Radiotherapy Confined to the Tumor Bed Following Breast Conserving Surgery Current Status, Controversies, and Future Projects

Background: The standard technique of radiotherapy (RT) after breast conserving surgery (BCS) is to treat the entire breast up to a total dose of 45-50 Gy with or without tumor bed boost. The majority of local recurrences occur in close proximity to the tumor bed. Thus, the necessity of whole breast radiotherapy has been questioned, and several centers have evaluated the feasibility and efficacy of sole tumor bed irradiation. The aim of this study was to review the current status, controversies, and future prospects of tumor bed irradiation alone after breast conserving surgery. Material and Methods: Published prospective trials evaluating the feasibility and efficacy of radiotherapy confined to the tumor bed following breast conserving surgery were reviewed in order to analyze treatment results. Results: In three earlier studies, using tumor bed radiotherapy for unselected patients, the incidence of intra-breast relapse was reported in the range of 15.6-37%. However, in nine prospective phase I-II trials, sole brachytherapy (BT) with different dose rates, strict patient selection, and meticulous quality assurance, resulted in 95.6-100% local control rates. To date, only one phase III protocol has been intiated comparing the efficacy of tumor bed brachytherapy alone with conventional whole breast radiotherapy. The ideal extend of the planning target volume (PTV) for tumor bed radiotherapy alone has not been established yet. In most series, PTV was defined as the excision cavity with generous (1-3 cm) safety margins. Minimal requirement for PTV localization is the use of titanium clips to mark the walls of the excision cavity intraoperatively, but the combination of clip demarcation and three-dimensional (3-D) visual information obtained from cross-sectional images seems to be the best method to determine the target volume. 3-D virtual brachytherapy is also a promising method to minimize the chance of geographic miss. Recently developed techniques, such as intraoperative radiotherapy (IORT), as well as accelerated 3-D conformal external beam radiation therapy (3-D-CRT) were also found to be feasible for tumor bed radiotherapy alone. Conclusions: In spite of the existing arguments against limiting radiotherapy to the tumor bed after breast conserving surgery, results of phase I-II studies suggest that tumor bed radiotherapy alone might be an appropriate treatment option for selected breast cancer patients. Whole breast radiotherapy remains the standard radiation modality used in the treatment of breast cancer, and brachytherapy as the sole modality should be considered as investigational. Further phase-III trials are suggested to determine the equivalence of sole tumor bed radiotherapy, compared with whole breast radiotherapy. Preliminary results with recently developed techniques (CT-image based conformal brachytherapy, 3-D virtual brachytherapy, IORT, 3-D-CRT) are promising. However, more experience is required to define whether these methods might improve outcome for patients treated with tumor bed radiotherapy alone. Hintergrund: Die derzeitige Technik der Radiotherapie (RT) nach brusterhaltender Therapie (BET) ist die Bestrahlung der gesamten Mamma bis zu einer Gesamtdosis von 45-50 Gy mit oder ohne Boost-Bestrahlung des Tumorbetts. Die meisten lokalen Rezidive treten in unmittelbarer Nähe des Tumorbetts auf. Somit kann die Notwendigkeit einer Radiotherapie der gesamten Mamma in Frage gestellt werden. Die Anwendbarkeit und Wirksamkeit einer alleinigen Radiotherapie des Tumorbetts wurde bereits in mehreren Zentren untersucht. Das Ziel dieser Studie ist, die derzeitigen Behandlungsstrategien, Indikationen, technischen Aspekte sowie kontrovers geführte Debatten vorzustellen und neue Therapieansätze bzgl. einer alleinige Radiotherapie nach brusterhaltender Therapie vorzustellen. Patientengut und Methode: Diese Arbeit gibt einen Überblick über publizierte prospektive Studien, welche die Wirksamkeit und die Anwendbarkeit der alleinigen Strahlentherapie des Tumorbetts nach brusterhaltender Operation untersuchen, und analysiert die Behandlungsergebnisse. Ergebnisse: In drei älteren Studien mit alleiniger Tumorbettbestrahlung bei nicht selektiertem Patientengut wurden die lokalen Rezidivraten mit 15,6-37% beschrieben. Allerdings konnten neun Institute über 95,6-100% lokale Kontrollraten berichten unter Anwendung alleiniger Brachytherapie (BT), verschiedener Dosisraten, strikter Patientenauswahl und minutiöser Qualitätssicherung. In unserem Institut in Budapest wurde mit einem Phase-III-Protokoll, das die Wirksamkeit einer alleinigen Radiotherapie des Tumorbetts mit der konventionellen Radiotherapie der ganzen Mamma vergleicht, begonnen. Definierte Parameter bzgl. des geplanten Zielvolumens (PTV) einer Radiotherapie des Tumorbetts existieren nicht, jedoch umschließt in den meisten Studien das PTV die Resektionshöhle mit einem Sicherheitsabstand von 1-3 cm. Die intraoperative Anwendung von Titanclips zur Darstellung der Resektionshöhle stellt die minimale Voraussetzung zur PTV-Lokalisierung dar. Jedoch ist die Kombination von Clipmarkierung und dreidimensionaler (3-D) Darstellung unter Zuhilfenahme von Schnittbildverfahren die beste Methode, um das PTV zu definieren. Auch bietet die virtuelle 3-D-Brachytherapie (3-D-BT) eine gute Möglichkeit, um Planungsfehler zu vermeiden. Bereits ausgereifte Techniken wie die intraoperative Radiotherapie (IORT) und die akzelerierte perkutane 3-D-konforme Radiotherapie (3-D-KRT) sind geeignet, um eine alleinige Tumorbettstrahlung zu gewährleisten. Schlussfolgerung: Trotz kontroverser Argumente bzgl. einer alleinigen Bestrahlung des Tumorbetts nach Brust erhaltender Therapie weisen Ergebnisse von Phase-I- und -II-Studien darauf hin, dass die alleinige Radiotherapie des Tumorbetts eine entsprechende Behandlungsoption für ein ausgewähltes Patientengut mit Mammakarzinom darstellen kann. Die Bestrahlung der gesamten Brust bleibt aber die Standardbehandlung im postoperativen Management nach brusterhaltender Therapie. Die Brachytherapie als alleinige Behandlungsmethode ist derzeit noch als experimentell zu bezeichnen. Weitere Phase-III-Studien sind erforderlich, umd die Gleichwertigkeit einer alleinigen Radiotherapie des Tumorbetts mit einer Bestrahlung der gesamten Brust zu untersuchen. Derzeitige Ergebnisse mit den bekannten Techniken (CT-gestützte konforme Brachytherapie, virtuelle 3-D-BT, IORT, 3-D-KRT) sind viel versprechend. Mehr klinische Erfahrung wird notwendig sein, um festzustellen, welche der aufgeführten Methoden letztendlich eine Verbesserung der Behandlungsergebnisse bei Brustkrebspatientinnen mit alleiniger Radiotherapie des Tumorbetts erzielt.     

