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 chemotherapy and autologous bone marrow transplantation for patients with poor prognosis nonseminomatous germ cell tumours.

Twenty-one patients with poor prognosis nonseminomatous germ cell tumours (six with extreme burden disease at presentation in whom partial remission had been achieved with initial induction therapy, and 15 with recurrent disease after induction therapy) were treated with high-dose chemotherapy and autologous bone marrow transplantation (BMT). The first six received etoposide 3.0 g m-2, ifosfamide 6.0 g m-2 and carboplatin 1.2 g m-2 (Regimen 1), and the subsequent 15 received etoposide 2.4 g m2 (continuous infusion), cyclophosphamide 7.2 g m-2 and carboplatin 0.8 g m-2 (Regimen 2) followed by infusion of previously stored autologous marrow. Regimen 1 was associated with considerable renal toxicity and mucositis, whereas Regimen 2 was relatively well tolerated. Two patients died as a consequence of the treatment: one of candidemia and one of interstitial pulmonary fibrosis. Only one of 17 patients who were autografted in or approaching marker remission subsequently developed disease progression (event-free survival 82%, 95% confidence interval [CI] 55% to 94%), whereas all four patients who had progressive disease at autografting subsequently developed further disease progression and died. Fourteen patients remain well and free of disease 0.5 to 6.5 years (median 3.3) post-BMT (event-free survival 67%, 95% CI 43% to 83%). A strategy of prompt reinduction followed by high-dose chemotherapy and autologous BMT at the first sign of failure of standard therapy may allow cure to be a realistic expectation.     

High-dose tri-alkylator chemotherapy with autologous stem cell rescue in patients with refractory malignancies

Forty patients with refractory solid tumors or non-Hodgkin's lymphoma were treated with high-dose cyclophosphamide, thiotepa, and carmustine (BCNU), followed by autologous stem cell rescue, in a phase I dose escalation study. The dose-limiting toxic effect was delayed drug-induced pulmonary disease, seen in three patients who received 660-750 mg of BCNU/m2 in combination with cyclophosphamide and thiotepa. The early death rate due to toxic effects was 20%; all deaths were attributed to sepsis or respiratory failure. The overall response rate was 63%. The median time to disease progression was 14 weeks. Although this regimen provided effective cytoreduction, its use in heavily pretreated patients with bulky disease is of limited value.     

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 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 chemotherapy supported with autologous bone marrow transplantation (ABMT) in germ cell tumors: a phase two study.

In this paper, the first Italian multicentre experience with high-dose chemotherapy and ABMT in germ cell cancer is presented. Twenty-eight patients underwent treatment with a carboplatin-etoposide w/o ifosfamide high-dose combination. Seventeen patients were in progression of disease, 9 were responsive to salvage treatments or failed to achieve CR to front line, and 2 had stable disease (both with an elevated marker level) at the time of transplantation. Five patients, all of whom were in sensitive relapse at transplantation, are alive and disease-free at > 17 months' follow-up. Two patients died 15 days after ABMT, one of veno-occlusive disease and one of rapid uncontrolled tumor progression. In highly pretreated patients this schedule seems to provide an option of cure for a cohort of patients failing to achieve CR to standard salvage regimens for germ cell cancer. Definitive conclusions may eventually be drawn with a more homogeneous group of patients. This type of approach should continue to be taken in sensitive relapse patients only, as responses in progressive cases are very transient, with virtually no cures. The question of whether high-dose programs are better than standard chemotherapy will in any case be answered only in a randomized prospective trial.     

高剂量化疗联合自体造血干细胞移植治疗男性生殖细胞肿瘤

生殖细胞肿瘤是15～35岁男性最常见的恶性肿瘤.大多数患者可以治愈,但仍有少数患者死于该病.多项临床研究应用高剂量化疗联合自体外周血干细胞移植治疗复发或预后不良的男性生殖细胞肿瘤,以期提高疗效.本文综述高剂量化疗联合自体外周血干细胞移植治疗男性生殖细胞肿瘤的治疗、安全性及病例选择等方面的问题.     

