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.     

Effects of interleukin 2 on engraftment following autologous bone marrow transplantation (ABMT) in dogs.

Beagle dogs were treated with recombinant human interleukin 2 (IL-2) 6 x 10(6) International Units (IU)/day for 7 consecutive days following conditioning with sublethal (200 cGy) or lethal (400 cGy) doses of high-dose rate whole body irradiation (WBI) and reconstitution with 2 x 10(8)/kg autologous bone marrow cells, in order to assess the effect of IL-2 on engraftment. Engraftment of dogs conditioned by lethal doses of WBI was not impaired following treatment with IL-2 6 x 10(6) IU/day. At an RIL-2 dose of 6 x 10(6) and 9 x 10(4) IU/day, enhanced engraftment of autologous bone marrow cells was observed in dogs irradiated with a sublethal WBI dose in comparison with controls not treated by IL-2(p < 0.05). We conclude that therapeutic doses of IL-2 may be safely utilized during hematopoietic reconstitution. Under certain conditions IL-2 may even enhance hematopoietic reconstitution following ABMT.     

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.     

Art therapy with adult bone marrow transplant patients in isolation: a pilot study

Psycho-social interventions for cancer patients in isolation for bone marrow transplant (BMT) have been advocated in the recent literature. It is not clear what type of interventions would be most appropriate. This study was conducted at Memorial Sloan-Kettering Cancer Center (MSKCC), with three aims. (1) To test the feasibility of introducing art therapy as a supportive intervention for adult BMT patients in isolation. Nine patients were seen in art therapy sessions twice a week while in isolation, and were helped to develop free personal images. The three art therapists used the same art therapy program as a model. (2) To assess how patients would use the program. Forty-two images were made by the nine patients during the art therapy sessions. A thematic analysis of the images showed that the patients used art therapy effectively in three ways: (a) to strengthen their positive feelings, (b) to alleviate their distress, and (c) to clarify their existential/spiritual issues. (3) The third aim was to identify which patients would most benefit from art therapy. Our results suggest that the non-verbal metaphorical modality of art therapy may be especially beneficial for patients who need to deal with emotional conflicts, and with feelings about life and death, in a safe setting.     

New strategies in marrow purging for breast cancer patients receiving high-dose chemotherapy with autologous bone marrow transplantation

Summary High-dose chemotherapy and autologous bone marrow transplantation (ABMT) are commonly used to treat selected patients with high-risk breast cancer. A limitation of ABMT is that clonogenic cancer cells could be collected with the bone marrow and produce a relapse of disease when reinfused into patients. Purging the marrowex vivo may eliminate the tumor cells, but it can also delay engraftment. We employed two different purging methods whereby breast cancer cells were depleted without delaying engraftment. The addition of WR-2721 (amifostine) to 4-hydroperoxycyclophosphamide (4-HC) reduced the time to engraftment by 10 days compared with marrow purged with 4-HC alone (26 versus 37 days, respectively). The positive selection of CD34+ hematopoietic progenitors produced engraftment within 21 days. The use of granulocyte colony-stimulating factor (G-CSF) accelerated the engraftment time of CD34+ hematopoietic progenitors to 11 days.Held in conjunction with the 15th Annual San Antonio Breast Cancer Symposium, December 1992, and supported by an educational grant from Lederle Oncology; editing by The Medicine Group USA, Inc.     

The prognostic significance of autologous bone marrow transplant in advanced neuroblastoma

This report provides strong evidence for conducting a controlled randomized clinical trial of autologous bone marrow transplantation versus conventional chemotherapy in childhood neuroblastoma, which is disseminated beyond the intracavity nodes, and which is diagnosed in children older than 12 months of age. On the basis of two Pediatric Oncology Group (POG) studies, one a surgery plus conventional chemotherapy study (POG 8441) and the other an elective autologous transplant pilot protocol (POG 8340), there was no significant prognostic benefit of switching in remission from the surgery plus chemotherapy protocol to the transplant protocol (P = .91) or of switching in remission from the surgery plus chemotherapy protocol to any transplant (P = .75). The analysis is based on 116 patients achieving a complete or partial remission, 32 of whom received transplants on the pilot protocol, and 17 of whom received transplants outside the pilot protocol. While potential selection bias precludes cause-effect conclusions, these data strongly suggest that a large randomized trial of autologous bone marrow transplantation should be conducted before accepting this form of therapy as standard.     

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.     

Hematopoietic recovery after autologous bone marrow transplantation in high-dose chemotherapy of cancer patients

In order to evaluate the possible utility of autologous bone marrow transplantation (ABMT), eighteen cancer patients were treated with high-dose combination chemotherapy supported by ABMT. We investigated CFU-GM/kg infused as well as bone marrow nucleated cells/kg to predict for hematopoietic recovery. Although hematopoietic recovery was not related to the nucleated cell number of the transfused bone marrow, CFU-GM infused related significantly to neutrophil recovery to 500/mm3 (correlation coefficient, r = -0.73, p less than 0.001) and platelet recovery to 50,000/mm3 (r = -0.69, p less than 0.001). Furthermore, a significant relationship of CFU-GM infused to the period of neutropenia below 500/mm3 was observed (r = -0.67, p less than 0.001). Taken together, CFU-GM dose can predict for neutrophil and platelet recovery, suggesting that ABMT can shorten the period of bone marrow suppression following high-dose chemotherapy.     

