Treatment-related Fatalities Research Articles

Reporting clinical trial information: colorectal cancer trials at Sydney Cancer Centre

Clinical trial units are integral to the functioning of a medical oncology department with patient access to clinical trials an important component in patient care. There has been a paucity of potential key performance indicators in medical oncology and clinical trial information may be utilised for this purpose. The aim of this study was to record retrospectively and collate prospectively collected information regarding basic demographics, response rate, progression and survival plus grade 3 or 4 toxicity in patients enrolled in clinical trials for metastatic colorectal cancer at the Sydney Cancer Centre between 1999 and 2007. Baseline patient demographics, clinical response, progression dates, grade 3 or 4 toxicities plus treatment-related fatalities were collected from individual clinical trials. Outcome measures were clinical response, progression-free survival and overall survival. There was a total of 14 trials undertaken during the defined period for patients with metastatic colorectal cancer. There was available information for 243 patient trials with sufficient information regarding response rates, toxicity, progression and survival. Tumour response rates ranged from 27% to 66% for first line chemotherapy trials and 0% to 20% for non-first line chemotherapy trials. The overall progression-free survival was 6.4 months and overall survival 14.0 months for all trials. There was one treatment-related fatality on clinical trial during this period. Results of our clinical database have been used here to illustrate the concept and value of reporting clinical trial information in medical oncology. Public reporting of such information may allow for comparisons between units and for quality improvement.

Prospective Trial of High-Dose Reirradiation Using Daily Image Guidance With Intensity-Modulated Radiotherapy for Recurrent and Second Primary Head-and-Neck Cancer

To report a single-institutional experience using intensity-modulated radiotherapy with daily image-guided radiotherapy for the reirradiation of recurrent and second cancers of the head and neck. Twenty-one consecutive patients were prospectively treated with intensity-modulated radiotherapy from February 2006 to March 2009 to a median dose of 66 Gy (range, 60-70 Gy). None of these patients received concurrent chemotherapy. Daily helical megavoltage CT scans were obtained before each fraction as part of an image-guided radiotherapy registration protocol for patient alignment. The 1- and 2-year estimates of in-field control were 72% and 65%, respectively. A total of 651 daily megavoltage CT scans were obtained. The mean systematic shift to account for interfraction motion was 1.38 ± 1.25 mm, 1.79 ± 1.45 mm, and 1.98 ± 1.75 mm for the medial-lateral, superior-inferior, and anterior-posterior directions, respectively. Pretreatment shifts of >3 mm occurred in 19% of setups in the medial-lateral, 27% in the superior-inferior, and 33% in the anterior-posterior directions, respectively. There were no treatment-related fatalities or hospitalizations. Complications included skin desquamation, odynophagia, otitis externa, keratitis, naso-lacrimal duct stenosis, and brachial plexopathy. Intensity-modulated radiotherapy with daily image guidance results in effective disease control with relatively low morbidity and should be considered for selected patients with recurrent and second primary cancers of the head and neck.

Adjuvant lipiodol I-131 after curative resection/ablation of hepatocellular carcinoma

Aim. A total of 329 patients with hepatocellular carcinoma have been treated at our unit since 1990. Following the randomized controlled trial in Hong Kong by Lau et al. in 1999, patients have been offered adjuvant lipiodol I-131. The aim of this study was to determine the effectiveness of adjuvant lipiodol I-131, following potentially curative surgery with resection and/or ablation, on overall and disease-free survival rates. Material and methods. The prospectively updated hepatocellular carcinoma database was analysed retrospectively. A total of 34 patients were identified to have received adjuvant lipiodol I-131 post-curative treatment with surgical resection and/or ablation. Patient demographics, clinical, surgical, pathology, and survival data were collected and analysed. Results. Three patients received ablation alone, 24 resection, and 7 resection and ablation. Of the 34 patients treated, there were 2 possible cases of treatment-related fatality (pneumonitis and liver failure). Potential prognostic factors studied for effect on survival included age, gender, serum AFP concentration, Child-Pugh score, cirrhosis, tumor size, portal vein tumor thrombus, tumor rupture, and vascular and margin involvement. The median follow-up duration was 23.3 months. The overall median survival was 40.1 months, while the overall survival rates at 1, 2, 3, and 4 years were 87.1%, 71.7%, 60.7%, and 49.6%, respectively. Median duration to recurrence was 22.3 months. Conclusion. Administration of adjuvant lipiodol I-131 is associated with good overall survival.

