Courses Of Intensive Chemotherapy Research Articles

Autologous or Allogeneic Bone Marrow Transplantation Compared with Intensive Chemotherapy in Acute Myelogenous Leukemia

Allogeneic or autologous bone marrow transplantation and intensive consolidation chemotherapy are used to treat acute myelogenous leukemia in a first complete remission. After induction treatment with daunorubicin and cytarabine, patients who had a complete remission received a first course of intensive consolidation chemotherapy, combining intermediate-dose cytarabine and amsacrine. Patients with an HLA-identical sibling were assigned to undergo allogeneic bone marrow transplantation; the others were randomly assigned to undergo autologous bone marrow transplantation (with unpurged bone marrow) or a second course of intensive chemotherapy, combining high-dose cytarabine and daunorubicin. Comparisons were made on the basis of the intention to treat. A total of 623 patients had a complete remission; 168 were assigned to undergo allogeneic bone marrow transplantation, and 254 were randomly assigned to one of the other two groups. Of these patients, 343 completed the treatment assignment: 144 in the allogeneic-transplantation group, 95 in the autologous-transplantation group, and 104 in the intensive-chemotherapy group. The relapse rate was highest in the intensive-chemotherapy group and lowest in the allogeneic-transplantation group, whereas the mortality rate was highest after allogeneic transplantation and lowest after intensive chemotherapy. The projected rate of disease-free survival at four years was 55 percent for allogeneic transplantation, 48 percent for autologous transplantation, and 30 percent for intensive chemotherapy. However, the overall survival after complete remission was similar in the three groups, since more patients who relapsed after a second course of intensive chemotherapy had a response to subsequent autologous bone marrow transplantation. Other differences were also observed, especially with regard to hematopoietic recovery (it occurred later after autologous transplantation) and the duration of hospitalization (it was longer with bone marrow transplantation). Autologous as well as allogeneic bone marrow transplantation results in better disease-free survival than intensive consolidation chemotherapy with high-dose cytarabine and daunorubicin. Transplantation soon after a relapse or during a second complete remission might also be appropriate.

Intensive treatment in order to minimize the ph‐positive clone in chronic myelogenic leukemia

Several studies indicate that interferon (IFN) treatment, intensive chemotherapy and autologous bone marrow transplantation (ABMT) effectively reduce the Ph-positive clone in Chronic Myelogenic Leukemia (CML). In the present study on patients < or = 55 years, we have combined these three treatment modalities. The aim of the study was to eliminate or minimize the Ph-positive clone to see whether a status of minimal residual or Ph-negative disease could be maintained for a longer period of time. After diagnosis, patients received interferon (IFN-a-2b) and hydroxyurea (HU) to keep the white blood cell (WBC) and platelet count below 2-4 and 100-150 x 10(9)/l, respectively. After six months of treatment, Ph-analysis was performed. Patients with Ph-positive cells in bone marrow then received 1-3 courses of intensive chemotherapy. In patients Ph-negative after two courses, bone marrow was harvested and used for ABMT. After a third course, patients with up to 50% Ph-positive metaphases were accepted for ABMT. As of January 1, 1993, 97 patients were registered in the study. Six months of IFN+HU reduced the percentage of Ph-positive metaphases in 57% of the patients (7% became Ph-negative). The corresponding figures after two intensive cytotherapies were 70% (40% Ph-negative). Eighteen patients were autotransplanted. Seven have relapsed with Ph-positivity 3-22 months after ABMT, while nine are Ph-negative at 1-32+ months after ABMT (two not yet analyzed). Seventeen patients are alive and well, while one died one month after ABMT due to interstitial pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)

LIMITED SMALL-CELL LUNG-CARCINOMA - HIGH COMPLETE RESPONSE RATE AND SURVIVAL WITH SHORT INTENSIVE CHEMOTHERAPY AND EXTENSIVE IRRADIATION - RESULTS OF A PILOT-STUDY