Partial Breast Irradiation after Breast-Conserving Surgery

BACKGROUND: The standard technique of postoperative radiotherapy after breast-conserving surgery is percutaneous irradiation of the entire breast to a total dose of 45-50 Gy which is usually followed by a tumor bed boost. Since the majority of local recurrences in selected patients occur close to the former tumor bed, the question arises whether a sole tumor bed irradiation might be a therapeutic alternative to total breast irradiation. METHODS: A systematic review of relevant literature concerning partial breast irradiation (PBI) up to November 2004 was undertaken. Studies of any design were included for comparison and discussion. RESULTS: Nine unique brachytherapy studies using the multi-catheter technique, one the balloon technique (MammoSite), and eight particular intraoperative radiotherapy (IORT) trials were located of which only one was a randomized trial. Only minor postoperative complications were reported. Preliminary results are similar in terms of local tumor control, disease-free and overall survival. However, the current evidence base of IORT studies is poor. CONCLUSION: Despite controversies regarding PBI after breast-conserving surgery, results of phase I-II trials suggest that sole tumor bed irradiation might be an appropriate therapeutic alternative for selected breast cancer patients. However, more experience and data from ongoing phase III trials are required to define these new methods to be an appropriate treatment option. Therefore, total breast irradiation still remains the standard irradiation modality even in the treatment of early breast cancer, and PBI should be considered investigational.     

