DEGRO practical guideline for partial-breast irradiation.

PURPOSE: This consensus statement from the Breast Cancer Working Group of the German Society for Radiation Oncology (DEGRO) aims to define practical guidelines for accelerated partial-breast irradiation (APBI). METHODS: Recent recommendations for relevant aspects of APBI were summarized and a panel of experts reviewed all the relevant literature. Panel members of the DEGRO experts participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for implementing APBI in clinical routine, focusing on patient selection, target definition, and treatment technique. RESULTS: Appropriate patient selection, target definition for different APBI techniques, and basic rules for appropriate APBI techniques for clinical routine outside of clinical trials are described. Detailed recommendations for APBI in daily practice, including dose constraints, are given. CONCLUSION: Guidelines are mandatory to assure optimal results of APBI using different techniques.

Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II.

Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664.

DEGRO practical guidelines for radiotherapy of breast cancer VI: therapy of locoregional breast cancer recurrences.

OBJECTIVE: To update the practical guidelines for radiotherapy of patients with locoregional breast cancer recurrences based on the current German interdisciplinary S3 guidelines 2012. METHODS: A comprehensive survey of the literature using the search phrases "locoregional breast cancer recurrence", "chest wall recurrence", "local recurrence", "regional recurrence", and "breast cancer" was performed, using the limits "clinical trials", "randomized trials", "meta-analysis", "systematic review", and "guidelines". CONCLUSIONS: Patients with isolated in-breast or regional breast cancer recurrences should be treated with curative intent. Mastectomy is the standard of care for patients with ipsilateral breast tumor recurrence. In a subset of patients, a second breast conservation followed by partial breast irradiation (PBI) is an appropriate alternative to mastectomy. If a second breast conservation is performed, additional irradiation should be mandatory. The largest reirradiation experience base exists for multicatheter brachytherapy; however, prospective clinical trials are needed to clearly define selection criteria, long-term local control, and toxicity. Following primary mastectomy, patients with resectable locoregional breast cancer recurrences should receive multimodality therapy including systemic therapy, surgery, and radiation +/- hyperthermia. This approach results in high local control rates and long-term survival is achieved in a subset of patients. In radiation-naive patients with unresectable locoregional recurrences, radiation therapy is mandatory. In previously irradiated patients with a high risk of a second local recurrence after surgical resection or in patients with unresectable recurrences, reirradiation should be strongly considered. Indication and dose concepts depend on the time interval to first radiotherapy, presence of late radiation effects, and concurrent or sequential systemic treatment. Combination with hyperthermia can further improve tumor control. In patients with isolated axillary or supraclavicular recurrence, durable disease control is best achieved with multimodality therapy including surgery and radiotherapy. Radiation therapy significantly improves local control and should be applied whenever feasible.

DEGRO practical guidelines: radiotherapy of breast cancer III--radiotherapy of the lymphatic pathways.

AIM: The purpose of this work is to update the practical guidelines for adjuvant radiotherapy of the regional lymphatics of breast cancer published in 2008 by the breast cancer expert panel of the German Society of Radiation Oncology (DEGRO). METHODS: A comprehensive survey of the literature concerning regional nodal irradiation (RNI) was performed using the following search terms: "breast cancer", "radiotherapy", "regional node irradiation". Recent randomized trials were analyzed for outcome as well as for differences in target definition. Field arrangements in the different studies were reproduced and superimposed on CT slices with individually contoured node areas. Moreover, data from recently published meta-analyses and guidelines of international breast cancer societies, yielding new aspects compared to 2008, provided the basis for defining recommendations according to the criteria of evidence-based medicine. In addition to the more general statements of the German interdisciplinary S3 guidelines updated in 2012, this paper addresses indications, targeting, and techniques of radiotherapy of the lymphatic pathways after surgery for breast cancer. RESULTS: International guidelines reveal substantial differences regarding indications for RNI. Patients with 1-3 positive nodes seem to profit from RNI compared to whole breast (WBI) or chest wall irradiation alone, both with regard to locoregional control and disease-free survival. Irradiation of the regional lymphatics including axillary, supraclavicular, and internal mammary nodes provided a small but significant survival benefit in recent randomized trials and one meta-analysis. Lymph node irradiation yields comparable tumor control in comparison to axillary lymph node dissection (ALND), while reducing the rate of lymph edema. Data concerning the impact of 1-2 macroscopically affected sentinel node (SN) or microscopic metastases on prognosis are conflicting. CONCLUSION: Recent data suggest that the current restrictive use of RNI should be scrutinized because the risk-benefit relationship appears to shift towards an improvement of outcome.