Sixteen patients with limited small-cell lung carcinoma (SCLC) were treated with three monthly courses of intensive chemotherapy (cisplatin: 40 mg/m2/day (D), D1, D2 and D3; cyclophosphamide: 750 mg/m2/D, D4 and D5; adriamycin: 50 mg/m2/D, D5; vindesine: 2 mg/m2/D, D1 and D5; etoposide: 100 mg/m2/D, D1, D2 and D3; methylprednisolone: 120 mg/m2/D, D1 to D5). Thoracic and prophylactic brain plus spinal area irradiations were performed after completion of the third chemotherapy cycle. The complete response rate was 100%. Of these 16 patients, 7 experienced a relapse from 5 to 31 months after completion of treatment. The three-year survival rate was 54%. The main toxicities were hematological (neutropenia and thrombocytopenia) and digestive. We conclude from this pilot study that intensive five-drug chemotherapy is a highly effective regimen for limited SCLC. This intensive chemotherapy regimen and extensive irradiation is feasible without major toxicity. This type of intensive combined-modality program deserves further study to definitely establish its long-term efficacy in localized SCLC.

Intensive preoperative chemotherapy with colony-stimulating factor for resectable adenocarcinoma of the esophagus or gastroesophageal junction.

The curative resection rate in patients with potentially resectable carcinoma of the esophagus is approximately 55% and their median survival time is 11 months. Preoperative chemotherapy with high doses of chemotherapeutic agents was used to evaluate clinical and pathologic responses, curative resection rate, toxicity, and survival. Colony-stimulating factor (CSF) was added to reduce the severity of myelosuppression. Twenty-six consecutive assessable patients with potentially resectable adenocarcinoma of the esophagus or gastroesophageal junction were treated with two preoperative courses of intensive chemotherapy (etoposide, doxorubicin, and cisplatin [EAP]) with granulocyte-macrophage CSF (GM-CSF). Additional three conventional-dose postoperative chemotherapy courses without GM-CSF were given to patients who responded to preoperative chemotherapy. A median of three courses (range, one to six), were administered. Of 27 patients, 26 were assessable for response to preoperative EAP; 13 (50%) achieved a major response. Among 23 patients who underwent surgery, 15 (65%) had a curative resection (58% of 26 assessable patients); none of the patients had a pathologic complete response, but two patients had only microscopic carcinoma in the resected specimen. Six patients had carcinoma present at the resection margins and received postoperative radiotherapy. Two patients were found to have liver metastases at exploration. At a median follow-up of 22 months, the median survival of 26 patients was 12.5 months (range, 2 to 32 +). Fourteen patients died of their carcinoma; two patients died of treatment-related causes; one died of an unrelated CNS arterial malformation; and the causes of death in two patients remain unknown. Seven patients are alive with no evidence of relapse. Major toxicities of this regimen included severe myelosuppression, nausea and vomiting, infections, and severe constitutional symptoms related to GM-CSF. However, subcutaneous injection of GM-CSF was well tolerated. High-dose EAP is active against locoregional adenocarcinoma of the esophagus and gastroesophageal junction but can be associated with significant toxicity. Although this strategy remains attractive and needs to be developed further, less toxic and more effective regimens need to be identified.

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

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. 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. 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). The results of this study seem to be comparable to those results obtained with high-dose chemotherapies with autologous BMT.

Treatment of advanced neuroblastoma with emphasis on intensive induction chemotherapy. A report from the study group of Japan

