kg/day, thio-TEPA 6 mg/kg/day, Etoposide 500 or 600 mg/m2/day for 3 consecutive days. Of 9 patients with measurable lesions, there were 5 with complete responses (CR) and 4 with partial responses (PR). Severe bone marrow suppression, mucositis, and diarrhea were observed in all patients. Furthermore, biliary stasis, which was unpredictable side effect, was observed in most patients. So, mucositis and/or hepatotoxicity were thought to be the dose-limiting factors. But these were not life-threatening and clinically manageable. All patients were received recombinant human granulocyte colony stimulating factor (rhG-CSF) at a dose of 300 micrograms/m2/day and which was effective for shortening the duration of leukopenia. In vitro Colony Forming Unit-granulocyte macrophage assay (CFU-GM assay) showed a significant correlation between the ability of colony formation and the days to recovery of granulocytes.     

High-dose combination alkylating agent therapy with autologous bone marrow rescue for refractory solid tumors

Twenty-six adults, ages 27 to 60, with refractory metastatic solid tumors were treated with high-dose cyclophosphamide (Cy) + carmustine (BCNU) at one of three escalating dose schedules followed by autologous bone marrow transplantation (ABMT). Toxicity was severe and dose-related, with the maximum tolerated dose for the combination determined to be Cy 160 mg/kg and BCNU 900 mg/m2. Median time to WBC recovery (greater than or equal to 1,000/microL) was 13 days post-ABMT (range, nine to 22 days) and to a platelet count of greater than or equal to 50,000/microL, 22 days (range, 13 to 83 days). Sixteen of 20 evaluable patients (80%) responded to therapy with at least 50% reduction in measurable tumor, and three patients achieved complete remission (CR). Responders included eight of nine evaluable patients with breast carcinoma, two of five with melanoma, two of two with sarcoma, and four of four with colon carcinoma. Response durations were short (median, 4 months), even for complete responders, and relapses generally occurred at sites of previous metastases. In order for this approach to have a more significant impact on overall survival, it may need to be applied earlier in the natural history of the malignancy.     

High-dose combination cyclophosphamide,cisplatin, and melphalan with autologous bone marrow support

Summary A total of 23 patients were treated at five dose escalations with high-dose combination cyclophosphamide, cisplatin, and melphalan with autologous bone marrow support. The maximum tolerated doses of cyclophosphamide, cisplatin, and melphalan were 5,625, 180, and 80 mg/m², respectively. The dose-limiting toxicity was cardiac toxicity. Objective tumor regression occurred in 14 of 18 evaluable cases, with a median duration of 3.5 months. Pharmacokinetic evaluation of melphalan in 20 patients revealed a dose-related increase in maximum plasma concentration (C_max) and area under the curve (AUC). Perturbation of the melphalan plasma half-life and AUC, associated with severe toxicity, resulted when renal insufficiency occurred. The results suggest that high-dose combination cyclophosphamide, cisplatin, and melphalan produces frequent, rapid responses in breast cancer, melanoma, and sarcoma, although with significant extramedullary toxicity. The pharmacokinetics suggest that modification of the treatment schedule may result in a reduction of treatment-related toxicity.Supported in part by grant 5-PO1-CA32672 from the National Cancer Institute     

High-dose melphalan with 6-hydroxydopamine-purged autologous bone marrow transplantation for poor-risk neuroblastoma

