Late Toxicity and Long-Term Local Control in Patients With Ultra-Central Lung Tumours Treated by Intensity-Modulated Radiotherapy-Based Stereotactic Ablative Body Radiotherapy With Homogenous Dose Prescription.

AIMS: To report late toxicity and long-term outcomes of intensity-modulated radiotherapy (IMRT)-based stereotactic ablative body radiotherapy (SABR) in patients with ultra-central lung tumours. MATERIALS AND METHODS: This is a single-institution retrospective analysis of patients treated with SABR for ultra-central tumours between May 2008 and April 2016. Ultra-central location was defined as tumour (GTV) abutting or involving trachea, main or lobar bronchi. Respiratory motion management and static-field dynamic-IMRT were used, with dose prescribed homogeneously (maximum <120%). Descriptive analysis, Kaplan-Meier method, log-rank test and Cox regression were used to assess outcomes. RESULTS: Sixty-five per cent of patients had inoperable primary non-small cell lung cancer and 35% had lung oligometastases. The median age was 72 (range 34-85) years. The median gross tumour volume and planning target volume (PTV) were 19.6 (range 1.7-203.3) cm3 and 57.4 (range 7.7-426.6) cm3, respectively. The most commonly used dose fractionation was 60 Gy in eight fractions (n = 51, 87.8%). Median BED10 for D98%PTV and D2%PTV were 102.6 Gy and 115.06 Gy, respectively. With a median follow-up of 26.5 (range 3.2-100.5) months, fatal haemoptysis occurred in five patients (8.7%), of which two were directly attributable to SABR. A statistically significant difference was identified between median BED3 for 4 cm3 of airway, for patients who developed haemoptysis versus those who did not (147.4 versus 47.2 Gy, P = 0.005). At the last known follow-up, 50 patients (87.7%) were without local recurrence. Freedom from local progression at 2 and 4 years was 92 and 79.8%, respectively. The median overall survival was 34.3 (95% confidence interval 6.1-61.6) months. Overall survival at 2 and 4 years was 55.1 and 41.2%, respectively. CONCLUSION: In patients with high-risk ultra-central lung tumours, IMRT-based SABR with homogenous dose prescription achieves high local control, similar to that reported for peripheral tumours. Although fatal haemoptysis occurred in 8.7% of patients, a direct causality with SABR was evident in only 3%. Larger studies are warranted to ascertain factors associated with outcomes, especially toxicity, and identify patients who would probably benefit from this treatment.

Stereotactic Ablative Radiation Therapy for Large (≥5 cm) Non-small Cell Lung Carcinoma.