One hundred nine newly treated patients with advanced neuroblastoma were entered in this study between January 1985 and May 1989. The eligible patients included infants younger than 12 months of age with Stage IVA disease (bone cortex, distant lymph node, and/or remote organ metastases) and patients aged 12 months or older with Stage III or IV disease (IVA plus IVB with tumor crossing the mid-line and with metastases confined to bone marrow, liver, and skin). The patients first received six cyclic course of intensive chemotherapy (regimen A1), consisting of cyclophosphamide (1200 mg/m2), vincristine (1.5 mg/m2), tetrahydropyranyl adriamycin (pyrarubicin; 40 mg/m2), and cisplatin (90 mg/m2). Original tumors and the regional lymph node metastases were removed some time during these first six cycles of chemotherapy. The patients were further divided into three groups. Patients in course 1 received alternating treatment by regimen B (cyclophosphamide and ACNU) and intensified regimen A1, and those in course 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A1. Patients in course 3 were treated with bone marrow transplantation (BMT) preceded by high-dose preconditioning chemotherapy. Survival rates were 77% in Stage III and 54% in Stage IV at 2 years, and 70% in Stage III and 45% in Stage IV at 3 years. The major toxicities encountered were bone marrow suppression with leukocyte counts down to 100/mm3, mild cystitis, and hearing impairment. The 2-year survival rate was 78% in 21 patients who underwent BMT when complete remission was achieved. We concluded that our intensive induction chemotherapy is of significant value in increasing the rate of complete response, and in widening the indications for and achieving improved results of treatment with BMT.

Long-Term Complete Remission of Stage IV Breast Cancer After High-Dose Chemotherapy and Autologous Bone Marrow Transplantation

We randomized half of the 58 stage IV breast cancer patients we treated to receive no marrow infusion and half to receive marrow on day 8 after each high-dose chemotherapy regimen. Preliminary results show that in 25% of the patients randomized to the no-marrow arm hematopoietic recovery was delayed, almost always during the second course of intensive chemotherapy, necessitating salvage marrow infusion, as in our patient

Das Hepatoblastom: Eine katamnestische Untersuchung und Vorschlag eines Therapiekonzeptes

Since 1977, 28 infants and children with hepatoblastomas were seen in the Department of Paediatric Surgery, Hanover Medical School. Five tumours could only be biopsied. One 11-months-old infant had a successful liver transplantation done at the Dept. of Transplantation Surgery (Professor R. Pichlmayr). Following a biopsy for unresectable tumour, chemotherapy was instituted in 5 cases: three of these could be resected in a second look operation 10 to 26 weeks later. Altogether, 22 tumours (= 81%) were resected: 14 had an extended resection (trisegmentectomy), and 8 had a lobectomy. Operative mortality was 14%. Out of 27 patients which were operated upon (resection or biopsy) longer than one year ago, 11 are alive and free from disease (= 40%). Early metastatic disease was diagnosed 3 weeks to 5 months postoperatively in 5 cases: only one of these children survived, following an intensive course of chemotherapy. In another two patients lung metastases were found 14 resp. 20 months after operation: both of these are alive and free from disease following chemotherapy and thoracotomy. One patient died of brain metastases 3 years postoperatively. Results of therapy are correlated to primary findings, type of operation, chemotherapy and histological subtype of the tumour. In comparison with published data a possible advantage of more aggressive operative strategies is discussed, and the benefit of a preoperative chemotherapy is evaluated. As a result of these considerations a treatment protocol for hepatoblastomas is proposed, designed as a national multicentre prospective study conducted by the German Society of Paediatric Oncology (GPO).(ABSTRACT TRUNCATED AT 250 WORDS)

Recurrence of hepatitis B in children with serologic evidence of past hepatitis B virus infection undergoing antileukemic chemotherapy

Two patients showed an unusual serologic response to hepatitis B virus infection during intensive chemotherapy for acute lymphoblastic leukemia. Before treatment, one patient was anti-HBs- and anti-HBc-positive. During intensive chemotherapy these antibodies disappeared and HBsAg and HBeAg became detectable. Twenty months later, still on maintenance chemotherapy, active viral replication with high DNA polymerase levels was present. The second patient developed anti-HBc during the first course of intensive chemotherapy for acute lymphoblastic leukemia. She had anti-HBc and anti-HBe when a bone marrow relapse of the leukemia was diagnosed 3 years later and became HBsAg-positive together with high DNA polymerase levels in the serum while receiving intensive chemotherapy. Clinically no signs of active hepatitis were noted in these patients.

