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Litiere S.,European Organisation for Research and Treatment of Cancer EORTC | Werutsky G.,European Organisation for Research and Treatment of Cancer EORTC | Fentiman I.S.,Guys and St Thomas NHS Foundation Trust | Rutgers E.,Netherlands Cancer Institute | And 5 more authors.
The Lancet Oncology | Year: 2012

Background: The EORTC 10801 trial compared breast-conserving therapy (BCT) with modified radical mastectomy (MRM) in patients with tumours 5 cm or smaller and axillary node negative or positive disease. Compared with BCT, MRM resulted in better local control, but did not affect overall survival or time to distant metastases. We report 20-year follow-up results. Methods: The EORTC 10801 . trial was open for accrual between 1980 and 1986 in eight centres in the UK, the Netherlands, Belgium, and South Africa. 448 patients were randomised to BCT and 420 to MRM. Randomisation was done centrally, stratifying patients by institute, carcinoma stage (I or II), and menopausal status. BCT comprised of lumpectomy and complete axillary clearance, followed by breast radiotherapy and a tumour-bed boost. The primary endpoint was time to distant metastasis. This analysis was done on all eligible patients, as they were randomised. Findings: After a median follow-up of 22·1 years (IQR 18·5-23·8), 175 patients (42%) had distant metastases in the MRM group versus 207 (46%) in the BCT group. Furthermore, 506 patients (58%) died (232 [55%] in the MRM group and 274 [61%] in the BCT group). No significant difference was observed between BCT and MRM for time to distant metastases (hazard ratio 1·13, 95% CI 0·92-1·38; p=0·23) or for time to death (1·11, 0·94-1·33; 0·23). Cumulative incidence of distant metastases at 20 years was 42·6% (95% CI 37·8-47·5) in the MRM group and 46·9% (42·2-51·6) in the BCT group. 20-year overall survival was estimated to be 44·5% (95% CI 39·3-49·5) in the MRM group and 39·1% (34·4-43·9) in the BCT group. There was no difference between the groups in time to distant metastases or overall survival by age (time to distant metastases: <50 years 1·09 [95% CI 0·79-1·51] . vs ≥50 years 1·16 [0·90-1·50]; overall survival <50 years 1·17 [0·86-1·59] . vs ≥50 years 1·10 [0·89-1·37]). Interpretation: BCT, including radiotherapy, offered as standard care to patients with early breast cancer seems to be justified, since long-term follow-up in this trial showed similar survival to that after mastectomy. Funding: European Organisation for Research and Treatment of Cancer (EORTC). © 2012 Elsevier Ltd.


Romero A.M.,Erasmus Daniel Den Hoed Cancer Center | Hoyer M.,Aarhus University Hospital
Current Opinion in Supportive and Palliative Care | Year: 2012

Purpose of review The liver is a common site of metastatic disease. Systemic therapy is most frequently the preferred therapy for patients with liver metastases, but surgical excision or tumor ablation strategies are often considered for patients with limited disease and favorable histology. Advances in radiation therapy technology made it possible to deliver potent biological doses to limited volumes of the liver with high precision in a few fractions. This method is known as stereotactic body radiation therapy (SBRT). Low-dose radiation therapy administered to the whole-liver radiation therapy (WLRT) is not regularly used for palliation of patients with massive liver metastases. The purpose of this review is to present an update of the most recent literature on SBRT and WLRT. Recent findings Recently published studies confirm the role of SBRT as a highly effective treatment for ablation of liver metastases. The toxicity related to the therapy is mild or moderate. This treatment is indicated for patients with limited burden of intrahepatic and extrahepatic disease. Low-dose WLRT is a useful treatment for symptom palliation in patients with end-stage cancer and diffuse metastatic infiltration of the liver which became refractory to systemic treatment. Summary SBRT and WLRT are highly efficient in the treatment of patients with liver metastases. However, prospective randomized trials in radiation therapy for liver metastases are warranted. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Incrocci L.,Erasmus Daniel den Hoed Cancer Center | Jensen P.T.,University of Southern Denmark
Journal of Sexual Medicine | Year: 2013

