Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.

BACKGROUND: Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. METHODS: Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033. FINDINGS: Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8-14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001). INTERPRETATION: A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. FUNDING: Fonds Cancer, Belgium.

Curative treatment for central nervous system medulloepithelioma despite residual disease after resection. Report of two cases treated according to the GPHO Protocol HIT 2000 and review of the literature.

Medulloepithelioma of the central nervous system (CNS) is an uncommon primitive neuroectodermal tumor (PNET) usually occurring in early childhood. It is characterized by highly malignant behavior with a propensity for progression, recurrence, and dissemination despite intensive therapy. Due to its rarity, the optimal management is still unknown. However, gross total resection (GTR) has been considered crucial to achieve cure. In this article, the authors report on 2 cases of CNS medulloepithelioma in which long-term survival (more than 6 years) could be achieved despite evidence of, or suspected postoperative residual disease with an otherwise dismal prognosis.The patients were treated according to different strata of the protocol for primitive neuroectodermal tumors (PNET) of the German-Austrian multicenter trial of the German Society for Pediatric Oncology and Hematology (GPOH) for childhood brain tumors (HIT 2000). Treatment included postoperative hyperfractionated radiotherapy of the craniospinal axis followed by a boost to the tumor site in combination with chemotherapy. A review of the 2 reported and 37 previously published cases confirmed GTR and older age as positive prognostic factors.

Prognostic Factors for Local Control in Breast Cancer After Long-term Follow-up in the EORTC Boost vs No Boost Trial: A Randomized Clinical Trial.

IMPORTANCE: Prognostic factors of ipsilateral breast tumor recurrence (IBTR) may change over time following breast-conserving therapy. OBJECTIVE: The EORTC "boost no boost" trial showed that young age and high-grade invasive carcinoma were the most important risk factors for IBTR. This study reanalyses pathological prognostic factors related to IBTR using long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS: Participants included 5569 early-stage breast cancer patients, treated with breast-conserving surgery (BCS) and whole-breast irradiation (WBI), who were randomized between no boost and a 16-Gy boost in the EORTC phase III "boost no boost" trial (1989-1996). A total of 1616 patients with a microscopically complete resection (according to local pathologists), included in the central pathology review, have been analyzed in this study. Median follow-up was 18.2 years. INTERVENTIONS: No further treatment or 16-Gy boost, after BCS and 50-Gy WBI. MAIN OUTCOMES AND MEASURES: Time to ipsilateral breast tumor recurrence (IBTR) as first event. RESULTS: The 20-year cumulative incidence of IBTR in 1616 patients (160 events observed) was 15% (95% CI, 12%-17%). Young age (P < .001) and presence of ductal carcinoma in situ (DCIS) (HR, 2.15; 95% CI, 1.36-3.38; P = .001) were associated with an increased risk of IBTR in multivariable analysis. The cumulative incidence of IBTR at 20 years was 34% (95% CI, 25%-41%), 14% (95% CI, 10%-18%), and 11% (95% CI, 8%-15%), in patients 40 years or younger, 41 to 50 years and 50 years or older, respectively (P < .001). This incidence was 18% (95% CI, 14%-22%) and 9% (95% CI, 6%-12%) for tumors with and without DCIS (P < .001). High-grade tumors relapsed more frequently early during follow-up but the relative effect of age and presence of DCIS seemed stable over time. The boost reduced the 20-year IBTR incidence from 31% (95% CI, 22%-39%) to 15% (95% CI, 8%-21%) (HR, 0.37; 95% CI, 0.22-0.62; P < .001) in high-risk patients (≤50 years with DCIS present). CONCLUSIONS AND RELEVANCE: The association of high-grade invasive tumor with IBTR diminished during follow-up, while the effect of DCIS adjacent to invasive tumor seemed to remain stable. Therefore, patients with high-grade invasive tumors should be monitored closely, especially in the first 5 years, while additional DCIS is an indication for longer follow-up, emphasizing the importance of long-term trial follow-up to estimate absolute effects accurately. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02295033.

Intraoperative Boost Radiotherapy during Targeted Oncoplastic Breast Surgery: Overview and Single Center Experiences.

