Analysis of non-genetic risk factors for adverse skin reactions to radiotherapy among 284 Breast Cancer patients

OBJECTIVES: We analyzed non-genetic risk factors for adverse skin reactions to irradiation at 4 collaborating Japanese institutions, to design future investigation into genetic risk factors for adverse skin reactions to irradiation in a multicenter setting. METHODS: From April 2001, 284 breast cancer patients, who underwent radiotherapy with breast-conserving surgery, were enrolled from 4 collaborating institutions in Japan. We graded skin reactions according to international scoring systems. Clinical factors were tested against adverse effects. RESULTS: Grade 1+ skin reactions were observed in 261 (92%) of the patients in less than 3 months, 118 (42%) at 3 months, and 29 (10%) at 6 months in the late phase. Univariate analysis of treatment risk factors (such as the use of a multi-leaf colimeter, wedge-filter, or immobilization device) for skin reactions revealed a significant association (p< 0.0001). After a variable selection procedure with logistic regression, the institution, operative procedure, and magnitude of photon energy remained significantly associated with acute skin reactions. Only the institution was an explanatory variable for skin reactions at 3 and 6 months in the final logistic model. CONCLUSION: After stratification, substantial remaining variations in the occurrence of skin reactions of a given level suggested that individual genetic factors contribute markedly to individual radiosensitivity. Analysis of genetic factors associated with adverse effects would be possible by stratifying patients according to institution. Selection of eligible institutions, where appropriate treatment modalities could be performed, would also be possible when planning such a study.     

Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer

: To identify dosimetric, anatomic, and clinical factors that correlate with late rectal toxicity after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer.

: We retrospectively analyzed the dose-volume histograms and clinical records of 163 Stage T1b-T3c prostate cancer patients treated between 1992 and 1999 with 3D-CRT, to a total isocenter dose of 74–78 Gy at The University of Texas M. D. Anderson Cancer Center. The median follow-up was 62 months (range 24–102). All late rectal complications were scored using modified Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. The 6-year toxicity rate was assessed using Kaplan-Meier analysis and the log-rank test. A univariate proportional hazards regression model was used to test the correlation between Grade 2 or higher toxicity and the dosimetric, anatomic, and clinical factors. In a multivariate regression model, clinical factors were added to the dosimetric and anatomic variables to determine whether they significantly altered the risk of developing late toxicity.

: At 6 years, the rate of developing Grade 2 or higher late rectal toxicity was 25%. A significant volume effect was observed at rectal doses of 60, 70, 75.6, and 78 Gy, and the risk of developing rectal complications increased exponentially as greater volumes were irradiated. Although the percentage of rectal volume treated correlated significantly with the incidence of rectal complications at all dose levels (p <0.0001 for all comparisons), the absolute rectal volume appeared to be a factor only at the higher doses of 70, 75.6, and 78 Gy (p = 0.0514, 0.0016, and 0.0021, respectively). The following variables also correlated with toxicity on the univariate analysis: maximal dose to the clinical target volume, maximal dose to rectum, maximal dose to the rectum as a percentage of the prescribed dose, and maximal dose delivered to 10 cm³ of the rectum. Of the clinical variables tested, only a history of hemorrhoids correlated with rectal toxicity (p = 0.003). Multivariate analysis showed that the addition of hemorrhoids increased the risk of toxicity for each dosimetric variable found to be significant on univariate analysis (p <0.05 for all comparisons).

: Dose-volume histogram analyses clearly indicated a volume effect on the probability of developing late rectal complications. Therefore, dose escalation may be safely achieved by adherence to dose-volume histogram constraints during treatment planning and organ localization at the time of treatment to ensure consistent patient setup.     

Germline glutathione S-transferase variants in breast cancer: relation to diagnosis and cutaneous long-term adverse effects after two fractionation patterns of radiotherapy

