High-dose melphalan, misonidazole, and autologous bone marrow transplantation for the treatment of metastatic colorectal carcinoma. A phase I study

To augment the antitumor effect of high-dose melphalan and determine pharmacokinetics we conducted a phase I trial of escalating doses of high-dose IV melphalan with the chemosensitizer misonidazole for patients with advanced colorectal carcinoma. Fourteen patients with modified Dukes D adenocarcinoma of the colorectum were treated with a single course of melphalan (40-60 mg/m2 i.v. bolus q.d. X 3 days) and misonidazole (1-3 g/m2 p.o. q.d. X 3 days) followed by autologous bone marrow transplantation. Toxicity consisted of severe myelosuppression, moderate nausea and vomiting, and mild mucositis and diarrhea. One patient developed unexplained renal tubular acidosis, and a diffuse encephalopathy occurred in another patient. Three patients died within the first 30 days after the start of treatment, two due to tumor progression and one due to sepsis and disseminated intravascular coagulation-induced intracerebral hemorrhage. Six of 14 patients achieved a partial response, and the median response duration was 4 months (range 3-10 months). Analysis of misonidazole serum concentrations showed similar pharmacokinetics to those previously reported, suggesting no significant drug interaction with intravenous melphalan. Mean peak serum concentrations ranged from 81.8 micrograms/ml to 115.2 micrograms/ml at the second and third misonidazole dose levels, which approximate those known to provide effective chemosensitization with melphalan in animal models. In this phase I study, we showed that maximally tolerated doses of intravenous melphalan can safely be combined with oral misonidazole. In view of the large volumes of oral misonidazole required at the highest dose level, subsequent studies to determine the maximally tolerated dose of misonidazole should employ the intravenous form.     

Plasma pharmacokinetics of high-dose oral melphalan in patients treated with trialkylator chemotherapy and autologous bone marrow reinfusion

The pharmacokinetics of melphalan following high-dose p.o. administration were determined in 17 patients with various malignancies for the purpose of assessing interpatient and intrapatient pharmacokinetic variability. All patients underwent bone marrow harvest on day -8 (relative to bone marrow reinfusion). On days -7, -6, and -5, melphalan was given p.o. and the dose was escalated on each cohort consisting of at least 3 patients (beginning at 0.75 mg/kg). On days -6, -4, and -2, cyclophosphamide at 2.5 g/m2 and thiotepa at 225 mg/m2 were given i.v. On day -7 the peak melphalan concentration was 1.64 +/- 0.89 (SD) microM with a terminal half-life of 1.56 +/- 0.86 h. The area under the plasma concentration time curve (AUC) and oral clearance were 217.9 +/- 115.1 microM/min and 30.2 +/- 14.2 ml/min/kg. There was only a moderate correlation between the melphalan dose and both the peak concentration (r = 0.50, P less than 0.05) and AUC (r = 0.64, P less than 0.01) over the dosage range of 0.75-2.5 mg/kg. There was a trend towards greater interpatient variability in peak concentration, AUC, and oral clearance observed at the higher doses of melphalan. Analysis of intrapatient pharmacokinetic variability in 8 patients showed a significant difference between the doses given on days -7 and -5 in the peak concentration (2.09 versus 1.07 microM, P = 0.02), AUC (264.9 versus 134.8 microM/min, P = 0.01), and oral clearance (25.1 versus 53.1 ml/min/kg, P = 0.05) but no significant difference in the time to peak and terminal half-life. We conclude that there is marked interpatient and intrapatient variability in melphalan pharmacokinetics following high-dose p.o. administration. The data are consistent with saturable absorptive pathways for melphalan, which might be especially sensitive to concurrent high-dose chemotherapy.     

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.     