Strength and endurance training in the treatment of lung cancer patients in stages IIIA/IIIB/IV.

PURPOSE: This randomized controlled trial tested the effects of a specially designed strength and endurance training on the independence and quality of life in lung cancer patients in stages IIIA/IIIB/IV during palliative chemotherapy. METHODS: Between August 2010 and December 2011, 46 patients were randomized into two groups receiving either conventional physiotherapy or special physiotherapeutic training. The Barthel Index served as primary endpoint. The secondary endpoints were the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ C-30/LC-13) questionnaire, the 6-Minute Walk Test (6MWT), stair walking, the Modified Borg Scale, and muscle strength. Nonparametrical data were analyzed with the Wilcoxon and Mann-Whitney U test. For parametric, data student t tests were used. A p value of ≤.05 was accepted. RESULTS: Twenty-nine patients completed the trial (Intervention group (IG), n = 18; control group (CG), n = 11). Significant differences were detectable in the Barthel Index (IGmean = 92.08; CGmean = 81.67; p = .041), in single scores of the EORTC QLQ C-30/LC-13 questionnaire (physical functioning, p = .025; hemoptysis, p = .019; pain in arms or shoulder, p = .048; peripheral neuropathy, p = .050; cognitive functioning, p = .050), in the 6MWT, stair walking, strength capacity, and in the patient's dyspnoea perception during submaximal walking activities (IG > CG). CONCLUSION: According to these findings, lung cancer patients should receive enhanced physical activity intervention during palliative chemotherapy.

DEGRO practical guidelines: radiotherapy of breast cancer II: radiotherapy of non-invasive neoplasia of the breast.

PURPOSE: To complement and update the 2007 practice guidelines of the breast cancer expert panel of the German Society of Radiation Oncology (DEGRO) for radiotherapy (RT) of breast cancer. Owing to its growing clinical relevance, in the current version, a separate paper is dedicated to non-invasive proliferating epithelial neoplasia of the breast. In addition to the more general statements of the German interdisciplinary S3 guidelines, this paper is especially focused on indication and technique of RT in addition to breast conserving surgery. METHODS: The DEGRO expert panel performed a comprehensive survey of the literature comprising recently published data from clinical controlled trials, systematic reviews as well as meta-analyses, referring to the criteria of evidence-based medicine yielding new aspects compared to 2005 and 2007. The literature search encompassed the period 2008 to September 2012 using databases of PubMed and Guidelines International Network (G-I-N). Search terms were "non invasive breast cancer", "ductal carcinoma in situ, "dcis", "borderline breast lesions", "lobular neoplasia", "radiotherapy" and "radiation therapy". In addition to the more general statements of the German interdisciplinary S3 guidelines, this paper is especially focused on indications of RT and decision making of non-invasive neoplasia of the breast after surgery, especially ductal carcinoma in situ. RESULTS: Among different non-invasive neoplasia of the breast only the subgroup of pure ductal carcinoma in situ (DCIS; synonym ductal intraepithelial neoplasia, DIN) is considered for further recurrence risk reduction treatment modalities after complete excision of DCIS, particularly RT following breast conserving surgery (BCS), in order to avoid a mastectomy. About half of recurrences are invasive cancers. Up to 50 % of all recurrences require salvage mastectomy. Randomized clinical trials and a huge number of mostly observational studies have unanimously demonstrated that RT significantly reduces recurrence risks of ipsilateral DCIS as well as invasive breast cancer independent of patient age in all subgroups. The recommended total dose is 50 Gy administered as whole breast irradiation (WBI) in single fractions of 1.8 or 2.0 Gy given on 5 days weekly. Retrospective data indicate a possible beneficial effect of an additional tumor bed boost for younger patients. Prospective clinical trials of different dose-volume concepts (hypofractionation, accelerated partial breast irradiation, boost radiotherapy) are still ongoing. CONCLUSION: Postoperative radiotherapy permits breast conservation for the majority of women by halving local recurrence as well as reducing progression rates into invasive cancer. New data confirmed this effect in all patient subsets-even in low risk subgroups (LoE 1a).