AIMS: Stereotactic ablative radiation therapy (SABR) is a standard of care for medically inoperable early stage non-small cell lung carcinoma. Tumours greater than 5 cm have been excluded from randomised trials using SABR and, hence, it is not used as a standard for larger lung tumours. However, improvements in radiation therapy techniques and the success of SABR in treatment of early stage disease may allow safe delivery of ablative doses to larger tumours. We analysed our experience with tumours ≥5 cm to determine the efficacy and toxicity profile of SABR in this setting. MATERIALS AND METHODS: We evaluated survival, control rates, patterns of failure and toxicity in patients with a tumour diameter larger than 5 cm that had no nodal or distant metastases treated with SABR technology. Patients had been treated in two centres since 2009 and were retrospectively analysed. All patients had positron emission tomography staging, were discussed at a tumour board and were documented to have no nodal or distant metastatic disease. Treatment outcomes were analysed using Kaplan-Meier estimates and compared using the Log-rank test. Cox regression was used to investigate the association between the survival outcomes and predictor variables. RESULTS: In total, 86 patients were identified. Six patients had no follow-up imaging. Therefore, 80 patients were available for analysis. All patients were reclassified according to the updated AJCC eighth edition. The median follow-up was 19.6 months. No patients received neoadjuvant or concurrent systemic therapy. One patient received adjuvant systemic therapy. The median age at treatment was 77 years (range 58-91). Eighty-four per cent were stage T3N0M0 and 16% were staged T4N0M0. The median tumour diameter was 5.8 cm (range 5.0-9.3 cm). The median gross tumour volume, measured on a single phase of the respiratory cycle, was 45.7 cm3 (range 12.1-203.3 cm3). The median overall survival was 20.9 months (95% confidence interval 12.6-29.1 months). One-, 2- and 3-year overall survival was 71%, 48% and 32%, respectively. The median local failure-free survival was 19.5 months (95% confidence interval 14.4-24.6). The median disease-free survival was 15.1 months (95% confidence interval 9.9-20.4 months). Local control at 1, 2 and 3 years was 85% (95% confidence interval 76-94%), 71% (95% confidence interval 58-84%) and 57% (95% confidence interval 40-74%), respectively. Forty-four patients (55%) had any treatment failure (local, mediastinal, intrapulmonary or distant metastases). Out-of-field intrapulmonary disease progression was the most common mode of failure, occurring in 21 patients (26%). Local failure occurred in 19 patients (24%) - alone or in combination with other progression. Distant metastases occurred in 20 patients (25%). Neither histological subtype, tumour size nor gross tumour volume had a statistically significant effect on local failure-free survival. Two patients experienced grade 3 late dyspnoea. There were no other reported grade 3 or higher acute or late toxicities. CONCLUSION: SABR for larger lung tumours ≥5 cm results in high local control and acceptable survival in patients with medically inoperable large non-small cell lung carcinoma treated with radiation alone. Such patients should be considered for SABR owing to fewer treatment fractions and acceptable toxicity. Local control analysis reveals a sustained pattern of local failure emphasising the need for long-term follow-up. Improvements in technical strategies are required to further improve local control.

Multiplex profiling identifies clinically relevant signalling proteins in an isogenic prostate cancer model of radioresistance.

The exact biological mechanism governing the radioresistant phenotype of prostate tumours at a high risk of recurrence despite the delivery of advanced radiotherapy protocols remains unclear. This study analysed the protein expression profiles of a previously generated isogenic 22Rv1 prostate cancer model of radioresistance using DigiWest multiplex protein profiling for a selection of 90 signalling proteins. Comparative analysis of the profiles identified a substantial change in the expression of 43 proteins. Differential PARP-1, AR, p53, Notch-3 and YB-1 protein levels were independently validated using Western Blotting. Pharmacological targeting of these proteins was associated with a mild but significant radiosensitisation effect at 4Gy. This study supports the clinical relevance of isogenic in vitro models of radioresistance and clarifies the molecular radiation response of prostate cancer cells.

(ICORG 05-03): prospective randomized non-inferiority phase III trial comparing two radiation schedules in malignant spinal cord compression (not proceeding with surgical decompression); the quality of life analysis.

BACKGROUND: The optimal primary external beam radiation therapy (EBRT) radiation schedule for malignant epidural spinal cord compression (MSCC) remains to be determined. The ICORG 05-03 trial assessed if a 10 Gy single fraction radiation schedule was not inferior to one with 20 Gray (Gy) in five daily fractions, in terms of functional motor outcome, for the treatment of MSCC in patients not proceeding with surgical decompression. This article reports on two of the secondary endpoints, Quality of life (QoL), assessed according to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) version 3.0 (EORTC Data Center, Brussels, Belgium) and pain control assessed using a visual analog scale. METHODS: A randomized, parallel group, multicenter phase III trial was conducted by Cancer Trials Ireland (formerly All-Ireland Cooperative Oncology Research Group, ICORG), across five hospital sites in Ireland and Northern Ireland. Patients were randomized to 10 Gy single fraction of EBRT or 20 Gy in five fractions in a 1:1 ratio. Patients with baseline and 5-week follow up QoL data are included in this analysis. FINDINGS: From 2006 to 2014, 112 eligible patients were enrolled for whom 57 were evaluated for this secondary analysis. After adjusting for pre-intervention scores, there was no statistically significant difference in post-treatment Summary scores (excl. FI and QL), or pain scores between the two RT schedules at 5 weeks and 3 months following EBRT. There was a statistically significant relationship between the pretreatment and post-treatment Summary scores (p = .002) but not between the pre-treatment and post-treatment pain scores. INTERPRETATION: Primary radiotherapy for the treatment of MSCC significantly improves QoL in patients not proceeding with surgical decompression. After adjusting for pre-intervention scores, there was no statistically significant difference between a 10 Gy single fraction radiation schedule and one with 20 Gy in five daily fractions on post-treatment QoL Summary scores. For most patients, an effective treatment with low burden would be desirable. A single fraction schedule should be considered for this group of patients.