Sequential versus alternating chemotherapy for high-grade non-Hodgkin's lymphomas: preliminary results of a phase III multicentre trial

In a multicentre phase III trial 105 previously untreated patients with high-grade non-Hodgkin's lymphomas stage II-IV were randomized to receive either 4 cycles of CHOEP (cyclophosphamide 750 mg/m2 i.v. day 1, doxorubicin 50 mg/m2 i.v. day 1, vincristine 2 mg i.v. day 1, etoposide 100 mg/m2 i.v. days 3-5, prednisolone 100 mg p.o. days 1-5) (treatment arm A), or 4 cycles of chemotherapy with hCHOP (cyclophosphamide 1,200 mg/m2 i.v. day 1, doxorubicin 40 mg/m2 i.v. days 1 + 2, vincristine 2 mg i.v. day 1, prednisolone 100 mg p.o. days 1-5) alternating with IVEP (ifosfamide 1,500 mg/m2 i.v. days 1-5, vindesine 3 mg/m2 i.v. day 1, etoposide 120 mg/m2 i.v. days 3-5, prednisolone 100 mg p.o. days 1-5) in treatment arm B. After 4 cycles of chemotherapy an involved field irradiation with a total dose of 35 Gy was given to all patients demonstrated to be in complete or partial remission without persisting extranodal disease. A complete response (CR) was seen in 86/105 patients (82%) with 88% CR in arm A vs. 76% CR in arm B. During a median follow-up of 11 months (range 2-31 months) 13 patients relapsed (6 patients arm A, 7 patients arm B). The overall survival at 30 months is projected to be 72% vs. 83% for arm A and B respectively. Disease-free survival is projected to be 78% in arm A and 45% in arm B at 28 months. So far, the differences in CR, survival and disease-free survival are not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

A phase II trial of docetaxel plus capecitabine in patients with previously treated non-small cell lung cancer

BACKGROUND: A combination of docetaxel (T) and capecitabine (X) showed synergistic effects in preclinical studies and phase III randomized trials of metastatic breast cancer. We conducted this phase II study to examine its efficacy in previously treated non-small cell lung cancer (NSCLC) patients. METHODS: Patient eligibility required advanced NSCLC with measurable lesion(s), at least one prior regimen failure and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Treatment consisted of T 36 mg/m(2) i.v. on days 1 and 8 plus X 1000 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle (level I) or T 30 mg/m(2) i.v. on days 1 and 8 plus X 625 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle (level II). RESULTS: A total of 35 patients (M/F=24/11) were enrolled; 29 had received one prior regimen and 19 had received platinum-based regimens. Significant non-hematologic toxicities were observed after the treatment given at level I, including one treatment-related death. Subsequently 29 patients were treated at level II. The treatment at level II was well tolerated with grade 3 or 4 neutropenia only in 10%, grade 3 asthenia in 21% and stomatitis in 14% of patients. Four (15%) of 27 evaluable patients had partial response (PR) at level II and eight (30%) had stable disease (SD). CONCLUSIONS: The TX regimen showed modest antitumor effects in patients with previously treated NSCLC. For further studies, we recommend T 30 mg/m(2) i.v. on days 1 and 8 plus X 625 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle.     

Results of treatment of acute myeloid leukemia in adults

Sixty-five previously untreated patients (34 women, 31 men) with acute myelocytic leukemia, ranging in age from 15 to 71 (median 43) years, were treated for remission induction with 7-day courses of cytarabine (100 mg/m2/day continuous i.v. infusion) together with daunorubicin (45 mg/m2/day rapid i.v. injection) on days 1, 2 and 3. Supportive care consisted of broad spectrum antibiotics for fever in the presence of granulocytopenia and substitution of erythrocytes and platelets. The complete remission (CR) rate was 55.3%. The mean numbers of chemotherapy courses and days to achieve CR were 1.5 and 41, respectively. Sex and age appeared to have no effect on the remission rate. For remission maintenance, cyclic courses of cytarabine (i.v. 100 mg/m2 q 12 hr X 10) were given with each of four drugs, 6-thioguanine (p.o. 100 mg/m2 q 12 hr X 10), cyclophosphamide (i.v. 800 mg/m2 on day 1), CCNU (p.o. 100 mg on day 1) or daunorubicin (i.v. 45 mg/m2 on days 1 and 2) in rotational sequence. The median remission duration was 44 weeks, the median survival time for all patients 31 weeks, for those responding to therapy 74, and those not responding 8 weeks.     

