Dan Lundstedt

ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer

BACKGROUND AND PURPOSE Delineation of clinical target volumes (CTVs) is a weak link in radiation therapy (RT), and large inter-observer variation is seen in breast cancer patients. Several guidelines have been proposed, but most result in larger CTVs than based on conventional simulator-based RT. The aim was to develop a delineation guideline obtained by consensus between a broad European group of radiation oncologists. MATERIAL AND METHODS During ESTRO teaching courses on breast cancer, teachers sought consensus on delineation of CTV through dialogue based on cases. One teacher delineated CTV on CT scans of 2 patients, followed by discussion and adaptation of the delineation. The consensus established between teachers was sent to other teams working in the same field, both locally and on a national level, for their input. This was followed by developing a broad consensus based on discussions. RESULTS Borders of the CTV encompassing a 5mm margin around the large veins, running through the regional lymph node levels were agreed, and for the breast/thoracic wall other vessels were pointed out to guide delineation, with comments on margins for patients with advanced breast cancer. CONCLUSION The ESTRO consensus on CTV for elective RT of breast cancer, endorsed by a broad base of the radiation oncology community, is presented to improve consistency.

Tobacco smoking and long-lasting symptoms from the bowel and the anal-sphincter region after radiotherapy for prostate cancer

BACKGROUND AND PURPOSE Tobacco smoking can cause vascular injury, tissue hypoxia and fibrosis as can ionizing radiation. However, we do not know if tobacco smoking increases the risk of long-term side effects after radiotherapy for prostate cancer. METHODS We identified 985 men treated with radiotherapy for prostate cancer between 1993 and 2006. In 2008, long-lasting symptoms appearing after radiotherapy for prostate cancer were assessed through a study-specific questionnaire as were smoking habits and demographic factors of all these men. In the questionnaire the prostate-cancer survivors were asked to report symptom occurrence the previous six months. RESULTS We obtained information on tobacco smoking from 836 of the 985 prostate-cancer survivors with a median time to follow-up of six years (range 2-14 years). The prevalence ratio of defecation urgency among current smokers compared to never smokers was 1.6 (95% CI 1.2-2.2). Corresponding prevalence ratio for diarrhea was 2.8 (95% CI 1.2-6.5), the sensation of bowel not completely emptied after defecation 2.1 (95% CI 1.3-3.3) and for sudden emptying of all stools into clothing without forewarning 4.7 (95% CI 2.3-9.7). CONCLUSION Tobacco smoking among prostate-cancer survivors treated with radiotherapy increases the risk of certain long-lasting symptoms from the bowel and anal-sphincter region.

Long-term symptoms after radiotherapy of supraclavicular lymph nodes in breast cancer patients

BACKGROUND AND PURPOSE Irradiation of the supraclavicular lymph nodes has historically increased the risk of brachial plexopathy. We report long-term symptoms after modern radiotherapy (based on 3D dose planning) in breast cancer patients with or without irradiation of the supraclavicular lymph nodes. MATERIAL AND METHODS We collected information from 814 women consecutively treated with adjuvant radiotherapy for breast cancer. The women had breast surgery with axillary dissection (AD) or sentinel node biopsy (SNB). The breast area was treated to 50 Gy in 2.0 Gy fractions. Women with >three lymph node metastases had regional radiotherapy (RRT) to the supraclavicular lymph nodes. Three to eight years after radiotherapy, they received a questionnaire asking about paraesthesia, oedema, pain, and strength in the upper limb. RESULTS Paraesthesia was reported by 38/192 (20%) after AD with RRT compared to 68/505 (13%) after AD without RRT (relative risk [RR] 1.47; 95% confidence interval [CI] 1.02-2.11) and by 9/112 (8%) after SNB without RRT (RR 2.46; 95% CI 1.24-4.90). Corresponding risks adjusted for oedema (RR 1.28; 95% CI 0.93-1.76) and (RR 1.75; 95% CI 0.90-3.39). In women ≤ 49years with AD and RRT, 27% reported paraesthesia. No significant pain or decreased strength was reported after RRT. CONCLUSION Radiotherapy to the supraclavicular lymph nodes after axillary dissection increases the occurrence of paraesthesia, mainly among younger women. When adjusted for oedema the contribution from radiotherapy is no longer formally statistically significant indicating that there is also an indirect effect mediated by the oedema.