A Phase II Toxicity End Point Trial (ICORG 99-09) of Accelerated Dose-escalated Hypofractionated Radiation in Non-small Cell Lung Cancer.

AIMS: The objective of this phase II clinical trial was to prospectively evaluate the safety and efficacy of accelerated hypofractionated three-dimensional conformal radiation therapy (3DCRT) in localised non-resectable/non-operable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Sixty patients with stage I-III NSCLC were enrolled in a prospective single-arm All Ireland Co-operative Oncology Research Group (ICORG 99-09) toxicity end point phase II trial. The protocol allocated patients between three radiation schedule dose levels (60, 66 or 72 Gy, in 20, 22 and 24 fractions, respectively, 3 Gy daily, five fractions per week) according to combined lung V25Gy (V25Gy ≤ 30%) with built-in early stopping toxicity rules. The primary end point was toxicity with evaluation of dose-limiting toxicity. The secondary objectives included radiological tumour response rate at 3 months after the completion of radiation therapy and the thoracic progression-free survival time. RESULTS: Sixty patients were recruited from August 1999 to June 2009. Forty-nine patients were included in the primary per-protocol analysis. Eleven patients were not evaluable. In the first 30 evaluable patient cohort, severe oesophageal toxicity was reported in two patients (2/49; 4% experiencing grade 5 oesophageal late toxicity, related to the 97% oesophageal length). The trial was temporarily closed and was then reopened to validate an oesophageal dose volume constraint (DVC) of limiting the length of oesophagus fully encompassed by the 97% isodose to less than 1 cm (applied to 21 patients). The trial prospectively showed the safety of the oesophageal DVC, with no oesophageal toxicity above grade 3 thereafter. Thirty-nine per cent of patients had disease progression at 3-4 months after radiotherapy, 22% had stable disease, 20% had a complete response and 14% had a partial response. The median overall survival was 13.6 months (95% confidence interval 10.5-16.7) and overall survival at 1 and 3 years was 57% and 29%, respectively. CONCLUSION: A strategy using accelerated hypofractionated 3DCRT is feasible and reasonably safe for patients with inoperable NSCLC. It is safe to deliver for centrally located tumours if DVCs are applied to the oesophagus, which is the primary dose-limiting toxicity. Further studies are required to assess the efficacy of hypofractionated regimens for centrally located tumours using an oesophageal DVC and monitoring for oesophageal toxicity.

Stereotactic radiosurgery for the treatment of brain metastases; results from a single institution experience.

BACKGROUND: Stereotactic radiosurgery is frequently used for the treatment of brain metastases. This study provides a retrospective evaluation of patients with secondary lesions of the brain treated with stereotactic radiosurgery (SRS) at our institution. AIMS: To provide outcome data from a single institutional experience with SRS and identify any significant prognostic factors in the cohort. METHODS: Sixty-seven patients received first time SRS to 86 intracranial metastases between 2007 and 2010. Sixteen patients were excluded from this study due to the absence of post-treatment neuroimaging, resulting in 51 patients with 64 treated lesions. Of these patients, 37 (72.5%) received SRS electively, while 14 (27.5%) received salvage SRS after brain metastasis progression following whole brain radiotherapy. RESULTS: Median survival for the entire group was 15 months from the date of radiosurgery. Patients without active extracranial disease had statistically significant survival time than those with active extracranial disease (P=0.03). 45 (70.3%) lesions achieved local tumour control in 34 patients (66.7%) with a mean follow-up period of 10.7 months (range 1.7-33.6 months, 95 % confidence interval 6.6-9.8 months). CONCLUSIONS: The results reported in this study equate to those reported in other series consolidating SRS as an effective treatment option with few serious complications. Developments in systemic disease control will see further improvements in overall survival.