High-dose chemotherapy with autologous stem cell rescue for children with recurrent malignant brain tumors

BACKGROUND: High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been reported to be effective in treating children with recurrent central nervous system (CNS) malignancies. METHODS: To evaluate the efficacy and toxicities of HDCT and ASCR, the medical records of 27 children with recurrent CNS malignancies who received such therapy at St. Jude Children's Research Hospital between 1989 and 2004 were reviewed. RESULTS: The median age at diagnosis was 4.5 years (range, 0.4-16.6 years) and that at ASCR was 6.7 years (range, 1.1-18.5 years). Diagnoses included medulloblastoma (13 patients), primitive neuroectodermal tumor (3 patients), pineoblastoma (2 patients), atypical teratoid rhabdoid tumor (2 patients), ependymoma (3 patients), anaplastic astrocytoma (2 patients), and glioblastoma multiforme (2 patients). The 5-year overall and progression-free survival (PFS) rates were 28.2% and 18.5%, respectively. The 5-year PFS rate for patients aged<3 years at diagnosis (57.1%) was significantly better than older patients (5.0%) (P=.019). Among the 6 long-term survivors (5 with M0 disease and 1 with M3 disease at diagnosis), 5 received both radiotherapy and HDCT as part of their salvage regimen; 4 were aged<3 years at diagnosis and had received chemotherapy only as part of frontline therapy. Two patients died of transplant-related toxicities; 44% experienced grade 3 or 4 transplant-related toxicities (toxicities were graded according to the National Cancer Institute Common Toxicity Criteria). CONCLUSIONS: HDCT with ASCR is not an effective salvage strategy for older children with recurrent CNS malignancies. The significantly better outcome in the younger cohort was most likely related to the use of radiotherapy as part of the salvage strategy.     

High-dose chemotherapy with autologous stem-cell support for germ cell tumors: a critical review

High-dose chemotherapy (HDC) with autologous stem-cell support (ASCS) has been investigated in patients with cisplatin-resistant, relapsed, or poor-prognosis germ cell tumor (GCT). Although some of these patients have benefited from this approach, it is unknown when best to administer such therapy. This review categorizes the HDC/ASCS trials into those performed as (1) salvage therapy for second or greater relapse, (2) salvage therapy for first relapse, and (3) first-line therapy. From the trials performed to date, earlier use of HDC/ASCS (first-line or salvage therapy in first relapse) achieved a higher durable remission rate than when used later as salvage therapy in second or greater relapse (approximately 50% v 15%, respectively). HDC/ASCS is not beneficial for relapsed or cisplatin-resistant primary extragonadal GCT patients, but may have a role in testicular GCT who are not "absolutely" cisplatin-resistant. Trial differences regarding the patients selected and the high-dose transplant preparative regimen used have made precise comparative analyses difficult. There has been only one phase III trial and it did not show a survival advantage to the HDC/ASCS arm, although this trial had significant methodological difficulties. In the future, more definitive treatment recommendations may be made upon completion of two ongoing phase III trials comparing HDC/ASCS with standard chemotherapy in the first salvage and front-line settings.     

High-dose cyclophosphamide with autologous bone marrow rescue after conventional chemotherapy in the treatment of small cell lung carcinoma

Summary Whithin an original consecutive series of 94 patients, 36 eligible patients with small cell lung carcinoma were treated with high-dose cyclophosphamide 7 g/m² after conventional chemotherapy with VP16, adriamycin, and vincristine. The first 17 also underwent autologous bone marrow rescue. Treatment was well tolerated apart from one treatment-related death. Measurable tumour was still present in 15 patients before high-dose cyclophosphamide, and although 12 (80%) of these achieved further tumour response, these responses were all short-lived, with a median duration of 9 weeks. In 14 limited-disease patients already in complete remission before high-dose therapy the initial result was better, but 11 (79%) have now relapsed following overall median response duration of 10 months. High-dose cyclophosphamide after conventional chemotherapy is feasible and achieves a high response rate, but it does not appear to be associated with significant survival benefit either overall or in patient subgroup.     

High-dose chemotherapy with bone marrow rescue for high-grade gliomas in adults

High-grade malignant gliomas are inevitably fatal, despite every effort to improve this prognosis, including various radiotherapeutic modalities, radio- and chemotherapeutic associations, and combinations of several drugs. High-dose chemotherapy and autologous bone-marrow transplantation (ABMT) have been increasingly used in the last 10 years for solid tumors, and several phase II studies in high-grade glioma patients have been conducted in the setting of both adjuvant treatment and recurrent disease. The most frequently used drug in the conditioning regimens is BCNU at doses higher than that employed by other regimens in other pathologies (800-1000 mg/m²). These dosages involve a high toxicity that is not balanced by a significant improvement in survival. New drugs and/or regimens must be tested in randomized trials.     

Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors.