Long-term results are presented of 28 patients who were diagnosed with neuroblastoma at more than 12 months of age and who received melphalan 180 mg/m2 (n = 6) or 240 mg/m2 (n = 22) to consolidate remissions of Stage IV disease or to control refractory disease. Twenty-four patients also received dianhydrogalactitol 180 to 240 mg/m2, and 11 received total body irradiation 450 to 600 cGy. Autologous bone marrow transplantation (ABMT) was performed with marrow that was unpurged (n = 2) or purged ex vivo (n = 26) with 6-hydroxydopamine (6-OHDA) 20 micrograms/ml plus ascorbate 200 micrograms/ml. The median time to an absolute neutrophil count of 500/microliters was 21 days and to self-sustaining platelet counts more than 20,000/microliters, 28 days. One patient required infusion of unpurged reserve marrow. Two groups of patients underwent ABMT: (1) 17 patients (Group I) who were in first remission a median of 7 months after diagnosis; and (2) 11 patients (Group II) who had refractory disease or were in second remission. For Group I, event-free survival was 29% at 12 months and 6% at 24 months post-ABMT. All Group II patients died of disease or ABMT-related toxicity. Overall, of the 28 patients, one is a long-term relapse-free survivor; five died of ABMT-related toxicity; ten patients with tumors present at ABMT had progressive disease within 6 months of ABMT; and 12 patients with no measurable disease at ABMT relapsed 4 to 32 months (median, 12) post-ABMT. Among the latter, six relapses involved the primary site, and six were restricted to distant sites. These results--in accord with the long-term outcome in other series--suggest that for neuroblastoma high-dose melphalan cannot be relied on to ablate residual disease or to salvage patients with refractory tumors. In addition, the pattern of relapse in several patients could be explained by infusion of incompletely purged autografts; this would support recent laboratory evidence that 6-OHDA/ascorbate is a suboptimal purging method.     

High-dose melphalan and total body irradiation with bone marrow transplantation for refractory malignancies

We investigated if high dose melphalan and total body irradiation could be administered to adult patients with acceptable toxicity. Nineteen adult patients with relapsed disease, 15 of them having hematologic malignancies, were treated with high-dose melphalan (100 mg/m²–140 mg/m²) divided over 2 consecutive days followed by a rest period of 4, days before receiving total body irradiation, 850 rad administered in five fractionated doses over 3, days. Subsequently 11 patients received autologous, seven allogeneic and one syngeneic, bone marrow transplantation. All patients had severe myelosuppression and the major extramedullary toxicity was mucositis. There were three early deaths, two related to septicemia and one to graft-versus-host disease with associated cytomegalovirus pneumonitis. All patients were heavily pretreated, and 16 were demonstrating progressive disease on alternative salvage therapies at the time of bone marrow transplantation. Two of the 16 evaluable patients (12.5%) achieved complete remissions, and 10 (63%) achieved partial remissions for a total response rate of 75%. One patient is a long-term disease-free survivor (over 1 yr). An occasional patient may be cured by this approach. The combination of melphalan, an alternative alkylating agent to cyclophosphamide and total body irradiation are associated with moderate gastrointestinal toxicity in heavily pretreated adult patients. The combination warrants further investigation in a less heavily pretreated population to determine more accurately the complete response rate.     

High-dose chemotherapy and autologous bone marrow or stem cell reconstitution for solid tumors