Phase II study of preoperative sequential FEC and docetaxel predicts of pathological response and disease free survival

Purpose This multicenter phase II study examined the impact of pathological effect on survival after preoperative chemotherapy in Japanese women with early stage breast cancer. Patients and methods Prior to surgery, patients received four cycles of FEC (fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2) q3w) followed by four cycles of docetaxel (75 mg/m(2) q3w). Primary endpoint was 3 year disease free survival (DFS) stratified by the absence or presence of Quasi-pCR (QpCR; absence of invasive tumor or only focal residual tumor cells). Secondary endpoints were predictors for QpCR, clinical response, breast conservation rate, and safety. Results Between June 2002 and June 2004, 202 women were enrolled. Among 191 assessable patients, 25% achieved QpCR. With 40 months median follow-up, 3 year DFS was estimated at 91% for all patients. 3 year DFS for patients with QpCR was 98% vs. 89% without QpCR (hazard ratio 0.38 [95% Confidence Interval 0.09-0.84], P = 0.0134). HER2 status and response to FEC were independent predictors of QpCR. The overall clinical response was 75%; 85% of patients achieved breast conservation. Grade 3/4 neutropenia was the most common adverse event, observed in 44% and 35% of patients during FEC and docetaxel, respectively. Treatment related side effects were manageable; there were no treatment related fatalities. Conclusion FEC followed by docetaxel is an active and manageable preoperative regimen for women with early stage breast cancer. QpCR following preoperative chemotherapy predicts favorable DFS. HER2 overexpression and clinical response to FEC predict QpCR.

A phase II evaluation of aerosolized GM-CSF (AGM-CSF) plus standard I-MAP/ GM-CSF/MAP/ surgery/ irradiation in the reduction of pulmonary metastases (P-METS) in soft tissue sarcoma (STS) patients (PTS)

10058 Background: P-METs remain illusive with standard treatments for STS. AGM-CSF demonstrated tolerability with promising efficacy in reducing P-METS. We evaluated the 2-yr P-MET free rate in chemonaiive pts with extremity STS. Methods: ECOG PS 0/1 and Gr 3/4 primary STS of the limb girdle/extremities, were required. Treatment sequence: 2 cycles of IMAP (Ifosfamide, Mitomycin, Doxorubicin, Cisplatin) plus s.q. GM-CSF (preload d -6 to -3, d1–14); MAP (d0, 28) during irradiation (d1–35) plus AGM-CSF 250 mcg bid (d1–7, 15- 22, 28–35); surgery; post-op irradiation plus AGM-CSF 250 mcg bid (d1–7, 15–22, 28–35, 42–49). 6 of 35 pts with P-METS in ≤ 2 yrs implied lack of efficacy w.r.t. reducing P-METS. Results: 38 eligible pts were enrolled (20 male, median age 51 yrs, 24 PS 0). Median size of tumor 9 cm (2.3–26.7 cm).Location of tumors included: proximal extremity-16, distal extremity-11, and limb girdle-12. 79% received debulking surgery; 29 rendered disease-free. 38 pts are evaluable for toxicity (see table ). More common Gr 3+ events related to treatment appear below. 79% had Gr 4 neutropenia, despite s.q. GM-CSF. 6 pts have died, with 2.5 yrs median follow-up on survivors (range .4- 4.6). No treatment related fatalities occurred. 10 pts had P-METS ≤ 2 yrs. The estimated 2 yr P-MET free rate is 75% (95% CI 62–91). Conclusions: Although high, neutropenia was as expected. AGM-CSF failed to improve the 2 yr P-MET free rate in this group of STS pts. Other strategies need to be explored. Supported by NIH Grant CA15083–32 and Berlex Corporation. Max Severity (Gr 3+) [Table: see text] No significant financial relationships to disclose.