CT-image-based conformal brachytherapy of breast cancer. The significance of semi-3-D and 3-D treatment planning.

PURPOSE: To compare the conventional 2-D, the simulator-guided semi-3-D and the recently developed CT-guided 3-D brachytherapy treatment planning in the interstitial radiotherapy of breast cancer. PATIENTS AND METHODS: In 103 patients with T1-2, N0-1 breast cancer the tumor bed was clipped during breast conserving surgery. Fifty-two of them received boost brachytherapy after 46 to 50 Gy teletherapy and 51 patients were treated with brachytherapy alone via flexible implant tubes. Single, double and triple plane implant was used in 6, 89 and 8 cases, respectively. The dose of boost brachytherapy and sole brachytherapy prescribed to dose reference points was 3 times 4.75 Gy and 7 times 5.2 Gy, respectively. The positions of dose reference points varied according to the level (2-D, semi-3-D and 3-D) of treatment planning performed. The treatment planning was based on the 3-D reconstruction of the surgical clips, implant tubes and skin points. In all cases the implantations were planned with a semi-3-D technique aided by simulator. In 10 cases a recently developed CT-guided 3-D planning system was used. The semi-3-D and 3-D treatment plans were compared to hypothetical 2-D plans using dose-volume histograms and dose non-uniformity ratios. The values of mean central dose, mean skin dose, minimal clip dose, proportion of underdosaged clips and mean target surface dose were evaluated. The accuracy of tumor bed localization and the conformity of planning target volume and treated volume were also analyzed in each technique. RESULTS: With the help of conformal semi-3-D and 3-D brachytherapy planning we could define reference dose points, active source positions and dwell times individually. This technique decreased the mean skin dose with 22.2% and reduced the possibility of geographical miss. We could achieve the best conformity between the planning target volume and the treated volume with the CT-image based 3-D treatment planning, at the cost of worse dose homogeneity. The mean treated volume was reduced by 25.1% with semi-3-D planning, however, it was increased by 16.2% with 3-D planning, compared to the 2-D planning. CONCLUSION: The application of clips into the tumor bed and the conformal (semi-3-D and 3-D) planning help to avoid geographical miss. CT is suitable for 3-D brachytherapy planning. Better local control with less side effects might be achieved with these new techniques. Conformal 3-D brachytherapy calls for new treatment planning concepts, taking the irregular 3-D shape of the target volume into account. The routine clinical application of image-based 3-D brachytherapy is a real aim in the very close future.     

Intraoperative radiation therapy in the management of early stage breast cancer

Adjuvant radiotherapy (RT) following breast conserving surgery (BCS) is associated with an improvement in local control and a reduction in breast cancer mortality. While traditionally delivered with whole breast irradiation (WBI), novel approaches have looked to reduce the duration, target volume, and toxicity of adjuvant RT. One such approach is intraoperative radiation therapy (IORT), which delivers radiation at the time of surgery with 80–90% of patients not requiring additional WBI. The current review presents IORT techniques and outcomes from modern series evaluating IORT as monotherapy or as a tumor bed boost. Based on two randomized trials (TARGIT-A and ELIOT) with recent updates, concern regarding higher rates of local recurrence with IORT exist, whether using electrons or low-energy techniques. In contrast, data is promising regarding IORT used as a boost, with ongoing studies evaluating its role prospectively. With respect to toxicity, the data suggest IORT is associated with comparable to slightly lower rates of toxicity though there may be a higher risk of seroma requiring aspiration and fat necrosis with IORT. Given current data and guidelines, WBI or other partial breast techniques should remain the standard of care in early stage breast cancer patients, while IORT should not be utilized outside of prospective clinical trials at this time.     