DEGRO practical guidelines: radiotherapy of breast cancer I: radiotherapy following breast conserving therapy for invasive breast cancer.

BACKGROUND AND PURPOSE: The aim of the present paper is to update the practical guidelines for postoperative adjuvant radiotherapy of breast cancer published in 2007 by the breast cancer expert panel of the German Society for Radiooncology (Deutsche Gesellschaft für Radioonkologie, DEGRO). The present recommendations are based on a revision of the German interdisciplinary S-3 guidelines published in July 2012. METHODS: A comprehensive survey of the literature concerning radiotherapy following breast conserving therapy (BCT) was performed using the search terms "breast cancer", "radiotherapy", and "breast conserving therapy". Data from lately published meta-analyses, recent randomized trials, and guidelines of international breast cancer societies, yielding new aspects compared to 2007, provided the basis for defining recommendations according to the criteria of evidence-based medicine. In addition to the more general statements of the DKG (Deutsche Krebsgesellschaft), this paper addresses indications, target definition, dosage, and technique of radiotherapy of the breast after conservative surgery for invasive breast cancer. RESULTS: Among numerous reports on the effect of radiotherapy during BCT published since the last recommendations, the recent EBCTCG report builds the largest meta-analysis so far available. In a 15 year follow-up on 10,801 patients, whole breast irradiation (WBI) halves the average annual rate of disease recurrence (RR 0.52, 0.48-0.56) and reduces the annual breast cancer death rate by about one sixth (RR 0.82, 0.75-0.90), with a similar proportional, but different absolute benefit in prognostic subgroups (EBCTCG 2011). Furthermore, there is growing evidence that risk-adapted dose augmentation strategies to the tumor bed as well as the implementation of high precision RT techniques (e.g., intraoperative radiotherapy) contribute substantially to a further reduction of local relapse rates. A main focus of ongoing research lies in partial breast irradiation strategies as well as WBI hypofractionation schedules. The potential of both in replacing normofractionated WBI has not yet been finally clarified. CONCLUSION: After breast conserving surgery, no subgroup even in low risk patients has yet been identified for whom radiotherapy can be safely omitted without compromising local control and, hence, cancer-specific survival. In most patients, this translates into an overall survival benefit.

When are breast cancer patients old enough for the quitclaim of local control?

BACKGROUND: Although postoperative radiotherapy (RT) after breast-conserving surgery (BCS) halves the 10-year recurrence rate in breast cancer patients through all age groups, the question of whether RT may be omitted and replaced by endocrine therapy for women aged 70 years and older with low-risk factors has recently become an issue of debate. METHODS: Survey of the relevant recent literature (Medline) and international guidelines. RESULTS: Three randomized studies investigating the effect of RT in older women revealed significantly increased local recurrence rates when RT was omitted, and a negative impact on disease-free survival was observed in two of these trials. Despite these findings, in one of the studies omission of RT in women over 70 is recommended, leading to a respective amendment in the guidelines of the American National Comprehensive Cancer Network. Several large retrospective cohort studies analyzing the outcome of patients over 65 years with and without RT have since been published and showed a significantly improved local control in all subgroups of advanced age and stage, which predominantly translated into improved disease-free and overall survival. CONCLUSION: No subgroup of elderly patients has yet been identified that did not profit from RT in terms of local control. Therefore, chronological age alone is not an appropriate criterion for deciding against or in favor of adjuvant RT. The DEGRO breast cancer expert panel explicitly discourages determination of a certain age for the omission of postoperative RT in healthy elderly women with low-risk breast cancer. For frail elderly women, treatment decisions should be individually decided on the basis of standardized geriatric assessment.