High-dose chemotherapy—in conjunction with the transplantation of either mononuclear cells harvested from the marrow or CD 34+ cells harvested from the peripheral blood—has proved effective in curing certain patients with leukemia, lymphoma, and, to a lesser extent, multiple myeloma. Though the CD 34+ therapy is a relatively new treatment and the mononuclear cell therapy is more standard, both have been successfully used to reconstitute lethally damaged hematopoietic stem cells. Allogeneic transplants have been more effective than autologous transplants against tumors, but they also pose a greater hazard of death from complications, graft-versus-host disease, and infections. More currently, this approach has been used in patients with certain solid tumors, either in a metastatic or recurrent disease setting or as an adjuvant to surgery and/or standard doses of chemotherapy in patients with a known high risk of recurrence.Unfortunately, the majority of the studies about the impact of this therapy have been small and nonrandomized against standard therapy, and they have encompassed diverse populations of patients. This makes comparisons with contemporary standard—dose approaches—already problematic from a statistical point of view—even more dangerous because of the dissimilarity of the groups being compared. Particularly in the high-risk adjuvant setting, data suggest that those patients that meet the eligibility criteria for high-dose therapy and transplantation exhibit the prognostic factors for a positive outcome. When one compares these results with those of a more heterogeneous group of patients treated with conventional therapy, the conclusion might be drawn that high-dose therapy is superior to standard therapy, when a longer follow-up of the patients in the study will show this to be untrue. Thus there is a plea from clinicians and physicians conducting trials for prospective, randomized trials that would allow a fair comparison between high-dose therapy in combination with transplant procedures and a more conventional, standard chemotherapy, which is often less toxic and definitely less expensive.This article reviews the data for transplantation in four tumors: breast cancer, ovarian cancer, small-cell lung cancer, and germ cell testis cancer. There is such a small number of randomized trials that an attempt must be made to compare these small high-dose therapy studies with similar, though not identical, large studies of conventional therapy. This article attempts to make those comparisons, and several conclusions are drawn, which are detailed below.First, few data support the use of high-dose chemotherapy in any patient with recurrent and drug-resistant breast cancer or ovarian cancer. Similarly, few data support the use of high-dose approaches for patients with extensive small-cell lung cancer. For patients with metastatic breast cancer that has responded completely to conventional chemotherapy, no data suggest a survival advantage for the immediate consolidation of that response with high-dose chemotherapy. The only trial addressing this issue found that immediate transplantation led to a better disease-free survival rate, but overall survival, as compared with that of patients who received transplants at relapse, was not affected, and the study did not address the issue of the relative merits of conventional chemotherapy in either case. The only study of high-dose versus conventional chemotherapy was statistically underpowered, and it showed poorer-than-anticipated outcomes in the patients who received conventional therapy. Ongoing or recently completed trials will, it is hoped, address the many unanswered questions in this area.For patients with high-risk, non-metastatic breast cancer, no completed and analyzed phase III randomized studies address the relative merits of conventional versus high-dose therapy. Early results from high-dose approaches suggest a better disease-free survival than has typically been observed with standard chemotherapy, but the patients who have received transplants are often highly selected and may have favorable prognostic factors as compared with the more heterogeneous groups that have received conventional therapy over the years. Several trials underway address the value of high-dose therapy in early stage, high-risk breast cancer patients (the group most likely to benefit from this type of therapy, based on the knowledge gleaned from the studies of transplants in patients with hematologic tumors), and these results are anxiously awaited by patients and health care professionals alike.In ovarian cancer, where high-dose chemotherapy and transplantation is becoming increasingly more common, many small phase II trials have shown high response rates but short response durations, and the data currently available make it difficult to maintain enthusiasm for this approach in patients with drug-resistant or large-volume disease. Several trials underway randomized patients with demonstrated drug sensitivity and a low volume of tumors (achieved either surgically or with conventional chemotherapy) to receive either high-dose therapy or more conventional consolidation approaches. Until these trials are complete, the value of high-dose therapy will remain unknown.There are little data regarding transplantation in patients with limited-stage small-cell lung cancer. A single randomized trial demonstrated an outcome advantage for high-dose therapy, but the patient numbers were too small to allow any definitive conclusions to be made. Large randomized trials in this population are needed to address the value of high-dose approaches. The preferred population in which to perform these trials would be patients with limited disease who respond to initial conventional chemotherapy and are subsequently randomized to receive conventional consolidation with chest and cranial radiation or high-dose therapy with the same radiation. Survival would be the only pertinent endpoint. No trials of this sort are currently underway.For patients with testis cancer, data suggest a clear survival benefit from high-dose chemotherapy and transplantation. Two groups of patients still have very poor outcomes—those with mediastinal primary disease and those who progress or relapse within 4 weeks of completion of standard, cisplatin-based therapy. It is unclear if high-dose approaches can salvage these patients. However, in patients whose disease recurs at a point more distant from conventional therapy, there is a potential for a long-term, disease-free survival rate that may be as much as or more than 50% better than that of patients who have been treated with conventional salvage approaches. Finally, it is now possible to identify patients who are at a high risk of a poor outcome and who are candidates for high-dose approaches as part of initial therapy. These patients are currently being studied in an intergroup, randomized trial.     

High-dose melphalan with autologous bone marrow transplant. Treatment of poor prognosis tumors

Seventeen patients were treated with high-dose melphalan with autologous bone marrow transplant (ABMT) and cyclophosphamide pretreatment. All of the patients had marrow reconstitution. Although there was one death caused by infection, high-dose melphalan with ABMT causes toxicity that is generally acceptable, and can achieve a high-response rate, but with responses of short duration in tumors resistant to standard-dose combination chemotherapy. In other poor-prognosis tumors that are sensitive to chemotherapy, or can be debulked surgically, or locally irradiated, high-dose melphalan with ABMT given as late intensification therapy may significantly prolong time to relapse, and ultimately prolong survival.     