Risk Factors of Developing Long-Lasting Breast Pain After Breast Cancer Radiotherapy

PURPOSE Postoperative radiotherapy decreases breast cancer mortality. However, studies have revealed a long-lasting breast pain among some women after radiotherapy. The purpose of this study was to identify risk factors that contribute to breast pain after breast cancer radiotherapy. METHODS AND MATERIALS We identified 1,027 recurrence-free women in two cohorts of Swedish women treated for breast cancer. The women had breast-conserving surgery and postoperative radiotherapy, the breast was treated to 48 Gy in 2.4-Gy fractions or to 50 Gy in 2.0-Gy fractions. Young women received a boost of up to 16 Gy. Women with more than three lymph node metastases had locoregional radiotherapy. Systemic treatments were given according to health-care guidelines. Three to 17 years after radiotherapy, we collected data using a study-specific questionnaire. We investigated the relation between breast pain and potential risk modifiers: age at treatment, time since treatment, chemotherapy, photon energy, fractionation size, boost, loco-regional radiotherapy, axillary surgery, overweight, and smoking. RESULTS Eight hundred seventy-seven women (85%) returned the questionnaires. Among women up to 39 years of age at treatment, 23.1% had breast pain, compared with 8.7% among women older than 60 years (RR 2.66; 95% CI 1.33-5.36). Higher age at treatment (RR 0.96; 95% CI 0.94-0.98, annual decrease) and longer time since treatment (RR 0.93; 95% CI 0.88-0.98, annual decrease) were related to a lower occurrence of breast pain. Chemotherapy increased the occurrence of breast pain (RR 1.72; 95% CI 1.19-2.47). In the multivariable model only age and time since treatment were statistically significantly related to the occurrence of breast pain. We found no statistically significant relation between breast pain and the other potential risk modifiers. CONCLUSIONS Younger women having undergone breast-conserving surgery with postoperative radiotherapy report a higher occurrence of long-lasting breast pain compared to older women. Time since treatment may decrease the occurrence of pain.

Mean Absorbed Dose to the Anal-Sphincter Region and Fecal Leakage among Irradiated Prostate Cancer Survivors

PURPOSE To supplement previous findings that the absorbed dose of ionizing radiation to the anal sphincter or lower rectum affects the occurrence of fecal leakage among irradiated prostate-cancer survivors. We also wanted to determine whether anatomically defining the anal-sphincter region as the organ at risk could increase the degree of evidence underlying clinical guidelines for restriction doses to eliminate this excess risk. METHODS AND MATERIALS We identified 985 men irradiated for prostate cancer between 1993 and 2006. In 2008, we assessed long-term gastrointestinal symptoms among these men using a study-specific questionnaire. We restrict the analysis to the 414 men who had been treated with external beam radiation therapy only (no brachytherapy) to a total dose of 70 Gy in 2-Gy daily fractions to the prostate or postoperative prostatic region. On reconstructed original radiation therapy dose plans, we delineated the anal-sphincter region as an organ at risk. RESULTS We found that the prevalence of long-term fecal leakage at least once per month was strongly correlated with the mean dose to the anal-sphincter region. Examining different dose intervals, we found a large increase at 40 Gy; ≥ 40 Gy compared with <40 Gy gave a prevalence ratio of 3.8 (95% confidence interval 1.6-8.6). CONCLUSIONS This long-term study shows that mean absorbed dose to the anal-sphincter region is associated with the occurrence of long-term fecal leakage among irradiated prostate-cancer survivors; delineating the anal-sphincter region separately from the rectum and applying a restriction of a mean dose <40 Gy will, according to our data, reduce the risk considerably.

Response to Radiotherapy After Breast-Conserving Surgery in Different Breast Cancer Subtypes in the Swedish Breast Cancer Group 91 Radiotherapy Randomized Clinical Trial