PURPOSE: To evaluate the efficacy and toxicity of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in patients with relapsed or progressive CNS germ cell tumors (GCTs). PATIENTS AND METHODS: Twenty-one patients with CNS GCTs who experienced relapse or progression despite having received initial chemotherapy and/or radiotherapy were treated with thiotepa-based HDC regimens followed by ASCR. RESULTS: Estimated overall survival (OS) and event-free survival (EFS) rates for the entire group 4 years after HDC were 57% +/- 12% and 52% +/- 14%, respectively. Seven of nine (78%) patients with germinoma survived disease-free after HDC with a median survival of 48 months. One patient died as a result of progressive disease (PD) 39 months after HDC, and another died as a result of pulmonary fibrosis unrelated to HDC 78 months after ASCR without assessable disease. However, only four of 12 patients (33%) with nongerminomatous germ cell tumors (NGGCTs) survived without evidence of disease, with a median survival of 35 months. Eight patients with NGGCTs died as a result of PD, with a median survival of 4 months after HDC (range, 2 to 17 months). Patients with germinoma fared better than those with NGGCTs (P =.016 and.014 for OS and EFS, respectively). Patients with complete response to HDC also had significantly better outcome (P <.001 for OS and EFS) compared with patients with only a partial response or stable disease. There were no toxic deaths because of HDC. CONCLUSION: Dose escalation of chemotherapy followed by ASCR is effective therapy for patients with recurrent CNS germinomas and might be effective in patients with recurrent NGGCTs with a low tumor burden.     

High-dose salvage chemotherapy without bone marrow transplantation for adult patients with refractory Hodgkin's disease.

PURPOSE: For patients with Hodgkin's disease (HD) who do not achieve complete response (CR), who experience a relapse within the first year of CR, and for those who have two or more relapses, the outcome is poor. Salvage chemotherapy regimens at conventional doses produce a CR rate that ranges from 10% to 50% and a 5-year disease-free survival (DFS) between 10% and 25%. On the other hand, high-dose chemotherapy regimens given in combination with bone marrow transplantation (BMT) produce a CR rate that ranges from 40% to 80% and a 3-year DFS of approximately 40%. We report the 5-year results of a prospective study in patients with refractory HD who were treated with three courses of intensive chemotherapy without BMT. PATIENTS AND METHODS: Thirty-nine adult patients with refractory HD were treated with three courses of intensive chemotherapy. Each cycle of chemotherapy comprised vindesine 1 mg/m2/d in continuous intravenous (IV) infusion from day 1 to day 5; Adriamycin (doxorubicin; Roger Bellon Laboratories, Neuilly, France) 40 mg/m2/d in continuous IV infusion from day 1 to day 3; carmustine 140 mg/m2/d at day 3; etoposide 200 mg/m2/d from day 3 to day 5; and methylprednisolone 120 mg/m2/d from day 1 to day 5. After the third cycle of chemotherapy, irradiation (20 Gy) was performed whenever possible and depended on previous irradiation. RESULTS: At the end of the treatment, 31 patients (79%) were in CR. Among these patients, 10 relapsed after a median time of 3 months. The overall 5-year survival rate was 46%. The freedom from progression (FFP) and the freedom from treatment failure (FFTF) rates were 48% and 43%, respectively. The main toxicities were hematologic (neutropenia and thrombocytopenia) and digestive. Four patients died due to treatment-related complications (two from septic shocks, one from respiratory insufficiency, and one from posttransfusional AIDS). CONCLUSION: The results of this study seem to be comparable to those results obtained with high-dose chemotherapies with autologous BMT.     