70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808

Purpose To prospectively evaluate the feasibility of delivering 70 Gy once-daily thoracic radiotherapy (TRT), concurrent with chemotherapy, in the treatment of limited-stage small-cell lung cancer (L-SCLC). Materials and methods Eligible patients received two cycles of induction paclitaxel (175 mg/m 2 on Day 1) and topotecan (1 mg/m 2 on Days 1–5) with granulocyte colony stimulating factor support, followed by three cycles of carboplatin (area under the curve = 5 on Day 1) and etoposide (100 mg/m 2 on Days 1–3). TRT (70 Gy, 2 Gy/fx/7 weeks) was initiated with the first cycle of carboplatin and etoposide. Prophylactic cranial irradiation was offered to patients achieving a complete response or good partial response. Results Ninety percent of patients (57 of 63) proceeded to protocol TRT. There was one treatment-related fatality. Nonhematologic Grade 3/4 toxicities affecting more than 10% of patients, during or after TRT, were dysphagia (16%/5%) and febrile neutropenia (12%/4%). The response rate to all therapy was 92% and the median overall survival is 22.4 months (95% confidence interval 16.1, ∞). Twenty-eight patients remain alive with a median follow-up of 24.7 months. Conclusion 70 Gy once-daily TRT can be delivered safely in the cooperative group setting for patients with L-SCLC. Initial efficacy data are encouraging. The hypothesis that high-dose once-daily TRT results in comparable or improved survival compared with twice-daily accelerated TRT warrants testing in a Phase III trial.

External beam radiotherapy in bone metastatic prostate cancer: Impact on patients' pain relief and quality of life

Bone metastases are a severe problem in oncology, since they usually are associated with pain. External beam radiation therapy (EBRT) has been, for many years, an important component of the treatment regimen to relieve pain. We have performed a clinical study to evaluate the relationship of response to EBRT in terms of pain relief and improvement in quality of life (QoL). We were also interested in the incidence of acute toxicity with EBRT. We have prospectively evaluated 75 patients (median age 68 years, range 64-79 years) with bone metastases from prostate cancer treated with EBRT, radiographically documented from June 1999 to September 2000. Additional therapies in these patients included: second-line hormonal therapy (HT) in 20 patients, chemotherapy (CT) in 25 patients, biphosphonates in 45 patients. For all patients a pain and narcotic evaluation was done before entering the study. Assessment of response was carried out by evaluating pain relief. QoL was measured by using the EORTC QLQ-C30 questionnaire. Toxicity analysis was based on the ROTG grading system. Survival was calculated by Kaplan-Meier estimate from the start of EBRT treatment until the last follow-up or death. A total of 61 out of 75 patients (81%) experienced some type of pain relief after treatment. The complete response rate was 23%. No significant difference in the response rates was found between the group treated with EBRT alone versus the groups treated with EBRT + CT or EBRT + HT. We noted a significant improvement in some of the scales of the considered EORTC-QLQC30 questionnaire. As expected all treatment-related complications were either grade 1-2 acute or subacute and transitory in nature. The group treated with EBRT + CT experienced slightly higher toxicity rates. There were no treatment-related fatalities. Forteen patients of 61 (23%) responders was alive at 12 months. Our results confirm the ability of EBRT to relieve bony pain in the majority of the cancer patients treated as measured by prospective analysis of pain scales prior to and after EBRT. Minimal side effects were experienced and QoL improved as shown by the results of the specific questionnaire.

Causes of death among HIV-infected patients in the era of highly active antiretroviral therapy, Bordeaux, France, 1998-1999.