Recombinant human granulocyte colony-stimulating factor hastens granulocyte recovery after high-dose chemotherapy and autologous bone marrow transplantation in Hodgkin's disease

To determine whether recombinant human granulocyte colony-stimulating factor (rhG-CSF) can accelerate granulocyte recovery after high-dose combination chemotherapy with autologous bone marrow transplantation (ABMT) in patients with Hodgkin's disease, we performed a nonrandomized phase II study using historical controls as a comparison. Eighteen relapsed/refractory Hodgkin's disease patients who received cyclophosphamide at 1.5 g/m2/day (days -6 to -3), carmustine (BCNU) at 300 mg/m2 (day -6), and etoposide (VP-16) at 125 mg/m2 every 12 hours (days -6 to -4), followed by ABMT (day 0) were treated with rhG-CSF at 60 micrograms/kg/day for a maximum of 28 days beginning on day 1. rhG-CSF dosage was gradually diminished and stopped once an adequate granulocyte count was maintained. rhG-CSF significantly accelerated absolute granulocyte count (AGC) compared with historical controls recovery to the 100/microL level (median, 9 days v 13 days; P = .103 x 10(-4), 500/microL level (median, 13 days v 22 days; P = 0.189 x 10(-2), and 1000/microL level (median, 16 days v 30 days levels; P = .125 x 10(-5). Platelet recovery to 50,000/microL was not significantly altered (P = .370). rhG-CSF was well tolerated, bone pain and myalgia being the only side effects noted. rhG-CSF hastens granulocyte recovery after high-dose chemotherapy with ABMT in patients with relapsed/refractory Hodgkin's disease without significant toxicity.     

A phase I trial of 1,3-bis(2-chloroethyl)-1-nitrosourea plus temozolomide: a North American Brain Tumor Consortium study

The North American Brain Tumor Consortium conducted a phase I trial of the combination 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide. Eligibility included a patient with a cancer type that was considered refractory to standard therapy. Prior nitrosourea treatments were not permitted. There were parallel dose escalations in two treatment schedules. Forty-five patients were enrolled during an 18-month period. The maximum tolerated doses (MTDs) when temozolomide followed BCNU (Arm A) were temozolomide at 550 mg/m2/p.o. and BCNU at 150 mg/m2/i.v.), whereas the MTD when temozolomide preceded BCNU (Arm B) was temozolomide at 400 mg/m2/p.o. and BCNU at 100 mg/m2/i.v. Toxicity was predominantly hematologic, although there were three instances of pulmonary toxicity, which in one case could have represented potentiation of nitrosourea-induced pulmonary fibrosis. The half-life of temozolomide was 1.86 (+/-0.31) h. There was a moderate relationship between dose and peak concentration and a strong relationship between dose and plasma concentration time curve. Pharmacokinetic parameters of temozolomide were unaffected by the treatment schedule, so the difference in MTD between the schedules is likely due to a biologic rather than a pharmacokinetic sequence interaction. There were 9 partial responses among 43 patients evaluable for response, including 5 of 25 with a histologic diagnosis of glioblastoma. The recommended dose and schedule for phase II trials of this regimen are BCNU 150 mg/m2/i.v. followed in 2 h by temozolomide 550 mg/m2/p.o. repeated every 6 weeks. We are also recommending screening and periodic pulmonary function testing during treatment to assess the possible potentiation of nitrosourea-induced pulmonary fibrosis.     