Breast-conserving surgery followed by whole-breast irradiation is the standard local therapy for early breast cancer. The international discussion of reduced importance of wider tumor-free resection margins than "tumor not touching ink" leads to the development of five principles in targeted oncoplastic breast surgery. IORT improves local recurrence risk and diminishes toxicity since there is less irradiation of healthy tissue. Intraoperative radiotherapy (IORT) can be delivered in two settings: an IORT boost followed by a conventional regimen of external beam radiotherapy or a single IORT dose. The data from TARGIT-A and ELIOT reinforce the conviction that intraoperative radiotherapy during breast-conserving surgery is a reliable alternative to conventional postoperative fractionated irradiation, but only in a carefully selected population at low risk of local recurrence. We describe our experiences with IORT boost (50 kV energy X-rays; 20 Gy) in combination with targeted oncoplastic breast surgery in a routine clinical setting. Our experiences demonstrate the applicability and reliability of combining IORT boost with targeted oncoplastic breast surgery in breast-conserving therapy of early breast cancer.

Neoadjuvant radiochemotherapy and radical resection for advanced squamous cell carcinoma of the oral cavity. Outcome of 134 patients.

BACKGROUND AND PURPOSE: Several multimodal strategies have been developed to treat patients with squamous cell carcinoma of the oral cavity. The advantages of preoperative radiochemotherapy are downstaging of the primary tumor, an increased resectability rate, and the elimination of micrometastases. After successful phase II trials, the following therapy regimen for resectable advanced oral carcinoma was applied. PATIENTS AND METHODS: 134 patients with resectable squamous cell carcinoma of the oral cavity stage II-IV received neoadjuvant radiochemotherapy consisting of 39.6 Gy in daily fractions of 1.8 Gy and concomitant carboplatin (70 mg/m(2) days 1-5). Radical resection and neck dissection were carried out afterwards. RESULTS: After a median follow-up of 73 months, 82 patients (61%) had died. 54 patients (40%) experienced locoregional relapses or distant metastases. The overall survival was 65% +/- 4% after 2 years and 45% +/- 4% after 5 years. Cox regression survival analysis identified tumor regression, extracapsular lymph node spread and resection state as prognostic factors. Side effects of grade 3-4 were rare. CONCLUSION: Neoadjuvant radiochemotherapy with subsequent radical surgery can be recommended as an effective and safe treatment for primary resectable advanced tumors of the oral cavity. Acute and long-term toxicities appear to be moderate.

Intensified external-beam radiation therapy improves the outcome of stage 4 neuroblastoma in children > 1 year with residual local disease.

BACKGROUND AND PURPOSE: In neuroblastoma, the value of radiation therapy in high-intensive first-line treatment protocols is still not exactly known but radiation-associated long-term effects need to be considered. The impact of external-beam radiation therapy (EBRT) on event-free (EFS) and overall survival (OS) of stage 4 neuroblastoma patients of the NB97 trial was analyzed. PATIENTS AND METHODS: The authors retrospectively analyzed data of 110 stage 4 neuroblastoma patients > or = 1 year who underwent induction therapy and high-dose chemotherapy with stem cell transplantation without relapse. Intensified local EBRT (36 Gy) of the residual tumor volume was reserved for patients with residual viable tumor documented by MRI and corresponding metaiodobenzylguanidine (MIBG) uptake. RESULTS: 13 patients who received EBRT for local residual disease had similar outcome (3-year EFS 85 +/- 10%, 3-year OS 92 +/- 7%) as 74 patients without any MIBG residual (3-year EFS 61 +/- 6%, 3-year OS 75 +/- 6%). Outcome was worse in 23 children without EBRT to residual primary (3-year EFS 25 +/- 10%, 3-year OS 51 +/- 11%). Separate analysis of 14 patients with isolated localized residual disease found far better outcome of eight patients with EBRT (3-year EFS 100%, 3-year OS 100%) compared to six patients without EBRT (3-year EFS 20 +/- 18%, 3-year OS 20 +/- 18%). Multivariate analysis identified EBRT as influential on EFS (hazard ratio 0.27) and OS (hazard ratio 0.17) in addition to MYCN amplification and presence of primary tumor site MIBG residual. CONCLUSION: EBRT appeared effective in high-intensive treatment of stage 4 neuroblastoma. It seems to compensate the disadvantage of incomplete response to induction chemotherapy. These retrospective results need confirmation by a prospective randomized trial.