Update and new trends in antiemetic therapy: the continuing need for novel therapies.

Chemotherapy-induced nausea and vomiting (CINV) continues to be one of the most feared side effects of chemotherapy. Inadequately controlled CINV can have a significant negative impact on quality of life and can in some cases compromise adherence to treatment. However, the repercussions of CINV for patients are often underestimated. Advances in our understanding of the physiology of CINV and the identification of risk factors have greatly contributed towards improvements in the control of CINV. A number of antiemetic agents are currently available for the prophylaxis and treatment of CINV, including 5-hydroxytryptamine 3 receptor antagonists corticosteroids, neurokinin 1 receptor antagonists, dopamine receptor antagonists, benzodiazepines, neuroleptics and cannabinoids. With the correct use of these agents, CINV can be prevented to a great extent; however, adherence to guidelines is disappointingly low. Furthermore, a significant number of patients still experience nausea and vomiting despite optimal treatment. More effective therapies are, therefore, greatly needed, with the ultimate goal of attaining complete control of CINV. This review focuses on the current understanding of CINV, problems associated with its management and the status of promising antiemetic therapies.

Immediate toxicity during fractionated total body irradiation as conditioning for bone marrow transplantation.

BACKGROUND: Total body irradiation followed by bone marrow transplantation is well established as a part of the conditioning regimen in high dose therapy. The immediate tolerance of fractionated total body irradiation (FTBI) was investigated prospectively. METHODS: From January 1995 to December 1998 162 patients received a FTBI, 6x2 Gy on 3 consecutive days, lung dose 10 Gy, for allogeneic (n=112) or autologous (n=50) bone marrow transplantation. High dose chemotherapy (mostly Cyclophosphamide) was administered after the FTBI. A standardized supportive therapy was administered. The immediate toxicity of FTBI was evaluated prospectively prior to each radiation fraction using a defined questionnaire. RESULTS: Main symptoms distressing the patient during irradiation period were gastrointestinal symptoms like nausea and emesis. The prevalence of nausea per fraction increased to 26.1% after the 4th fraction, with a significant higher prevalence in children younger than 10 years at 1st and 2nd fractions. 42.6 and 22. 8%, respectively, of all patients complained of nausea and episodes of emesis, during FTBI. Mild xerostomia and parotiditis were observed in 29.9 and 7.1% of all patients. Further gastrointestinal side effects during FTBI were loss of appetite in 16.0%, indisposition in 25.3%, mild oesophagitis in 3.7% and diarrhoea in 3. 7% of the patients. During FTBI 41.4% of the patients developed a temporary skin irritation (mild erythema). Pruritus was registered in 3.7% of the patients. Headache was observed in 14.8% and Fatigue syndrome in 49.2% of women and 28.3% of men (P<0.005). CONCLUSION: FTBI is a well tolerated therapeutic regimen in high dose therapy. The 162 patients investigated revealed no severe immediate side effects.

Efficacy of an ondansetron orally disintegrating tablet: a novel oral formulation of this 5-HT(3) receptor antagonist in the treatment of fractionated radiotherapy-induced nausea and emesis. Emesis Study Group for the Ondansetron Orally Disintegrating Tablet in Radiotherapy Treatment.

A significant number of patients who are receiving radiotherapy experience the distressing side effects of emesis and nausea. Although prophylactic antiemetics are often given to patients who are receiving single-fraction, high-dose radiotherapy to the abdomen, a survey has revealed that antiemetic prophylaxis is not routinely offered to those receiving fractionated radiotherapy. Hence there is a need for an effective treatment of emesis for use in this group of patients. Ondansetron is an effective and well-tolerated antiemetic, which is used for the prevention of both chemotherapy and radiotherapy-induced emesis and nausea. This agent has been developed as a novel freeze-dried oral formulation. Ondansetron orally disintegrating tablets (ondODT) disperse rapidly when placed on the tongue. As the tablet does not need to be swallowed with water, it is a particularly useful formulation for patients who have difficulty with swallowing or who do not feel able to drink. This study was undertaken to investigate the efficacy of ondODT in the treatment of established emesis and nausea induced by radiotherapy. Two doses of ondODT, 8 mg and 16 mg, were compared with placebo in patients who developed emesis and/or moderate/severe nausea after receiving fractionated radiotherapy to sites located between the thorax and the pelvis. The study showed that ondODT was clinically superior to placebo in treating emesis and nausea successfully over a 12-hour period after taking the medication. There were no statistically significant differences between the two doses of ondODT. In the 2 hours after taking the study medication, patients who received ondODT (8 mg and 16 mg) had significantly fewer emetic episodes compared with those who received placebo. They also experienced significantly less nausea. In conclusion, ondODT 8 mg is effective in the treatment of radiotherapy-induced emesis and nausea and provides an effective alternative to the conventional ondansetron tablet.