Laparoscopic pelvic sling placement facilitates optimum therapeutic radiotherapy delivery in the management of pelvic malignancy.

BACKGROUND: Radiotherapy has a significant role in the management of pelvic malignancies. However, the small intestine represents the main dose limiting organ. Invasive and non-invasive mechanical methods have been described to displace bowel out of the radiation field. We herein report a case series of laparoscopic placement of an absorbable pelvic sling in patients requiring pelvic radiotherapy. METHODS: Six patients were referred to our minimally invasive unit. Four patients required radical radiotherapy for localised prostate cancer, one was scheduled for salvage localised radiotherapy for post-prostatectomy PSA progression and one patient required adjuvant radiotherapy post-cystoprostatectomy for bladder carcinoma. All patients had excessive small intestine within the radiation fields despite the use of non-invasive displacement methods. RESULTS: All patients underwent laparoscopic mesh placement, allowing for an elevation of small bowel from the pelvis. The presence of an ileal conduit or previous surgery did not prevent mesh placement. Post-operative planning radiotherapy CT scans confirmed displacement of the small intestine allowing all patients to receive safely the planned radiotherapy in terms of both volume and radiation schedule. CONCLUSION: Laparoscopic mesh placement represents a safe and efficient procedure in patients requiring high-dose pelvic radiation, presenting with unacceptable small intestine volume in the radiation field. This procedure is also feasible in those that have undergone previous major abdominal surgery.

Radiation enteropathy.

Radiation enteritis is a functional disorder of the intestine that occurs during or after a course of radiotherapy to the abdomen, pelvis or rectum. It presents in both an acute and chronic form and has sequelae that can be life threatening. As radiotherapy is now being used more than ever before in the treatment of solid organ malignancies in the abdomen and pelvis, the incidence of radiation enteropathy is likely to increase in the future. We present two patients with severe forms of this condition in order to clarify the salient issues regarding its diagnosis and, in particular, its distinction from mechanical bowel obstruction. We also review its pathophysiology, management and current preventative strategies.

Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis.

PURPOSE: The modulation of fluorouracil (FU) by folinic acid (leucovorin [LV]) has been shown to be effective in terms of tumor response rate in patients with advanced colorectal cancer, but a meta-analysis of nine trials previously published by our group failed to demonstrate a statistically significant survival difference between FU and FU-LV. We present an update of the meta-analysis, with a longer follow-up and the inclusion of 10 newer trials. PATIENTS AND METHODS: Analyses are based on individual data from 3,300 patients randomized in 19 trials on an intent-to-treat basis. Two trials had multiple comparisons, leading to a total of 21 pair-wise comparisons. FU doses were similar in both arms in 10 pair-wise comparisons, 15% to 33% higher in the FU-alone arm in six comparisons, and more than 66% higher in five comparisons. RESULTS: Overall analysis showed a two-fold increase in tumor response rates (11% for FU-LV v 21% for FU-LV v 11% for FU [corrected] alone; odds ratio, 0.53; 95% CI, 0.44 to 0.63; P <.0001) and a small but statistically significant overall survival benefit for FU-LV over FU alone (median survival, 11.7 v 10.5 months, respectively; hazards ratio, 0.90; 95% CI, 0.87 to 0.94; P =.004), which were primarily seen in the first year. We observed a significant interaction between treatment benefit and dose of FU, with tumor response and overall survival advantages of FU-LV over FU-alone being restricted to trials in which a similar dose of FU was prescribed in both arms. CONCLUSION: This updated analysis demonstrates, on a large data set, that FU-LV improves both response rate and overall survival compared with FU alone and that this benefit is consistent across various prognostic factors.

