Individual radiosensitivity measured with lymphocytes may predict the risk of acute reaction after radiotherapy

PURPOSE: We tested whether the chromosomal radiosensitivity of in vitro irradiated lymphocytes could be used to predict the risk of acute reactions after radiotherapy. METHODS AND MATERIALS: Two prospective studies were performed: study A with 51 patients included different tumor sites and study B included 87 breast cancer patients. Acute reaction was assessed using the Radiation Therapy Oncology Group score. In both studies, patients were treated with curative radiotherapy, and the mean tumor dose applied was 55 Gy (40-65) +/- boost with 11 Gy (6-31) in study A and 50.4 Gy +/- boost with 10 Gy in study B. Individual radiosensitivity was determined with lymphocytes irradiated in vitro with X-ray doses of either 3 or 6 Gy and scoring the number of chromosomal deletions. RESULTS: Acute reactions displayed a typical spectrum with 57% in study A and 53% in study B showing an acute reaction of Grade 2-3. Individual radiosensitivity in both studies was characterized by a substantial variation and the fraction of patients with Grade 2-3 reaction was found to increase with increasing individual radiosensitivity measured at 6 Gy (study A, p = 0.238; study B, p = 0.023). For study B, this fraction increased with breast volume, and the impact of individual radiosensitivity on acute reaction was especially pronounced (p = 0.00025) for lower breast volume. No such clear association with acute reaction was observed when individual radiosensitivity was assessed at 3 Gy. CONCLUSION: Individual radiosensitivity determined at 6 Gy seems to be a good predictor for risk of acute effects after curative radiotherapy.     

Indicators of late normal tissue response after radiotherapy for head and neck cancer: fibroblasts, lymphocytes, genetics, DNA repair, and chromosome aberrations.

PURPOSE: To investigate the relationship between late tissue response after radiotherapy, cellular sensitivity and DNA repair capacity measured in dermal fibroblasts and chromosomal aberrations measured in lymphocytes. The study was in particular designed to compare cellular parameters of patients with maximum differences in late tissue reactions.MATERIALS AND METHODS: The study was performed with 16 pair-wise matched head and neck cancer patients 2-7 years after curative therapy exhibiting maximum differences (grade 1 vs. grade 3) in late normal tissue reactions. Clinical endpoints were fibrosis, telangiectasia, mucositis and xerostomia using the radiation therapy oncology group score. Patients with grade 3 reactions were tested for mutations in ataxia telangiectasia (AT), Nijmegen Breakage Syndrome (NBS), MRE11, RAD50 and DNA ligase IV genes by means of polymerase chain reaction-single-strand conformation polymorphism and sequencing analysis. Skin fibroblasts obtained from biopsies were used to determine the cellular sensitivity by colony formation and the induction and repair of DNA double-strand breaks (dsb) using constant-field gel electrophoresis. Lymphocytes were taken to measure chromosomal damage either in metaphase using conventional chromosome analysis or in G(0) using premature chromosome condensation (PCC)-technique.RESULTS: Patients with extreme late reactions (grade 3) showed no evidence for an AT, NBS, MRE11 or RAD50 mutation. Studies with fibroblasts revealed that extreme late reactions were associated neither with a pronounced cellular radiosensitivity nor with a difference in dsb repair capacity. In contrast, there was a significant difference in chromosomal damage measured in lymphocytes. After in vitro irradiation with 6Gy, lymphocytes taken from overreacting patients showed on average a significantly higher number of lethal aberrations than lymphocytes isolated from patients with mild reactions (7.2+/-0.8 vs. 5.0+/-0.3). Similar differences were found for PCC fragments.CONCLUSION: This study suggests that lymphocytes are more promising than fibroblasts to predict patient's normal tissue response after radiotherapy.     

