Autologous stem cell transplantation for non-Hodgkin's lymphoma: comparison of radiation-based and chemotherapy-only preparative regimens

The aim of this study was to compare toxicity and efficacy of total body irradiation (TBI), cyclophosphamide (CY) and etoposide (E) (TBI/CY/E) vs busulfan, melphalan and thiotepa (Bu/Mel/T) in patients receiving autologous stem cell infusion (ASCI) for malignant lymphoma (NHL). Between September 1990 and July 1998, 351 patients with NHL were treated with TBI/CY/E (n = 221) or Bu/Mel/T (n = 130) followed by ASCI. Patients in first, or second remission, first responding or untreated relapse were defined as having less advanced disease before transplantation. The median follow-up was 5 years (range 1-9) and 3.5 years (1-6) for patients receiving TBI/CY/E and Bu/Mel/T, respectively. The cumulative probabilities of survival, event-free survival (EFS) and relapse at 5 years were 44%, 32%, 49% following TBI/CY/E and 42%, 34% and 42% following Bu/Mel/T. The probability of EFS at 5 years for patients who had prior dose-limiting radiation (n = 59) was 32% after Bu/Mel/T therapy. Transplant-related mortality was 16% for TBI/CY/E and 21% for Bu/Mel/T. In univariate and multivariate analyses, more advanced disease status was associated with poor outcome (TBI/CY/E: RR 0.70, CI 0.50 to 0.97 P = 0.04; Bu/Mel/T: RR 0.61, CI 0.39 to 0.97 P = 0.03). No significant differences in toxicities and outcomes were observed between these two regimens despite the inclusion of patients who had received dose-limiting irradiation in the Bu/Mel/T regimen.     

Prognostic significance of the immunocytochemical detection of contaminating tumor cells (CTC) in apheresis products of patients with high-risk breast cancer treated with high-dose chemotherapy and stem cell transplantation

The aim of this study was to determine whether the detection of CTC in the apheresis product contribute significantly to treatment failure of patients with high-risk breast carcinoma treated with high-dose chemotherapy (HDC) and stem cell transplantation (SCT). Patients were with stage II and III adenocarcinoma of the breast with > or = 10 axillary lymph nodes affected after primary surgery (> or = 10 N+) who had received HDC with SCT. We analyzed retrospectively the presence of CTC as assessed by immunocytochemistry (ICC) in the apheresis products obtained after standard adjuvant chemotherapy. We compared the clinical outcome of patients who received HDC and SCT with or without CTC-positive apheresis. One hundred and twenty-seven apheresis products samples were obtained from 51 patients. Fourteen (27.4%) of these samples were CTC positive. After a median follow-up of 4.6 years, 20 patients have relapsed, 14 died from progression of their disease and 30 patients remain alive and free of progression. For the whole group of patients the 5 year probabilities of DFS and OS were 60% (IC 95%, 47-75%) and 71% (IC 95%, 55-83%), respectively. However, the 5 year probabilities of DFS were 23% (IC 95%, 0-46) and 75% (IC 95%, 60-89) for patients with CTC positive and negative, respectively. The 5 year probabilities of OS were 42% (IC 95%, 15-68) and 83% (IC 95%, 70-95) for patients with CTC positive and negative, respectively. Both univariate and multivariate analysis showed that the presence of CTC in the apheresis product was the only prognostic factor associated with a higher incidence of clinically overt disease relapse (P = 0.002) and shorter survival (P = 0.003). The presence of cytokeratin-positive metastatic cells in the apheresis product increases the risk of relapse after HDC and SCT in patients with stage II and III adenocarcinoma of the breast with > or = 10 N+.     

Cardiac sequelae of doxorubicin and paclitaxel as induction chemotherapy prior to high-dose chemotherapy and peripheral blood progenitor cell transplantation in women with high-risk primary or metastatic breast cancer