Role of autologous bone marrow transplantation in cancer chemotherapy

Over the past 9 years, total number of 147 patients with various types of malignant solid tumors were treated 220 times with high-dose chemotherapy supported by autologous bone marrow transplantation. Two most frequently used chemotherapeutic protocols were: cyclophosphamide 1,600 mg/m2 + adriamycin 80 mg/m2 + ACNU 3 mg/kg and cyclophosphamide 1,600-2,400 mg/m2 + adriamycin 80 mg/m2 + CDDP 100-120 mg/m2. There were 89 patients with advanced and/or recurrent diseases. The overall response (CR + PR) rate was 44.1% with the complete response (CR) rate, being 11.8% among 68 evaluable patients in this group. The most favorable response was obtained in breast cancer patients with 77.3% response rate and 13.6% CR rate. Nearly 50% of patients with gastric, lung, gynecological and pediatric malignancies responded, whereas poor responses were observed in the cases of pancreato-biliary, colorectal, esophageal cancers and melanoma. In 8 complete responders, three are alive and well without any evidence of disease 5 years after the treatment. There were 58 patients who underwent this treatment in adjuvant settings. There are 5 patients with breast cancer who have been followed over 5 years after treatment. All of them are alive and well without any demonstrable diseases. Four of them were in stage IIIa and histologically examined axillary nodes were positive in 14/15, 11/17, 37/44, 22/25. Autologous bone marrow transplantation seems to be instrumental in shortening the period of myelosuppression, thus allowing safe dose escalation in chemotherapy. Adequacy of cryopreserved marrow as marrow inoculum was ascertained with mononuclear cell count, cellular viability, CFU-GM, CFU-E, BFU-E and CFU-Mk.     

Phase II study of intensive chemotherapy with autologous bone marrow transplantation in patients in complete remission of disseminated breast cancer

SummaryBackground This trial studied the disease-free survival after high-dose chemotherapy in patients in complete remission of metastatic breast cancer.Patients and methods Thirty women, mean age 42.2 years (range 33–55) with metastatic breast cancer, received high-dose chemotherapy in a phase II study. Patients were eligible if they were 55 years of age, had achieved complete remission within 6 months of the initiation of chemotherapy, and had a WHO performance scale of 0 or 1. The high-dose regimen consisted of melphalan 180 mg/m² and mitoxantrone 60 mg/m² both divided over 3 days. On day 7 bone marrow and/or peripheral stem cells were infused. After bone marrow recovery, external beam radiation was administered to sites of previous metastatic disease in 15 patients.Results Apart from leuko- and thrombocytopenia, mucositis was the major side effect. One patient died during the bone marrow transplant period due to an aspergillus infection. The median follow-up since highdose chemotherapy is 25 months (range 13 to 56 months). The median disease-free survival since high-dose chemotherapy is 27 months and the disease free survival is still 43% with an overall survival of 53% at 3 years. In two patients tumor relapse occurred only in the brain; in one patient the only relapse sign was a meningeal carcinosis. At the moment 17 patients are disease-free (13+–56+) months after high-dose chemotherapy.Conclusion Until now this high-dose regimen in selected patients with complete remission after induction chemotherapy for metastatic breast cancer has a promising disease free survival.     

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.     

Systemic bacterial infections in bone marrow transplant patients

The clinical microbiology department at CMC&H, Vellore in conjunction with the haematology department carries out routine surveillance of patients admitted to the hematology department. Since 1994 in a sample population of 55 patients with various underlying clinical conditions who have had bone marrow transplant, sepsis was observed in 16 patients (29%). The predominant Gram negatives associated with sepsis were non-fermenting Gram negative bacilli and all the 5 Gram positives were coagulase negative staphylococci. These organisms were susceptible to most of the routinely used antimicrobial agents. Continued surveillance is needed to determine changing trends with respect to organisms causing systemic infections and their susceptibility to antimicrobials.     