PURPOSE: To explore whether certain glutathione S-transferase (GST) polymorphisms are associated with an increased risk of breast cancer or the level of radiation-induced adverse effects after two fractionation patterns of adjuvant radiotherapy. METHODS AND MATERIALS: The prevalence of germline polymorphic variants in GSTM1, GSTP1, and GSTT1 was determined in 272 breast cancer patients and compared with that in a control group of 270 women from the general population with no known history of breast cancer. The genetic variants were determined using multiplex polymerase chain reaction followed by restriction enzyme fragment analysis. In 253 of the patients surveyed for radiotherapy-induced side effects after a median observation time of 13.7 years (range, 7-22.8 years), the genotypes were related to the long-term effects observed after two fractionation patterns (treatment A, 4.3 Gy in 10 fractions for 156 patients; and treatment B, 2.5 Gy in 20 fractions for 97; both administered within a 5-week period). RESULTS: None of the GST polymorphisms conferred an increased risk of breast cancer, either alone or in combination. Compared with treatment B, treatment A was followed by an increased level of moderate to severe radiation-induced side effects for all the endpoints studied (i.e., degree of telangiectasia, subcutaneous fibrosis and atrophy, lung fibrosis, costal fractures, and pleural thickening; p <0.001 for all endpoints). A significant association was found between the level of pleural thickening and the GSTP1 Ile105Val variant. CONCLUSION: The results of this study have illustrated the impact of hypofractionation on the level of adverse effects and indicated that the specific alleles of GSTP1, M1, and T1 studied here may be significant in determining the level of adverse effects after radiotherapy.     

中高危局限期前列腺癌大分割及常规分割放疗疗效对比——Meta分析

目的 比较中高危局限期前列腺癌大分割放疗与常规分割放疗的疗效、不良反应的差异。方法 通过计算机检索国内外相关数据库,搜集有关中高危局限期前列腺癌大分割放疗及常规分割放疗比较的临床对照研究资料,采用Stata12.0软件进行分析。两组间差异采用HR和RR及95%CI描述。结果 根据纳入排除和标准,最终纳入5项包括1621例患者的临床对照研究资料。Meta分析结果显示两组OS率(HR=1.00,95%CI为0.85-1.17,P=0.980)和生化失败结果(RR=0.87,95%CI为0.68-1.12,P=0.274)均相似。与常规分割放疗比较,大分割放疗组≥2级急性胃肠反应发生率偏高(RR=1.94,95%CI为1.23-3.06,P=0.004)。两组≥2级急性泌尿系统不良反应(RR=1.03,95%CI为0.92-1.14,P=0.626),晚期≥2级胃肠(RR=1.17,95%CI为0.90-1.51,P=0.238)和泌尿系统(RR=1.11,95%CI为0.94-1.30,P=0.228)不良反应均相似(P值均>0.05)。结论 中高危局限期前列腺癌大分割放疗与常规分割放疗疗效相当,虽然大分割放疗组急性胃肠反应发生率略高于常规分割组,但两组晚期胃肠和泌尿系统反应并无差异,患者可耐受。     

Association between single nucleotide polymorphisms in the DNA repair gene LIG3 and acute adverse skin reactions following radiotherapy

Many genes have been associated with radiotherapy toxicity, but most have only been found in a single study. Using our cohort of 480 breast cancer patients, we provide replicated evidence that a polymorphism near the LIG3 gene is associated with acute skin toxicity following radiotherapy.     

Postmastectomy radiotherapy for all node positive patients: The case against

Postmastectomy radiotherapy (PMRT) is accepted as the standard of care for women with early breast cancer with 4 or more involved axillary nodes. However the role of PMRT in women with 1–3 involved nodes remains controversial and guidelines vary.We present the arguments against advocating postmastectomy radiotherapy for all women with node positive breast cancer.     

Treatment results of adjuvant radiotherapy and salvage radiotherapy after radical prostatectomy for prostate cancer

Background The indications for and the efficacy of radiation therapy after radical operation for patients with prostate cancer are not clear. We analyzed the treatment results of adjuvant radiotherapy and salvage radiotherapy after radical prostatectomy. Methods Between September 1997 and November 2004, 57 patients received adjuvant radiotherapy or salvage radiotherapy after radical prostatectomy. Fifteen patients received radiation therapy because of positive margins and/or extracapsular invasion in surgical specimens (adjuvant group). Forty-two patients received radiation therapy because of rising prostate-specific antigen (PSA) during follow-up (salvage group). Radiation therapy was delivered to the fossa of the prostate ± seminal vesicles by a three-dimensional (3-D) conformal technique to a total dose of 60–66 Gy (median, 60 Gy). Biochemical control was defined as the maintenance of a PSA level of less than 0.2 ng/ml. Results The median follow-up period after radiation therapy was 33 months (range, 12–98 months). Three-year biochemical control rates were 87% for the adjuvant group and 61% for the salvage group. For patients in the salvage group treated without hormone therapy, the preradiation PSA value was the most significant factor for the biochemical control rate. The 3-year biochemical control rate was 93% in patients whose preradiation PSA was 0.5 ng/ml or less and 29% in patients whose preradiation PSA was more than 0.5 ng/ml. No severe adverse effects (equal to or more than grade 3) were seen in treated patients. Conclusion Radiation therapy after radical prostatectomy seemed to be effective for adjuvant therapy and for salvage therapy in patients with a preradiation PSA of 0.5 ng/ml or less. Also, radiation to the fossa of the prostate ± seminal vesicles, to a total dose of 60–66 Gy, using a three-dimensional (3-D) conformal technique, seemed to be safe.     