Purpose To evaluate the effect of adjuvant radiotherapy (RT) after breast conservation surgery in different breast cancer subtypes in a large, randomized clinical trial with long-term follow-up. Patients and Methods Tumor tissue was collected from 1,003 patients with node-negative, stage I and II breast cancer who were randomly assigned in the Swedish Breast Cancer Group 91 Radiotherapy trial between 1991 and 1997 to breast conservation surgery with or without RT. Systemic adjuvant treatment was sparsely used (8%). Subtyping was performed with immunohistochemistry and in situ hybridization on tissue microarrays for 958 tumors. Results RT reduced the cumulative incidence of ipsilateral breast tumor recurrence (IBTR) as a first event within 10 years for luminal A-like tumors (19% v 9%; P = .001), luminal B-like tumors (24% v 8%; P < .001), and triple-negative tumors (21% v 6%; P = .08), but not for human epidermal growth factor receptor 2-positive (luminal and nonluminal) tumors (15% v 19%; P = .6); however, evidence of an overall difference in RT effect between subtypes was weak ( P = .21). RT reduced the rate of death from breast cancer (BCD) for triple-negative tumors (hazard ratio, 0.35; P = .06), but not for other subtypes. Death from any cause was not improved by RT in any subtype. A hypothesized clinical low-risk group did not have a low risk of IBTR without RT, and RT reduced the rate of IBTR as a first event after 10 years (20% v 6%; P = .008), but had no effect on BCD or death from any cause. Conclusion Subtype was not predictive of response to RT, although, in our study, human epidermal growth factor receptor 2-positive tumors seemed to be most radioresistant, whereas triple-negative tumors had the largest effect on BCD. The effect of RT in the presumed low-risk luminal A-like tumors was excellent.

Radiation Therapy to the Plexus Brachialis in Breast Cancer Patients: Analysis of Paresthesia in Relation to Dose and Volume

PURPOSE To identify volume and dose predictors of paresthesia after irradiation of the brachial plexus among women treated for breast cancer. METHODS AND MATERIALS The women had breast surgery with axillary dissection, followed by radiation therapy with (n=192) or without irradiation (n=509) of the supraclavicular lymph nodes (SCLNs). The breast area was treated to 50 Gy in 2.0-Gy fractions, and 192 of the women also had 46 to 50 Gy to the SCLNs. We delineated the brachial plexus on 3-dimensional dose-planning computerized tomography. Three to eight years after radiation therapy the women answered a questionnaire. Irradiated volumes and doses were calculated and related to the occurrence of paresthesia in the hand. RESULTS After treatment with axillary dissection with radiation therapy to the SCLNs 20% of the women reported paresthesia, compared with 13% after axillary dissection without radiation therapy, resulting in a relative risk (RR) of 1.47 (95% confidence interval [CI] 1.02-2.11). Paresthesia was reported by 25% after radiation therapy to the SCLNs with a V40 Gy ≥ 13.5 cm(3), compared with 13% without radiation therapy, RR 1.83 (95% CI 1.13-2.95). Women having a maximum dose to the brachial plexus of ≥55.0 Gy had a 25% occurrence of paresthesia, with RR 1.86 (95% CI 0.68-5.07, not significant). CONCLUSION Our results indicate that there is a correlation between larger irradiated volumes of the brachial plexus and an increased risk of reported paresthesia among women treated for breast cancer.

P3-13-03: Long-Term Symptoms after Radiotherapy of Supraclavicular Lymph Nodes in Breast Cancer Patients.

Background and Purpose: Irradiation of the supraclavicular lymph nodes has historically been shown to increase the risk of brachial plexopathy with neurological problems in the upper limb. The purpose of this study was to compare long-term symptoms after modern radiotherapy (based on 3D dose planning) in breast cancer patients with or without irradiation of the supraclavicular lymph nodes. Material and Methods: We collected information from 814 recurrence free women consecutively treated with adjuvant radiotherapy for breast cancer at the Sahlgrenska University Hospital in Gothenburg, Sweden, 1999 to 2004. The women had breast conserving surgery or mastectomy with axillary dissection or sentinel node biopsy. The breast area was irradiated to 50 Gy in 2.0 Gy fractions. Women with more than three lymph node metastases had regional radiotherapy to the supraclavicular lymph nodes delivered in 2.0 Gy fractions up to 50 Gy. Systemic treatments were given according to regional guidelines. In this study the women were classified into three groups depending on if they had axillary dissection and regional radiotherapy. The first group had both axillary dissection and regional radiotherapy, the second group had axillary dissection without regional radiotherapy, and the third group had sentinel node biopsy (i.e. no axillary dissection) without regional radiotherapy. Three to eight years after radiotherapy, the women received a questionnaire asking about paresthesia, pain and strength in the upper limb. Results: Among women with axillary dissection and regional radiotherapy 38/192 (19.8%) reported paresthesia in the hand compared to 68/505 (13.5%) among women with axillary dissection without regional radiotherapy; relative risk (RR) 1.47; 95% confidence interval (95% CI) 1.02 - 2.11, and compared to 9/112 (8.0%) among women with sentinel node biopsy without regional radiotherapy; RR 2.46 (95% CI 1.24−4.90). Type of breast surgery, number of examined axillary lymph nodes, and chemotherapy had no impact on the occurrence of paresthesia. Age was an effect modifier among the women with axillary dissection and regional radiotherapy; up to 49 years of age 26.8% reported paresthesia (RR 2.45; 95% CI 1.05−5.73), between 50 and 59 years of age 19.7% reported paresthesia (RR 1.81; 95% CI 0.73−4.44), and above 59 years of age 10.9% reported paresthesia (RR 1.00 Reference). We found no statistically significant differences between the groups regarding pain or decreased strength. Conclusions: Radiotherapy to the supraclavicular lymph nodes increases the occurrence of paresthesia in the hand. The effect was mainly seen among younger women. Dose/volume-response analysis regarding paresthesia will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-03.