Relationship between DNA double-strand breaks, cell killing, and fibrosis studied in confluent skin fibroblasts derived from breast cancer patients

PURPOSE: To investigate the relationship between DNA double-strand breaks (dsbs), cell killing, and fibrosis using skin fibroblasts derived from breast cancer patients who received postmastectomy radiotherapy. METHODS AND MATERIALS: Experiments were performed with 12 lines of normal skin fibroblasts derived from recurrence-free breast cancer patients. Cells were irradiated in confluence and cell survival was determined either after immediate or delayed (14 h) plating using a colony-forming assay. Dsbs were measured by constant-field gel electrophoresis. The "excess risk of fibrosis" was previously scored by Johansen et al. (IJRB 1994;66:407-412). RESULTS: The 12 cell lines showed a typical spectrum of radiosensitivity. The mean value of surviving fraction after 3.5 Gy (SF3.5) was 0.063 for immediate and 0.174 for delayed plating with a coefficient of variation (CV) of 44 and 39%, respectively. There was also a broad variation in the extent of recovery from potentially lethal damage (RPLD), which was not correlated with the immediate sensitivity. The number of initial dsbs as well as the half-times of dsb repair showed little variation, whereas there were considerable differences in the number of residual dsbs (CV = 29%). The number of residual dsbs after 100 Gy was correlated significantly only with SF3.5 after delayed (r2 = O.59; p = 0.006) but not after immediate plating (r2 = 0.21, p = 0.16). There was also no significant relationship between residual dsbs and the "excess risk of fibrosis" determined for the respective patients. CONCLUSION: It is shown that the number of residual dsbs measured in confluent human fibroblast lines can be used to predict the cellular radiosensitivity after delayed but not after immediate plating and also not to predict the excess risk of fibrosis of the respective breast cancer patients.     

Partial breast irradiation with interstitial 60CO brachytherapy results in frequent grade 3 or 4 toxicity. Evidence based on a 12-year follow-up of 70 patients

PURPOSE: To investigate the radiation-induced toxicity and cosmesis of brachytherapy (BT) alone in early stage breast cancer. METHODS AND MATERIALS: A total of 70 women diagnosed with Stage I or II breast carcinoma participated in a BT study at the Municipal Oncoradiological Center, Uzsoki Hospital, Budapest, Hungary, between November 1987 and June 1992. They had undergone breast-conserving surgery with an unknown surgical margin. The postoperative tumor bed irradiation was performed with interstitial (60)Co sources with an active length of 4 cm, with 10-mm center-to-center spacing arranged in a single plane. The median number of inserted sources was 5 (range, 2-8), with a linear activity of 133-137 MBq/cm at the beginning of the study. The 50 Gy delivered dose at 5 mm from the surface of the (60)Co sources was administered during 10-22 h to the virtual postoperative lumpectomy cavity (i.e., plane). For radiobiologic considerations, the clinical target volume (CTV) was calculated retrospectively with a 10-mm safety margin, resulting in a 72-cm(3) median CTV (range, 36-108 cm(3)) irradiated with a reference dose of 28 Gy. In the assessment of the skin and subcutaneous toxicity, the RTOG late radiation morbidity scoring system was applied. The radiosensitivity of the cultured fibroblasts was determined by clonogenic assay to check whether individual radiosensitivity played a role in the development and course of radiation-induced side-effects. RESULTS: The median follow-up was 12 years (range, 10-15 years). The population of the final study (34 cases) comprised all survivors with tumor-free breasts (27 cases) and patients with breasts erroneously ablated/excised for misinterpreted radiation-induced sequelae (7 patients). A total of 97% of the cohort (33/34) had grade > or =2, and 59% (20/34) had grade > or =3 radiation-induced toxicity. By the end of the follow-up, 85% of the patients experienced Grade > or =2 telangiectasis and 41% had Grade 3 telangiectasis. Eighty-eight percent had fibrosis of some form, and 35% had grade > or =3 fibrosis. Forty-one percent of the cohort displayed fat necrosis, which was always accompanied by Grade > or =3 fibrosis or telangiectasis. The cosmetic results were poor in 50% (17/34) of the patients. The radiosensitivity of the fibroblasts was increased in only 2/24 patients (8% of the investigated cases, in agreement with data published for the general population). Comparisons of our fibrosis prevalence data with those of others allowed an estimate of 0.47 h(-1) for the rate of recovery of DNA damage in the fibroblasts. CONCLUSIONS: Interstitial (60)Co BT of the breast tumor bed alone with a limited CTV (median, 72 cm(3)) and a total dose of 28 Gy is associated with a high rate (59%) of grade > or =3 radiation-induced toxicity and a high rate (50%) of poor cosmetic outcome at the end of a median follow-up of 12 years. A relatively high BT dose rate (1.3-2.8 Gy/h) applied during a short overall treatment time (10-22 h) and a possible geographic miss (close to skin implantation) might have contributed to the development of these sequelae.     