High-dose chemotherapy with autologous bone marrow transplantation in patients with refractory ovarian cancer

Eleven patients with persistent ovarian cancer after remission-induction chemotherapy were treated with high-dose cyclophosphamide and etoposide followed by autologous bone marrow transplantation (ABMT). Six complete responses (CR), of which five were pathologically confirmed, were achieved in eight patients who had microscopic or residual disease ≤2 cm at the start of high-dose chemotherapy. The median duration of response was 15 months with two sustained CRs after respectively 43 and 75 months. None of the three patients with residual disease >2 cm responded. The median survival measured from the start of the ABMT regimen was for all patients 23 months.These results suggest that high-dose systemic chemotherapy followed by ABMT is a therapeutic option in patients with refractory ovarian cancer deserving further investigation.     

High-dose melphalan and autologous bone marrow transplant for relapsed acute leukaemia

Summary Seven patients with relapsed acute leukaemia were treated with high-dose melphalan (HDM) followed by the infusion of autologous cryopreserved remission marrow. Toxicy was minimal and all seven patients had a complete response. Four patients are still in unmaintained remission at 14, 13, 10, and 3 months, the first two having received a second course of HDM to consolidate the result. The role of HDM as a form of intensification therapy for patients with acute myeloid leukaemia in first remission should be investigated.     

Busulfan, cyclophosphamide, and melphalan conditioning for autologous bone marrow transplantation in hematologic malignancy

Sixteen patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL) underwent conditioning with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (BUCY-2) plus melphalan (90 or 135 mg/m2) and autologous bone marrow transplantation (AuBMT) in a phase I study. At the melphalan dose of 90 mg/m2, grade greater than or equal to 3 regimen-related toxicity (RRT) was observed in five patients (31%; 95% confidence interval [CI], 11% to 59%), with hepatic (venoocclusive disease [VOD]) and urinary (hemorrhagic cystitis) RRT being the most frequent complications. Further escalation of the melphalan dose to 135 mg/m2 was deemed excessively toxic, as three of five patients had grade greater than or equal to 3 RRT. Following this experience, 21 patients with multiple myeloma (MM) and chronic myelogenous leukemia (CML) were treated with BUCY-2 plus melphalan 90 mg/m2 and AuBMT in separate studies. Three of these patients--all with extensively pretreated MM--had grade greater than or equal to 3 RRT (14%; 95% CI, 3% to 36%); no others had grade greater than or equal to 3 RRT. Therefore, a total of eight of the 37 patients (22%; 95% CI, 10% to 38%) who received BUCY-2 plus melphalan 90 mg/m2 conditioning developed grade greater than or equal to 3 RRT; three of these patients (8%; 95% CI, 3% to 25%) died of RRT. Although limited by the relatively small number of patients, our analysis of the patients receiving this regimen showed that the presence of parameters denoting the lymphoid diagnostic group (ie, ALL, NHL, and MM), more extensive pretreatment, and/or more advanced disease status were associated with a higher incidence of grade greater than or equal to 3 RRT. Response data on the AML, ALL, and NHL patients who received BUCY-2 plus melphalan 90 mg/m2 were analyzed: three patients (all with AML in first or second remission) are leukemia-free at 3.0, 2.8, and 1.4 years after AuBMT. The actuarial 2-year event-free survival in this group is 17% (95% CI, 5% to 54%). Response data on the MM and CML patients will be reported subsequently. BUCY-2 plus melphalan at a dose of 90 mg/m2 before AuBMT produces acceptable toxicity in patients who are not heavily pretreated. A full evaluation of the antineoplastic effects of this regimen requires further study.     

Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer

Thirty-three adult and pediatric patients with refractory malignancies were treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days) followed by reinfusion of previously harvested and cryopreserved autologous marrow. The hematological and nonhematological toxicities and the therapeutic effects of this regimen were evaluated. Increasing doses of melphalan did not alter the rate of decline nor the recovery of peripheral blood counts. Granulocyte (greater than 500/microL) and platelet count (greater than 20,000/microL) recovery occurred in a median of 19 (range 12-54) and 24 (range: 12-54) days after bone marrow transplantation, respectively. Five patients experienced severe infection, three of which were fatal, and one patient died due to thrombocytopenic hemorrhage. Toxicity to the gastrointestinal system was dose limiting. The maximum tolerated dose of melphalan was 180 mg/m2; only three of 24 patients experienced severe stomatitis, esophagitis, and diarrhea at this level or less, while eight of nine patients at 225 mg/m2 were affected (p less than 0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before melphalan therapy did not reduce the incidence of severe gastrointestinal toxicity. Plasma melphalan concentration peaked 30-60 min after infusion (4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid concentration was 10% of the corresponding plasma concentration and was undetectable at 3 hours. Antitumor responses occurred in nine of 13 patients with malignant melanoma (five complete and four partial remissions), and ranged 2-12+ months with a median of 5 months. Four of six neuroblastomas demonstrated responses (three complete and one partial remission( lasting a median of 7.5 (range: 5-10) months. Other tumors in which this regimen had activity included breast cancer and Ewing's sarcoma. The overall response rate for the 33 patients was 30% complete remissions (10 patients) and 21% partial remissions (seven patients). High dose melphalan and autologous bone marrow transplantation is a promising therapy for patients with malignancies for which no effective treatment is known or for patients whose cancer is refractory to conventional therapeutic agents.     

High-dose thio-TEPA with escalating doses of epirubicin and autologous hematopoietic stem cell transplant for refractory cancers]

We studied high-dose chemotherapy with autologous hematopoietic stem cell transplant for patients (pts) with non-Hodgkin's lymphoma (NHL) and breast cancer (BC) refractory to conventional therapies. The conditioning regimen consisted of thio-TEPA 6 mg/kg/day for 3 consecutive days with escalating doses of epirubicin (EPI) in dose steps of 120, 150, 180 and 210 mg/m2 on day 1. Mucositis was dose limiting toxicity at 210 mg/m2 on this regimen, and the recommended dose of EPI was judged to be 180 mg/m2. No cardiotoxicities were observed. There were 3 with complete responses (CR), one partial response (PR) in pts with NHL, 3CR and 5PR in pts with BC. The median duration of response was 8 months (mos) and 4 mos, respectively. Hematological recovery was significantly earlier in the pts receiving both autologous bone marrow transplant (ABMT) and peripheral blood stem cell transplant (PBSCT) than ABMT alone. This approach made it possible to overcome the prolonged PLT recovery, which was one of the major problems on ABMT.     

High-dose cyclophosphamide with autologous marrow transplantation for small cell carcinoma of the bronchus

Summary Twenty-five patients with previously untreated small cell carcinoma of the bronchus have been treated with cyclophosphamide 160–200 mg/kg and subsequent radiotherapy to the primary site. Eighty-four percent of patients responded to the single cycle of chemotherapy, with 56% attaining a complete response. Median duration of remission was 43 weeks and median survival 69 weeks. 2-Mercaptoethane sulphonate was given to prevent urothelial toxicity. Autologous bone marrow transplantation was used to mitigate bone marrow depression but sequential delay in reinfusing cryopreserved bone marrow did not alter the period of cytopenia. Other toxicities were mild. The procedure proved safe and manageable. High-dose chemotherapy may prove to be useful in the initial management of this tumour.     

Treatment of recurrent and refractory pediatric solid tumors with high-dose busulfan and cyclophosphamide followed by autologous bone marrow rescue.

PURPOSE: The purpose of this study was to determine the toxicities of and responses to high-dose busulfan and cyclophosphamide with autologous bone marrow transplant (ABMT) in patients with recurrent or refractory pediatric solid tumors. PATIENTS AND METHODS: We treated 18 patients (ages, 2 to 38 years; median, 14) who had tumors that were resistant to conventional chemotherapy and radiotherapy with busulfan 16 mg/kg and cyclophosphamide 200 mg/kg. Seventeen patients received bone marrow purged with 4-hydroperoxycyclophosphamide; one received unpurged marrow. RESULTS: Despite extensive prior treatment, including radiotherapy in 16 patients, toxicity generally was acceptable. For seven patients with measurable disease, there were three partial responses of 2, 10, and 20 months' duration, three patients with stable disease (SD), and one early, toxic death. Of the 11 patients with no measurable disease at the time of transplantation, one patient with osteosarcoma continues in remission at 57+ months and one third of the patients survived for at least 16 months. Mucositis was the predominant nonhematopoietic toxicity. CONCLUSION: Although the high-dose busulfan and cyclophosphamide combination showed modest activity, changes in the preparative regimen should be considered to improve the response rate in refractory tumors.     