Radiotherapy for Metastatic Lesions

Modern imaging and the development of new precise techniques in radiotherapy has changed the possibilities to detect and treat metastatic lesions. Metastatic breast cancer includes a wide range of clinical scenarios, and the use of radiotherapy must be adjusted to the patient need, all the way from symptom control with a single fraction late in life to potentially curative extensive radiotherapy in oligometastatic disease. The role of palliative radiotherapy in various metastatic sites and the evidence behind different fractionation schedules are reviewed. Treatments of metastatic spinal cord compression and radiotherapy in locally recurrent disease are discussed. The possibilities of stereotactic radiotherapy for brain metastases as well as stereotactic body radiotherapy for oligometastatic disease are presented and summarized. The integration of the systemic treatment with the radiotherapy and the importance of listening to the patient need and to put the radiotherapy decision within the context of a multidisciplinary team are emphasized.

Abstract P4-10-03: Long-Term Follow-Up of SweBCG 91RT, a Randomized Trial of Breast Conservation Surgery with and without Radiotherapy from the Swedish Breast Cancer Group

Background: Postoperative radiotherapy remains the golden standard after breast conservation surgery. However, national breast screening programmes and increased public awareness of breast cancer have resulted in earlier detection of small tumours with favourable prognosis. The Swedish SweBCG 91RT multicentre study of breast conservation with and without radiotherapy was initiated in 1991. Five year results have been published.(Malmstrom P et al. Eur J Cancer 39: 1690, 2003). A gene expression signature for radioresistance has also been defined from this patient material. (Nimeus-Malmstrom E et al. Breast Cancer Res 2008, 10: R3(doi10:1186/brc1997). Increasing knowledge of genetically defined subgroups of breast cancer is likely to have an impact on breast conservation treatment. We now present outcome after 15 years of follow-up. Patients and methods: After a standardised radical sector resection 1187 patients with T1-2N0M0 breast cancer were randomised to postoperative radiotherapy or no further treatment. 1178 patients fulfilled the inclusion criteria. The two treatment groups were well balanced with respect to prognostic factors. Median tumour size was 12 mm, and 65 % of cases were detected by mammography screening. Radiotherapy with tangential MV photons, 48-54 Gy in 24-27 fractions, was administered to the remaining breast parenchyma. CT-based 3-D treatment planning was used. Adjuvant systemic therapy was prescribed according to regional treatment programmes. Nine percent received adjuvant systemic therapy. Patients were followed annually with bilateral mammography for 10 years and thereafter referred to the national Swedish breast screening programme. Results: With a median follow-up of 15 years, the addition of postoperative radiotherapy did not affect overall survival, 70.8 % with RT vs 68.2 % without RT, p=0.79. This result is based on follow-up for survival until April 2010 for all patients. However, recurrence-free survival, RFS, was significantly improved by radiotherapy, 62,6 % vs 53.7 % after 15 years, P Conclusions: Postoperative breast radiotherapy is indicated for the majority of patients operated with breast conservation surgery. Analysis of treatment efficacy in subgroups of patients may identify groups for which radiotherapy can be omitted in the future. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-03.