To describe the causes of death in HIV-infected patients in the era of highly active antiretroviral therapy (HAART). A retrospective survey conducted in Bordeaux, France. Medical records of all deaths that had occurred in 1998 and 1999 amongst patients followed within the Aquitaine cohort were reviewed by the same physician. Immediate and underlying causes of death were described, taking into account the morbidity at the time of death. Sixty-six deaths occurred in 1998, and 41 in 1999. Sixty-seven per cent of deceased patients were male. Median age at time of death was 43 years (range 25-71), median CD4 was 162 cells/microL (0-957); 28% of patients had a CD4 count > 200 cells/microL and 7% plasma viral load < 500 HIV-RNA copies/mL. Amongst morbidity present at the time of death, there were 23 bacterial infections, 16 non-Hodgkin's lymphomas, 16 cirrhoses, 15 non HIV-related malignancies, 13 central nervous system diseases and 10 myocardiopathies. The main immediate causes of death were: multiple organ failure (21%), coma (18%), septic shock (15%) and acute respiratory failure (14%). Underlying causes of death were AIDS-defining events (48%), non AIDS HIV-related infection (3%), hepatitis B- or C-associated cirrhosis (14%), non HIV-related malignancies (11%), cardiovascular events (10%), suicide and overdose (6%), treatment-related fatalities (4%), injury (2%) and unknown (2%). Patients dying from AIDS-related events were more often female, had a lower CD4 count, a higher level of HIV-RNA, a shorter history of HIV infection and were less often coinfected with hepatitis B and C viruses than those dying from other underlying causes. AIDS-related events are no longer the major causes of death of HIV-infected patients in the era of HAART. This evolving mortality pattern justifies an adaptation of both the epidemiological surveillance and the clinical monitoring of HIV-infected patients.

Risk-Adapted Therapy for Clinical Stage I–II Hodgkin's Disease: 7-Year Results of Radiotherapy Alone for Low-Risk Disease, and ABVD and Radiotherapy for High-Risk Disease

Treatment outcomes were documented for 204 adult patients with clinical Stage I–II Hodgkin's disease who were treated with risk-adapted ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and radiotherapy (RT) at the Toronto–Sunnybrook Regional Cancer Centre between 1984 and 1994. Forty-nine patients with clinical Stage I disease (excluding bulky mediastinal presentations) and 50 patients with a combination of clinical Stage IIA disease, age 50 years or less, and favourable pathology (lymphocyte predominant or nodular sclerosing histology) were identified as low risk and treated with RT alone to 35 Gy. One hundred and five high-risk patients were treated with chemotherapy (86 with ABVD) followed by RT to 25 Gy. The 7-year cause-specific, overall and disease-free survivals were 95%, 90% and 75% respectively for the low-risk cohort, and 91%, 90% and 88% respectively for the high-risk cohort. In-field relapses accounted for 50% of the failures in both groups. Sixteen of 24 (67%) patients with RT failure and 6/14 (43%) with combined modality therapy (CMT) failure were salvaged. Twenty-eight per cent of the patients treated with RT and 21% of those treated with CMT developed hypothyroidism by 7 years. Fatal complications were recorded in 6% of the low-risk patients managed with RT and 8% of high-risk patients managed with CMT. Septic death and second malignancy accounted for the majority of treatment-related fatalities. Risk-adapted therapy emphasizing RT alone for selected patients with favourable prognostic factors and CMT based on ABVD provides excellent long-term disease control. Further treatment refinements, including the wider application of CMT with lower doses of chemotherapy and RT, will be required to reduce the rate of fatal complications to more acceptable levels.

Doxorubicin versus methotrexate both combined with cyclophosphamide, 5-fluorouracil and tamoxifen in postmenopausal patients with advanced breast cancer—a randomised study with more than 10 years follow-up from the danish breast cancer cooperative group