Cyclophosphamide and thiotepa with autologous bone marrow transplantation in patients with solid tumors

Autologous bone marrow transplantation to avoid dose-limiting myelosuppression may allow significant drug dose escalations and exploitation of the linear-log correlation between chemotherapy and tumor cytotoxicity. In a phase I trial of cyclophosphamide and thiotepa (with subsequent addition of melphalan), 23 patients were entered; there were two deaths due to toxic effects. The maximum tolerated dose was 6 g of cyclophosphamide/m2 and 720 mg of thiotepa/m2. No significant dose of melphalan could be added. Stomatitis was dose limiting. Eleven of 20 patients who were able to be evaluated responded. Plasma thiotepa concentrations correlated more closely with toxicity and response than with drug dose level. Continuous infusion cyclophosphamide and thiotepa is an active core regimen for the further design of high-dose combination chemotherapy regimens.     

Intensive cytoreductive therapy followed by autologous bone marrow transplantation for patients with hematologic malignancies or solid tumors

Fifty patients were studied. Twenty patients with non-Hodgkin's lymphomas (NHL) of high-grade malignancy and 21 patients with acute leukemia (AL) were treated with high-dose cyclophosphamide and total body irradiation, and three patients with Hodgkin's disease (HD) and six patients with solid tumors were treated with high-dose cyclophosphamide and VP16-213. Those procedures were followed by autologous bone marrow transplantation (ABMT). All patients had received conventional chemo(radio)therapy before the ABMT procedure. Although remissions were obtained in patients with cytotoxic drug-resistant diseases (lymphomas and solid tumors), none has become a long-term survivor, as occurred also in patients with solid tumors in partial remission (PR). Two of five patients with NHL in PR at the time of ABMT have become long-term disease-free survivors (28+, 56+ months). Ten patients with NHL were treated in complete remission (CR) and seven are in unmaintained CR; four with long follow-up (14+ to 59+ months). All patients with AL were treated in CR; two patients received ABMT in second CR, and both relapsed. Ten of nineteen patients in first CR relapsed; eight are alive in CR, five with long follow-up. Four deaths were therapy-related, all were patients in poor clinical condition. Intensive cytoreductive therapy followed by ABMT can produce prolonged disease-free survival (and probably cure) in a fair number of patients with poor risk NHL in CR and PR and probably also in patients with acute myeloblastic leukemia in first CR. This procedure was not successful in achieving long-term disease-free survival in patients with refractory lymphomas or solid tumors.     

High-dose melphalan with autologous marrow for treatment of advanced neuroblastoma.

A group of 12 children with advanced neuroblastoma (7 Stage IV and 5 Stage III), selected by their initial response to chemotherapy with pulsed cyclophosphamide/vincristine/Adriamycin (CVA), were given consolidation therapy with high-dose melphalan (140 mg/m2) and then surgical removal of residual disease. Twenty-two high-dose melphalan procedures were combined with autologous marrow grafting to offset myelotoxicity and were well tolerated. In each of 2 additional children, procedures carried out without marrow autografting led to serious marrow and mucosal toxicity. There were no treatment-related deaths. In 7/11 patients with evaluable computerized tomographic (CT) scans there was a decrease in maximum diameter of the primary tumour after melphalan. Complete response was achieved in 6 patients, of whom 3 are well and have no evidence of disease at 35, 33 and 18 months from completion of all treatment; however, although survival (median 23 months) of all 12 autografted patients is longer than that of 28 comparable children treated between 1970-77 with conventional chemotherapy (median 14 months) the difference is not statistically significant. High-dose melphalan is a safe and tolerable treatment in children when combined with autologous marrow grafting, but further study is required to determine whether the procedure can improve prognosis for patients with advanced neuroblastoma.     

