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 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 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.

Rectal cancer : when is the local recurrence risk low enough to refrain from the aim to prevent it?

Recently, preliminary results of the OCUM study (optimized surgery and MRI-based multimodal therapy of rectal cancer) were published and raised concern in the scientific community. In this observational study, the circumferential resection margin status assessed in preoperative MRI (mrCRM) was used to decide for either total mesorectal excision (TME) alone or neoadjuvant radiochemotherapy (nRCT). In contrast to current guidelines, neither T3 stage (with negative CRM) nor clinically positive lymph nodes were an indication for nRCT. Pathologically node-positive patients received chemotherapy (ChT). Overall, 230 patients were included, of whom 96 CRM-positive patients received nRCT. The CRM was accurately predicted in MRI, the rate of mesorectal plane resection was high. Recurrence rates have not yet been reported, but an impressive rate of down-staging for both T and N stage after nRCT was observed, while acute side effects were minimal. Nonetheless, the authors conclude that a substantial number of patients could be "spared severe radiation toxicity" and propagate their concept for prospectively replacing current guidelines. This is based on the hypothesis that CRM is a valid surrogate parameter for the risk of local recurrence and in case of a negative CRM, nRCT becomes dispensable. Moreover, it is assumed that lymph node status is no more relevant. Both assumptions are a contradiction to recent data from randomized studies as specified below. As 5-year locoregional recurrence rate (LRR) of only of 5-8% and < 5% in low risk rectal cancer can be achieved by the addition of RT, the noninferiority of surgery alone can not be presumed unless the expected 5-year LRR is ≤ 5-8%, whereas any excess of this range renders the study design inacceptable. Unless a publication explicitly specifies 5-year LRR, results are not exploitable for clinical decisions.

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.

Genetic polymorphisms in DNA repair and damage response genes and late normal tissue complications of radiotherapy for breast cancer.

Breast-conserving surgery followed by radiotherapy is effective in reducing recurrence; however, telangiectasia and fibrosis can occur as late skin side effects. As radiotherapy acts through producing DNA damage, we investigated whether genetic variation in DNA repair and damage response confers increased susceptibility to develop late normal skin complications. Breast cancer patients who received radiotherapy after breast-conserving surgery were examined for late complications of radiotherapy after a median follow-up time of 51 months. Polymorphisms in genes involved in DNA repair (APEX1, XRCC1, XRCC2, XRCC3, XPD) and damage response (TP53, P21) were determined. Associations between telangiectasia and genotypes were assessed among 409 patients, using multivariate logistic regression. A total of 131 patients presented with telangiectasia and 28 patients with fibrosis. Patients with variant TP53 genotypes either for the Arg72Pro or the PIN3 polymorphism were at increased risk of telangiectasia. The odds ratios (OR) were 1.66 (95% confidence interval (CI): 1.02-2.72) for 72Pro carriers and 1.95 (95% CI: 1.13-3.35) for PIN3 A2 allele carriers compared with non-carriers. The TP53 haplotype containing both variant alleles was associated with almost a two-fold increase in risk (OR 1.97, 95% CI: 1.11-3.52) for telangiectasia. Variants in the TP53 gene may therefore modify the risk of late skin toxicity after radiotherapy.

T-level downstaging and complete pathologic response after preoperative long-term radiochemotherapy for locally advanced rectal cancer.

Advantages of neoadjuvant chemoradiotherapy for locally advanced carcinoma of the middle and the lower third of the rectum are downstaging and downsizing of the tumor. Results of pathologic results are affected by post-treatment tissue changes and may influence the choice of surgical procedure. Forty-three consecutive patients (27 male, 16 female; mean age 64 years) were operated after receiving a long-term chemoradiotherapy during a period of 16 months. The data of initial staging procedure (high resolution magnetic resonance imaging) and results of pathological examination of the surgical specimens were analyzed. Regression of tumor was assessed by the absence of vital tumor cells and the post-treatment fibrotic tissue alterations. Regression of tumor size was seen in 42/43 patients leading to an improved T-stage in 27 patients. R0-resection was possible in all cases, although there was a perirectal tumor infiltration to less than 2 mm to circumference of the surgical specimen in 2 cases and unexpected small liver metastasis in 5 cases. Complete remission rate was 23.3% (10 cases). Detecting small amounts of vital tumor cells in altered tissue after chemoradiotherapy is a major problem of pathological examination procedure and should be taken into consideration by the surgeons. The choice of operation (resection vs. abdominoperineal extirpation vs. local excision) should be committed to the initial imaging procedure and not to any restaging procedure after neoadjuvant chemoradiotherapy.

Radioimmunotherapy with monoclonal antibodies. A new horizon in nuclear medicine therapy?

Radioimmunotherapy (RIT) with labeled tumor-associated monoclonal antibodies (MAbs) is a promising concept in oncology, which essentially consists of biological targeting of ionising radiation to tumors. Some encouraging clinical results have been achieved with RIT. However, there are severe problems associated with both understanding the mechanisms and predicting the effectiveness of RIT. This paper reviews the results of some major clinical trials, especially in malignant lymphomas and in some solid tumors. Furthermore, problems with RIT are described such as the significance of dose inhomogeneity and dose-rate effects, the appropriate dose calculation method, the toxicity of RIT and the development of HAMAs. It is suggested that newer technologies including chimeric antibodies, multiple-step targeting protocols, bone marrow transplantation, parallel application of external radiation, heat or bioreductive drugs will enable RIT to make an essential contribution to strategies for combating cancer.

[Role of 131I-metaiodobenzylguanidine scintigraphy in the diagnosis of intestinal carcinoids]. / Die Rolle der 131J-Metajodbenzylguanidin-(MIBG-) Szintigraphie in der Diagnostik der intestinalen Karzinoide.

Iodine-131 metaiodobenzylguanidine (131I-MIBG) is concentrated in a variety of neuroendocrine tumors, such as pheochromocytoma and neuroblastoma. Other neuroendocrine tumors from the APUD-cell system such as carcinoid tumors, may possess this uptake capability as well. We investigated 11 patients suffering from intestinal carcinoid with 131I-MIBG in order to determine the value of MIBG scintigraphy in these tumors. MIBG scans were positive in 5 out of 11 patients (45%). False-positive MIBG-scans did not occur. No correlation between MIBG uptake, clinical symptoms and urinary 5-HIAA level could be found.

Late cervical lymph node recurrence in differentiated thyroid carcinoma. An inherent problem of 131I beta dose distribution in small tumor deposits?

In differentiated thyroid carcinoma, postoperative radioiodine therapy is an undisputed element of the integral therapeutic concept. Sometimes, however, and years after initial diagnosis and therapy, cervical lymph node metastases occur without any evidence of local relapse or distant metastases, indicating that radioiodine therapy has not achieved definite tumor cell sterilization. A Monte Carlo computer simulation of the spatial energy dose distribution of 131I in small functioning tumor manifestations was performed to explain this phenomenon. It appeared that only a small fraction of the total beta-energy dose can be deposited inside the tumor if the latter becomes smaller than 1 mm in diameter: for tumors with homogeneous 131I uptake and diameters of 1.0, 0.5, 0.2, 0.1, 0.05 and 0.02 mm, this value does not exceed 86, 73, 39, 16, 8 and 4%, respectively. These data suggest a potential therapeutic gap for small tumor manifestations not apparent at the time of initial diagnosis and could explain the occasional occurrence of late cervical lymph node metastases.