Introduction. Despite the decrease in overall cancer incidence and mortality rates in developed countries since the early 1990s, cancer remains a major public health problem. Sexual dysfunction is one of the more common consequences of cancer treatment. Aim. To shortly review the literature and level of evidence on sexual dysfunction in men and women following pelvic radiotherapy. Main Outcome Measures. Male and female sexual dysfunction. Methods. Literature review. Results. Sexual dysfunction in cancer patients is multidimensional and may result from biological, psychological, and social factors. Anatomic changes caused by surgery and/or radiotherapy, physiological changes following hormonal manipulation, and the secondary effect of medical intervention may impede or preclude sexual functioning, even when sexual desire is intact. Pelvic irradiation constitutes the primary or adjuvant treatment for a large number of both female and male cancers. No randomized controlled trials could be identified regarding the effect of radiotherapy on sexual dysfunction. However, prospective and clinical controlled trials all demonstrated a severe negative effect on sexual functioning in men and women following radiotherapy for a pelvic cancer. Following pelvic radiotherapy for prostate cancer, a positive effect of phosphodiesterase type 5 inhibitors on erectile dysfunction has been demonstrated, whereas no significant effect on female sexuality was found. Few studies evaluated treatment of female sexual dysfunction following radiotherapy; hormone replacement therapy and the use of vaginal dilator in combination with psycho-educational support is recommended. Conclusion. Pelvic radiotherapy plays a significant negative role in the complex scenario of male and female sexual dysfunction. The literature has focused on sexual dysfunction and intervention in prostate and cervical cancer patients. Sexual dysfunction following pelvic radiotherapy for cancer in other pelvic organs, e.g., bladder, rectum, and anus, requires more attention in future studies. Health care providers should pay attention to and provide psychological and medical support regarding sexual dysfunction to all patients who have received pelvic radiotherapy. Incrocci L and Jensen PT. Pelvic radiotherapy and sexual function in men and women. © 2013 International Society for Sexual Medicine.


Al-Mamgani A.,Erasmus Daniel den Hoed Cancer Center | Heemsbergen W.D.,Netherlands Cancer Institute | Levendag P.C.,Erasmus Daniel den Hoed Cancer Center | Lebesque J.V.,Netherlands Cancer Institute
Radiotherapy and Oncology | Year: 2010

Purpose: To investigate the effect of dose escalation within prognostic risk groups in prostate cancer. Patients and methods: Between 1997 and 2003, 664 patients with localized prostate cancer were randomly assigned to receive 68- or 78-Gy of radiotherapy. Two prognostic models were examined: a risk group model (low-, intermediate-, and high-risk) and PSA-level groupings. High-risk patients with hormonal therapy (HT) were analyzed separately. Outcome variable was freedom from failure (FFF) (clinical failure or PSA nadir + 2 μg/L). Results: In relation to the advantage of high-dose radiotherapy, intermediate-risk patients benefited most from dose escalation. However no significant heterogeneity could be demonstrated between the risk groups. For two types of PSA-level groupings: PSA < 10 and ≥10 μg/L, and <8, 8-18 and >8 μg/L, the test for heterogeneity was significant (p = 0.03 and 0.05, respectively). Patients with PSA 8-18 μg/L (n = 297, HR = 0.59) derived the greatest benefit from dose escalation. No heterogeneity could be demonstrated for high-risk patients with and without HT. Conclusion: Intermediate-risk group derived the greatest benefit for dose escalation. However, from this trial no indication was found to exclude low-risk or high-risk patients from high-dose radiotherapy. Patients could be selected for high-dose radiotherapy based on PSA-level groupings: for patients with a PSA < 8 μg/L high-dose radiotherapy is probably not indicated, but should be confirmed in other randomized studies. © 2010 Elsevier Ireland Ltd. All rights reserved.