Treatment of advanced neuroblastoma with high-dose melphalan and autologous bone marrow transplantation

Summary Fifteen children with advanced neuroblastoma according to Evans' classification (1 with stage III and 14 with stage IV) were treated with high-dose melphalan (HDM) followed by autologous bone marrow transplantation. Before HDM, all patients had been extensively treated with multimodality therapy for a median duration of 9 months. At the time of HDM, seven children were in partial remission (PR) with measurable residual tumor and 8 were in complete remission (CR) or good partial remission (GPR). No reduction in measurable tumor size was observed in any of the PR patients. However, when HDM was used as consolidation therapy (CR and GPR patients) survival appeared encouraging, since five of eight patients are alive with no evidence of disease at (NED) 29⁺ to 54⁺ mouths after HDM. Tolerance of this high-dose chemotherapy was satisfactory; gastrointestinal toxicity appeared to be the most important limiting factor. These results suggest that chemotherapy including high-dose melphalan is promising when used as consolidation therapy in patients who have already attained CR with conventional therapies.This study was presented in part at the workshop on high-dose chemotherapy with autologous bone marrow transplant. (Cancer Therapy evaluation program, NCI, Bethesda, March 1984)     

Haematological recovery following high-dose cyclophosphamide with autologous bone marrow transplantation

Summary A total of 31 patients with previously untreated small-cell carcinoma of the lung were treated with very-high-dose cyclophosphamide, using autologous bone marrow transplantation (ABMT) to assist haematological recovery. The period of neutropenia was shorter with 40 mg/kg cyclophosphamide x 4 (7 patients) than when the dose of cyclophosphamide was increased to 50 mg/kg x 4 (11 patients), despite ABMT 2 days after chemotherapy in each group. In all, 13 patients were treated with 50 mg/kg cyclophosphamide x 4, with infusion of bone marrow delayed to day 4, 6 or 8 after chemotherapy to determine the contribution of ABMT to haematological recovery. The period of neutropaenia was increased when marrow was returned 6 days following chemotherapy, confirming that ABMT contributed to haematological recovery after this schedule of treatment. A total of 11 patients had a second cycle of 50 mg/kg cyclophosphamide x 4 after recovery from the first cycle of high-dose chemotherapy. The period of myelosuppression was greater with the second cycle of chemotherapy, although ABMT was carried out during both cycles. The results show that ABMT contributes to haematological recovery when the dose of cyclophosphamide is high enough to produce prolonged hypoplasia. The increased myelosuppression observed after a second high-dose treatment in spite of ABMT suggests either that both transplanted and endogenous marrow activity contribute to recovery of myelopoiesis or that there is residual damage to marrow stroma after the first cycle of treatment. The data indicate the necessity of carefully assessing the role of ABMT in haematological recovery with high-dose chemotherapy regimens.This work was supported by a grant from the Cancer Research Campaign and by the Leukaemia Research Fund     

High-dose chemotherapy without autologous bone marrow transplantation in melanoma

High-dose chemotherapy with BCNU, melphalan, or both, followed by autologous bone marrow transplantation (ABMT) has been reported to produce response rates in excess of 60% in patients with advanced melanoma. We tested doses of BCNU associated with reversible bone marrow toxicity and acceptable extramedullary toxicity without the use of ABMT in 19 patients with a diagnosis of advanced malignant melanoma. All patients were evaluable for toxicity and 18 were evaluable for response; one patient had a new primary tumor. The patient population had a median age of 44 years (range, 16 to 71) and a median Karnofsky performance status of 80 (range, 50 to 100). Ten were women and nine were men, all had visceral dominant disease, and none had received previous chemotherapy. Our purpose was to test the feasibility of treatment without ABMT, its toxicity and efficacy, and the possibility of administering sequential repeated courses of therapy. Vincristine was added to the regimen to potentially increase efficacy. Treatment consisted of BCNU (750 mg/m2) and vincristine (2 mg days 1 and 8). Six patients who recovered bone marrow function received melphalan (60 mg/m2) and vincristine (2 mg days 1 and 8). Twenty-two percent (95% confidence limits, 3% to 39%) of patients had remissions (all partial) and these were of short duration. Toxicity was substantial with 16% early lethality and 29% incidence of lethal drug-related complications. Two patients (11%) died toxic after a second course of BCNU. Our results suggest that there is no practical role for high-dose BCNU in the treatment of melanoma.