To evaluate the substitution of methotrexate with doxorubicin (Dox) in CMF-(cyclophosphamide, methotrexate, 5-fluorouracil) containing regimen for advanced breast cancer, 415 postmenopausal patients below the age of 66 years, naı̈ve to chemotherapy, were accrued from 1980 to 1984 and followed-up until 1995. They received tamoxifen 30 mg daily orally and by randomisation either 400 mg/m 2, cyclophosphamide, 25 mg/m 2 doxorubicin and 500 mg/m 2 5-fluorouracil (CAF) or 40 mg/m 2 methotrexate instead of Dox (CMF) intravenously (i.v.) days 1+8 repeated every 4 weeks. Dox was substituted by methotrexate at a cumulative dose of 550 mg/m 2. Among 341 eligible patients the response rate and median time to progression was significantly in favour of CAF: 53% CAF versus 36% CMF ( P=0.002) and 11.8 months CAF versus 6.5 months CMF ( P=0.001). Median duration of response was 19.5 CAF versus 18.0 CMF months, and survival 20.8 CAF versus 17.4 CMF months (non-significant). The two regimens were equimyelotoxic. There were no treatment-related fatalities but 1 patient with congestive heart failure on CAF was reported. Nausea/vomiting, stomatitis and infections were modest in both groups, whilst alopecia was more common with CAF. Regression analysis showed that long recurrence free interval, good performance status, and no visceral involvement was significantly related to long-term survival, whilst the treatment regimen was not. It is concluded that in chemotherapy-naı̈ve patients with advanced breast cancer Dox-containing regimens are superior and remain the first choice of chemotherapy, especially in patients with visceral metastases, until newer drugs and combinations have been proven to be superior.

Adjuvant continuous infusion 5-FU, whole-abdominal radiation, and tumor bed boost in high-risk stage III colon carcinoma: A southwest oncology group pilot study

Results of a combined modality adjuvant pilot program of low-dose continuous-infusion 5-fluorouracil, whole-abdominal radiation, and tumor bed boost in patients with colon cancer with involved nodes and serosal involvement are presented. Forty-one eligible patients with completely resected T3N1-2M0 colon cancer (modified Astler-Coller C2) were treated with 5-fluorouracil (5-FU) at a dose of 200 mg/m2/day by continuous infusion and 30 Gy of concomitant whole-abdominal radiation in 1 Gy fractions. An additional 16 Gy boost to the tumor bed was administered in 1.6 Gy fractions. After completion of combined modality treatment and a 21-day rest period, patients received 4 days of 5-FU at a dose of 1000 mg/m2 by continuous infusion every 28 days for nine cycles. Five-year disease-free and overall survival estimates were 58 and 67%, respectively, for all T3N1-2 patients. Five-year disease-free and overall survival estimates for the 19 patients with four or fewer nodes were both 61%. Five-year disease-free survival and overall survival estimates for the 20 patients with more than four involved nodes were 55% and 74%, respectively (the exact number of involved nodes were unknown for two patients). Disease-free and overall survival estimates for patients treated with 5-FU and radiation compare favorably to the 5-FU plus levamisole arm of the intergroup adjuvant colon study (Int 0035/SWOG 8591) in patients with more than four positive nodes where the 5-year disease-free and overall survival estimates were 35% and 39%, respectively. Disease-free and overall survival estimates for patients with four or fewer nodes in the 5-FU plus levamisole arm of the intergroup study were 64 and 68%, which is not markedly different from results obtained with radiation and 5-FU in the current study. There were no treatment-related fatalities. Seventeen percent of patients had severe and 7% had life-threatening toxicity of any kind. One patient had an acute partial bowel obstruction and two patients had chronic low grade enteritis. Continuous infusion 5-FU and whole-abdominal radiation with tumor bed boost should be further investigated in a larger trial of T3N1-2 colon cancer.

Local and systemic toxicity of intra-hepatic-arterial 5-FU and high-dose or low-dose leucovorin for liver metastases of colorectal cancer

In an ongoing prospective study 11 patients with unresectable liver metastases from colorectal caracinoma have been treated with hepatic-arterial infusion of 5-FU (1 g m −2) for 24 h on days 1 to 5 combined with a rapid infusion of high-dose leucovorin (100 mg m −2) (HD-regimen) or low-dose leucovorin (20 mg m −2) (LD-regimen) on days 1, 3 and 5. There was only mild local toxicity grade 1 and grade 2 in both regimen. Twenty-four cycles with high-dose leucovorin and 42 cycles with low-dose leucovorin showed a mild to moderate systemic toxicity, including haematological changes, stomatitis and diarrhoea. We did not see any grade 4 toxicity and no treatment-related fatalities occurred in this series. Eighty per cent reduction of leucovorin dosage leads to a significant decrease in grade 2 and grade 3 haematological and gastrointestinal toxicity.