Cardiac exposures in breast cancer radiotherapy: 1950s-1990s

PURPOSE: To estimate the doses to the heart and coronary arteries from common breast cancer radiotherapy (RT) regimens used worldwide from the 1950s to the 1990s. METHODS AND MATERIALS: Virtual simulation and computed tomography planning were used to reconstruct the megavoltage and electron regimens. Manual planning was used for the orthovoltage and brachytherapy regimens. Several sources of variability associated with the dose estimates were assessed. RESULTS: Breast or chest wall RT resulted in whole heart doses of 0.9-14 Gy for left-sided and of 0.4-6 Gy for right-sided irradiation. Internal mammary chain RT delivered heart doses of 3-17 Gy and 2-10 Gy for left- and right-sided irradiation, respectively. For most regimens, the dose to the left anterior descending coronary artery was greater than the heart dose. Scar boost, supraclavicular fossa, and axillary RT delivered mean cardiac doses of 相似文献   

Fast neutron radiotherapy for locally advanced prostate cancer: results of an RTOG randomized study

Between June 1977 and April 1983, the Radiation Therapy Oncology Group (RTOG) sponsored a Phase III randomized study investigating fast neutron radiation therapy in the treatment of patients with locally advanced (Stage C and D1) adenocarcinoma of the prostate gland. Patients were randomized to receive either conventional photon radiation therapy or fast neutron irradiation used in a mixed-beam treatment schedule (neutron/photon). A total of 91 analyzable patients were entered in the study; 78 of them were treated without major protocol deviations. The two treatment groups were balanced in regard to all major prognostic variables. Actuarial curves for "overall" survival, "determinantal" survival and local/regional control are presented both for the entire group of 91 patients and the 78 patients treated within protocol guidelines. The overall local/regional tumor recurrence rate is 7% for the mixed-beam treated group of patients and is 22% for the photon (X ray) treated group of patients. The difference is statistically significant at the p = 0.05 level. For the entire group of 91 evaluable patients, the 5-year "overall" survival rate is 62% for the mixed-beam-treated group and 35% for the photon-treated group. This difference is also statistically significant (p less than 0.05). However, this statistical significance is lost when the smaller number of patients treated strictly within protocol guidelines is considered. The significance is regained (p less than 0.02) when one looks at "determinantal" survival, which uses active cancer at time of death as the failure endpoint. This study demonstrates that a regional treatment modality, in this case mixed-beam irradiation, can influence both local/regional tumor control and survival in patients with locally-advanced adenocarcinoma of the prostate gland.     

The Cambridge post-mastectomy radiotherapy (C-PMRT) index: A practical tool for patient selection

Background and purpose

Post mastectomy radiotherapy (PMRT) reduces loco-regional recurrence (LRR) and has been associated with survival benefit. It is recommended for patients with T3/T4 tumours and/or ?4 positive lymph nodes (LN). The role of PMRT in 1–3 positive LN and LN negative patients is contentious. The C-PMRT index has been designed for selecting PMRT patients, using independent prognostic factors for LRR. This study reports a 10 year experience using this index.

Materials and methods

The C-PMRT index was constructed using the following prognostic factors (a) number of positive LN/lymphovascular invasion, (b) tumour size (c) margin status and (d) tumour grade. Patients were categorised as high (H) risk, intermediate (I) risk and low (L) risk. PMRT was recommended for H and I risk patients. The LRR, distant metastasis and overall survival (OS) rates were measured from the day of mastectomy.

Results

From 1999 to 2009, 898 invasive breast cancers in 883 patients were treated by mastectomy (H: 323, I: 231 and L: 344). At a median follow up of 5.2 years, 4.7% (42/898) developed LRR. The 5-year actuarial LRR rates were 6%, 2% and 2% for the H, I and L risk groups, respectively. 1.6% (14/898) developed isolated LRR (H risk n = 4, I risk group n = 0 and L risk n = 10). The 5-year actuarial overall survival rates were 67%, 77% and 90% for H, I and L risk groups, respectively.