Doxorubicin plus paclitaxel has been shown to be an active regimen for metastatic breast cancer and is now frequently used as adjuvant therapy for high-risk primary breast cancer. Initial studies reported a higher than expected rate of cardiac toxicity with this regimen. We studied 105 patients with either high-risk primary breast cancer or metastatic breast cancer who were treated with doxorubicin (60 mg/m2) and 3-h infusions of paclitaxel (175 mg/m2) cycled every 3 weeks. Patients received three cycles of chemotherapy for high-risk primary or four cycles for metastatic disease. Patients then proceeded to high-dose chemotherapy (HDC) (STAMP I cyclophosphamide, cisplatin and carmustine) and peripheral blood progenitor cell transplantation (PBPCT). Patients underwent radionuclide multi-gated angiograms (MUGA) before and following induction chemotherapy and following HDC. During induction chemotherapy 40 (38%) of the patients had a reduction in left ventricular ejection fraction (LVEF). Fourteen had a decrease of 20% or greater and two were mildly symptomatic from CHF. There was additional reduction in the LVEF after HDC with a median value for LVEF of 59% (range, 20-78%). During HDC 10 patients developed clinical signs of congestive heart failure (CHF). Five patients responded to diuretic therapy and did not require any additional treatment. Four patients responded to vasodilation and/or digoxin with improvement in cardiac function. A clinically significant decrease in cardiac function was found in a small number of patients after induction chemotherapy and HDC with PBPCT. The majority of the patients tolerated this regimen without problems. Although there was a decline in LVEF as measured by radionuclide MUGA this did not prevent the majority of patients from proceeding with HDC. Bone Marrow Transplantation (2000).     

Adjuvant treatment of high-risk stage II breast cancer with doxorubicin followed by high-dose chemotherapy and autologous stem-cell transplantation: a single-institution experience with 132 consecutive patients

Several studies have shown conflicting results with the use of intensive consolidation chemotherapy for breast cancer. The aim of the present study was to investigate the efficacy, feasibility and toxicity of high-dose chemotherapy with stem cell support in patients with high-risk stage II breast cancer. From February 1994 to November 1998, 132 consecutive patients with multinode positive breast cancer were entered to the study. In total, 86 patients had >or=10 positive axillary lymph nodes, and 46 had 4-9 positive axillary lymph nodes with at least two additional predetermined risk factors at diagnosis. All patients were offered adjuvant chemotherapy (doxorubicin, 75 mg/m(2) x 4) followed by high-dose chemotherapy (cyclophosphamide 6000 mg/m(2), carboplatin 800 mg/m(2) and thio-tepa 500 mg/m(2)) and autologous stem cell support with growth factor. In all, 131 patients also received local radiation therapy and tamoxifen based on receptor status. After a median follow-up of 51 months (range 27-87), the disease-free and overall survival rates were 72 and 81%, respectively. There was no difference in the outcome for high-risk patients with > or < than 10 positive axillary lymph nodes. On Cox regression analysis only progesterone receptor status was predictive of disease-free, but not overall survival. There were no treatment-related deaths; grades III-IV toxicity was relatively low. This combined approach of doxorubicin followed by high-dose chemotherapy and stem-cell support, followed by locoregional radiotherapy, was safe and seems to be effective in patients with multinode positive stage II breast cancer. In previous trials of adjuvant high-dose therapy in this patient population, treatment-related morbidity and mortality markedly influenced the outcome. For this high-risk patient population, further testing of intensive chemotherapy regimens with a lower toxicity profile is warranted.     

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-gamma after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer

High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m(2) SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to +28 and interferon gamma (IFN-gamma) 0.025 mg/m(2) SQ every 2 days from day +7 to +28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-gamma arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.     

High-dose chemotherapy with autologous stem cell transplantation in extranodal NK/T-cell lymphoma: a retrospective comparison with non-transplantation cases

To determine the role of high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in extranodal NK/T-cell lymphoma patients, we conducted a retrospective analysis. In our previous study, we searched for patients who had received HDC/ASCT and identified 16 eligible patients and compared the treatment outcome with historical control group (n=246). Nine patients received HDC/ASCT in the first (CR1) or second complete remission (CR2), while seven patients received HDC/ASCT as salvage. Twelve of 16 patients achieved or maintained CR after HDC/ASCT. Among the 12 patients, five patients relapsed. Estimated 2-year overall survival (OS) and relapse-free survival (RFS) rates were 71.3+/-12.4% and 25.8+/-14.3%, respectively. There was a tendency of better survival in patients who received HDC/ASCT as compared to those who did not (P=0.091). In subset analysis, patients who underwent HDC/ASCT at CR (P=0.049) and patients with stage III or IV (P=0.001) had a favorable outcome. Patients with NKIPI 3,4 or EUNKTL, who underwent HDC/ASCT had more prolonged survival without statistical significance (P=0.055 and 0.056). In conclusion, HDC/ASCT may be considered as a treatment option for patients with extranodal NK/T-cell lymphoma, especially those in CR, with advanced disease (stage III/IV or EUNKTL) and high NKIPI scores.     

Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: A French randomised double-blind phase III trial (PRODIGE 50-ASPIK)

Oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. Two recent retrospective studies strongly suggested that low-dose aspirin used (100 mg/d) after surgical resection of colorectal cancer with a PIK3CA mutation could act as a targeted therapy with a major protective effect on the risk of recurrence.We propose a double-blind randomized phase III study to evaluate aspirin (100 mg/d during 3 years or until recurrence) versus placebo. Main inclusion criteria are patients aged 18 or 20, stage III or high risk stage II.The primary endpoint of the study is 3-year disease-free survival (DFS). Hypotheses are to improve 3-years DFS from placebo: 72% to aspirin: 83% (HR = 0.56). 94 events and 264 patients with PIK3CA mutation are required. The secondary endpoints are DFS at 5 years, the overall survival rate at 5 years, grade 3–4 severe bleeding.     

Weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) with folinic acid (FA) in adjuvant therapy of colon cancer

After curative resection (R-0) of primary colon cancer or curative metastases resection, the efficacy, toxicity and compliance of a weekly 24-h infusion of high-dose 5-FU with folinic acid was examined in a prospective feasibility trial. From June 1995 to June 1997, 19 patients were included, 11 patients with UICC stage III and 8 patients with UICC stage IV colon cancer. The patients received weekly 500 mg/m2 of calcium folinic acid (Rescuvolin) as a 1-2 h-infusion on an outpatient basis following a 24-h infusion of 2,000 mg/m2 5-FU via a pump system (intermate LV5 Baxter). The adjuvant therapy was administered for 6 months. 90% of the patients received the planned 18 chemotherapy applications. The total 5-FU dose given to each patient amounted to 34.4 g/m2 in 6 months, thus corresponding to 95% of the planned 5-FU total dose. The main toxicity was diarrhea CTC toxicity grade 3 in the case of 16% of the patients. After a median follow-up of 51 months (range: 37-59 months), 82% of the patients (9 out of 11) with stage III remained free of recurrence. The 2 cases of recurrence belonged to the pN2 subgroup. In stage IV only 12% of the patients (1 out of 8) remained free of recurrence. On an adjuvant basis, a weekly 24-h infusion of high-dose 5-FU with folinic acid is accompanied by a good complicance and a high-dose intensity of 5-FU. Now it is tested within randomized phase III trials of the "Arbeitsgemeinschaft Gastroenterologische Onkologie (AGO)" of the "Deutsche Gesellschaft für Verdauungs- und Stoffwechselerkrankungen" for UICC stage III colon cancer. Concerning stage IV, adjuvant therapy was not effective, a fact that seems to justify new drugs and new therapeutic strategies.     

Busulfan, cyclophosphamide, and etoposide as high-dose conditioning regimen in patients with malignant lymphoma

We investigated the efficacy and toxicity of the combination of busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP-16) as a preparative regimen prior to autologous hematopoietic stem cell transplantation (ASCT) in patients with Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL). Fifty-three patients with recurrent ( n=30), refractory ( n=20), or high-risk ( n=3) lymphoma were enrolled. The 10 patients with HD and 43 with NHL (median age: 46 years, range: 18-64) received busulfan (16 mg/kg), cyclophosphamide (120 mg/kg), and etoposide (30 or 45 mg/kg) followed by ASCT. A total of 50 patients (94%) were consolidated in complete ( n=25) or partial ( n=25) remission, whereas 3 patients had chemoresistant disease before Bu/Cy/VP-16. Thirty-five patients (66%) had received prior radiotherapy (RT) excluding total body irradiation (TBI) as part of the conditioning regimen. The main nonhematological toxicities (grade II-IV according to the Bearman score) in 52 evaluable patients were mucositis (79%) and hepatic toxicity (15%). Severe veno-occlusive disease (VOD) occurred in three patients (5.8%) including one treatment-related death caused by VOD. Overall, treatment-related mortality was 3.8%. After a median follow-up for surviving patients of 21 months (range: 6-118), 20 patients (38%) are in continuous complete remission, 8 patients (15%) are alive in relapse, and 25 patients (47%) died. Probabilities of relapse, event-free survival, and overall survival at 3 years were 63% [95% confidence interval (CI): 48-79%], 31% (95% CI: 17-46%), and 43% (95% CI: 27-59%), respectively. In conclusion, Bu/Cy/VP-16 is an effective and well-tolerated conditioning regimen in patients with HD and NHL. Both toxicity and outcome were not significantly different in patients treated with 30 mg/kg and 45 mg/kg etoposide, respectively. The observed long-term results are even comparable to those published for other established high-dose protocols, including TBI-based regimens. However, further investigations are necessary to evaluate the value of Bu/Cy/VP-16 as a high-dose protocol for malignant lymphoma, especially in patients who have already received extensive RT.     