High-dose chemotherapy with autologous stem cell rescue in breast cancer

SummaryBackground Because metastatic breast cancer is a lethal disease despite some responsiveness to systemic chemotherapy, high-dose chemotherapy with autologous stem cell rescue is being utilized with increasing frequency. This analysis was undertaken to determine the outcome for such patients treated with intensive chemotherapy between 1989–1994, at the Hoag Cancer Center in Newport Beach, CA.Methods During 1989, only patients with metastatic disease who had failed more than two standard breast cancer chemotherapy regimens were considered eligible for such treatment. They received high-dose BCNU/ cyclophosphamide/cisplatinum chemotherapy with autologous bone marrow rescue. After January 1990, patients with metastatic disease were eligible only if they had received limited prior chemotherapy and demonstrated responsiveness to induction chemotherapy. Beginning June 1990, patients with metastatic disease were to receive mitoxantrone and thiotepa (MiTepa) followed by peripheral blood stem cell rescue, then ifosfamide, carboplatin and etoposide (ICE) chemotherapy followed by peripheral blood stem cell rescue. High-risk adjuvant patients were to receive one course of ICE followed by rescue.Results Between 1/89–12/94, 48 breast cancer patients underwent 65 intensive chemotherapy treatments followed by autologous stem cell rescue. During 1989, three of the eight patients with metastatic disease died within 60 days because of therapy-related complications. The longest failure-free survival (FFS) of these eight was 12.2 months, and the longest overall survival (OS) 20.5 months. Since 1/90, one physician has treated 24 patients with metastatic breast cancer, 17 of whom actually underwent two successive transplants with MiTepa/ICE. For the latter group, median FFS is 23.2 months; median OS is 39.7 months. There were no acute deaths, but two patients died > 60 days after initial transplant from therapy-related complications, venoocclusive disease (5.2 months) and myelodysplastic syndrome (30.5 months), while five died of progressive disease at 22.5, 32.8, 39.4, 46.3, and 51.3 months. For the 24 metastatic patients treated 1990–1994, 1-, 2-, and 3-year FFS rates are 86%, 40%, and 17%, respectively, while OS rates are 91%, 80%, and 65%. Of 11 patients treated in the adjuvant setting, only one has relapsed (9.8 months) with follow-up from 3–61 months.Conclusions Modifications made in the program, including selection of patients responsive to induction chemotherapy, transfusion of peripheral blood stem cells, implementation of hematopoietic colony stimulating factors, and use of tandem intensive treatments has been associated with a low rate of acute morbidity and encouraging survival rates.Presented in part at the 16th Annual San Antonio Breast Cancer Symposium, November 5, 1993     

High-dose carboplatin and etoposide with autologous bone marrow transplantation in refractory germ cell cancer: an Eastern Cooperative Oncology Group protocol.

PURPOSE: A phase II trial was undertaken to assess the feasibility, toxicity, and efficacy of high-dose carboplatin and etoposide with autologous bone marrow transplantation in patients with relapsed or refractory germ cell tumors. PATIENTS AND METHODS: Forty patients with recurrent germ cell cancer received carboplatin 500 mg/m2 and etoposide 400 mg/m2 given at 7, 5, and 3 days before marrow infusion. Autologous marrow infusion (day 0) was accomplished using one half of the bone marrow harvested before chemotherapy. Patients who achieved a complete or partial response with the first cycle of treatment received a second identical cycle of chemotherapy followed by infusion of the remaining cryopreserved bone marrow. RESULTS: Objective responses were obtained in 17 of the 38 patients (45%) assessable for response, including eight partial and nine complete remissions. Five of these patients remain in continuous complete remission with minimal follow-up of 1 year. Toxicity encountered was primarily hematologic, and five patients (13%) died of treatment-related complications. Significant toxicities often seen with high-dose cisplatin (ototoxicity, neurotoxicity, and renal toxicity) were manageable in this regimen of high-dose carboplatin. CONCLUSIONS: This trial confirms the curative potential of high-dose carboplatin and etoposide in highly refractory germ cell cancer.     

High dose chemotherapy with autologous bone marrow rescue for children with diffuse pontine brain stem tumors

Purpose. Diffuse pontine tumors are highly lethal, and there are few long-term survivors with the standard treatment of external beam irradiation. We investigated the effectiveness of high-dose thiotepa and etoposide-based chemotherapy regimens with autologous bone marrow rescue (ABMR) in children with pontine tumors. Patients and methods. Sixteen children with diffuse pontine tumors were treated. Ten had resistant or recurrent tumors. All ten had previously received irradiation; five had also received chemotherapy and one, beta-interferon. Three high-dose chemotherapy regimens were employed. Six patients received three days of thiotepa (300 mg/m²/day) and etoposide (250–500 mg/m²/day) (TE); two received three days of carmustine (BCNU) (200 mg/m²/day divided every 12 hours) followed by TE (BTE); and two received three days of carboplatin (500 mg/m²/day) followed by TE (CTE). Six other patients had newly-diagnosed tumors and had not received any prior treatment. They all received the BTE regimen and subsequently were treated with hyperfractionated irradiation (7200–7800 cGy) beginning approximately six weeks post-ABMR. Results. There were two toxic deaths (13%), both in previously treated patients, due to multiorgan system failure and Candida septicemia in one case each. Median survival of the patients with resistant or recurrent disease was 4.7 months (range 0.1–18.7) from time of ABMR. Median survival of the newly-diagnosed patients was 11.4 months (range 7.6–17.1) from the time of ABMR. Conclusion. High-dose chemotherapy utilizing these regimens followed by ABMR did not appear to prolong survival compared to conventional therapy in these children with pontine tumors. Alternative strategies need to be developed for this highly lethal disease.for the Children's Cancer Group     