乳腺癌保乳术后全乳加瘤床补量照射不同治疗计划的比较

目的 探讨乳腺癌保乳术后全乳加瘤床照射不同治疗计划靶区剂量适形度、靶区剂量分布均匀性及肺脏、心脏和对侧乳腺受照剂量体积的差异。方法 选择术腔各边界放置银夹且无腋窝淋巴结转移的12 例左侧乳腺癌保乳术后患者, 每例患者分别制定常规放疗(CRT)、无挡肺子野调强放疗(IMRT-F)、挡肺子野调强(IMRT-F-L) 和瘤床同步整合补量调强放疗(SIB-IMRT) 计划。比较不同治疗计划全乳靶区和瘤床靶区的剂量适形度和剂量分布均匀性, 对比不同治疗计划肺脏、心脏和对侧乳腺受照剂量体积。结果 各计划中V_{处方剂量- PTV}1 V_PTV1、V_PTV1 处方剂量 V_PTV2、V_{处方剂量-PTV2 V- 处方剂量、VPTV2-处方剂量 VPTV2组间差异均有统计学意义;CRT 计划中患侧肺V20显著高于不同方式的IMRT 计划, 但不同方式的IMRT 计划之间V20差异无统计学意义;CRT 计划中心脏受照剂量显著高于IMRT 和SIB-I MRT 计划。CRT 计划中对侧乳腺最大照射剂量 Dmax和平均剂量Dmean明显高于不同实现方式的IMRT计划, 但不同实现方式的IMRT 计划中 Dmax和Dmean差异无统计学意义。结论 IMRT-F、IMRT-F-L、SIB-I MRT 计划均显著优于 CRT 计划, 而不同方式I MRT 计划间除个别参数外差异无统计学意义。}     

CT-Image Based Conformal Brachytherapy of Breast Cancer The Significance of Semi-3-D and 3-D Treatment Planning

