Gustavo Arruda Viani

Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials.

PURPOSE To determine in a meta-analysis whether the outcomes in men with localized prostate cancer treated with high-dose radiotherapy (HDRT) are better than those in men treated with conventional-dose radiotherapy (CDRT), by quantifying the effect of the total dose of radiotherapy on biochemical control (BC). METHODS AND MATERIALS The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as the proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing HDRT with CDRT for localized prostate cancer. To evaluate the dose-response relationship, we conducted a meta-regression analysis of BC ratios by means of weighted linear regression. RESULTS Seven RCTs with a total patient population of 2812 were identified that met the study criteria. Pooled results from these RCTs showed a significant reduction in the incidence of biochemical failure in those patients with prostate cancer treated with HDRT (p < 0.0001). However, there was no difference in the mortality rate (p = 0.38) and specific prostate cancer mortality rates (p = 0.45) between the groups receiving HDRT and CDRT. However, there were more cases of late Grade >2 gastrointestinal toxicity after HDRT than after CDRT. In the subgroup analysis, patients classified as being at low (p = 0.007), intermediate (p < 0.0001), and high risk (p < 0.0001) of biochemical failure all showed a benefit from HDRT. The meta-regression analysis also detected a linear correlation between the total dose of radiotherapy and biochemical failure (BC = -67.3 + [1.8 x radiotherapy total dose in Gy]; p = 0.04). CONCLUSIONS Our meta-analysis showed that HDRT is superior to CDRT in preventing biochemical failure in low-, intermediate-, and high-risk prostate cancer patients, suggesting that this should be offered as a treatment for all patients, regardless of their risk status.

Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials

BackgroundBreast cancer is the most common cancer in women in the U.S. and Western Europe. Amplification of the her-2/neu gene occurs in approximately 25% of invasive ductal carcinomas of the breast. The first HER-2/neu-targeted approach to reach the clinic was trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER-2/neu protein. Trastuzumab therapy prolongs the survival of patients with metastático HER-2/neu-overexpressing breast cancer when combined with chemotherapy and has recently been demonstrated to lead to dramatic improvements in disease-free survival when used in the adjuvant therapy setting in combination with or following chemotherapy. Here, we performed a meta-analysis of completed clinical trials of adjuvant trastuzumab in the adjuvant setting. Survival, recurrence, brain metastases, cardiotoxicity and directions for future research are discussed.MethodsA meta-analysis of randomized controlled trials (RCT) was performed comparing adjuvant trastuzumab treatment for HER2-positive early breast cancer (EBC) to observation. The MEDLINE, EMBASE, CANCERLIT and Cochrane Library databases, and abstracts published in the annual proceedings were systematically searched for evidence. Relevant reports were reviewed by two reviewers independently and the references from these reports were searched for additional trials, using guidelines set by QUOROM statement criteria.ResultsPooled results from that five randomized trials of adjuvant Trastuzumab showed a significant reduction of mortality (p < 0.00001), recurrence (p < 0.00001), metastases rates (p < 0.00001) and second tumors other than breast cancer (p = 0.007) as compared to no adjuvant Trastuzumab patients. There were more grade III or IV cardiac toxicity after trastuzumab (203/4555 = 4.5%) versus no trastuzumab (86/4562 = 1.8%). The likelihood of cardiac toxicity was 2.45-fold higher (95% CI 1.89 – 3.16) in trastuzumab arms, however that result was associated with heterogeneity. The likelihood of brain metastases was 1.82-fold higher (95% CI 1.16 – 2.85) in patients who received trastuzumab.ConclusionThe results from this meta-analysis are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER-2-positive EBC based on the risk: benefit ratio demonstrated in these studies. Adequate assessment of HER-2/neu status is critical, and careful cardiac monitoring is warranted because of cardiac toxicity. Clinical trials should be designed to answer unsolved questions.

Whole brain radiotherapy with radiosensitizer for brain metastases.