Adjuvant radiotherapy in Stage I endometrial cancer. Where do we stand?

This paper reviews the anatomical spread and failure patterns of surgical Stage I endometrial cancer. The controversial aspects of the optimal adjuvant treatment are presented. An attempt is made to identify the most effective management approach based on the pertinent literature data.

Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer.

Two meta-analyses were conducted to quantify the benefit of combining alpha-IFN to 5FU in advanced colorectal cancer in terms of tumour response and survival. Analyses were based on a total of 3254 individual patient data provided by principal investigators of each trial. The meta-analysis of 5FU +/- LV vs. 5FU +/- LV + alpha-IFN combined 12 trials and 1766 patients. The meta-analysis failed to show any statistically significant difference between the two treatment groups in terms of tumour response or survival. Overall tumour response rates were 25% for patients receiving no alpha-IFN vs. 24% for patients receiving alpha-IFN (relative risk, RR = 1.02), and median survivals were 11.4 months for patients receiving no alpha-IFN vs. 11.5 months for patients receiving alpha-IFN (hazard ratio, HR = 0.95). The meta-analysis of 5FU + LV vs. 5FU + alpha-IFN combined 7 trials, and 1488 patients. This meta-analysis showed an advantage for 5FU + LV over 5FU + alpha-IFN which was statistically significant in terms of tumour response (23% vs. 18%; RR = 1.26;P = 0.042), and of a borderline significance for overall survival (HR = 1.11;P = 0.066). Metastases confined to the liver and primary rectal tumours were independent favourable prognostic factors for tumour response, whereas good performance status, metastases confined to the liver or confined to the lung, and primary tumour in the rectum were independent favourable prognostic factors for survival. We conclude that alpha-IFN does not increase the efficacy of 5FU or of 5FU + LV, and that 5FU + alpha-IFN is significantly inferior to 5FU + LV, for patients with advanced colorectal cancer.

Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer.

BACKGROUND: Treatment of advanced colorectal cancer has progressed substantially. However, improvements in response rates have not always translated into significant survival benefits. Doubts have therefore been raised about the usefulness of tumour response as a clinical endpoint. METHODS: This meta-analysis was done on individual data from 3791 patients enrolled in 25 randomised trials of first-line treatment with standard bolus intravenous fluoropyrimidines versus experimental treatments (fluorouracil plus leucovorin, fluorouracil plus methotrexate, fluorouracil continuous infusion, or hepatic-arterial infusion of floxuridine). Analyses were by intention to treat. FINDINGS: Compared with bolus fluoropyrimidines, experimental fluoropyrimidines led to significantly higher tumour response rates (454 responses among 2031 patients vs 209 among 1760; odds ratio 0.48 [95% CI 0.40-0.57], p<0.0001) and better survival (1808 deaths among 2031 vs 1580 among 1760; hazard ratio 0.90 [0.84-0.97], p=0.003). The survival benefits could be explained by the higher tumour response rates. However, a treatment that lowered the odds of failure to respond by 50% would be expected to decrease the odds of death by only 6%. In addition, less than half of the variability of the survival benefits in the 25 trials could be explained by the variability of the response benefits in these trials. INTERPRETATION: These analyses confirm that an increase in tumour response rate translates into an increase in overall survival for patients with advanced colorectal cancer. However, in the context of individual trials, knowledge that a treatment has benefits on tumour response does not allow accurate prediction of the ultimate benefit on survival.

Analysis by alkaline comet assay of cancer patients with severe reactions to radiotherapy: defective rejoining of radioinduced DNA strand breaks in lymphocytes of breast cancer patients.