Intensive combination chemotherapy, concurrent chest irradiation, and warfarin for the treatment of limited-disease small-cell lung cancer: a Cancer and Leukemia Group B pilot study.

In prior Cancer and Leukemia Group B (CALGB) studies, combined chemotherapy and thoracic irradiation was superior to chemotherapy alone in limited-disease (LD) small-cell lung cancer (SCLC). A combined modality pilot study was performed to test the feasibility of adding warfarin to aggressive chemoradiotherapy for LD SCLC. Combination chemotherapy with doxorubicin 45 mg/m2 intravenously (IV) on day 1, cyclophosphamide 800 mg/m2 IV on day 1, and etoposide (ACE) 80 mg/m2 on days 1 to 3 was given every 21 days for the first three courses. The fourth and fifth courses substituted cisplatin 33 mg/m2 IV on days 1 to 3 for the doxorubicin, with concurrent chest irradiation to a total of 4,000 cGy given in 20 fractions during a 4-week period followed by a boost of 1,000 cGy in five fractions during a 1-week period. Prophylactic cranial irradiation, 3,000 cGy was given concurrently in 10 fractions during a 2-week period. Courses 6 to 8 again used ACE chemotherapy, but courses 4 to 8 were given on a 28-day schedule with dose adjustment for hematologic or renal toxicity. Warfarin was given throughout the treatment period titrated to achieve a prothrombin time (PT) of 1.5 to 2 times the control. Patients with histologically proven limited-stage SCLC, good performance status, and normal renal, hematologic, and hepatic functions were eligible. Sixty-one of 66 patients entered onto the study were eligible and assessable. Fifty-four (89%) (95%) confidence interval [CI], 78% to 95%) experienced an objective response, 35 (57%) achieved a complete response (CR) (95% CI, 44% to 70%), and 17 (28%) achieved a partial response (95% CI, 16% to 39%). Median durations were CR, 26.3 months; failure-free survival, 11.8 months; and survival, 18 months. Forty-one percent of the patients were alive at 2 years, 33% were alive at 3 years, and 25% were alive at 4 or more years. Median follow-up for survivors is 5 years (range, 3.5 to 5.9 years). Severe or life-threatening myelosuppression occurred in 90%, infection occurred in 34%, fever without documented infection occurred in 26%, and pulmonary toxicity occurred in 6%. Another 6% of patients experienced severe or life-threatening hemorrhages. There were four treatment-related fatalities. The pulmonary toxicities have been associated with the resumption of ACE chemotherapy after chest irradiation. These highly encouraging response and survival results compare favorably with any prior CALGB group study. Although they are somewhat more toxic, they are comparable to the best published results. A randomized study that examines the role of warfarin is underway.

A clinical trial of biochemical modulation of 5-fluorouracil with N-phosphonoacetyl-L-aspartate and thymidine in advanced gastric and anaplastic colorectal cancer

A novel sequential administration schedule of PALA (N-phosphonoacetyl-L-aspartate) and thymidine to enhance the cytotoxic effect of 5-fluorouracil (5FU) was tested in 36 patients with advanced gastric cancer and 21 patients with advanced poorly differentiated (anaplastic) colorectal cancer. The potency of 5FU was dramatically increased as indicated by the observation of dose-limiting leukopenia at less than one tenth the maximum tolerated dose of 5FU when given as a single agent by intravenous bolus technique. Twenty-five percent of gastric cancer patients and 33% of colorectal cancer patients experienced an objective tumor response, including three patients with complete response. However, response duration was brief (median, 6 months), and there were four treatment-related fatalities due to severe and unpredictable leukopenia leading to sepsis. Survival was short with a median of 6 months for gastric cancer patients and 3 1/2 months for colorectal cancer patients. We conclude that therapeutic index of 5FU was not improved by the addition of PALA and thymidine in this patient population based on considerations of objective tumor response rate, patient survival, and toxicity.