The Salzburg concept of intraoperative radiotherapy for breast cancer: results and considerations

Aim of this study is to show that ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery can be reduced by proper surgery and modern radiotherapy techniques. Three hundred and seventy eight women with stage I or II breast cancer had breast conserving surgery and received 51-56.1 Gy of postoperative radiation to the whole breast in 1.7 Gy fractions, but patients received different boost strategies. Group 1 (n = 188) received electron boost radiation of 12 Gy subsequent to the irradiation to the whole breast, group 2 (n = 190) received intraoperative electron boost radiation of 9 Gy directly to the tumor bed, followed by whole breast irradiation. After a median follow up period of 81.0 months in group 1 and a median follow up period of 51.1 months in group 2, 12 IBTRs (6.4%) could be observed in group 1 and no IBTR could be observed in group 2 (0.0%). The 5-year actuarial rates of IBTR were 4.3% (95% CI, 1.9-8.3%) and 0.0% (95% CI, 0.0-1.9%), respectively (p = 0.0018). The 5-year actuarial rates of distant recurrence were 8.6% (95% CI, 4.9-13.5%) and 4.2% (95% CI, 1.8-8.2%), respectively (p = 0.08). The 5 year disease-free survival rates were 90.9% (95% CI, 85.8-94.7%) in group 1 and 95.8% (95% CI, 91.8-98.2%) in group 2 (p = 0.064). Immediate IORT-boost and whole breast irradiation yields excellent local control at 5 years, and was associated with a statistically significant decreased rate of IBTR compared with a similar cohort of patients treated with whole breast irradiation and conventional electron boost.     

The influence of the boost technique on local control in breast conserving treatment in the EORTC 'boost versus no boost' randomised trial.

BACKGROUND AND PURPOSE: The EORTC Trial 22881/10882 investigating the role of a boost dose in breast conserving therapy demonstrated a significantly better local control rate with the higher radiotherapy dose, especially in women younger than 50 years of age. This paper investigates the potential impact of the different boost techniques on local control and on fibrosis after breast conserving therapy. PATIENTS AND METHODS: From 1989 to 1996, 2661 patients were randomised to receive a boost dose of 16Gy to the primary tumour bed after microscopically complete tumorectomy and 50Gy whole breast irradiation. The choice of the boost technique was left to the treating investigator. Treatment data were prospectively recorded as well as the clinical outcome in terms of local control and fibrosis. Sixty-three percent of the patients received a boost dose with fast electrons, 28% with photon beams and 9% with interstitial brachytherapy. RESULTS: At 5 years, local recurrences were seen in 74 of the 1635 patients who received an electron boost (4.8%, CI 3.6-5.9%), in 28 of the 753 patients who received a photon boost (4.0%, CI 3.4-5.5%) and in 6 of the 225 patients after an interstitial boost (2.5%, CI 0.3-4.6%). The grade of fibrosis in the whole breast as well as at the primary tumour bed, as scored by the treating radiation oncologist, was similar in the three groups. CONCLUSIONS: Although the three groups are of a rather unequal size, the results of the interstitial boost seem similar in terms of fibrosis and at least as good in terms of local control, despite a lower treatment volume and a longer overall treatment time.     

