Long-course preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study.

BACKGROUND: This trial evaluated whether preoperative short-course radiotherapy and consolidation chemotherapy (CCT) were superior to chemoradiation in rectal cancers with clinical (c)T4 or fixed cT3. Previously, we reported early results showing no differences in the radical surgery rate (primary end point). In the short-course/CCT group, we observed lower acute toxicity of preoperative treatment and better overall survival (OS). We updated results to determine whether the benefit in OS was sustained and to evaluate late complications. PATIENTS AND METHODS: Patients with cT4 or fixed cT3 rectal cancer were randomized either to preoperative 5 × 5 Gy and three cycles of FOLFOX4 or to chemoradiation (50.4 Gy with bolus 5-Fu, leucovorin and oxaliplatin). RESULTS: Patients (N = 515) were eligible for analysis, 261 in the short-course/CCT group and 254 in the chemoradiation group. The median follow-up was 7.0 years. The difference in OS was insignificant [hazard ratio (HR) 0.90; 95% confidence interval (CI) 0.70-1.15; P = 0.38). However, the difference in early OS favouring short-course/CCT previously reported was observed again, being 9% at 3 years (95% CI 0.5% to 17%). This difference disappeared later; at 8 years OS was 49% in both groups. There was no difference in disease-free survival (HR 0.95; 95% CI 0.75-1.19; P = 0.65) at 8 years 43% versus 41% in the short-course/CCT group versus the chemoradiation group, respectively. The corresponding values for cumulative incidences of local failure and distant metastases did not differ and were HR = 1.08, 95% CI 0.70-1.23, P = 0.60, 35% versus 32% and HR = 1.10, 95% CI 0.68-1.23, P = 0.54, 36% versus 34%, respectively. The rate of late complications was similar (P = 0.66), grade 3+ being 11% versus 9% in the short-course/CCT group versus the chemoradiation group, respectively. CONCLUSION: The superiority of preoperative short-course/CCT over chemoradiation was not demonstrated. CLINICAL TRIAL NUMBER: The trial is registered as ClinicalTrials.gov number NCT00833131.

Quality of life after whole brain radiotherapy compared with radiosurgery of the tumor bed: results from a randomized trial

Background. A recent randomized trial (NCT01535209) demonstrated no difference in neurocognitive function between stereotactic radiotherapy of the tumor bed (SRT-TB) and whole brain radiotherapy (WBRT) in patients with resected single brain metastasis. Patients treated with SRT-TB had lower overall survival compared with the WBRT arm. Here, we compared the health-related quality of life (HRQOL) in patients who received WBRT vs. SRT-TB. Methods. A self-reported questionnaire was used to assess HRQOL (EORTC QLQ-C30 with the QLQ-BN20 module) before RT, 2 months after RT, and every 3 months thereafter. HRQOL results are presented as mean scores and compared between groups. Results. Of 59 randomized patients, 37 (64%) were eligible for HRQOL analysis, 15 received SRT-TB, and 22 had WBRT. There were no differences between groups in global health status and main function scales/symptoms (except for drowsiness and appetite loss, which were worse with WBRT 2 months after RT). Global health status decreased 2 and 5 months after RT, but significantly only for SRT-TB (p = 0.025). Physical function decreased significantly 5 months after SRT-TB (p = 0.008). Future uncertainty worsened after RT, but significantly only for SRT-TB after 2 months (p = 0.036). Patients treated with WBRT had significant worsening of appetite, hair loss, and drowsiness after treatment. Conclusions. Despite higher symptom burden after WBRT attributed to the side effects of RT (such as appetite loss, drowsiness, and hair loss), global health status, physical functioning, and future uncertainty favored WBRT compared with SRT-TB. This may be related to the compromised brain tumor control with omission of WBRT (AU)

No disponible

Quality of life after whole brain radiotherapy compared with radiosurgery of the tumor bed: results from a randomized trial.