Voet P.W.J.,Erasmus Daniel Den Hoed Cancer Center | Dirkx M.L.P.,Erasmus Daniel Den Hoed Cancer Center | Breedveld S.,Erasmus Daniel Den Hoed Cancer Center | Heijmen B.J.M.,Erasmus Daniel Den Hoed Cancer Center
Medical Physics | Year: 2013

Purpose: To compare IMRT planning strategies for prostate cancer patients with metal hip prostheses. Methods: All plans were generated fully automatically (i.e., no human trial-and-error interactions) using iCycle, the authors' in-house developed algorithm for multicriterial selection of beam angles and optimization of fluence profiles, allowing objective comparison of planning strategies. For 18 prostate cancer patients (eight with bilateral hip prostheses, ten with a right-sided unilateral prosthesis), two planning strategies were evaluated: (i) full exclusion of beams containing beamlets that would deliver dose to the target after passing a prosthesis (IMRT remove) and (ii) exclusion of those beamlets only (IMRT cut). Plans with optimized coplanar and noncoplanar beam arrangements were generated. Differences in PTV coverage and sparing of organs at risk (OARs) were quantified. The impact of beam number on plan quality was evaluated. Results: Especially for patients with bilateral hip prostheses, IMRT cut significantly improved rectum and bladder sparing compared to IMRTremove. For 9-beam coplanar plans, rectum V60Gy reduced by 17.5% ± 15.0% (maximum 37.4%, p = 0.036) and rectum D mean by 9.4% ± 7.8% (maximum 19.8%, p = 0.036). Further improvements in OAR sparing were achievable by using noncoplanar beam setups, reducing rectum V60Gy by another 4.6% ± 4.9% (p = 0.012) for noncoplanar 9-beam IMRTcut plans. Large reductions in rectum dose delivery were also observed when increasing the number of beam directions in the plans. For bilateral implants, the rectum V60Gy was 37.3% ± 12.1% for coplanar 7-beam plans and reduced on average by 13.5% (maximum 30.1%, p = 0.012) for 15 directions. Conclusions: iCycle was able to automatically generate high quality plans for prostate cancer patients with prostheses. Excluding only beamlets that passed through the prostheses (IMRTcut strategy) significantly improved OAR sparing. Noncoplanar beam arrangements and, to a larger extent, increasing the number of treatment beams further improved plan quality. © 2013 American Association of Physicists in Medicine.


Meijneke T.R.,Erasmus Daniel Den Hoed Cancer Center | Petit S.F.,Erasmus Daniel Den Hoed Cancer Center | Wentzler D.,Erasmus Daniel Den Hoed Cancer Center | Hoogeman M.,Erasmus Daniel Den Hoed Cancer Center | Nuyttens J.J.,Erasmus Daniel Den Hoed Cancer Center
Radiotherapy and Oncology | Year: 2013

Purpose To assess the accumulated dose and the toxicity after reirradiation for tumors in the lung using non-rigid registration. Material and methods Twenty patients with a tumor in the lung were reirradiated with or after stereotactic radiotherapy. The summed dose distribution was calculated using non-rigid registration. All doses were recalculated to an equivalent dose of 2 Gy per fraction (EQD2). The median follow-up time was 12 months (range 2-52). Results The median Dmax of the lung in the summed plans was 363 Gy3 (range 123-590). The median accumulated V20 of the lungs was 15.2%. Seven patients had in the heart and the trachea an accumulated dose ≥70 Gy3, with a median Dmax of the heart of 115 Gy 3 and 89 Gy3 for the trachea. Eight patients had in the esophagus an accumulated dose ≥70 Gy3, with a median accumulated dose of 85 Gy3. No grade 3-5 toxicity was observed. Conclusion Reirradiation of the lung with or after stereotactic radiotherapy is feasible to a median Dmax of 363 Gy3 to the lung, as low toxicity was observed. © 2013 Elsevier Ltd. All rights reserved.