T1-2N0-1M0期乳腺癌保乳术后大分割调强放疗近期临床观察

目的:观察T1-2N0-1M0期乳腺癌保乳术后大分割调强放疗的疗效、美容效果及不良反应。方法:选择2011年11月-2012年11月间就诊于山西省肿瘤医院乳腺疾病诊治中心的乳腺癌保乳患者41例,予大分割调强放疗,全乳计划靶体积43.5Gy/15次,瘤床区电子线补量8.7Gy/3次,2.9Gy/次,5次/周,疗程共24天。局部区域控制率和总生存率用Kaplan-Meier法计算。结果:中位随访时间27个月,随访率100%。3年局部区域控制率、生存率均为100%,急性放射性皮肤反应Ⅰ级4例,Ⅱ级3例;血液系统不良反应白细胞下降Ⅰ级5例,Ⅱ级3例,Ⅲ级2例;急性放射性肺炎I级2例,晚期放射性肺炎1例;患肢水肿轻度2例。放疗前、后美容效果评价优秀+良好率为95.1%、87.8%,放疗后1、3、6、12个月优秀+良好率均为90.2%。结论:早期乳腺癌保乳术后调强大分割放疗疗效和美容效果较好,且不良反应发生率低,可以缩短放疗时间。     

辐射所致残存染色体易位与放射敏感性关系研究

目的 :应用荧光原位杂交 (FISH)方法研究人肿瘤细胞放射敏感性与染色体残存易位关系及临床应用的可行性。方法 :采用 3种放射敏感性不同的人肿瘤细胞系 :鼻咽鳞癌 (CNE)、肺腺癌 (SPC)和乳腺腺癌 (MCF 7)。通过克隆形成方法测定 2Gy、4Gy、6Gy和 8GyX线照射剂量下肿瘤细胞的存活率。采用常规染色体制片过程和 2号染色体涂染探针及FISH方法 ,测定 2Gy、4Gy和 6GyX线照射2 4h后 ,肿瘤细胞 2号染色体内在和诱导的畸变量。结果 :未照射的对照细胞 2号染色体存在不同程度的内在畸变。 2Gy、4Gy和 6Gy照射后 2 4h ,CNE、SPC和MCF 7细胞诱导生成的残存染色体畸变与剂量关系一致 ,能够反映细胞的放射敏感性 ,所有细胞系诱导 2号染色体生成的畸变与细胞存活率均存在良好相关性 (rs=0 96)。结论 :诱导的残存染色体畸变与照射剂量呈线性关系 ,采用FISH方法计数照射诱导的残存染色体畸变 ,可以预测肿瘤细胞间的放射敏感性差异并具有重要的临床意义     

Why recent studies relating normal tissue response to individual radiosensitivity might have failed and how new studies should be performed

PURPOSE: New insights into the kinetics of late complications occurring after radiation therapy indicated that all patients have a constant risk of developing late tissue complications. These observations might have a great impact on studies relating normal tissue complications to individual radiosensitivity. METHODS AND MATERIALS: Data previously published by Peacock et al. were used for analysis. In this study, 39 breast cancer patients with severe reactions (responders) were compared with 65 matched patients showing no reactions (nonresponders). Cellular radiosensitivity as measured in vitro in terms of D(0.01) did not show significant differences between the two groups, both for high-dose-rate (5.84 +/- 0.06 vs. 5.85 +/- 0.07 Gy) and low-dose-rate (7.44 +/- 0.10 vs. 7.56 +/- 0.09 Gy) irradiation. RESULTS: A theoretical distribution was calculated for the individual radiosensitivity of patients with Grade or=(MV + SD), a normal group with a sensitivity between MV - SD and MV + SD, and a sensitive group 相似文献   

Association of single nucleotide polymorphisms in ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with clinical and cellular radiosensitivity

Purpose

To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position -509), XPD (codon 751), and XRCC1 (codon 399) with fibrosis and also individual radiosensitivity.

Methods and materials

Retrospective analysis with 69 breast cancer patients treated with breast-conserving radiotherapy; total dose delivered was restricted to vary between 54 and 55 Gy. Fibrosis was evaluated according to LENT/SOMA score. DNA was extracted from blood samples; cellular radiosensitivity was measured using the G0 assay and polymorphisms by PCR-RFLP and MALDI-TOF, respectively.