BACKGROUND: A recent randomized trial (NCT01535209) demonstrated no difference in neurocognitive function between stereotactic radiotherapy of the tumor bed (SRT-TB) and whole brain radiotherapy (WBRT) in patients with resected single brain metastasis. Patients treated with SRT-TB had lower overall survival compared with the WBRT arm. Here, we compared the health-related quality of life (HRQOL) in patients who received WBRT vs. SRT-TB. METHODS: A self-reported questionnaire was used to assess HRQOL (EORTC QLQ-C30 with the QLQ-BN20 module) before RT, 2 months after RT, and every 3 months thereafter. HRQOL results are presented as mean scores and compared between groups. RESULTS: Of 59 randomized patients, 37 (64%) were eligible for HRQOL analysis, 15 received SRT-TB, and 22 had WBRT. There were no differences between groups in global health status and main function scales/symptoms (except for drowsiness and appetite loss, which were worse with WBRT 2 months after RT). Global health status decreased 2 and 5 months after RT, but significantly only for SRT-TB (p = 0.025). Physical function decreased significantly 5 months after SRT-TB (p = 0.008). Future uncertainty worsened after RT, but significantly only for SRT-TB after 2 months (p = 0.036). Patients treated with WBRT had significant worsening of appetite, hair loss, and drowsiness after treatment. CONCLUSIONS: Despite higher symptom burden after WBRT attributed to the side effects of RT (such as appetite loss, drowsiness, and hair loss), global health status, physical functioning, and future uncertainty favored WBRT compared with SRT-TB. This may be related to the compromised brain tumor control with omission of WBRT.

Does the addition of oxaliplatin to preoperative chemoradiation benefit cT4 or fixed cT3 rectal cancer treatment? A subgroup analysis from a prospective study.

BACKGROUND: Whether there is any benefit derived from adding oxaliplatin to fluoropyrimidine-based preoperative chemoradiation is currently unknown in cases of advanced cT3 or cT4 tumours. Our aim was to evaluate this issue by analysing a randomized trial, which compared two schedules of preoperative treatment (chemoradiation vs. 5 × 5 Gy with 3 cycles of consolidation chemotherapy) for cT4 or fixed cT3 rectal cancer. PATIENTS AND METHODS: Delivery of oxaliplatin was mandatory to the first part of the study. For the second part, its delivery in both treatment-assigned groups was left to the discretion of the local investigator. We analysed a subgroup of 272 patients (136 in the oxaliplatin group and 136 in the fluorouracil-only group) from institutions that had omitted oxaliplatin in the second part of the study. RESULTS: Circumferential resection margin negative (CRM-) status rate was 68% in the oxaliplatin group and 70% in the fluorouracil-only group, p = 0.72. The pathological complete response rate (pCR) was correspondingly 14% vs. 7%, p = 0.10. Following multivariable analysis, when comparing the CRM- status in the oxaliplatin group to the fluorouracil-only group, the odds ratio was 0.79 (95 CI 0.35-1.74), p = 0.54; there being no interaction between concomitant chemoradiation and 5 × 5 Gy with consolidation chemotherapy; pinteraction = 0.073. For pCR, the corresponding results were 0.47 (95 CI 0.19-1.16), p = 0.10, pinteraction = 0.84. CONCLUSION: No benefit was found of adding oxaliplatin in terms of CRM nor pCR rates for either concomitant or sequential settings in preoperative radiochemotherapy for very advanced rectal cancer.

Clinical target volume in postoperative radiotherapy for gastric cancer: identification of major difficulties and controversies

Purpose: To identify the main difficulties in postoperative clinical target volume (CTV) delineation in gastric cancer (GC). Methods: Before and after a training course, 20 radiation oncology residents were asked to delineate the CTV for the postoperative GC case on four computed tomography scans: dome of the diaphragm, anterior abdominal wall, duodenal stump and porta hepatis level, and to determine the lower CTV border. CTV volume was reconstructed from requested planar contours. Area of intersection (AI) for each requested scan and volume of intersection (VI), defined as the overlap of delineated area/volume with respective reference area (RA)/reference volume (RV) proposed by the senior radiation oncologist, were computed. The degree of agreement between the reference and participants’ contours was quantified using the Concordance Index (CI): AI/RA 9 100 % or VI/RV 9 100 %. The lower CTV border was analyzed separately. Pre- and post-training CIs were compared. A questionnaire investigated the difficulties with contouring. Results: Mean CI value was the lowest for the dome of the diaphragm (24 % pre-training, 35 % post-training) and for the duodenal stump (49 % pre-training, 61 % post-training). Mean CI for the CTV volume was 49 % pre-training and 59 % post-training, p = 0.39. Mean distance from the reference to the participants’ lower CTV borders was 2.73 cm pre-training and 2.0 cm post-training, p = 0.71. In a questionnaire, 75 % of respondents indicated the elective nodal area as the main difficulty. Conclusions: Delineation of the dome of the diaphragm and the duodenal stump, as yet not recognized as the source of variation, should be addressed in the international consensus guidelines and clarified (AU)

No disponible

Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study.