Therapeutic exposure to ionising radiation reveals inter-individual variations in normal tissue responses. To examine whether a defect in DNA repair capacity might be involved in such hypersensitive phenotypes, we analysed, using the alkaline comet assay, the response as a function of time to in vitro irradiation at 5 Gy of lymphocytes from 17 breast cancer and 9 Hodgkin's disease patients who developed severe reactions to radiotherapy in comparison with 22 patients with "average" reactions and 24 healthy donors. A difference between breast cancer over-reactors and both patients with normal reactions and healthy donors was observed 30 and 60 min after exposure. A subgroup of breast cancer over-reactors (7/17) reproducibly demonstrated increased levels of residual damage. When the kinetic analyses were prolonged to 120 min, results were in favour of delayed kinetics of rejoining in these patients. Among Hodgkin's disease over-reactors, only one patient showed defective repair. Interestingly, all patients with the most severe complications (grade 4 RTOG/EORTC), i.e., 5 breast cancer and 1 Hodgkin's disease, showed impaired rejoining. Our results suggest that impairment in DNA strand break processing may be associated, in specific subgroups of breast cancer patients, with an individual risk of major toxicity of radiation therapy. Thus, the alkaline comet assay appears to be useful for documenting the DNA repair phenotype in cancer patients.

[Role of radiotherapy in the treatment of adult nodal non-Hodgkin's lymphoma]. / Place de la radiothérapie dans le traitement des formes ganglionnaires des lymphomes non hodgkiniens de l'adulte.

RADIOTHERAPY OF ADULT NODAL NON HODGKIN'S LYMPHOMA: The role of radiotherapy in the treatment of nodal non-Hodgkin's lymphoma has been modified by the introduction of efficient chemotherapy and the development of different pathological classifications. INTERMEDIATE GRADE OR HIGH GRADE LYMPHOMA: The recommended treatment of early-stage aggressive lymphomas is primarily a combination chemotherapy. The interest of adjuvant radiotherapy remains unclear and has to be established through large prospective trials. If radiation therapy has to be delivered, the historical results of exclusive radiation therapy showed that involved-fields and a dose of 35-40 Gy (daily fraction of 1.8 Gy, 5 days a week) are the optimal schedule. The interest of radiotherapy in the treatment of advanced-stage aggressive lymphoma is yet to be proven. Further studies had to stratify localized stages according to the factors of the International Prognostic Index. LOW-GRADE LYMPHOMA: For early-stage low-grade lymphoma, radiotherapy remains the standard treatment. However, the appropriate technique to use is controversial. Involved-field irradiation at a dose of 35 Gy seems to be the optimal schedule, providing a 10-year disease-free survival rate of 50% and no major toxicity. There is no standard indication of radiotherapy in the treatment advanced-stage low-grade lymphoma. RARE AND NEW ENTITY: For "new" nodal lymphoma's types, the indication of radiotherapy cannot be established (mantle-zone lymphoma, marginal zone B-cell lymphoma) or must take into account the natural history (Burkitt's lymphoma, peripheral T-cell lymphoma) and the sensibility to others therapeutic methods.

Survival impact of chemotherapy in patients with colorectal metastases confined to the liver: a re-analysis of 1458 non-operable patients randomised in 22 trials and 4 meta-analyses. Meta-Analysis Group in Cancer.