Results

Twenty-five percent of all patients developed fibrosis of grade 2 or 3. This proportion tends to be higher in patients being polymorphic in TGFB1 or XRCC1 when compared to patients with wildtype genotype, whereas for ATM, GSTP1, SOD2 and XPD the polymorphic genotype appears to be associated with a lower risk of fibrosis. However, none of these associations are significant. In contrast, when a risk score is calculated based on all risk alleles, there was significant association with an increased risk of fibrosis (per risk allele odds ratio (ORs) = 2.09, 95% confidence interval (CI): 1.32-3.55, p = 0.0005). All six polymorphisms were found to have no significant effect on cellular radiosensitivity.

Conclusions

It is most likely that risk for radiation-induced fibrosis can be assessed by a combination of risk alleles. This finding needs to be replicated in further studies.     

早期乳腺癌保乳术中低能X线放疗安全及可行性初步研究

目的 探讨早期乳腺癌保乳手术中放疗的短期并发症及美容效果。方法 回顾分析2013—2015年间30例早期乳腺癌患者资料。全部患者均行乳腺癌保乳手术及低能X线术中放疗,术中予以适配器表面20 Gy处方剂量,术后观察手术区域并发症、放射性损伤、乳房美容效果。结果无严重3、4级不良反应;短期并发症为4例(13%)出现血清肿,其中2例需要外科抽吸处理;3例(10%)出现1—2级乳腺皮肤红斑;美容效果优秀率为50%。患者均未出现LR及远处转移。结论 低能X线术中放疗在乳腺癌保乳手术中安全可行,在部分早期低危乳腺癌患者中可作为瘤床补量的一种选择参考。     

Feasibility of accelerated whole-breast radiation in the treatment of patients with ductal carcinoma in situ of the breast

BACKGROUND: We report the results of a prospective trial investigating the use of accelerated, hypofractionated whole-breast radiation therapy after breast-conservation surgery for ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: A total of 59 patients with a median age of 54 years (range, 36-78 years) completed a phase I/II study of hypofractionated radiation therapy for treatment of DCIS. Eligibility criteria included patients with mammographically detected DCIS, status after segmental mastectomy with negative margins, and no residual calcifications. All patients were treated with external-beam radiation therapy without a boost, over 3 weeks, to a total dose of 42 Gy to the entire breast (2.8 Gy per fraction in 15 fractions). To optimally spare heart and lung, 34 of the 59 patients (57%) were treated in the prone position. Twenty-nine of 59 patients (49%) received adjuvant hormonal therapy. RESULTS: Overall, radiation therapy was well tolerated, with modest acute toxicity limited to grade 1 radiation dermatitis (76%), breast edema (17%), and fatigue (12%). With a median follow-up of 36 months, late toxicities included grade 1 hyperpigmentation changes (85%), induration (66%), asymmetry (64%), and breast fibrosis (17%), with 3 cases of grade 2 fibrosis and 1 case of grade 2 hyperpigmentation. Among the patients with >or= 3 years of follow-up, cosmesis was scored as good to excellent in 21 patients (91%) and fair in 2 patients (9%). At the time of this report, no ipsilateral or contralateral breast recurrences have occurred. CONCLUSION: These data demonstrate the feasibility of treating the whole breast for DCIS with a hypofractionated regimen, with modest acute and late toxicity.     

The use of chromosome aberrations in predicting breast cancer risk

In order to assess the usefulness of chromosome aberrations in predicting breast cancer risk, 10 patients with breast cancer diagnosis and appropriately matching 10 healthy controls were chosen. Spontaneous and radiation induced unstable chromosome aberrations in peripheral blood lymphocytes were compared in the two groups. When the spontaneous aberration frequencies were compared, acentric chromosome frequency, scored in the group of patients was significantly higher than that found in the control group (p<0.01). Absolute aberration frequencies as a determinant of radiosensitivity were calculated by subtracting spontaneous aberration frequencies from the frequencies that were obtained following 2 Gy of Co-60 gamma irradiation. Absolute dicentric chromosome frequency significantly increased in the patients1 group (p<0.01) as compared to that observed in the control group. Increases in either spontaneous acentric chromosome frequency or dicentric chromosome frequency as a determinant of an enhanced radiosensitivity in the group of patients may be valuable in predicting breast cancer risk. The studies involving unstable chromosome aberrations can be easily performed and can facilitate cancer diagnosis with minor effort and low cost.     