PurposeTo study the efficacy of whole brain radiotherapy (WBRT) with radiosensitizer in comparison with WBRT alone for patients with brain metastases in terms of overall survival, disease progression, response to treatment and adverse effects of treatment.MethodsA meta-analysis of randomized controlled trials (RCT) was performed in order to compare WBRT with radiosensitizer for brain metastases and WBRT alone. The MEDLINE, EMBASE, LILACS, and Cochrane Library databases, in addition to Trial registers, bibliographic databases, and recent issues of relevant journals were researched. Significant reports were reviewed by two reviewers independently.ResultsA total of 8 RCTs, yielding 2317 patients were analyzed. Pooled results from this 8 RCTs of WBRT with radiosensitizer have not shown a meaningful improvement on overall survival compared to WBRT alone OR = 1.03 (95% CI0.84–1.25, p = 0.77). Also, there was no difference in local brain tumor response OR = 0.8(95% CI 0.5 – 1.03) and brain tumor progression (OR = 1.11, 95% CI 0.9 – 1.3) when the two arms were compared.ConclusionOur data show that WBRT with the following radiosentizers (ionidamine, metronidazole, misonodazole, motexafin gadolinium, BUdr, efaproxiral, thalidomide), have not improved significatively the overall survival, local control and tumor response compared to WBRT alone for brain metastases. However, 2 of them, motexafin- gadolinium and efaproxiral have been shown in recent publications (lung and breast) to have positive action in lung and breast carcinoma brain metastases in association with WBRT.

Breast-conserving surgery with or without radiotherapy in women with ductal carcinoma in situ: a meta-analysis of randomized trials

BackgroundTo investigate whether Radiation therapy (RT) should follow breast conserving surgery in women with ductal carcinoma in situ from breast cancer (DCIS) with objective of decreased mortality, invasive or non invasive recurrence, distant metastases and contralateral breast cancer rates. We have done a meta-analysis of these results to give a more balanced view of the total evidence and to increase statistical precision.MethodsA meta-analysis of randomized controlled trials (RCT) was performed comparing RT treatment for DCIS of breast cancer to observation. The MEDLINE, EMBASE, CANCERLIT, Cochrane Library databases, Trial registers, bibliographic databases, and recent issues of relevant journals were searched. Relevant reports were reviewed by two reviewers independently and the references from these reports were searched for additional trials, using guidelines set by QUOROM statement criteria.ResultsThe reviewers identified four large RCTs, yielding 3665 patients. Pooled results from this four randomized trials of adjuvant radiotherapy showed a significant reduction of invasive and DCIS ipsilateral breast cancer with odds ratio (OR) of 0.40 (95% CI 0.33 – 0.60, p < 0.00001) and 0.40 (95% CI 0.31 – 0.53, p < 0.00001), respectively. There was not difference in distant metastases (OR = 1.04, 95% CI 0.57–1.91, p = 0.38) and death rates (OR = 1.08, 95%CI 0.65 – 1.78, p = 0.45) between the two arms. There was more contralateral breast cancer after adjuvant RT (66/1711 = 3.85%) versus observation (49/1954 = 2.5%). The likelihood of contralateral breast cancer was 1.53-fold higher (95% CI 1.05 – 2.24, p = 0.03) in radiotherapy arms.ConclusionThe conclusion from our meta-analysis is that the addition of radiation therapy to lumpectomy results in an approximately 60% reduction in breast cancer recurrence, no benefit for survival or distant metastases compared to excision alone. Patients with high-grade DCIS lesions and positive margins benefited most from the addition of radiation therapy. It is not yet clear which patients can be successfully treated with lumpectomy alone; until further prospective studies answer this question, radiation should be recommended after lumpectomy for all patients without contraindications.

Whole brain radiotherapy for brain metastases from breast cancer: estimation of survival using two stratification systems

BackgroundBrain metastases (BM) are the most common form of intracranial cancer. The incidence of BM seems to have increased over the past decade. Recursive partitioning analysis (RPA) of data from three Radiation Therapy Oncology Group (RTOG) trials (1200 patients) has allowed three prognostic groups to be identified. More recently a simplified stratification system that uses the evaluation of three main prognostics factors for radiosurgery in BM was developed.MethodsTo analyze the overall survival rate (OS), prognostic factors affecting outcomes and to estimate the potential improvement in OS for patients with BM from breast cancer, stratified by RPA class and brain metastases score (BS-BM). From January 1996 to December 2004, 174 medical records of patients with diagnosis of BM from breast cancer, who received WBRT were analyzed. The surgery followed by WBRT was used in 15.5% of patients and 84.5% of others patients were submitted at WBRT alone; 108 patients (62.1%) received the fractionation schedule of 30 Gy in 10 fractions. Solitary BM was present in 37.9 % of patients. The prognostic factors evaluated for OS were: age, Karnofsky Performance Status (KPS), number of lesions, localization of lesions, neurosurgery, chemotherapy, absence extracranial disease, RPA class, BS-BM and radiation doses and fractionation.ResultsThe OS in 1, 2 and 3 years was 33.4 %, 16.7%, and 8.8 %, respectively. The RPA class analysis showed strong relation with OS (p < 0.0001). The median survival time by RPA class in months was: class I 11.7, class II 6.2 and class III 3.0. The significant prognostic factors associated with better OS were: higher KPS (p < 0.0001), neurosurgery (P < 0.0001), single metastases (p = 0.003), BS-BM (p < 0.0001), control primary tumor (p = 0.002) and absence of extracranial metastases (p = 0.001). In multivariate analysis, the factors associated positively with OS were: neurosurgery (p < 0.0001), absence of extracranial metastases (p <0.0001) and RPA class I (p < 0.0001).ConclusionOur data suggests that patients with BM from breast cancer classified as RPA class I may be effectively treated with local resection followed by WBRT, mainly in those patients with single BM, higher KPS and cranial extra disease controlled. RPA class was shown to be the most reliable indicators of survival.