BACKGROUND: Improvements in local control are required when using preoperative chemoradiation for cT4 or advanced cT3 rectal cancer. There is therefore a need to explore more effective schedules. PATIENTS AND METHODS: Patients with fixed cT3 or cT4 cancer were randomized either to 5 × 5 Gy and three cycles of FOLFOX4 (group A) or to 50.4 Gy in 28 fractions combined with two 5-day cycles of bolus 5-Fu 325 mg/m(2)/day and leucovorin 20 mg/m(2)/day during the first and fifth week of irradiation along with five infusions of oxaliplatin 50 mg/m(2) once weekly (group B). The protocol was amended in 2012 to allow oxaliplatin to be then foregone in both groups. RESULTS: Of 541 entered patients, 515 were eligible for analysis; 261 in group A and 254 in group B. Preoperative treatment acute toxicity was lower in group A than group B, P = 0.006; any toxicity being, respectively, 75% versus 83%, grade III-IV 23% versus 21% and toxic deaths 1% versus 3%. R0 resection rates (primary end point) and pathological complete response rates in groups A and B were, respectively, 77% versus 71%, P = 0.07, and 16% versus 12%, P = 0.17. The median follow-up was 35 months. At 3 years, the rates of overall survival and disease-free survival in groups A and B were, respectively, 73% versus 65%, P = 0.046, and 53% versus 52%, P = 0.85, together with the cumulative incidence of local failure and distant metastases being, respectively, 22% versus 21%, P = 0.82, and 30% versus 27%, P = 0.26. Postoperative and late complications rates in group A and group B were, respectively, 29% versus 25%, P = 0.18, and 20% versus 22%, P = 0.54. CONCLUSIONS: No differences were observed in local efficacy between 5 × 5 Gy with consolidation chemotherapy and long-course chemoradiation. Nevertheless, an improved overall survival and lower acute toxicity favours the 5 × 5 Gy schedule with consolidation chemotherapy. CLINICAL TRIAL NUMBER: The trial is registered as ClinicalTrials.gov number NCT00833131.

Clinical target volume in postoperative radiotherapy for gastric cancer: identification of major difficulties and controversies.

PURPOSE: To identify the main difficulties in postoperative clinical target volume (CTV) delineation in gastric cancer (GC). METHODS: Before and after a training course, 20 radiation oncology residents were asked to delineate the CTV for the postoperative GC case on four computed tomography scans: dome of the diaphragm, anterior abdominal wall, duodenal stump and porta hepatis level, and to determine the lower CTV border. CTV volume was reconstructed from requested planar contours. Area of intersection (AI) for each requested scan and volume of intersection (VI), defined as the overlap of delineated area/volume with respective reference area (RA)/reference volume (RV) proposed by the senior radiation oncologist, were computed. The degree of agreement between the reference and participants' contours was quantified using the Concordance Index (CI): AI/RA × 100% or VI/RV × 100%. The lower CTV border was analyzed separately. Pre- and post-training CIs were compared. A questionnaire investigated the difficulties with contouring. RESULTS: Mean CI value was the lowest for the dome of the diaphragm (24% pre-training, 35 % post-training) and for the duodenal stump (49% pre-training, 61% post-training). Mean CI for the CTV volume was 49% pre-training and 59% post-training, p = 0.39. Mean distance from the reference to the participants' lower CTV borders was 2.73 cm pre-training and 2.0 cm post-training, p = 0.71. In a questionnaire, 75% of respondents indicated the elective nodal area as the main difficulty. CONCLUSIONS: Delineation of the dome of the diaphragm and the duodenal stump, as yet not recognized as the source of variation, should be addressed in the international consensus guidelines and clarified.

Anorectal and sexual functions after preoperative radiotherapy and full-thickness local excision of rectal cancer.

AIMS: Local excision with preoperative radiotherapy may be considered as alternative management to abdominal surgery alone for small cT2-3N0 tumours. However, little is known about anorectal and sexual functions after local excision with preoperative radiotherapy. Evaluation of this issue was a secondary aim of our previously published prospective multicentre study. METHODS: Functional evaluation was based on a questionnaire completed by 44 of 64 eligible disease-free patients treated with preoperative radiotherapy and local excision. Additionally, ex post, these results were confronted with those recorded retrospectively in the control group treated with anterior resection alone (N = 38). RESULTS: In the preoperative radiotherapy and local excision group, the median number of bowel movements was two per day, incontinence of flatus occurred in 51% of patients, incontinence of loose stool in 46%, clustering of stools in 59%, and urgency in 49%; these symptoms occurred often or very often in 11%-21% of patients. Thirty-eight per cent of patients claimed that their quality of life was affected by anorectal dysfunction. Nineteen per cent of men and 20% of women claimed that the treatment negatively influenced their sexual life. The anorectal functions in the preoperative radiotherapy and local excision group were not much different from that observed in the anterior resection alone group. CONCLUSIONS: Our study suggests that anorectal functions after preoperative radiotherapy and local excision may be worse than expected and not much different from that recorded after anterior resection alone. It is possible that radiotherapy compromises the functional effects achieved by local excision.