Conclusion

Based on published literature, one would have expected a higher LRR rate in the I risk group without adjuvant RT. We hypothesise that the I risk group LRR rates have been reduced to that of the L risk group by the addition of RT. Apart from LN status and tumour size, other prognostic factors should also be considered in selecting patients for PMRT. This pragmatic tool requires further validation.     

10-year survival and quality of life in patients with high-risk pN0 prostate cancer following definitive radiotherapy

PURPOSE: To evaluate long-term overall survival (OS), cancer-specific survival (CSS), clinical progression-free survival (cPFS), and health-related quality of life (HRQoL) following definitive radiotherapy (RT) given to T(1-4p)N(0)M(0) prostate cancer patients provided by a single institution between 1989 and 1996. METHODS AND MATERIALS: We assessed outcome among 203 patients who had completed three-dimensional conformal RT (66 Gy) without hormone treatment and in whom staging by lymphadenectomy had been performed. OS was compared with an age-matched control group from the general population. A cross-sectional, self-report survey of HRQoL was performed among surviving patients. RESULTS: Median observation time was 10 years (range, 1-16 years). Eighty-one percent had high-risk tumors defined as T(3-4) or Gleason score (GS) > or =7B (4+3). Among these, 10-year OS, CSS, and cPFS rates were 52%, 66%, and 39%, respectively. The corresponding fractions in low-risk patients (T(1-2) and GS < or =7A [3+4]) were 79%, 95%, and 73%, respectively. Both CSS and cPFS were predicted by GS and T-classification; OS was associated with GS only. High-risk, but not low-risk, patients had reduced OS compared with the general population (p < 0.0005). When pelvis-related side effects were included in multivariate analyzes together with physical function and pain, sexual, urinary, and bowel function were not independently associated with self-reported global quality of life. CONCLUSIONS: Despite surgically proven (p)N(0), RT with dosage <70 Gy as monotherapy does not give satisfactory CSS rates after 10 years in patients with T(3-4) or GS > or =7B.     

Intensity-modulated radiotherapy of pelvic lymph nodes in locally advanced prostate cancer: planning procedures and early experiences

PURPOSE: We present planning and early clinical outcomes of a study of intensity-modulated radiotherapy (IMRT) for locally advanced prostate cancer. METHODS AND MATERIALS: A total of 43 patients initially treated with an IMRT plan delivering 50 Gy to the prostate, seminal vesicles, and pelvic lymph nodes, followed by a conformal radiotherapy (CRT) plan delivering 20 Gy to the prostate and seminal vesicles, were studied. Dose-volume histogram (DVH) data for the added plans were compared with dose-volume histogram data for the sum of two CRT plans for 15 cases. Gastrointestinal (GI) and genitourinary (GU) toxicity, based on the Radiation Therapy Oncology Group scoring system, was recorded weekly throughout treatment as well as 3 to 18 months after treatment and are presented. RESULTS: Treatment with IMRT both reduced normal tissue doses and increased the minimum target doses. Intestine volumes receiving more than 40 and 50 Gy were significantly reduced (e.g., at 50 Gy, from 81 to 19 cm(3); p = 0.026), as were bladder volumes above 40, 50, and 60 Gy, rectum volumes above 30, 50, and 60 Gy, and hip joint muscle volumes above 20, 30, and 40 Gy. During treatment, Grade 2 GI toxicity was reported by 12 of 43 patients (28%), and Grade 2 to 4 GU toxicity was also observed among 12 patients (28%). With 6 to 18 months of follow-up, 2 patients (5%) experienced Grade 2 GI effects and 7 patients (16%) experienced Grade 2 GU effects. CONCLUSIONS: Use of IMRT for pelvic irradiation in prostate cancer reduces normal tissue doses, improves target coverage, and has a promising toxicity profile.     

乳腺癌的术中放疗

乳腺癌是全球女性最高发的恶性肿瘤,不仅威胁患者生命,同时也影响患者的生存质量和生理功能。因此,采用优化的综合治疗策略,延长患者生命,改善患者生存质量,是目前乳腺癌治疗的趋势。放射治疗是乳腺癌综合治疗的重要组成部分,近年来,乳腺癌放射治疗具有照射范围缩小,分割次数减少两大趋势。术中放疗(intraoperative radiotherapy,IORT)由于在手术中直视下给予单次大剂量照射,具有缩短疗程,有效保护正常组织的优势。目前IORT对接受保乳术的乳腺癌患者可作为外照射的局部剂量追加技术方法,或作为替代术后外照射的技术方法。现就IORT技术的优缺点及其临床适应证、疗效和不良反应进行系统回顾,为指导临床开展IORT提供依据。