BACKGROUND: Metastases confined to the liver is a frequent situation in patients with advanced colorectal cancer. For non-operable patients, 5-FU-based chemotherapy is often proposed but the importance of the choice of first line 5-FU regimen remains debatable. DESIGN: In four previously performed meta-analyses, our group had compared bolus intravenous fluoropyrimidines (bolus FU group) with experimental fluoropyrimidines (experimental FU group), consisting of 5-FU plus leucovorin, 5-FU plus methotrexate, continuous infusion 5-FU, or hepaticartery infusion FUDR. We re-analysed this data set to focus on 1458 patients with non-operable colorectal metastases confined to the liver, randomised in 22 trials. All analyses were stratified by trial and used individual patient data. RESULTS: Median survival times were 11.3 months in the bolus FU group (95% CI: 10.5-12.0 months) compared to 12.7 months in the experimental FU group (95% CI: 120-13.1 months). This difference, although clinically small, was statistically significant, with an overall survival hazard ratio of 0.88 (95% CI: 0.79-0.99, P = 0.037). In a multivariate analysis, performance status was the only significant predictor of survival (P < 10(-4)), whereas the statistical significance of allocated treatment was borderline (P = 0.058). CONCLUSIONS: The outcome of patient with non-operable colorectal metastases confined to the liver is poor, and mainly driven by their initial performance status. Experimental chemotherapy schedules yield a small improvement in their overall survival, indicating the importance of the choice of first-line chemotherapy.

Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors.

PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.

[Adjuvant chemotherapy of soft tissue sarcoma]. / Chimiothérapie adjuvante des sarcomes des tissus mous.

The rôle of chemotherapy in the treatment of operable soft tissue sarcomas is still debatable. In high-grade tumors, randomized trials using adjuvant chemotherapy have resulted in controversial results. A recent meta-analysis showed a higher median disease-free survival in groups with chemotherapy compared to controls. Doxorubicin, ifosfamide and dacarbazine are the majors drugs. Their combination in adjuvant treatment is currently being investigated. Neoadjuvant chemotherapy has allowed conservative surgery in initially unoperable tumors, but its role in primarily operable tumors remains to be defined.

Combined Modality Treatment for Poor Prognosis Stages I and II Hodgkin's Disease.

Recommendations for the treatment of "poor prognosis" stages I and II Hodgkin's disease (HD) depend on the extent of staging. For centers that favor exploratory laparotomy and splenectomy, the standard treatment after negative surgical staging remains subtotal lymphoid irradiation. However, most centers recommend excluding selected patients from surgical staging. In particular, most specialists agree that patients with bulky mediastinal disease (large mediastinal adenopathy) should receive combined chemotherapy and radiotherapy without surgical staging. Centers that have eliminated staging laparotomy rely on clinical staging and have identified a number of poor prognostic factors that influence treatment recommendations. In 1995, the following factors were considered to be associated with an unfavorable prognosis in clinical stages (CS) I and II HD: advanced age, systemic symptoms, high erythrocyte sedimentation rate, large number of individual sites, and presence of bulky disease. For example, these factors have been used in the H7 and H8 European Organization for the Research and Treatment of Cancer trials and have been adopted by almost 100 participant groups. For CS I and II patients with unfavorable presentations, the literature suggests that the optimal treatment is a combination of chemotherapy and radiotherapy. Nevertheless, the optimal delivery of chemotherapy and radiotherapy is still debated and a number of the questions listed below are awaiting answers: 1. The chemotherapy schedule: Mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) alone can no longer be recommended (for toxicity reasons) for the routine treatment of poor prognosis CS I and II HD. Many centers, on theoretical arguments, favor seven or eight drug combinations (MOPP/ABV hybrid), although the advantage of these combinations in toxicity and efficacy over doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone has not been demonstrated. 2. The number of chemotherapy courses: Most groups use six cycle regimens, but reduction to three to four cycles is currently being investigated both in pilot and randomized studies. 3. Timing of chemotherapy: Chemotherapy is given first in most instances. Whether or not a "sandwiched" scheme is better than all the chemotherapy given upfront remains to be answered. 4. Volumes to be irradiated: Data suggest that the irradiated volumes can be safely limited to initially involved lymph node regions after effective chemotherapy. The question is presently being addressed in a few ongoing randomized trials. 5. Radiation dose to be delivered: The decrease of the radiation dose to 35 to 36 Gy after effective chemotherapy has gained a wide acceptance. Further dose reduction is being investigated. In conclusion, except for selected CS I and II patients still referred for surgical staging, combined modality therapy appears to be the treatment of choice for poor prognosis CS I and II HD.