Cardiac conduction abnormalities in patients with breast cancer undergoing high-dose chemotherapy and stem cell transplantation

Cardiac toxicities in 39 consecutive patients with breast cancer receiving high-dose chemotherapy (HDC) with stem cell transplantation were reviewed. All 39 patients received various anthracycline-containing regimens in adjuvant settings and/or for metastatic disease before HDC. As a cytoreductive regimen, all received cyclophosphamide 2000 mg/m2 and thiotepa 200 mg/m2 for 3 consecutive days. No immediate fatal toxicities were observed, but one patient developed chronic congestive heart failure and two had transient left ventricular dysfunction. Pericardial effusion was observed in another three patients. ST-T abnormalities during HDC were observed in two patients and arrhythmias were observed in nine, four of which occurred during stem cell infusion (SCI). There were three atrial arrhythmias, two ventricular arrhythmias, and four atrioventricular (AV)-block episodes. Two patients developed advanced and complete AV-block with an asystolic pause. Notably, three patients experienced AV-block with uncontrolled vomiting. No relationship was observed between the cumulative dose of anthracycline and cardiac toxicities during HDC. These results suggest that abnormalities in the conduction system during HDC may be more frequent than previously reported. Vagal reflex secondary to emesis may play an important role in the development of AV-block. Bone Marrow Transplantation (2000) 25, 185-189.     

The hyper-CVAD–rituximab chemotherapy programme followed by high-dose busulfan,melphalan and autologous stem cell transplantation produces excellent event-free survival in patients with previously untreated mantle cell lymphoma

The hyper-CVAD + rituximab (R) programme consists of fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + R alternating with high-dose methotrexate + cytarabine (HD MTX/ARA-C) + R. This regimen, when used as initial therapy for patients under 65 years of age with previously untreated mantle cell lymphoma (MCL), results in remission rates of > 85% with a median event-free survival (EFS) of > 50 months, but with a pattern of continuous relapse out to 60 months. We performed a study of hyper-CVAD + R, followed by consolidative peripheral blood progenitor cells autograft [autologous stem cell transplant (AuSCT)] with high-dose busulfan and melphalan (Bu/Mel) conditioning, in patients with responsive disease. Thirteen patients with a median age of 54 (range = 33–61) were treated. Complete remission (CR) was achieved in 12 patients (92%) after hyper-CVAD + R and 12 completed AuSCT after Bu/Mel conditioning. One patient died during the autograft and another declined AuSCT after achieving a CR with hyper-CVAD + R. With a median follow-up from diagnosis of 36 months (range = 16–53 months), the observed 36 months overall survival and EFS are both 92% for the whole cohort. These data confirm the excellent CR rates achieved by the use of hyper-CVAD + R in patients with MCL and suggest that consolidation with Bu/Mel and AuSCT may improve durable disease control when compared to published outcomes of hyper-CVAD + R alone.     