Al-Mamgani A.,Erasmus Daniel Den Hoed Cancer Center | Rooij P.V.,Erasmus Daniel Den Hoed Cancer Center | Fransen D.,Erasmus Daniel Den Hoed Cancer Center | Levendag P.,Erasmus Daniel Den Hoed Cancer Center
Radiotherapy and Oncology | Year: 2013

Background and purpose: To investigate the impact of unilateral neck irradiation (UNI) of well-lateralized oropharyngeal cancer (OPC) on outcome and toxicity. Materials and methods: Unilateral neck IMRT was applied to 185 consecutive patients with well-lateralized OPC (restricted to tonsillar fossa, soft palate with at least 1 cm from midline or lateral pharyngeal wall). Endpoints were regional control (RC), local control (LC), disease-free survival (DFS), overall survival (OS), and toxicity. Results: Six regional failures were reported (3.2%); 2 were contralateral (1.1%). The 5-year Kaplan-Meier estimates of RC, LC, DFS, and OS were 96%, 91%, 84%, and 70%, respectively. Feeding tube was given to 11.3%. Chemotherapy was significantly predictive for toxicity. However, no patient was still feeding tube dependent 6 weeks after treatment. Overall grade 3 late toxicity was 2.2%. Grade 3 xerostomia was reported in only 1 patient while no patient developed grade 3 dysphagia. Conclusion: This largest study on unilateral neck IMRT for well-lateralized OPC showed excellent outcome and favorable toxicity profile. Given the increasing incidence of OPC, especially among younger patients, and the favorable results reported in the current study and by other investigators, expanding the indications for UNI still needs to be further investigated in prospective, preferably, randomized trials. © 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology.


Kruit W.H.,Erasmus Daniel den Hoed Cancer Center
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Active immunization against the tumor-specific MAGE-A3 antigen is followed by a few but impressive and durable clinical responses. This randomized phase II trial evaluated two different immunostimulants combined with the MAGE-A3 protein to investigate whether a more robust and persistent immune response could be associated with increased clinical benefit. Patients with MAGE-A3-positive stage III or IV M1a melanoma were randomly assigned to receive the MAGE-A3 protein combined either with AS02B or with AS15 immunostimulant. Clinical end points were toxicity and rates of objective clinical responses, progression-free survival (PFS), and overall survival (OS). Seventy-five patients were treated, with 36 eligible patients per arm. Both treatments were well tolerated. In the AS15 arm, four objective responses were observed (three complete responses and one partial response) versus one partial response in the AS02B arm. In the AS15 and AS02B arms, the PFS rates after 6 months were 25% and 14%, respectively; and the median OS times were 33 months and 19.9 months, respectively, with a median observation period of 48 months. Antibodies against MAGE-A3, found in all patients, showed three-fold higher titers in the AS15 arm. The anti-MAGE-A3 cellular response was also more pronounced in the AS15 arm. In the MAGE-A3+AS15 arm, clinical activity was higher and the immune response more robust. Therefore, the AS15 immunostimulant was selected for combination with the MAGE-A3 protein in phase III trials.