Intensive chemotherapy with autologous bone marrow transplantation for small-cell lung cancer

Summary Since 1980, 75 patients with small-cell lung cancer (SCLC) have been entered into four consecutive studies of high-dose chemotherapy using autologous bone marrow transplantation (ABMT) to assist haematological recovery. In the first study, 25 patients were treated with cyclophosphamide (160–200 mg/kg) as the sole chemotherapy; in the second (26 patients), the cycle of high-dose cyclophosphamide (with or without 800–1,200 mg/m² etoposide) was repeated as induction treatment. In the first study, response was high [14 complete responses (CR), 7 partial responses (PR)] but was not increased by repeating the cycle (15 CR, 8 PR), and survival was slightly worse in the second trial. In the third study, 15 patients were treated with doxorubicin, vincristine and etoposide for two cycles and then with 200 mg/kg cyclophosphamide. Although high-dose cyclophosphamide increased the complete response rate, the additional responses were short-lived. In the final study, an attempt was made to increase the initial CR rate by combination chemotherapy using carboplatin (400–600 mg/m²), etoposide (120 mg/ m²x4) and either high-dose cyclophosphamide (40 mg/kg x4) or melphalan (140 mg/m²). Although all nine patients responded, none underwent a CR. The long-term survival (up to 7 years) does not appear to be different from that in comparably selected cases treated with conventional chemotherapy.This work was supported by the Cancer Research Campaign     

Validation of the Distress Thermometer with bone marrow transplant patients

The Distress Thermometer (DT) is a one-item screening measure of psychological distress in cancer patients. This study examines the operating characteristics of the DT in patients about to undergo bone marrow transplant (BMT). Patients (N=491) completed the DT, the Center for Epidemiological Studies-Depression Scale (CES-D), the State-Trait Anxiety Inventory-State Version (STAI-S), the ECOG Performance Status Scale, and the Patient Problem List. DT scores were related to higher depression, higher anxiety, and poorer performance status. Receiver operating characteristic (ROC) curve analyses of DT scores yielded area under the curve estimates of 0.75 when compared to the CES-D cutoff score of 16, suggesting the DT has acceptable overall accuracy. The DT cutoff score of 4 had the greatest sensitivity and specificity when compared to the CES-D cutoff score. Patients above this cutoff score reported worse ECOG scores and more practical, family, emotional, and physical problems (all p's< or =0.05) than those below the cutoff. The findings suggest the DT is a useful tool for screening for distress in BMT patients. The optimal DT cutoff score of 4 found here was identical to that found in another study using different criteria. This cutoff score also identified patients with problems likely to reflect psychological distress.     

The role of autologous bone marrow transplantation in cancer treatment

Autologous bone marrow transplantation (ABMT) has been increasingly used in the treatment of malignant diseases. Since myelosuppression is one of the major dose limiting factors in cancer chemotherapy, ABMT is effective for hematologic reconstitution after marrow-lethal intensive therapy, which increases the anti-tumor effect. Diseases for which ABMT is indicated are selected on the basis of sensitivity to escalation of drug and radiation dose. These diseases include non-Hodgkin's lymphoma, leukemia, small cell carcinoma of the lung, melanoma, neuroblastoma, metastatic breast cancer and Ewing's sarcoma. Phase I and phase II studies have demonstrated that dose escalation to several times the conventional dosage may be feasible with the use of ABMT. Clinical trials of intensive therapy plus ABMT have produced encouraging results in terms of response rate and long-term survival for selected patients with poor-prognosis malignant diseases which are resistant or refractory to conventional forms of cancer therapy. When these preliminary results are analysed, it is apparent that the outcome of this treatment modality is affected by several factors such as disease status or tumor burden at the time of ABMT, the anti-tumor effect of the pretransplant intensive therapy and the extent of bone marrow invasion by tumor cells. Since ABMT is not yet well established in comparison with allogeneic bone marrow transplantation, carefully designed clinical trials will be required in order to assess the efficacy of ABMT.     

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.     

Histomorphologic study of bone marrow in acute leukemia following chemotherapy and autologous bone marrow transplantation

Twenty-six patients with acute myeloid leukemia, acute lymphoid leukemia and chronic granulocytic leukemia in blast crisis were studied by means of multiple biopsies during a polychemotherapeutic or autologous bone marrow transplant protocol. Following chemotherapy, 3 main phases were observed: leukemic cellular depletion, stromal bone marrow reconstruction, and bone marrow hemopoietic restoration. Following intensive chemotherapy (in 2 patients after cyclophosphamide and total body irradiation) and autologous bone marrow transplantation, the 3 phases appeared to be shorter. A focal or diffuse increase in marrow fibrosis was a common finding in leukemia. An effective antileukemic therapy resulted in a decrease in fibrosis, whereas in some cases a further increase was a precocious sign of leukemia relapse.     

Transplantation of non-purified autologous bone marrow in patients with AML in first remission

Four patients with acute myeloid leukemia (AML) were treated with high-dose cyclophosphamide and total body irradiation followed by reinfusion of a portion of their own bone marrow collected during remission. This procedure was applied when the patients were in complete remission. They did not receive further maintenance chemotherapy after grafting. The use of bone marrow for grafting that had been pre-exposed to high-dose chemotherapy for remission induction did not preclude good hematologic regeneration. All patients showed stable remissions that lasted for 64+, 21, 40+, and 19+ months, respectively. Death in the second patient was due to a medullary relapse of the leukemia. Autologous bone marrow transplantation in patients with AML in remission may permit lasting remissions, even when applied without additional chemotherapy and attempts to purify the marrow of neoplastic cells.