3-D Conformal Photon Boost in the Treatment of Early Stage Breast Cancer: Four Year Follow Up Results

In the treatment of early stage breast cancer, breast conserving surgery (BCS) followed by whole breast irradiation (WBI) is the standard treatment. The impact of the tumor bed boost following WBI is well-defined, but there are various delivery methods. In this study we demonstrate our 4?year experience with the 3-D conformal boost technique. Between January 2004 and June 2005, 77 early stage (Stage I?CII) breast cancer patients were treated in our institute with whole breast irradiation (WBI, 50.4?Gy in 28 fractions) after breast conserving surgery. Following WBI, 3-D conformal photon boost was delivered (10?C16?Gy in five to eight fractions) for all patients. The clinical outcome was retrospectively recorded in terms of survival and local control. The side effect profile (fibrosis, fat necrosis and cosmetic outcome) was also recorded and studied. In our patient group the mean follow up time was 46.8?months (median: 52, range: 17?C71, SD: 14.4) The 4-year probability of local tumor control was 96% (crude rate: 74/77?C96.1%), the 4-year probability of overall survival was 96% (crude rate: 74/77?C96.1%) in this patient group. In case of the distant metastasis free survival the probability was 89, 5% (crude rate: 70/77?C90, 1%). Probability of disease specific survival was 98% (crude rate: 76/77?C98. 7%). Local relapse occurred in three cases (3.9%). In ten cases (12.9%) asymptomatic grade I?CII breast fibrosis, in eight cases (10.4%) asymptomatic breast fat necrosis were registered. For 14 patients (18.2%) asymptomatic lung fibrosis was recorded on the control CT scans. In term of the relapse free survival, the close resection margin and the nodal positivity resulted in significant difference in favor of the clear resection margin group and the node negative group. In this study the 3-D conformal photon boost resulted in good local control and side effect profile. The presence of tumor bed clips resulted in significantly lower boost PTV volumes, but no correlation was found between the irradiated boost volume and the breast fibrosis. In the relapse free survival analysis, nodal negativity and clear margin status resulted in significantly better RFS.     

External and Interstitial Radiation Therapy of Locally Advanced Carcinoma of the Breast

The present report concerns 164 cases of locally advanced breast cancer (stage III), treated between December 1977 and January 1987. The local therapy consisted exclusively of radiation therapy including external beam irradiation (⁶⁰Co) up to 45-50 Gy supplemented with a boost, delivered either by interstitial ¹⁹²Ir (30-40 Gy) or by external irradiation from limited fields (15-22 Gy). Eighty-one patients also received adjuvant systemic chemotherapy. A total of 51 local failures (31%) occurred. The actuarial rate of survival with local tumor control was 53% at 5 years and 49% at 6.5 years. A total of 69 patients developed distant metastases (42%). The actuarial survival without distant failure was 43% at 5 years and 37% at 6 years. The actuarial survival rate at 5 years was 53% and 38% at 7 years. The cosmetic results were excellent in 58 patients and poor in 13 patients (9.7%). The result suggests that stage III breast cancer can be satisfactorily treated with radiation therapy alone as local treatment.     

Individualization of radiotherapy in breast cancer patients: possible usefulness of a DNA damage assay to measure normal cell radiosensitivity.