M-BACOD treatment for intermediate- and high-grade malignant lymphomas: a Southwest Oncology Group phase II trial.

One hundred six eligible patients with advanced intermediate- or high-grade malignant lymphoma were treated with methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) in a Southwest Oncology Group phase II trial. Patients were stratified by estimated bone marrow reserve, and impaired marrow reserve patients received reduced doses of cyclophosphamide and doxorubicin. The complete remission rate for normal marrow reserve patients was 65%, while the complete remission rate for impaired marrow reserve patients was 29%. With a median follow-up period of 41 months, 64% of complete responders in the normal marrow group are disease-free 3 years after their response. Three-year survival is 61% in the normal marrow reserve group and is 29% in the impaired marrow reserve group. Eighty-seven percent of treatment courses were given in accordance with protocol dosing and schedule. For doxorubicin, relative dose intensities were 0.75 and 0.61 (normal and impaired marrow reserve arms, respectively), for cyclophosphamide, 0.76 and 0.61, and for methotrexate, 0.55 and 0.45. Serum lactic dehydrogenase (LDH) level was the only pretreatment characteristic found to have a significant effect on overall survival. Severe or greater toxicity occurred in 97% and 89% of the normal and impaired marrow reserve groups, respectively, with granulocytopenia the principal toxicity. Treatment-related fatalities occurred in 8% of patients. m-BACOD is an effective but toxic treatment program for intermediate- and high-grade malignant lymphomas.

Advanced neuroblastoma: results of two treatment programs including sequential hemibody irradiation

Results of two consecutive treatment programs for advanced neuroblastoma, including sequential hemibody irradiation, are analyzed and compared. The first treatment program (I-TP) included one single-fraction (7 Gy) irradiation to the upper and lower halves of the body as consolidation of remission achieved by previous chemotherapy with CDDP and VP16. A fractionated technique (2 Gy daily for 4 consecutive days to each hemibody) was used in the second treatment program (II-TP) for children in remission following a combination of CDDP + VP16 and ADM + VCR + CTX. In both treatment programs, chemotherapy was continued according to the same pre-radiation regimen following the two sessions of hemibody irradiation. Overall response rate to pre-radiation chemotherapy was 84% and 60% for I-TP and II-TP, respectively. Thirty-month overall progression-free survival was 0 for I-TP and 20% for II-TP. No treatment-related fatalities occurred. In the subsets of patients who reached complete or good partial remission during the pre-radiation chemotherapeutic phase, 30-month progression-free survival in I-TP and II-TP was 0 and 33%, respectively. The role of fractionated hemibody irradiation in prolonging the progression-free survival can be inferred.

A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer. A mayo clinic/north central cancer treatment group study

The Mayo Clinic and the North Central Cancer Treatment Group (NCCTG) conducted a randomized clinical trial comparing five different combination chemotherapeutic regimens to single-agent 5-fluorouracil (5-FU), given by intravenous bolus technique (500 mg/m2 for 5 days) as a control, in the treatment of advanced colorectal cancer. This report summarizes the results of treatment in 208 patients who were randomized to 5-FU alone or 5-FU with leucovorin in either a high-dose (200 mg/m2) or a low-dose regimen (20 mg/m2) intravenously for 5 days. Both of the 5-FU with leucovorin regimens were associated with improved survival compared with single-agent 5-FU (P less than 0.03). The interval to tumor progression, measurable tumor response rates, and measures of quality of life (performance status, weight gain, and symptomatic relief) were also improved significantly with the addition of leucovorin. There was no therapeutic advantage associated with the use of high-dose compared with low-dose leucovorin. The dose-limiting toxicity of 5-FU/leucovorin was stomatitis. There was one treatment-related fatality (due to sepsis) among the 138 patient receiving 5-FU/leucovorin (0.7%). The most favorable regimen in this trial was 5-FU with low-dose leucovorin, based upon considerations of therapeutic effectiveness, toxicity, and cost. A national intergroup trial is being coordinated by the National Cancer Institute that will test the efficacy of low-dose leucovorin with 5-FU as one approach to adjuvant therapy after a curative surgical resection in selected patients with Dukes' Stage B2 or C colon cancer.