Treatment of relapsed Hodgkin's disease using a weekly chemotherapy of short duration: results of a pilot study in 20 patients

Twenty patients with relapsed Hodgkin's disease have been treated with a weekly regimen of chemotherapy (VAPEC-B) comprising Adriamycin 35 mg/m2 i.v. weeks 1, 3, 5, 7, 9, 11; cyclophosphamide 350 mg/m2 i.v. weeks 1, 5, 9; etoposide 100 mg/m2 p.o. daily for 5 days, weeks 3, 7, 11; vincristine 1.4 mg/m2 i.v. weeks 2, 4, 6, 8, 10; bleomycin 10 mg/m2 i.v. weeks 2, 6, 10 and prednisolone 50 mg p.o. daily weeks 1-5, 25 mg p.o. daily weeks 6-11. All had previously received an Adriamycin containing combination and in nine cases this was for relapse following MVPP. In all but one case relapse occurred less than one year after the completion of previous treatment and in 14 cases, disease recurred within 24 weeks. Thirteen patients had extra-nodal involvement. Following six weeks of treatment 14 patients had responded (6 CR; 4 CR, uncertain; 4 PR), four had stable disease, one had progressed and one had died of sepsis. Fourteen patients proceeded to high dose cyclophosphamide and BCNU with autologous bone marrow rescue and seven of these are progression free between 4 and 156 weeks later. High dose therapy was not possible in five patients, three of whom achieved CR. Of these, two (one with bulky nodal disease and skin infiltration; one with extensive bone marrow involvement) are alive and relapse free without further treatment at 95 and 114 weeks. Overall, the regimen was well tolerated but haematological toxicity was moderate or severe in ten patients and four were admitted to hospital for treatment of suspected or confirmed septicaemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combination chemotherapy with vinblastine, BCNU and cisplatin in advanced malignant melanoma

A combination chemotherapy including vinblastine (6 mg/m2 i.v. days 1-2), BCNU (100 mg/m2 i.v. day 3), and cisplatin (50 mg/m2 i.v. day 5) was given as salvage treatment in 46 consecutive, previously treated patients affected by metastatic malignant melanoma. Courses were planned every 4 weeks provided that a complete bone marrow recovery occurred, otherwise they were delayed for 1-2 additional weeks. Objective responses (3 CRs and 10 PRs) were observed in 13/46 (28%) patients; 12 cases had stable disease and 21 patients progressive disease during treatment. Median duration of response was 13 months (range, 5-18), and median survival was 11 months (range, 3-20) for all patients. Nausea and vomiting were the most distressing side effects, whereas a grade I leukopenia caused a delayed treatment in 90% of patients. In conclusion, the combination chemotherapy was moderately toxic and did not seem to give substantially better results than obtained with other reported regimens.     

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.     

A pilot study of three sequential chemotherapeutic regimens in metastatic breast cancer

The aim of this pilot study was to estimate the toxicity and response rate of an alternating chemotherapeutic program in chemotherapy-naive metastatic breast cancer patients. Treatment consisted of regimen A (given days 1-28): cyclophosphamide 100 mg/m2 PO days 1-14, doxorubicin 30 mg/m2 i.v. days 1 and 8, and 5-fluorouracil 500 mg/m2 i.v. days 1 and 8 (CAF regimen); regimen B (given days 29-56): dibromodulcitol 135 mg/m2 p.o. days 30-39, mitoxantrone 9 mg/m2 i.v. day 29, and vincristine 1.2 mg/m2 i.v. (maximum 2.0 mg) day 29 (DMV regimen); and regimen C (given days 57-84): thiotepa 12 mg/m2, doxorubicin 45 mg/m2 and vinblastine 4.5 mg/m2 all i.v. on day 57. There were 27 eligible patients with a median age of 51 years (range 34-78). On 14 episodes the leukocyte count fell to less than 1 X 10(9)/L during the first six cycles of treatment (14% of 99 cycles). There were no treatment-related deaths. Common non-life-threatening toxicities included thrombocytopenia, anemia, vomiting, and alopecia. Despite having no drugs in common, the leukocyte and platelet nadirs after CAF correlated with the nadir counts after DMV (r values of 0.6829 and 0.5892, respectively; p = 0.01). Among the 23 patients with measurable and/or evaluable disease there were five complete responses (22%) and nine partial responses (39%), with a median time to treatment failure of 29 weeks. The overall median survival was 19 months.     