Palliative radiotherapy and chemotherapy instead of surgery in symptomatic rectal cancer with synchronous unresectable metastases: a phase II study.

BACKGROUND: In stage IV rectal cancer, palliative surgery is often carried out upfront. This study investigated whether the surgery can be avoided. PATIENTS AND METHODS: Forty patients with symptomatic primary rectal adenocarcinoma and synchronous distant metastases deemed to be unresectable received 5 × 5 Gy irradiation and then oxaliplatin-based chemotherapy. Before treatment, 38% of patients had a near-obstructing lesion. The palliative effect was evaluated by questionnaires completed by the patients. RESULTS: The median follow-up for living patients was 26 months (range 19-34). The median overall survival was 11.5 months. Eight patients (20%) required surgery during the course of their disease: seven patients required stoma creation and one had local excision. Thirty percent of patients had a complete resolution of pelvic symptoms during the whole course of the disease, and 35% had significant improvement. In the subgroup with a near-obstructing lesion, 23% of patients required stoma creation. In all patients, the probability of requiring palliative surgery at 2 years was 17.5% [95% confidence interval (CI) 13% to 22%), and the probability of sustained good palliative effect after radiotherapy and chemotherapy was 67% (95% CI 58% to 76%). CONCLUSION: Short-course radiotherapy and chemotherapy allowed most patients to avoid surgery, even those with a near-obstructing lesion. CLINICALTRIALS: The trial is registered with ClinicalTrials.gov: number NCT01157806.

Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC).

BACKGROUND: Continuous hyperfractionated accelerated radiotherapy (CHART) counteracts repopulation and may significantly improve outcome of patients with non-small-cell lung cancer (NSCLC). Nevertheless high local failure rates call for radiation dose escalation. We report here the final results of the multicentric CHARTWEL trial (CHART weekend less, ARO 97-1). PATIENTS AND METHODS: Four hundred and six patients with NSCLC were stratified according to stage, histology, neoadjuvant chemotherapy and centre and were randomized to receive 3D-planned radiotherapy to 60Gy/40 fractions/2.5weeks (CHARTWEL) or 66Gy/33 fractions/6.5weeks (conventional fractionation, CF). RESULTS: Overall survival (OS, primary endpoint) at 2, 3 and 5yr was not significantly different after CHARTWEL (31%, 22% and 11%) versus CF (32%, 18% and 7%; HR 0.92, 95% CI 0.75-1.13, p=0.43). Also local tumour control rates and distant metastases did not significantly differ. Acute dysphagia and radiological pneumonitis were more pronounced after CHARTWEL, without differences in clinical signs of pneumopathy. Exploratory analysis revealed a significant trend for improved LC after CHARTWEL versus CF with increasing UICC, T or N stage (p=0.006-0.025) and after neoadjuvant chemotherapy (HR 0.48, 0.26-0.89, p=0.019). CONCLUSIONS: Overall, outcome after CHARTWEL or CF was not different. The lower total dose in the CHARTWEL arm was compensated by the shorter overall treatment time, confirming a time factor for NSCLC. The higher efficacy of CHARTWEL versus CF in advanced stages and after chemotherapy provides a basis for further trials on treatment intensification for locally advanced NSCLC.

Radiochemotherapy for lung cancer in developing countries.

Radiochemotherapy has become a standard approach in locally advanced non-small cell lung cancer and limited disease small cell lung cancer. Most of the data supporting this observation come from the developed world and only extremely rarely have good-quality clinical trials been carried out in developing countries. It is therefore of paramount importance to put the experience of the developed world into the context of the limited resources and other health care problems of developing countries. In this overview, the problems with the implementation of such data are discussed. The necessity of carrying out clinical trials specifically designed to address the needs of developing countries is emphasised. The research on cheaper ways of radiochemotherapy combination should be encouraged. The specific national guidelines for local needs should be created and followed. The availability of radiotherapy equipment is of major importance, as radiotherapy has a pivotal role in non-surgical treatment of lung cancer, especially in the developing world.

Local excision after radio(chemo)therapy for rectal cancer: is it safe?