High dose chemotherapy with autologous bone marrow rescue for small cell lung cancer]

The efficacy of high dose chemotherapy with autologous bone marrow rescue (ABMR) was given to 10 patients with small cell lung cancer (SCLC). Four patients received high dose methotrexate plus ABMR followed by chest irradiation. Six patients giving complete response after induction chemotherapy were given intensive chemotherapy plus ABMR only. The over-all survival of these 10 patients was 30.5 months with a range of 6-96 months. Five of them are surviving as of this writing, 3 survived for more than two years and 2 for more than 5 years. Toxic reactions were not severe. Systemic metastasis was the Leading cause of treatment failure. ABMR was effective and safe. When combined with radiotherapy ABMR could be expected to improve the result of intensive chemotherapy for limited SCLC.     

High-dose cyclophosphamide or melphalan with escalating doses of mitoxantrone and autologous bone marrow transplantation for refractory solid tumors

As the dose-limiting toxicity of mitoxantrone is hematological, the drug is suitable for dose escalation and use in intensive chemotherapy followed by autologous bone marrow rescue. Adult patients with therapy-resistant solid tumors received a regimen of high-dose cyclophosphamide (7 g/m2) and escalating doses of mitoxantrone in dose steps of 30, 45, 60, and 75 mg/m2. Both drugs were given i.v. on 3 consecutive days. Despite the addition of mesnum (3.5 to 7 g/m2), hemorrhagic cystitis occurred on the second day in four of eight patients, irrespective of the mesnum or mitoxantrone dose. Therefore, the cyclophosphamide in the combination regimen was replaced by high-dose melphalan (180 mg/m2). Mucositis was dose limiting at 75 mg/m2 of mitoxantrone. Responses were seen in eight of ten evaluable patients with four complete responses. Three responders received, after the autologous bone marrow transplantation program, radiotherapy or surgery on pretreatment bulky tumor localizations. Five patients still have disease-free survival after 9 to 36 mo. Pharmacokinetic studies of mitoxantrone were performed by high-performance liquid chromatography with UV detection. The plasma disappearance of mitoxantrone fitted into a three-compartment model with a mean t1/2 alpha of 10 min, a mean t1/2 beta of 96 min, and a slow elimination phase of 172 h. The mean distribution volume was 4294 +/- 3836 liters. We conclude that the high-dose cyclophosphamide-mitoxantrone regimen led to unexpected bladder toxicity, but the combination of melphalan (180 mg/m2) and mitoxantrone (60 mg/m2) can probably be given without major extramedullary toxicity. However, more patients should be evaluated at this dose before definite conclusions can be drawn about toxicity.     

High-dose, multiple-alkylator chemotherapy with autologous bone marrow reinfusion in patients with advanced non-small cell lung cancer

Fifteen patients with Stage IV lung cancer both untreated and previously treated were enrolled into a high-dose chemotherapy program with multiple alkylating agents and autologous bone marrow reinfusion. Eight patients received cyclophosphamide at 7.5 gm/m2 over 3 days with thiotepa escalated from levels of 1.8 mg/kg to 6.0 mg/kg over 3 days. Seven patients received the above dose of cyclophosphamide plus thiotepa at 675 mg/m2 and oral melphalan escalated from levels of 0.75 mg/kg to 2.5 mg/kg over 3 days. Both regimens are part of larger Phase I-II clinical studies. The median time to recovery of more than 500 granulocytes and more than 50,000 platelets per microliter was 16 and 27 days, respectively. Two patients died as a consequence of severe, overwhelming infections during their period of aplasia. Of the 13 evaluable patients, no patients achieved a complete response and seven patients (47%) obtained a partial response. The median duration of response was 12 weeks. Other nonhematologic toxicities included nausea/vomiting, diarrhea, mucositis, skin rash, hemorrhagic cystitis, and cardiomyopathy. Since there are substantial toxicities associated with high-dose chemotherapy and responses of such brief duration, further investigation with these drug combinations is not warranted.