Histomorphologic tumor regression and lymph node metastases determine prognosis following neoadjuvant radiochemotherapy for esophageal cancer: implications for response classification.

OBJECTIVE: We sought to quantitatively and objectively evaluate histomorphologic tumor regression and establish a relevant prognostic regression classification system for esophageal cancer patients receiving neoadjuvant radiochemotherapy. PATIENTS AND METHODS: Eighty-five consecutive patients with localized esophageal cancers (cT2-4, Nx, M0) received standardized neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, 36 Gy). Seventy-four (87%) patients were resected by transthoracic en bloc esophagectomy and 2-field lymphadenectomy. The entire tumor beds of the resected specimens were evaluated histomorphologically, and regression was categorized into grades I to IV based on the percentage of vital residual tumor cells (VRTCs). A major response was achieved when specimens contained either less than 10% VRTCs (grade III) or a pathologic complete remission (grade IV). RESULTS: Complete resections (R0) were performed in 66 of 74 (89%) patients with 3-year survival rates of 54% +/- 7.05% for R0-resected cases and 0% for patients with incomplete resections or tumor progression during neoadjuvant therapy (P < 0.01). Minor histopathologic response was present in 44 (59.5%) and major histopathologic response in 30 (40.5%) tumors. Significantly different 3-year survival rates (38.8% +/- 8.1% for minor versus 70.7 +/- 10.1% for major response) were observed. Univariate survival analysis identified histomorphologic tumor regression (P < 0.004) and lymph node category (P < 0.01) as significant prognostic factors. Pathologic T category (P < 0.08), histologic type (P = 0.15), or grading (P = 0.33) had no significant impact on survival. Cox regression analysis identified dichotomized regression grades (minor and major histomorphologic regression, P < 0.028) and lymph node status (ypN0 and ypN1, P < 0.036) as significant independent prognostic parameters. A 2-parameter regression classification system that includes histomorphologic regression (major versus minor) and nodal status (ypN0 versus ypN1) was established (P < 0.001). CONCLUSIONS: Histomorphologic tumor regression and lymph node status (ypN) were significant prognostic parameters for patients with complete resections (R0) following neoadjuvant radiochemotherapy for esophageal cancer. A regression classification based on 2 parameters could lead to improved objective evaluation of the effectiveness of treatment protocols, accuracy of staging and restaging modalities, and molecular response prediction.

Endovascular gamma irradiation of femoropopliteal de novo stenoses immediately after PTA: interim results of prospective randomized controlled trial.

PURPOSE: To report an interim analysis of whether centered endovascular irradiation with the iridium 192 ((192)Ir) source immediately after percutaneous transluminal angioplasty (PTA) of de novo femoropopliteal stenoses lowers the restenosis rate. MATERIALS AND METHODS: Thirty patients undergoing PTA to treat femoropopliteal stenoses were randomized for prophylaxis against restenosis with centered endovascular irradiation with a (192)Ir source (a dose of 14 Gy 2 mm deep to the vessel wall, irradiation group) or no irradiation (control group). Angiographic follow-up was available for 22 patients at 6 months (irradiation group, n = 10) and 12 patients at 12 months (irradiation group, n = 6). Duplex sonography, treadmill testing, and interviews were performed the day before and the day after PTA and after 1, 3, 6, 9, and 12 months. Results of angiography, duplex sonography, treadmill testing, and interviews were evaluated with a t test and multivariate analysis of variance (clinical characteristics, chi(2) test). RESULTS: Baseline characteristics were comparable in the two groups. Interim analysis of the 6-month follow-up data revealed a trend toward a significantly lower restenosis rate in the irradiation group. The change in the degree of stenosis compared with that after PTA was -14.7% +/- 20.8 (mean +/- SD) in the irradiation group versus 37.7% +/- 27.3 in the control group (P =.001) and became even more marked at 12 months (-9.5% +/- 34.5 vs 45.5% +/- 40.7 [P =.03], respectively). The follow-up results of treadmill testing and interviews showed a nonsignificant benefit for the irradiation group. One thromboembolic complication occurred during irradiation. No side effects were observed during follow-up. CONCLUSION: Endovascular irradiation with a centered (192)Ir source immediately after PTA of de novo femoropopliteal stenoses reduces the restenosis rate.