Radiotherapy-induced emesis. An overview.

BACKGROUND: A significant number of patients receiving radiotherapy experience the distressing side effects of emesis and nausea. These symptoms are some of the most distressing problems for the patients influencing their quality of life. METHODS: International study results concerning radiotherapy-induced emesis are demonstrated. A German multicenter questionnaire examining the strategies to prevent or to treat radiotherapy-induced nausea and emesis is presented. An international analysis concerning incidence of emesis and nausea in fractionated radiotherapy patients is discussed. Finally the consensus of the consensus conference on antiemetic therapy from the Perugia International Cancer Conference V is introduced. RESULTS: Untreated emesis can lead to complications like electrolyte disorders, dehydration, metabolic disturbances and nutrition problems with weight loss. Prophylactic antiemetics are often given to patients receiving single high-dose radiotherapy to the abdomen. A survey has revealed that antiemetic prophylaxis is not routinely offered to the patients receiving fractionated radiotherapy. However, there is a need for an effective treatment of emesis for use in this group of patients, too. In 20% of patients nausea and emesis can cause a treatment interruption because of an inadequate control of symptoms. Like in chemotherapy strategies there exists high, moderate, and low emetogenic treatment regimens in radiotherapy as well. The most emetogenic potential has the total body irradiation followed by radiotherapy to the abdomen. Radiotherapy induced emesis can be treated effectively with conventional antiemetics up to 50%. CONCLUSION: Studies with total body irradiation, fractionated treatment and high-dose single exposures have clearly demonstrated the value of 5-HT3-receptor antagonist antiemetics. There is a response between 60 and 97%. There is no difference in the efficacy of the different 5-HT3-antagonists. High-risk patients should be prophylactic treated with 5-HT3-antagonists. The additional administration of glucocorticoids and benzodiazepins can optimize the response.

Verification of set-up deviations in patients with breast cancer using portal imaging in clinical practice.

AIM: The aim of this study was to determine set-up deviations during irradiation of patients with breast cancer using Electronic Portal Imaging (EPI). PATIENTS AND METHOD: In order to monitor the intrafractional set-up deviations multiple portal image readings were carried out on 5 patients with breast cancer. Moreover interfractional set-up deviations were determined by the acquisition of daily EPIs in a total of 20 patients. RESULTS: The results of intrafractional set-up deviation based on 130 EPIs revealed a maximum lateral and longitudinal (cranio-caudal) deviation of 2 mm (range:-10 mm to 8 mm) as well as 1 degree in rotation (range: -2 degree to 2 degrees). The interfractional set-up deviations in 20 breast cancer patients during a treatment series of 25 fractions showed mean standard deviations of 5 mm in lateral and longitudinal direction, respectively. Only in few cases deviations up to maximally 24 mm were observed. The mean standard deviation of the rotational error was 2 degrees and reached a maximum of 6.5 degrees. CONCLUSION: These results show that intrafractional set-up deviations in breast cancer patients are negligible in clinical practice. They can be attributed to random errors due to patient movement and breathing. The set-up deviations during a treatment series can be differentiated in systematic and random errors. Patient fixation and immobilization is crucial in minimizing random errors. Taking into account 10 mm safety margins as used in our department around the "clinical target volume" (CTV), set-up errors outside of this volume (PTV) were exceptional. The enlarged PTV definition of 15 mm for lateral and cranio-caudal field margins, respectively as used in this study covers 99% of the CTV in all patients.