Recurrent fungal pneumonias in patients with acute nonlymphocytic leukemia undergoing multiple courses of intensive chemotherapy

The records of 40 consecutive patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) were reviewed to determine the risk of recurrent fungal pneumonia during multiple episodes of chemotherapy-induced granulocytopenia. Fungal pneumonias were diagnosed as proven or probable using defined pathologic, microbiologic, radiologic, and clinical criteria. Sixteen patients died without a complete remission; of these, all 11 who underwent autopsy were found to have invasive fungal pneumonia. The 24 patients who achieved a complete remission received one to nine (median, four) additional courses of intensive chemotherapy for remission consolidation and/or relapse, and experienced 132 episodes of severe granulocytopenia. Seven patients never had a pulmonary infection despite 34 granulocytopenic episodes. However, fungal pneumonia complicated 32 (33 percent) of 98 granulocytopenic episodes in the other 17 patients. Fifteen of the patients who achieved a complete remission had at least one episode of fungal pneumonia; 12 received further chemotherapy, and nine (75 percent) of these had a subsequent fungal pneumonia. In all, 17 (52 percent) of 33 subsequent granulocytopenic episodes experienced by patients with a prior fungal pneumonia were complicated by another fungal pneumonia. All four patients with a probable fungal pneumonia diagnosed antemortem who subsequently underwent autopsy were found to have invasive fungal disease. It would appear that patients with ANLL who have had one episode of fungal pneumonia are at high risk for recurrence during subsequent episodes of granulocytopenia. Empiric or even prophylactic amphotericin B therapy may be warranted for such patients.

Prospective randomized cooperative medulloblastoma trial (MED 84) of the international society of paediatric oncology (SIOP) and of the (German) society of paediatric oncology (GPO)

This international, prospective, randomised therapeutic study is based on previous, separate studies of the two societies. The study asks two principal questions: Is it possible to improve the results of therapy by inserting, between surgery and post-operative irradiation, an intensive course of chemotherapy consisting of vincristine, procarbazine and methotrexate, followed by citrovorum factor rescue? In "low risk" patients (i.e. those with macroscopically "complete" resection and absence of metastases at diagnosis), can the radiotherapy to CNS areas outside the primary tumour site be reduced by 10 Gy with the aim of reducing late sequelae of irradiation but without compromising survival results? The study also aims at standardising diagnostic methods, neurosurgical procedure and radiotherapeutic technique employed in this tumour. For statistical reasons, results can only be disclosed after the end of the recruitment phase. It is intended to include approximately 350 patients in the study, which is planned to continue until the end of 1988.

Repetitive cycles of cytoreductive therapy followed by stem cell autografting for nonlymphoblastic transformation of chronic granulocytic leukaemia

Treatment of nonlymphoblastic transformation of chronic granulocytic leukaemia (CGL) by marrow ablative chemotherapy, followed by autologous stem cell reinfusion, induced a 2nd chronic phase with a median duration of 5.5 months at the cost of high morbidity and mortality. One course of intensive cytoreductive chemotherapy, similar to a remission induction course in acute nonlymphoblastic leukaemia (ANLL), followed by a buffy coat reinfusion, induced a short-lived 2nd chronic phase in 4 out of 9 patients. Two successive courses, each followed by an autologous stem cell reinfusion, induced a new chronic phase in 4 out of 5 consecutive patients. Multiple intensive chemotherapy courses, followed by autologous stem cell rescue, offer an effective palliative treatment of nonlymphoblastic transformation of CGL with a relatively low morbidity due to the treatment itself.

Pituitary-gonadal function following therapy of testicular relapse in boys with acute lymphoblastic leukemia

Testicular function was evaluated in 8 boys with acute lymphoblastic leukemia (ALL) and testicular relapse following another course of intensive chemotherapy with unilateral or bilateral orchidectomy and/or testicular irradiation. LH- and FSH-secretion was studied in all using a standardized LHRH-test. In addition, a HCG-test was performed in 6 boys. In prepuberty, all boys examined showed normal LH- and FSH-values. Beginning at 9 to 10 years, elevated basal and/or stimulated LH- and FSH-values were occasionally noted in contrast to the consistently elevated values after the age of 12. Using the HCG-test, we found a testosterone response only in patients receiving gonadal irradiation of 1 100 and 1 500 rads (2 patients). No response was elicited in those with radiation doses of 2 400 and 3 000 rads. We conclude that high dose gonadal irradiation and chemotherapy cause temporary and possibly permanent impairment of spermatogenesis and Leydig cell function in boys with ALL and testicular relapse.