High-dose chemotherapy with autologous bone marrow support in advanced malignant melanoma

Eight patients with advanced malignant melanoma were treated with high-dose melphalan (80-90 mg/m2) and BCNU (600-800 mg/m2). In all patients autologous bone marrow preservation was performed prior to therapy. Bone marrow was stored for 48 h in a refrigerator at 10 degrees C and reinfused 48 h post-therapy. Three patients had a complete response (CR), 1 a partial response and 4 patients no response. Two patients with CR died 4 and 5 months after therapy. One had an interstitial pneumonitis and 1 patient died from unknown cause. The third patient had a relapse 12 months after therapy. Major side effects were severe nausea/vomiting and a mild mucositis. Two patients suffered from BCNU-related encephalopathy. All patients had a full hematologic reconstitution after 6 weeks. High-dose chemotherapy with autologous bone marrow support achieves a high response rate. Long-term disease-free survival, however, was not seen with this approach.     

A phase I study of paclitaxel, etoposide, and cisplatin in extensive stage small cell lung cancer.

This Phase I study was designed to determine the maximally tolerated dose (MTD) of paclitaxel with standard doses of cisplatin and etoposide for patients with untreated extensive stage small cell lung cancer (SCLC). Secondary objectives were to determine the toxicities, response rate, response duration, and overall survival in this cohort. Twenty-eight SCLC patients were enrolled into four dose levels. All patients received a fixed dose of cisplatin at 80 mg/m2, i.v., day 1. The first group received etoposide 50 mg/m2, i.v. day 1 and 100 mg/m2 p.o., days 2-3, whereas all subsequent groups received etoposide 80 mg/m2, i.v., day 1 and 160 mg/m2, p.o., days 2-3. The paclitaxel starting dose was 135 mg/m2, i.v., over a 3-h period and was escalated to 175 and 200 mg/m2. Cycles were repeated every 21 days for a maximum of six cycles. Granulocyte-colony stimulating factor was not given prophylactically but was allowed in subsequent cycles according to the American Society of Clinical Oncologists guidelines. All 28 SCLC patients were evaluable for toxicity, and 23 patients were evaluable for response. Myelosuppression was the major toxicity, with grade 4 neutropenia occurring in 23 of 28 patients (82%), but febrile neutropenia was uncommon and developed in 4 patients (14%). Grade 4 thrombocytopenia and anemia were rare, occurring as isolated events in one patient each. Dose-limiting peripheral neuropathy was observed at a paclitaxel dose of 200 mg/m2. Grade 4 nausea/vomiting and diarrhea were also noted at this dose level. Five patients had complete responses (22%), and 14 patients had partial responses (61%). The overall response rate was 83% with a median time to progression of 7.5 months, a median survival of 10 months, and a 1-year survival rate of 39%. This three-drug combination of paclitaxel with cisplatin and etoposide is active with acceptable toxicity. Neurotoxicity was dose limiting at 200 mg/m2 of paclitaxel. Neutropenia was frequent but not associated with significant morbidity. The recommended doses for future clinical trials are 175 mg/m2 paclitaxel, i.v., over a 3-h period on day 1 with 80 mg/m2 cisplatin, i.v., on day 1 and 80 mg/m2 etoposide, i.v., on day 1 and 160 mg/m2 p.o. on days 2 and 3 with growth factor support. The Southwestern Oncology Group has instituted a Phase II study with this dose schedule.     

VP16, epirubicin and procarbazine in the treatment of advanced non-small-cell lung cancer

We report the results obtained in the treatment of 52 advanced non-small-cell lung cancer patients with the combination chemotherapy VP16 (120 mg/m2 i.v., days 1-2-3), epirubicin (50 mg/m2 i.v., day 1) and procarbazine (100 mg/m2 p.o., days 1 through 8). The courses were repeated every 21 days. No patient had been pretreated. A median of 5 courses was administered. Partial response was obtained in 33% and no change in 21% of patients. Median remission time was 6.5 months, and median survival of responders was 10 months. The best response rate and median survival were obtained in the lowest grade performance status patients and in locally advanced disease patients. Major chemotherapy related toxicities were grade 1-2 leukopenia and grade 2-3 alopecia.     