According to current opinion, local excision in rectal cancer should be limited to selected T1N0 tumours. Preoperative radio(chemo)therapy provides an opportunity for expanding the use of local excision for more advanced tumours. The key rationale of this approach is the correlation between the radiosensitivity and inherited low aggressiveness of rectal cancer and the correlation between the radiosensitivity of the primary tumour and the radiosensitivity of mesorectal nodal disease. This allows for a selection of local excision for radiosensitive tumours or conversion to abdominal surgery in radioresistant cases. Eleven reports including a total of 311 patients treated with preoperative radio(chemo)therapy and local excision have been published. In some series, the tumours were initially large and unresectable by the transanal approach. Pathological data suggest that local excision must involve all tissue invaded on pre-treatment examination with a margin, even in patients with a clinical complete response. The pooled analysis has shown a local recurrence rate of 1% (1/83) for patients achieving a pathological complete response, 8% (3/40) for ypT1, 11% (4/37) for ypT2 and 3/9 for ypT3. In conclusion, the results of preoperative radio(chemo)therapy and local excision are encouraging and warrant a population-based, multicentre controlled study.

Abdominoperineal resection or anterior resection for rectal cancer: patient preferences before and after treatment.

OBJECTIVE: Literature data do not provide any evidence as to whether oncological outcome and quality of life after anterior resection (AR) are superior to those observed after abdominoperineal resection (APR) for low-lying rectal cancer. In view of this, patient preferences should play an important role in the process of decision making. The aim of this study was to investigate these preferences. PATIENTS AND METHODS: A series of consecutive patients with rectal cancer (60 prior to surgery, 65 after APR and 124 after AR) who attended our outpatient clinic were asked to express their preference as to the type of surgery. The second part of the study was performed 4 years later; 30 patients evaluated before surgery, free of disease, were again asked to express their preference as to the type of treatment. RESULTS: Patient preferences as to performing APR, AR or as to leaving the decision to the surgeon were as follows: (i) the group prior to surgery - 5%, 30% and 65%, respectively, (ii) group after APR - 46%, 22% and 32%, respectively, and (iii) group after AR - 4%, 69% and 28%, respectively. Patients after AR pointed to the type of surgery that they had undergone more frequently than patients after APR (69%vs 46%, respectively, P < 0.001). Sixty per cent of patients evaluated twice had altered their initial preferences, usually choosing the type of surgery that they had undergone. CONCLUSIONS: Our results suggest that the sequelae of AR are generally perceived as more acceptable than those of APR. Nevertheless, approximately half of the patients after APR prefer the type of surgery that they have undergone, which suggests the positive reappraisal of APR, once experienced.

Postoperative complications in patients irradiated pre-operatively for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs chemoradiation.

OBJECTIVE: The primary outcome was sphincter preservation. No benefit was found with chemoradiation. The aim of this report is to analyse postoperative complications, which were the secondary outcome. MATERIAL AND METHODS: Patients with resectable T3-4 low rectal carcinoma were randomised to receive either pre-operative 5 x 5 Gy irradiation with subsequent total mesorectal excision (TME) performed within 7 days or chemoradiation (50.4 Gy, 1.8 Gy per fraction plus bolus 5-fluorouracil and leucovorin) followed by TME after 4-6 weeks. RESULTS: Three hundred and five patients (153 in 5 x 5 Gy group and 152 in chemoradiation group) were analysed. The rates of patients with postoperative complications for the 5 x 5 Gy group and for the chemoradiation group were 27 vs 21%, respectively (P = 0.27). If the values were expressed in terms of number of complications, the rates were 31 vs 22%, respectively (P = 0.06). The corresponding values for severe complications were 10 vs 11% (P = 0.85) of patients with complications and 12 vs 11% (P = 0.85) of events. CONCLUSION: The study did not demonstrate a statistically significant difference in the rate of postoperative complications after short-course pre-operative radiotherapy compared with full course chemoradiation.

Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure.

We describe the case of a 35-year old male who developed acute renal failure following high dose methotrexate therapy for Burkitt's non Hodgkin lymphoma. Serum methotrexate levels reached 37 micromol/l, and remained higher than 1 micromol/l for more than a week. Folinic acid rescue was intensified to 200-400 mg intravenously every 4 hours. As methotrexate binds markedly to proteins, plasma exchange was initially chosen, 4 sessions being performed from day 2 to day 4. The methotrexate pharmacokinetic profile was not significantly modified during plasma exchange, and serum drug level was 3 micromol/l. Continuous veno-venous hemodiafiltration was therefore performed from day 5 to day 10. This procedure also seemed ineffective, with evidence of low ultrafiltrate clearance. No extrarenal toxicity was observed in our patient. Thus, conventional extrarenal procedures appear to have a limited role in the setting of overexposure to methotrexate. The use of very high doses of folinic acid in our case probably played a major role in the eventual favorable outcome.