PURPOSE: The purpose of this study was to determine whether the distribution of sensitivities in breast cancer patients, measured using a DNA damage assay on lymphocytes, is likely to provide sufficient discrimination to enable the reliable identification of patients with abnormal sensitivities.MATERIAL AND METHODS: Radiosensitivity (x) was assessed in 226 samples of lymphocytes from unselected women with breast cancer and was quantified as the initial number of DNA double-strand breaks (dsb) induced per Gy and per DNA unit (200 Mbp).RESULTS: The existence of an inter-individual variation in the parameter (x) is described through the range (0.40-4.72 dsb/Gy/DNA unit) of values found, which have been fitted to the mathematical model defined by the log-normal distribution (mu = 0.42+/-0.03; sigma = 0.52+/-0.03; R(2)=0.9475). A total of 189 patients received radiotherapy after surgical treatment. Among them, we have detected 15 patients who developed severe skin reactions and we have compared their radiosensitivity values with the rest of patients treated.CONCLUSIONS: Our results suggest that DNA initial damage measured on lymphocytes offers an approach to predict the acute response of human normal tissues prior to radiotherapy. Values of x higher than 3.20 dsb/Gy/DNA unit theoretically should correspond to the highly radio-sensitive patients. Using the experimental results, we have calculated the strength of the test by means of the area under the receiver operator characteristic curves (A(Z)) to determine whether the radiosensitivity assay can discriminate between patients according to their radiation response. The value found (A(Z)=0.675+/-0.072) is indicative of a fair-poor discriminating capacity of the test to identify the patients with higher risk of developing a severe acute reaction during the radiotherapy treatment.     

A patient questionnaire for radiation-induced brachial plexopathy

We analyzed the usefulness of a symptom questionnaire to screen for radiation-induced brachial plexopathy (RIBP) after breast cancer treatment. Four questions addressed distal and proximal paresis: impaired hand functions, problems raising the arm, carrying weights, and lifting objects from a high shelf. Eighty-one relapse-free patients were neurologically examined. Treatment was mastectomy (51%) or breast-conserving surgery (49%), radiotherapy to the supraclavicular +/- axilla with median 60 Gy maximum dose. Sixty-five subsequent control patients had breast-conserving surgery and radiotherapy to the breast only with 55 Gy median dose. Median follow up was 10 and 7.4 years, respectively. Sixteen patients had RIBP, 7 had Radiation Therapy Oncology Group (RTOG) grade 1, 4 grade 2, 3 grade 3, and 2 grade 4 RIBP. Thirty-seven patients had fibrosis and 32 had arm edema. Four patients with RIBP had no fibrosis (n = 2) or fibrosis of the axilla only (n = 2). Specificity of the question "impaired hand functions" for RIBP was 0.66 (95% confidence interval [CI], 0.51-0.78); sensitivity was 0.80 (95% CI, 0.52-0.96). Specificity of the question "raising the arm" was 0.98 (95% CI, 0.9-0.99) and sensitivity was 0.18 (95% CI, 0.04-0.45); the rate of false-positive control patients was 3%. In multivariate analysis, "impaired hand functions" and fibrosis were independent indicators of RIBP (P <0.005). Patients with breast irradiation only stated moderate/pronounced impaired hand functions; and problems carrying weights and lifting objects from a high shelf in 38%, 58%, and 77%, not significantly different from patients with RIBP or the patients with supraclavicular radiation. RIBP is not necessarily associated with fibrosis. The aim of the questionnaire was screening of a population at risk for RIBP. In this group, the question "problems raising the arm" detected severe RIBP with high specificity. Negation of "impaired hand functions" excludes RIBP. Both questions should be included in follow-up questionnaires.     

Outcome of radiotherapy after breast conserving surgery in screen detected breast cancers

The treatment outcomes were reviewed for all the patients at this institute who underwent breast irradiation after breast conserving surgery in 1991. Of a total of 643 patients treated, 194 (30%) had presented with tumours detected by screening mammography. The breast was irradiated with a tangential pair of fields, giving a dose of 40 Gy in 15 fractions over 3 weeks in 97% of these patients. A boost was not used. With a median follow-up of 4.7 years, there was better cancer related survival in patients with screen detected cancers compared with those that were non-screen detected (94% versus 84% at 5 years; P = 0.002). The breast recurrence rate at 5 years was 1% for screen detected cancers compared with 6% for those that were non-screen detected (P = 0.01). Factors additional to screen detected status that were found to be significant for cancer survival were pathological stage (P = 0.03) and histological grade (P = 0.01). In a Cox multivariate analysis, only two factors were significant for breast recurrence: screen detected status (P = 0.023) and histological grade (P = 0.016). This study suggests that breast irradiation with 40 Gy given over 3 weeks after breast conserving surgery for screen detected breast cancer gives a high level of local control out to 5 years.     