Chemotherapy followed by consolidation radiation therapy for the treatment of clinical stage II aggressive histologic type non-Hodgkin's lymphoma.

Sixty-three eligible patients with Ann Arbor clinical Stage II or IIE aggressive histologic type non-Hodgkin's lymphomas received combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [COPA]) as the primary treatment technique. Moderate-dose radiation therapy (2500 to 3000 cGy in 2 to 3 weeks) was given to anatomic areas involved initially by lymphoma in patients demonstrated to be in complete remission after chemotherapy. Fifty-seven percent of the patients were free of lymphoma clinically after induction chemotherapy. The minimum patient follow-up from the start of chemotherapy is 3.7 years, and the median follow-up for patients still alive is 4.7 years. The progression-free survival is projected to be 62% at 4 years, and 86% of the patients achieving a complete response are projected to be in continuous remission at 4 years from the completion of all therapy. There were no treatment-related fatalities. This treatment sequence has produced durable tumor control in the majority of patients with acceptable toxicity. The need for consolidation radiation therapy is being studied currently in a controlled clinical trial.

Major complications and causes of death in patients treated for Hodgkin's disease.

A total of 340 patients with Hodgkin's disease were evaluated for the occurrence of intercurrent fatalities after treatment with radiotherapy, chemotherapy, combined modality therapy, and salvage chemotherapy. Mean follow-up time was 76.6 months. Causes of death were compared with the expected risk, calculated from mortality statistics of the Netherlands' population. Sixty-seven patients died of progressive Hodgkin's disease, whereas 37 patients died of causes unrelated to advanced disease. Patients showed an increased risk of dying of leukemia and solid tumors (P less than .001), whereas the risk of dying of cardiovascular complications was not increased. The 10-year actuarial risk of dying of leukemia varied between 0% for patients treated with radiotherapy only and 5.7% for those needing salvage chemotherapy. The 10-year risk of dying of solid tumors was 0% for patients treated with chemotherapy and 6.5% for those receiving radiotherapy. Treatment-related fatalities were highest after combined modality therapy (P less than .025); the corresponding 10-year risk was 6.1%. Compared with younger ones, patients greater than or equal to 40 years had an increased risk of dying of causes unrelated to progressive Hodgkin's diseases. The actuarial risk of developing intercurrent fatalities at 10 years was 4.9% in patients less than 40 years, and 34.7% in those greater than or equal to 40 years (P less than .001). Compared with population based statistics, patients successfully treated for Hodgkin's disease still showed an increased risk of dying (P less than .001). Treatment modality, stage, and histologic subtype were not predictors of intercurrent death.

Possible benefit of doxorubicin treatment in patients with refractory germ cell cancer

Forty patients with germ cell cancer (GCC) refractory to vinblastine, cisplatin, and bleomycin therapy were treated with etoposide (E), cisplatin +/- bleomycin +/- doxorubicin and were evaluated retrospectively to determine response to treatment. Thirty cancers were primary testicular and ten extragonadal in origin. Fifty-five percent (22/40 patients) of the group responded to therapy. Eight of 40 (20%) patients had complete responses (CR) and 14 of 40 (35%) had partial responses (PR). Seven of 30 (23%) patients with a testes primary had a CR in contrast to 1 of 10 patients with extragonadal origin cancer. Six of eight patients (75%) having a CR received doxorubicin in combination, while only 2 of 18 (11%) patients having no response were treated with a doxorubicin-combining regimen. Of the entire group, 12 of 14 patients (86%) treated with doxorubicin for the first time responded to therapy compared to 10 to 26 patients (38.5%) not receiving doxorubicin (P = 0.009 Fisher's exact test). Myelosuppression was more frequent in patients treated with doxorubicin (87%) than in those treated without doxorubicin (70%). No increased frequency of hospitalization was required and no treatment-related fatalities occurred. Salvage therapy of patients with GCC appears to be improved when doxorubicin is added to etoposide, cisplatin, and bleomycin.