Al-Mamgani A.,Erasmus Daniel Den Hoed Cancer Center | Tans L.,Erasmus Daniel Den Hoed Cancer Center | Van Rooij P.,Erasmus Daniel Den Hoed Cancer Center | Levendag P.C.,Erasmus Daniel Den Hoed Cancer Center
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To retrospectively analyze the outcomes, toxicity, quality of life, and voice quality of patients with T3 laryngeal cancer treated with radiotherapy and to identify subgroups of patients in whom the addition of chemotherapy to radiotherapy is necessary. Methods and Materials: Between March 1996 and November 2009, 170 consecutive patients with T3 tumor were treated with (chemo)radiotherapy. Endpoints of the study were local control (LC), locoregional control (LRC), disease-free survival (DFS), overall survival (OS), late toxicity, quality of life, and voice handicap index. Results: After a median follow-up time of 32 months (range, 7-172), the 3-year actuarial rates of LC, LRC, DFS, and OS were 73%, 70%, 64%, and 61%, respectively, and the 5-year figures were 68%, 65%, 60%, and 49%, respectively. At last follow-up, 84 patients (49.5%) were still alive, 65 of them (77.3%) without local progression. Laryngectomy was performed in 16 patients, leaving 49 patients with anatomic organ preservation, corresponding to an actuarial laryngectomy-free survival of 58.3% at 3 years. The figures for patients treated with chemoradiotherapy and radiotherapy alone were 76.8% and 53.5%, respectively (p = 0.001). Chemoradiotherapy was the only significant predictor for LC on multivariate analysis. The overall 5-year cumulative incidence of late Grade ≥2 toxicity was 28.2%. Chemoradiotherapy, compared with radiotherapy alone, resulted in slight increase in late toxicity and slight deterioration of quality of life and voice-handicap-index scores. However, the differences were statistically not significant. Conclusion: The addition of chemotherapy to radiotherapy in T3 laryngeal cancer significantly improved LC and laryngectomy-free survival without statistically significant increases in late toxicity or deterioration of quality of life or voice handicap index. © 2012 Elsevier Inc. All rights reserved.


Bondar L.,Erasmus Daniel Den Hoed Cancer Center | Hoogeman M.S.,Erasmus Daniel Den Hoed Cancer Center | Vasquez Osorio E.M.,Erasmus Daniel Den Hoed Cancer Center | Heijmen B.J.M.,Erasmus Daniel Den Hoed Cancer Center
Medical Physics | Year: 2010

Purpose: Modern radiotherapy requires assessment of patient anatomical changes. By using unidirectional registration methods, the quantified anatomical changes are asymmetric, i.e., depend on the direction of the registration. Moreover, the registration is challenged by the large and complex organ deformations that can occur in, e.g., cervical cancer patients. The aim of this work was to develop, test, and validate a symmetric feature-based nonrigid registration method that can handle organs with large-scale deformations. Methods: A symmetric version of the unidirectional thin plate spline robust point matching (TPS-RPM) algorithm was developed, implemented, tested, and validated. Tests were performed by using the delineated cervix and uterus and bladder in CT scans of five cervical cancer patients. For each patient, five CT scans with a large variability in organ shape, volume, and deformations were acquired. Both the symmetric and the unidirectional algorithm were employed to calculate the registration geometric accuracy (surface distance and surface coverage errors), the inverse consistency, the residual distances after transforming anatomical landmarks, and the registration time. Additionally, to facilitate the further use of our symmetric method, a large set of input parameters was tested. Results: The developed symmetric algorithm handled successfully the registration of bladders with extreme volume change for which TPS-RPM failed. Compared to the unidirectional algorithm the symmetric algorithm improved, for the registration of organs with large volume change, the inverse consistency by 78% and the surface coverage by 46%. Similarly, for organs with small volume change, the symmetric algorithm improved the inverse consistency by 69% and the surface coverage by 13%. The method allowed for anatomically coherent registration in only 35 s for cervix-uterus and 151 s for bladder, while keeping the inverse consistency errors around 1 mm and the surface matching errors below 1 mm. Compared to rigid alignment the symmetric method reduced the residual distances between anatomical landmarks from a range of 5.8±2-70.1±20.1 mm to a range of 1.9±0.2-8.5±5.2 mm. Conclusions: The developed symmetric method could be employed to perform fast, accurate, consistent, and anatomically coherent registration of organs with large and complex deformations. Therefore, the method is a useful tool that could support further developments in high precision image guided radiotherapy. © 2010 American Association of Physicists in Medicine.

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