The increment of micronucleus frequency in cervical carcinoma during irradiation in vivo and its prognostic value for tumour radiocurability.

A potential usefulness of micronucleus assay for prediction of tumour radiosensitivity has been tested in 64 patients with advanced stage (II B-IV B) cervical carcinoma treated by radiotherapy. The study of cellular radiosensitivity in vitro was conducted in parallel with the study of cellular damage after tumour irradiation in vivo. Radiosensitivity of in vitro cultured primary cells isolated from tumour biopsies taken before radiotherapy was evaluated using cytokinesis-block micronucleus assay. Frequency of micronuclei per binucleated cell (MN/BNC) at 2 Gy was used as a measure of radiosensitivity. Radiation sensitivity in vivo was expressed as per cent increment of micronucleus frequency in cells isolated from biopsy taken after 20 Gy (external irradiation, 10 x 2 Gy) over the pre-treatment spontaneous micronucleus level and was called MN20. Very low correlation (r = 0.324) was observed between micronucleus frequency in vitro and in vivo. Although micronucleus frequency at 2 Gy differed widely between tumours evaluated (mean MN/BNC was 0.224; range 0.08-0.416), no significant correlation was observed between this parameter and clinical outcome. The average increment of micronucleus frequency after 20 Gy amounted to 193% of spontaneous level (range 60-610%) and was independent of spontaneous micronucleation before radiotherapy. In contrast to in vitro results, these from in vivo assay seem to have a predictive value for radiotherapy of cervix cancer. The micronucleus increment in vivo that reached at least 117.5% of pretreatment value (first quartile for MN20 data set) correlated significantly with better tumour local control (P < 0.008) and overall survival (P < 0.045). Our results suggest that evaluation of increment of micronucleus frequency during radiotherapy (after fixed tested dose of 20 Gy) offers a potentially valuable approach to predicting individual radioresponsiveness and may be helpful for individualization of treatment strategy in advanced stage cervical cancer.     

乳腺癌保乳术后1~3个腋窝淋巴结阳性者锁骨上淋巴结复发风险分析

目的 分析乳腺癌保乳术后1~3个腋窝淋巴结阳性患者锁骨上淋巴结复发率(SCFR)及高危因素。方法 回顾分析2001—2014年本院收治的保乳术+腋窝淋巴结清扫术后乳腺癌患者,病理证实1~3个腋窝淋巴结阳性,无内乳和锁骨上淋巴结转移或远处转移。256例均行全乳腺放疗,剂量46~50 Gy (2 Gy/次)或43.5 Gy (2.9 Gy/次),瘤床总剂量50~70 Gy。245例接受了辅助化疗,45例Her-2受体阳性者18例接受曲妥珠单抗治疗。Kaplan-Meier法计算同侧SCFR、LRR、DM及OS,并Logrank法检验。结果 随访时间满5年的样本量为101例。全组5年SCFR、LRR、DM、OS分别为2.1%、2.1%、5.0%、98.0%,2~3个腋窝淋巴结阳性(P= 0.010)、脉管瘤栓(P= 0.030)、LuminalB型(P= 0.006)为锁骨上淋巴结复发的高危因素。腋窝淋巴结阳性数为2~3个和1个者的5年SCFR分别为5.3%和2.8%(P=0.010);脉管瘤栓阳性和阴性的5年SCFR分别为5.3%和1.8%(P=0.030);Luminal B型、三阴性、Luminal A型和Her-2阳性型的5年SCFR分别为7.1%、3.2%、1.2%和0%(P=0.006)。有0、1、2~3个高危因素患者的5年SCFR分别为0%、3.0%、10.6%(P=0.000)。结论 在接受现代化疗前提下,乳腺癌保乳术后1~3个腋窝淋巴结阳性者SCFR较低,不需要全部行锁骨上区预防照射。有高危因素患者是否行预防性锁骨上区照射需进一步研究。