The concept of GvHD-suppression by in vitro treatment with antisera.

Progress in chemotherapy during the past decade resulted in considerable improvement in treatment of acute leukemias. Once the first relapse occurs, however, prognosis for prolonged survival is poor. The patient finally reaches an end stage of the disease which no longer responds to chemotherapy. In these cases the application of bone marrow transplantation opens up a second chance for a long lasting remission. Leukemic cells were eradicated by a short intensive course of chemotherapy and total body irradiation followed by a marrow infusion from a suitable donor to rescue the patient from the otherwise lethal marrow cell damage. One major obstacle to the successful application of allogeneic bone marrow transplantation is the occurence of immunologic complications when donor and recipient are not monozygous twins and express differences in their histocompatibility properties. The bidirectional immunologic barrier may cause a rejection of the marrow graft or a graft-ver-sus-host reaction induced by immunocompetent T-lymphocytes in the donor marrow. Whereas graft rejection is supressed with increasing success by the intensive conditioning treatment of the leukemic patients, graftversus-host disease (GvHD) is still a frequent problem of clinical bone marrow transplantation (Thomas et al. 1977). The disease is presumably attributable to a cytopathogenic reaction of immunocompetent donor T lymphocytes of the graft on host target tissues (Slavin and Santos 1973). Even after transplantation of HLA-identical and MLC-negative marrow grafts the occurence of GvHD cannot be excluded due to genetic differences not detected by present histocompatibility typing techniques.

Intensive induction chemotherapy of extensive small cell bronchogenic carcinoma in protected environment--prophylactic antibiotic units. A preliminary report.

<h2>Abstract</h2> Twenty-two patients with disseminated small cell bronchogenic carcinoma and two patients with limited disease received 3 courses of intensive chemotherapy with ECHO (E = Epipodophyllotoxin VP-16-213, C=Cyclophosphamide, H=Hydroxydaunorubicin, O=Oncovin) in protected environment prophylactic antibiotic (PEPA) units. Maintenance therapy consisted of 3 additional courses of ECHO and 6 of PRIME (PR = Procarbazine, I=Ifosfamide, ME=Methotrexate). All patients received prophylactic brain irradiation. At the time of this evaluation, there were 5 patients who were too early (they had not completed 2 courses of ECHO chemotherapy) and 2 early deaths. All 15 evaluable patients with disseminated disease responded with either complete (53%) or partial (47% ) remission. This included 6 of 6 evaluable patients with signs of superior vena cava compression who achieved complete (5) or partial (1) remissions. Complete remissions were common in patients who had fewer organs involved; 7 of 9 (78%) patients with ≤2 metastatic sites vs. 3 of 8 (38%) patients with ≥3 metastatic sites. With a median followup of 7 months at this writing there have been 3 relapses and 3 deaths (2 early deaths and 1 death secondary to a cerebrovascular accident). There were 1 possible and 1 probable treatment related deaths in 2 nonambulatory patients who died within 1 and 4 weeks from onset of therapy. This approach has resulted in a high complete remission rate in this unfavorable group of patients with small cell bronchogenic carcinoma. Myelosuppression is severe and opportunistic infections are seen more commonly than with lower doses of chemotherapy. The longterm effects of this program are still unknown.

Genitourinary tuberculosis: a 7-year review.

Since 1970 short course regimes of chemotherapy have been adopted for the treatment of 87 patients suffering from genitourinary tuberculosis. The response to chemotherapy, the effect of surgery, the importance of hypertension and the relapse rate have been studied. It is concluded that all cases of genitourinary tuberculosis will respond to a short intensive course of chemotherapy, which need not be given for longer than 6 months.