Evaluation of biologic effective dose and schedule of fractionation for preoperative radiotherapy for rectal cancer: meta-analyses and meta-regression.

PURPOSE To evaluate whether the risk of local recurrence depends on the biologic effective dose (BED) or fractionation dose in patients with resectable rectal cancer undergoing preoperative radiotherapy (RT) compared with surgery alone. METHODS AND MATERIALS A meta-analysis of randomized controlled trials (RCTs) was performed. The MEDLINE, Embase, CancerLit, and Cochrane Library databases were systematically searched for evidence. To evaluate the dose-response relationship, we conducted a meta-regression analysis. Four subgroups were created: Group 1, RCTs with a BED >30 Gy(10) and a short RT schedule; Group 2, RCTs with BED >30 Gy(10) and a long RT schedule; Group 3, RCTs with BED ≤ 30 Gy(10) and a short RT schedule; and Group 4, RCTs with BED ≤ 30 Gy(10) and a long RT schedule. RESULTS Our review identified 21 RCTs, yielding 9,097 patients. The pooled results from these 21 randomized trials of preoperative RT showed a significant reduction in mortality for groups 1 (p = .004) and 2 (p = .03). For local recurrence, the results were also significant in groups 1 (p = .00001) and 2 (p = .00001).The only subgroup that showed a greater sphincter preservation (SP) rate than surgery was group 2 (p = .03). The dose-response curve was linear (p = .006), and RT decreased the risk of local recurrence by about 1.7% for each Gy(10) of BED. CONCLUSION Our data have shown that RT with a BED of >30 Gy(10) is more efficient in reducing local recurrence and mortality rates than a BED of ≤ 30 Gy(10), independent of the schedule of fractionation used. A long RT schedule with a BED of >30 Gy(10) should be recommended for sphincter preservation.

High-dose-rate brachytherapy for soft tissue sarcoma in children: a single institution experience

PurposeTo report our experience treating soft tissue sarcoma (STS) with high dose rate brachytherapy alone (HBRT) or in combination with external beam radiotherapy (EBRT) in pediatric patients.Methods and materialsEighteen patients, median age 11 years (range 2 – 16 years) with grade 2–3 STS were treated with HBRT using Ir-192 in a interstitial (n = 14) or intracavitary implant (n = 4). Eight patients were treated with HBRT alone; the remaining 10 were treated with a combination of HBRT and EBRT.ResultsAfter a median follow-up of 79.5 months (range 12 – 159), 14 patients were alive and without evidence of disease (5-year overall survival rate 84.5%). There were no local or regional failures in the group treated with HBRT alone. One patient developed distant metastases at 14 months and expired after 17 months. In the combined HBRT and EBRT group, there was 1 local failure (22 months), and 3 patients developed pulmonary metastatic disease 18, 38 and 48 months after diagnosis and no these patients were alive at the time of this report. The overall local control to HBRT alone and HBRT plus EBRT were 100 and 90%, respectively. The acute affects most common were local erythema and wound dehiscence in 6 (33%) and 4 (22%) patients.Late effects were observed in 3 patients (16.5%).ConclusionExcellent local control with tolerable side effects have been observed in a small group of paediatric patients with STS treated by HBRT alone or in combination with EBRT.