High-dose chemotherapy (CTM) for breast cancer

We designed and implemented a new mitoxantrone-based high-dose chemotherapy regimen to minimize pulmonary injury (seen in carmustine-based regimens) in patients with breast cancer. One hundred and ninety-one breast cancer patients (99 stage II/IIIA; 27 stage IIIB; 65 stage IV responsive to conventional-dose chemotherapy) were treated with high-dose chemotherapy (CTM) delivered over 4 days (cyclophosphamide (6 g/m2), thiotepa (600 mg/m2), and mitoxantrone (24-60 mg/m2)) followed by autologous hematopoietic stem cell rescue. Stage II/III patients received chest wall radiation and tamoxifen (if hormone-receptor positive) after CTM. The 5-year event-free survival (EFS) for stage II/IIIA patients with 10 or more involved axillary lymph nodes (n = 80) was 62 +/- 12%. Hormone receptor-positive patients with 10 or more nodes did significantly better than negative patients. The EFS for stage IIIB patients at 5 years was 44 +/- 19%; for stage IV patients at 5 years was 17 +/- 10%. Stage IV patients achieving complete response in viscera and/or soft tissue prior to CTM did significantly better than those achieving a partial response. There were six (3%) treatment-related deaths including two due to diffuse alveolar hemorrhage. There were no episodes of delayed interstitial pneumonitis. There were six severe cardiac events in 91 patients (6.6%) but none after instituting mitoxantrone dose-adjustment in the final 100 patients. We conclude that CTM is associated with a low treatment-related mortality and little pulmonary toxicity. CTM produces excellent outcomes in stage II/IIIA patients with 10 or more involved axillary lymph nodes.     

Preoperative high-dose chemotherapy with peripheral blood stem cell support as a primary management of locally advanced breast cancer

Locally advanced breast cancer (LABC) has a poor prognosis with a high risk of local recurrence and distant metastasis. Preoperative combined chemotherapy with or without granulocyte colony-stimulating factor (G-CSF) support does not improve the long-term survival rate. In our report, two patients with LABC received preoperative high-dose chemotherapy with peripheral blood stem cell support (HDC/PBSCs). Prior to high-dose chemotherapy with peripheral blood stem cell support, they both received induction chemotherapy of cyclophosphamide, epirubicin and 5-fluorouracil (FEC) for two cycles which resulted in a partial response. PBSC mobilization and collection were carried out following the second cycle of induction chemotherapy followed by G-CSF. High-dose cyclophosphamide (2500 mg/m2), carboplatin (600 mg/m2) and etoposide (600 mg/m2) were administered with PBSC support. A radical mastectomy was performed followed by adjuvant chemotherapy with FEC regimen for four cycles, followed by local irradiation, and endocrine therapy with tamoxifen. Both patients achieved a remarkable response in the primary lesion after HDC/PBSCs and tolerated the whole treatment well. Preoperative HDC/PBSCs as a new strategy in the treatment of LABC seems practical but it needs to be studied more deeply.     

Pharmacoeconomic evaluation of high-dose chemotherapy and peripheral blood stem cell support in high-risk or poor-prognosis malignancies

Discussion of the total costs and cost-effectiveness ratios of patients receiving high-dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) is controversial. In Germany, no reliable data are available, whereas in other countries this issue has been extensively studied. We performed a pharmacoeconomic evaluation on all patients (n?=?37) treated with HDC and PBSCS at our institution between July 1994 and June 1997. Patients suffered from high-risk or poor-prognosis breast cancer (n?=?24), Hodgkin's disease (n?=?3), high-grade non-Hodgkin's lymphoma (n?=?4), multiple myeloma (n?=?2), small-cell cervical cancer (n?=?1), malignant hystiocytosis (n?=?1) and testicular cancer (n?=?2). For pharmacoeconomic evaluation, the period from initiation of induction chemotherapy (IC) until reconstitution after the last course of HDC and PBSCS was considered. A total of 18 patients received IC/HDC/PBSCS for locally advanced or systemic disease, and 19 patients received adjuvant or consolidation IC/HDC/PBSCS. Treatment protocols were heterogeneous. Patients were treated with two to five courses (median two) respectively of IC and sequential mono-HDC (n?=?26), tandem-HDC (n?=?10) or triple-HDC (n?=?1). All patients received granulocyte/macrophage-colony-stimulating factor (G-CSF) for stem cell mobilisation and for amelioration of neutropenia after HDC. The relative costs (based on supplier prices) for the total amount of drugs prescribed during the in-patient period was 29.8% for G-CSF, 35.8% for blood products 18.5% for chemotherapy, 2.4% for antiemetics, 5.9% for antimicrobial drugs and 7.6% for other drugs. Contrary to expectations, antimicrobial drugs had only a minor pharmacoeconomic impact during IC/HDC/PBSCS in patients with high-risk or poor-prognosis malignancies, indicating that prolonged septic complications were uncommon in our institution. We conclude that pharmacoeconomic evaluations in IC/HDC/PBSCS might be integrated into the effort to ensure quality control and monitoring.     