Combination chemotherapy with adriamycin, cyclophosphamide, vincristine, methotrexate, etoposide and dexamethasone (ACOMED) followed by involved field radiotherapy induces high remission rates and durable long-term survival in patients with aggressive malignant non-Hodgkin's lymphomas: long-term follow-up of a pilot study

The aim of the present study was to evaluate the feasibility and efficacy of the intensified induction chemotherapy regimen ACOMED for patients with aggressive non-Hodgkin's lymphoma (NHL). Untreated adult patients with aggressive NHL, presenting with Ann Arbour stage II-IV disease or stage I with bulky disease, and with at least one of the following risk factors: age > 60 years, advanced disease, elevated serum lactate dehydrogenase level, Eastern Cooperative Oncology Group (ECOG) performance status >or= 2, presence of extranodal sites of disease and bulky disease, were treated with the ACOMED regimen consisting of 4-6 cycles of adriamycin 25 mg/m(2) i.v. on days 4-5, cyclophosphamide 250 mg/m(2) i.v. on days 1-5, vincristine 2 mg i.v. absolute on day 1, methotrexate 500 mg/m(2) i.v. on day 1 with leucovorin-rescue after 24 h 30 mg/m(2) i.v. and 3 x 15 mg p.o., etoposide 100 mg/m(2) i.v. on days 3-5, dexamethasone 10 mg/m(2) p.o. on days 1-5 and granulocyte colony-stimulating factor support, repeated on day 21. Twenty-two patients were treated within this study at a single center. After 4-6 cycles of ACOMED followed by additional involved field radiotherapy in 18 patients, the complete and overall response rates were 86% (19 of 22 patients) and 95% (21 of 22 patients), respectively. After a median observation time of 10 years and 2 months, 16/22 (73%) patients are alive in continuous complete response without evidence of any late toxicities. ACOMED followed by involved field radiation presents a highly effective regimen for remission induction and long-term survival in patients with aggressive NHL, and merits further investigation.     

Phase II randomized study of dacarbazine, carmustine, cisplatin and tamoxifen versus dacarbazine alone in advanced melanoma patients

This randomized phase II trial was performed to define the activity and toxicity of the combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP) and tamoxifen (DBDT regimen) versus DTIC alone in patients with metastatic melanoma. Sixty patients with metastatic melanoma were randomly assigned to receive BCNU 150 mg/m2 intravenously (i.v.) on day 1, cisplatin 25 mg/m2 i.v. daily on days 1 to 3, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and tamoxifen 160 mg orally daily for 7 days prior to chemotherapy (DBDT arm; arm A). Treatment cycles were repeated every 28 days, while BCNU was given every two cycles. The DTIC arm (arm B) patients received DTIC alone 1200 mg/m2 i.v. on day 1, repeated every 21 days. Patients were evaluated every two cycles; responding patients continued the treatment for a maximum of 12 cycles. The overall response rate was 26% in the DBDT arm and 5% in the DTIC arm. Complete responses were 2.5% for DBDT and 0% for DTIC. The median progression-free survival and the median survival were 4 and 9 months, respectively for DBDT, and 2 and 7 months for DTIC. DBDT was associated with significant haematological toxicity: 33% of the patients experienced a grade III or IV neutropenia and 28% a grade III or IV thrombocytopenia. In conclusion, the overall response rate obtained with DBDT was greater than that obtained with DTIC alone; however, this combination increases toxicity with limited impact on overall survival.     