RETRACTED: High-Dose Conformal Radiotherapy Reduces Prostate Cancer–Specific Mortality: Results of a Meta-analysis

PURPOSE To determine in a meta-analysis whether prostate cancer-specific mortality (PCSM), biochemical or clinical failure (BCF), and overall mortality (OM) in men with localized prostate cancer treated with conformal high-dose radiotherapy (HDRT) are better than those in men treated with conventional-dose radiotherapy (CDRT). METHODS AND MATERIALS The MEDLINE, Embase, CANCERLIT, and Cochrane Library databases, as well as the proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing conformal HDRT with CDRT for localized prostate cancer. RESULTS Five randomized, controlled trials (2508 patients) that met the study criteria were identified. Pooled results from these randomized, controlled trials showed a significant reduction in the incidence of PCSM and BCF rates at 5 years in patients treated with HDRT (p = 0.04 and p < 0.0001, respectively), with an absolute risk reduction (ARR) of PCSM and BCF at 5 years of 1.7% and 12.6%, respectively. Two trials evaluated PCSM with 10 years of follow up. The pooled results from these trials showed a statistical benefit for HDRT in terms of PCSM (p = 0.03). In the subgroup analysis, trials that used androgen deprivation therapy (ADT) showed an ARR for BCF of 12.9% (number needed to treat = 7.7, p < 0.00001), whereas trials without ADT had an ARR of 13.6% (number needed to treat = 7, p < 0.00001). There was no difference in the OM rate at 5 and 10 years (p = 0.99 and p = 0.11, respectively) between the groups receiving HDRT and CDRT. CONCLUSIONS This meta-analysis is the first study to show that HDRT is superior to CDRT in preventing disease progression and prostate cancer-specific death in trials that used conformational technique to increase the total dose. Despite the limitations of our study in evaluating the role of ADT and HDRT, our data show no benefit for HDRT arms in terms of BCF in trials with or without ADT.

Trinta anos de irradiação craniana profilática em pacientes com câncer de pulmão de pequenas células: uma meta-análise de ensaios clínicos randomizados

OBJECTIVE To determine the role of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC). METHODS We searched various databases, selecting randomized clinical trials published in journals or conference proceedings within the last 30 years and investigating the role of PCI in the mortality of patients with SCLC, submitted to PCI or not. RESULTS Sixteen randomized clinical trials, collectively involving 1,983 patients, were considered eligible for inclusion. Of those 1,983 patients, 1,021 were submitted to PCI and 962 were not. Overall mortality was 4.4% lower in the patients submitted to PCI than in those who were not (OR = 0.73; 95% CI: 0.57-0.97; p = 0.01), especially among the patients showing a complete response after induction chemotherapy (OR = 0.68; 95% CI: 0.50-0.93; p = 0.02) and in those submitted to PCI after that treatment (OR = 0.68; 95% CI: 0.49-0.94; p = 0.03). That decrease did not correlate with the stage of the disease: limited disease (OR = 0.73; 95% CI: 0.55-0.97; p = 0.03); and extensive disease (OR = 0.48; 95% CI: 0.26-0.87; p = 0.02). CONCLUSIONS Our findings suggest that PCI decreases mortality in patients with SCLC, especially in those showing a complete response after induction chemotherapy and in those submitted to PCI after that treatment, regardless of the stage of the disease.

High dose rate and external beam radiotherapy in locally advanced prostate cancer.

Purpose:To report the outcomes and toxicity of high dose rate brachytherapy as a boost for localized prostate cancer. Materials and Methods:Between 1997 and 2000, the medical records of 131 patients with prostate adenocarcinoma who were treated with external beam radiation therapy and high dose rate brachytherapy, were retrospectively analyzed. Furthermore, 55% of the patients received neoadjuvant/concurrent or adjuvant androgen deprivation therapy. Patients were stratified into 2 groups. Group 1 included 65 patients with Gleason score 7, pretreatment prostate specific antigen (PSA) between 10 and 20 ng/mL, and clinical stage T2b. Group 2 included 66 patients with Gleason score between 8 and 10, PSA greater than 20 ng/mL, and clinical stage greater than T2b. Results:At a median follow-up of 62.8 months, the 5-year biochemical control (BC) rate, as defined by the American Society for Therapeutic Radiology and Oncology Phoenix Consensus panel statement, was 81% and overall survival was 91%. BC in Groups 1 and 2 were 87% and 71%, respectively. On univariate analysis risk group, pretreatment PSA and age were significant predictors of BC. However, on multivariate analysis only pretreatment PSA was significant. Using the Radiation therapist oncology group criteria, there were 2 (1.5%) cases of grade 3 acute urinary toxicity. Regarding late side effects (n = 5), 4% of patients had grade 3 genitourinary toxicity and no grade 4 complication was observed. Conclusions:External beam radiation therapy and high dose rate brachytherapy for prostate cancer resulted in excellent BC, and overall survival with minimal severe, acute, or late complications.