Impression of prognosis regarding pathologic stage after preoperative chemoradiotherapy in rectal cancer

AIM: To ascertain pathologic stage as a prognostic indicator for rectal cancer patients receiving preoperative chemoradiotherapy(PCRT).METHODS: Patients with mid- and low rectal carcinoma(magnetic resonance imaging- based clinical stage Ⅱ or Ⅲ) between 2000 and 2009 and treated with curative radical resection were identified. Patients were divided into two groups: PCRT and No-PCRT. Recurrence-free survival(RFS) was examined according to pathologic stage and addition of adjuvant treatment.RESULTS: Overall, 894 patients were identified. Of these, 500 patients received PCRT. Adjuvant chemotherapy was delivered to 81.5% of the No-PCRT and 94.8% of the PCRT patients. Adjuvant radiotherapy was given to 29.4% of the patients in the No PCRT group. The 5-year RFS for the No-PCRT group was 92.6% for StageⅠ, 83.3% for Stage Ⅱ, and 72.9% for Stage Ⅲ. The 5-year RFS for the PCRT group was 95.2% for yp Stage 0, 91.7% for yp StageⅠ, 73.9% for yp Stage Ⅱ, and 50.7% for yp Stage Ⅲ.CONCLUSION: Pathologic stage can predict prognosis in PCRT patients. Five-year RFS is significantly lower among PCRT patients than No-PCRT patients in pathologic stage Ⅱ and Ⅲ. These results should be taken into account when considering adjuvant treatment for patients treated with PCRT.     

Receipt of recommended therapy by patients with advanced colorectal cancer

OBJECTIVES: To evaluate utilization of surgery, chemotherapy, and radiation therapy among patients with stage II or III colon cancer and stage II/III rectal or rectosigmoid cancer, as recommended by current national guidelines. METHODS: This cross-sectional study at the Michael E. DeBakey Veterans Affairs Medical Center (Houston, TX) used 1999-2003 administrative data to identify patients with a diagnostic code for colorectal cancer. Medical charts were then abstracted to identify an incident cohort with stage II or III cancer. Outcome of interest was receipt of recommended therapy defined as surgery only (stage II colon) or surgery with adjuvant chemo- or radiotherapy (stage III colon or stage II/III rectal/rectosigmoid cancer). Potential determinants of receipt of recommended therapy were analyzed using logistic regression. RESULTS: Among 197 incident cases diagnosed or treated, mean age of patients was 66 yr (SD, 11 yr), 64% were Caucasian, and 98.5% were men. A gastroenterologist diagnosed 72.5% tumors including 62 stage II colon, 62 stage III colon, and 73 stage II/III rectal cancers. Referral to oncology occurred in 76% of stage II colon, 92% of stage III colon, and 99% of rectal cancers. 87% of stage II and 71% of stage III colon cancer patients received recommended therapy, compared to only 42.5% of rectal cancer patients. Predictors of receipt of recommended therapy among rectal cancers included being married (OR, 5.3; 95% CI: 1.6-17.1), presentation at tumor board (OR, 3.6; 95% CI: 1.2-11.2), or age<65 yr (OR, 3.5; 95% CI: 1.3-9.3). When patient's comorbidity and physician's decision-making process were considered in the assessment of the outcome, only presentation at tumor board remained predictive of receipt of recommended therapy. CONCLUSIONS: Most colon cancer patients at a major VA medical center receive recommended therapy. Among rectal cancer patients, those presented at tumor board are most likely to receive recommended therapy.     

Comparative clinical trial of four regimens of dihydroartemisinin-mefloquine in multidrug-resistant falciparum malaria