High dose chemotherapy with G-CSF in refractory Hodgkin's disease

This study analyzed the long-term results in patients with Hodgkin's disease (HD) who were resistant or refractory to conventional chemotherapy and who were treated with intensive, non-myeloablative chemotherapy with granulocyte colony-stimulating factor (G-CSF) as hematological support. The study population included 86 patients who were treated with combination chemotherapy with high doses: BCNU, 300 mg/m2, on day 1, vincristine 1.4 mg/m2, and bleomycin 10 mg/m2 on days 1, 7, 14 and 21; etoposide 500 mg/m2, i.v., on days 14 and 15; and ifosfamide 4 g/m2, and epirubicin 180 mg/m2, on day 29. G-CSF 5 ug/kg/day, was used to ameliorate severe myelosuppression on days 3 to 13, 16 and 26 and 29 to 38. If a complete response was observed, two cycles of IOPP (ifosfamide 1.5 g/m2, i.v., on days 1 and 8; vincristine 1.4 mg/m2, i.v. on days 1 and 8; prednisone 60 mg/m2, p.o., daily, days 1 to 14 and procarbazine 100 ng/m2, p.o., daily, days 1 to 14 vere given as consolidation therapy. At 8-years, the overall survival rate vas 58% (50 out of 86 patients) being 38 and 76% in patients whose initial complete response was shorter or longer that 12 months, respectively or in 44% of induction failures. Hematological toxicity grade III or IV was observed in all cycles. However hematological recovery was already evident (median on day 13). Only transitory delay in continuing therapy was observed (median 3.9 days). Twenty-two patients developed infection-related granulocytopenia but no therapy related deaths were observed. G-CSF was well tolerated. This study indicates that the hematopoetic growth factor, G-CSF, was sufficient to act as hematological support in patients who received intensive, but non-myeloablative chemotherapy. In our opinion intensive chemotherapy without autologous transplant procedures can be considered in patients with refractory Hodgkin's disease because complete response rate and overall survival times are similar to more aggressive but more toxic regimens.     

Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma

Background: The combination of carmustine, etoposide, cytarabine and melphalan (BEAM) is an effective autologous transplantation preparative regimen for lymphoma and has little toxicity, but the feasibility and tolerance of BEAM as a preparative regimen for allogeneic transplantation has not been established.Patients and methods: Thirty adults with primary refractory or recurrent intermediate- or low-grade lymphoma were treated on a prospective phase II study with carmustine 300 mg/m2 i.v. day –6, etoposide 200 mg/m2 i.v. followed by cytarabine 200 mg/m2 i.v. twice daily days –5 to –2, melphalan 140 mg/m2 i.v. day –1, and marrow or blood stem cells from an HLA-identical donor on day 0. Tacrolimus and methotrexate were used to prevent graft-vs.-host disease (GVHD).Results: Median time from transplantation was 20 mos (range 6–32 months). Median maximal regimen-related toxicity grade was 2, and four patients (13%) had a grade 3–4 regimen-related toxicity. Two patients had idiopathic interstitial pneumonitis. One patient had primary graft failure, and a second had autologous reconstitution documented at three months posttransplant. Grades 2–4 acute GVHD occurred in 31%, grades 3–4 in 16%, and chronic GVHD in 54%. Day-100 survival was 70%. Twenty-three patients achieved a complete response. The two-year relapse rate was 23%, survival was 48%, and disease-free survival (DFS) was 42%.Conclusions: BEAM supports engraftment of allogeneic transplants and is a tolerable preparative regimen for allogeneic transplantation for lymphoma.     

Phase II pilot study with cisplatin, etoposide, and continuous-infusion 5-fluorouracil in metastatic non-small cell lung cancer

A pilot study was conducted using a combination of cisplatin (70 mg/m2 i.v., day 1), etoposide (60 mg/m2 i.v., days 1 through 5), continuous-infusion 5-fluorouracil (800 mg/m2 i.v., days 1 through 5), and allopurinol (600 mg p.o., days 1 through 7). Treatment was repeated every 3-4 weeks. Ten patients with metastatic non-small cell lung cancer were treated. Significant toxicities were observed, including electrocardiographic changes simulating acute myocardial infarction in three patients. There was no objective response, therefore the study was closed early according to its design.