We conducted a randomized, comparative trial at the Bangkok Hospital for Tropical Diseases during 1996-98 to evaluate the clinical efficacy and tolerability of four combination regimens of dihydroartemisinin-mefloquine. 207 male patients aged 18-25 years, weighing 49.3-55.1 kg were randomized to receive a single oral dose of 300 mg dihydroartemisinin plus one or two doses of mefloquine as follows: regimen I (n = 26): 750 mg mefloquine concurrently, or regimen II (n = 22): 750 mg mefloquine 24 h later, or regimen III (n = 78): 750 and 500 mg mefloquine at 24 and 30 h, or regimen IV (n = 81): 750 and 500 mg mefloquine (at 0 and 24 h). All patients improved clinically within 24 h of initiation of treatment. The initial therapeutic response was rapid and identical in all treatment groups (median PCT vs. FCT: 36 vs. 24, 36 vs. 28, 36 vs. 26, and 34 vs. 26 h, for regimen I, II, III and IV, respectively). All combination regimens generally showed acceptable tolerability profiles. Compliance with follow-up (42 days) was achieved by 86.5% (179 cases). Recrudescent parasitaemia was significantly higher in patients treated with low-dose mefloquine combinations (regimens I, II:8/23, 9/16) than in those who received high-dose mefloquine (regimens III, IV: 2/70, 3/70). No RII or RIII type of response was observed. There were no significant differences in susceptibility to mefloquine between primary and recrudescent isolates. Dose-adjusted whole blood mefloquine concentrations were significantly higher in high-dose mefloquine regimens (III and IV). Patients who vomited within the first hour of mefloquine administration had markedly lower whole blood mefloquine concentrations than those who did not vomit.     

Allogeneic stem cell transplantation (BMT) for AML and MDS following i.v. busulfan and cyclophosphamide (i.v. BuCy)

Pretransplant conditioning therapy with i.v. BuCy followed by allogeneic hematopoietic stem cell transplantation (BMT) was investigated in a phase II trial in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We gave i.v. Bu at a dose of 0.8 mg/kg every 6h x 16 doses, followed by Cy 60 mg/kg daily for 2 days. Twenty-six AML patients (18 males/eight females) were treated, only eight of whom were in CR1. The rest were either refractory to induction chemotherapy (four patients) or in a more advanced stage of their disease (14 patients). In addition, nine patients with MDS (1M/8F) were treated. Their median age was 41 years (range 21-64). Engraftment to > or =500 neutrophils/microl was reached at 14 days (range 10-29 days) post BMT, and the median time of neutropenia was only 11 days (range 4-28 days). The most common regimen-related toxicity was grade 2-3 nausea. In the post-BMT period (including BMT day +30), two patients died, one each from pulmonary hemorrhage secondary to CMV pneumonia and hepatic veno-occlusive disease (VOD), for an early treatment-related mortality (TRM) of 5.7%. Three patients developed VOD and two of them died. There was no direct regimen-related pulmonary or neurologic toxicity. Overall, the clinical side-effect spectrum was analogous to what would be expected from a high-dose oral Bu-based regimen; there was no unique toxicity experienced with the used solvent system. The disease-free survival in the high-risk subgroup (all patients not in CR1) at 1 and 2 years post transplant was 44% and 31%, respectively. The 13 patients still alive in CR have been followed for a median of 24 months (range 18-32). Pharmacokinetic analysis showed very good interdose reproducibility, and limited interpatient variability in area under the plasma concentration vs time curve, peak concentration, and clearance of Bu after this i.v. formulation. We conclude, that this new i.v. Bu formulation is well tolerated; it has an impressive safety profile, and we suggest that it should be considered as appropriate replacement for oral busulfan in pretransplant conditioning therapy prior to allogeneic BMT for patients with AML or MDS.     

High-dose chemotherapy containing busulfan followed by bone marrow transplantation in 24 children with refractory or relapsed non-Hodgkin's lymphoma.

Twenty-four children with relapsed or refractory non-Hodgkin's lymphoma underwent high-dose chemotherapy (HDC) with bone marrow transplantation (BMT). HDC comprised in all cases busulfan (16 mg/kg or 600 mg/m2), with either cyclophosphamide (200 mg/kg or 4.4 g/m2) and/or melphalan (140 mg/m2). Twenty-three of these children had received second-line therapy before receiving HDC. There were 16 B cell and eight T cell lymphomas. Twenty-three patients were evaluable at day 30 post-BMT; 19 were in complete remission, four did not respond. Eight patients are long-term survivors between 62 and 296 weeks after BMT. Among the seven children with resistant disease before HDC, only one is a long-term survivor. No toxic deaths occurred. The main adverse side effect was hepatic veno-occlusive disease which occurred in four patients, but resolved completely in all cases. Comparisons with other classic HDC regimens in relapsed childhood lymphomas show that HDC containing busulfan with BMT appears reasonably safe and is effective in refractory or relapsed lymphomas, even in these highly previously treated patients.