Purpose: To compare the conventional 2-D, the simulator-guided semi-3-D and the recently developed CT-guided 3-D brachytherapy treatment planning in the interstitial radiotherapy of breast cancer. Patients and Methods: In 103 patients with T1-2, N0-1 breast cancer the tumor bed was clipped during breast conserving surgery. Fifty-two of them received boost brachytherapy after 46 to 50 Gy teletherapy and 51 patients were treated with brachytherapy alone via flexible implant tubes. Single, double and triple plane implant was used in 6, 89 and 8 cases, respectively. The dose of boost brachytherapy and sole brachytherapy prescribed to dose reference points was 3 times, 4.75 Gy and 7 times 5.2 Gy, respectively. The positions of dose reference points varied according to the level (2-D, semi-3-D and 3-D) of treatment planning performed. The treatment planning was based on the 3-D reconstruction of the surgical clips, implant tubes and skin points. In all cases the implantations were planned with a semi-3-D technique aided by simulator. In 10 cases a recently developed CT-guided 3-D planning system was used. The semi-3-D and 3-D treatment plans were compared to hypothetical 2-D plans using dose-volume histograms and dose non-uniformity ratios. The values of mean central dose, mean skin dose, minimal clip dose, proportion of underdosaged clips and mean target surface dose were evaluated. The accuracy of tumor bed localization and the conformity of planning target volume and treated volume were also analyzed in each technique. Results: With the help of conformal semi-3-D and 3-D brachytherapy planing we could define reference dose points, active source positions and dwell times individually. This technique decreased the mean skin dose with 22.2% and reduced the possibility of geographical miss. We could achieve the best conformity between the planning target volume and the treated volume with the CT-image based 3-D treatment planning, at the cost of worse dose homogeneity. The mean treated volume was reduced by 25.1% with semi-3-D planning, however, it was increased by 16.2% with 3-D planning, compared to the 2-D planning. Conclusion: The application of clips into the tumor bed and the conformal (semi-3-D and 3-d) planning help to avoid geographical miss. CT is suitable for 3-D brachytherapy planning. Better local control with less side effects might be achieved with these new techniques. Conformal 3-D brachytherapy calls for new treatment planning concepts, taking the irregular 3-D shape of the target volume into account. The routine clinical application of image-based 3-D brachytherapy is a real aim in the very close future. Ziel: Zu vergleichen sind die konventionelle 2D-, die simulatorgestützte Semi-3D- und das heutzutage entwickelte CT-geplante 3D-Brachytherapie-Planungssystem bei der interstitiellen Radiotherapie des Mammakarzinoms. Patienten und Methode: Bei 103 Patientinnen mit Mammakarzinom der Stadien T1-2, N0-1 wurde das Tumorbett mit Klips während der brusterhaltenden Operation markiert. 52/103 Patientinnen haben einen Brachytherapie-Boost nach 46 bis 50 Gy Teletherapie bekommen, und 51 von ihnen wurden mit alleiniger Brachytherapie mit plastischen Kathetern behandelt. Die Dosen des Brachytherapie-Boosts und der alleinigen Brachytherapie (bezogen auf die Dosisreferenzpunkte) waren 3mal 4,75 Gy und 7mal 5,2 Gy. Die Positionen der Dosisreferenzpunkte änderten sich in Abhängigkeit von der verwendeten Bestrahlungsplanung (2D, Semi-3D und 3D). Die Implantation wurde in einer, zwei und drei Ebenen in sechs, 89 und acht Fällen appliziert. Die Behandlungsplanung gründete sich auf die 3D-Rekonstruktion der chirurgischen Klips, der Katheter und der Hautpunkte. In allen Fällen wurde die Implantation mit simulatorgestützter Semi-3D-Technik geplant. Bei zehn Patientinnen wurde ein CT-gestütztes 3D-Planungssystem angewendet. Die Semi-3D- und 3D-Bestrahlungspläne wurden mit den hypothetischen 2D-Plänen unter Verwendung des Dosis-Volumen-Histogramms und Dosis-Non-Uniformitäts-Verhältnisses verglichen. Die Werte der durchschnittlichen Zentraldosis, Hautdosis, minimaler Klipdosis, des Verhältnisses der unterdosierten Klips und der durchschnittlichen Dosis an der Oberfläche des Zielvolumens wurden berechnet. Die Genauigkeit der Lokalisation des Tumorbetts und die Konformität des Planungszielvolumens und des Bestrahlungsvolumen wurden bei allen Techniken analysiert. Ergebnisse: Mit Hilfe der konformellen Semi-3D- und 3D-Brachytherapie-Planung konnten wir die Referenzdosispunkte, die aktiven Quellenpositionen und Quellenstandzeiten definieren. Diese Technik verringerte die durchschnittliche Hautdosis um 22,2% und reduzierte die Möglichkeit des geographischen Fehlers. Die beste Konformität zwischen Zielvolumen und Bestrahlungsvolumen konnten wir mit der CT-gestützten 3D-Bestrahlungsplanung erreichen, allerdings auf Kosten einer schlechteren Dosishomogenität. Mit der Semi-3D-Planung reduzierte sich das durchschnittliche Bestrahlungsvolumen um 25,1%, mit der 3D-Planung wurde es, verglichen mit der 2D-Planung, um 16,2% erhöht. Schlußfolgerung: Klipmarkierung des Tumorbetts und die konformelle (Semi-3D- und 3D-) Planung Helfen, den geographischen Fehler zu verhindern. Das CT ist für die 3D-Brachytherapie-Planung geeignet. Mit dieser neuen Technik ist eine bessere lokale Kontrolle mit weniger Nebenwirkungen erreichbar. Die konformelle 3D-Brachytherapie braucht eine neue Bestrahlungskonzeption, die die irreguläre dreidimensionale Form des Zielvolumens berücksichtigt. Die Etablierung der CT-gestützten 3D-Brachytherapie in die klinische Routine ist ein erstrebenswertes Ziel.     

体外三维适形调强放疗联合近距离腔内放疗对Ⅱb~Ⅲb期子宫颈残端癌的疗效

目的探讨体外三维适形调强放疗联合近距离腔内放疗对Ⅱb~Ⅲb期子宫颈残端癌的治疗效果。方法选取2008年1月—2013年10月收治的50例Ⅱb~Ⅲb期子宫颈残端癌病人,随机分为研究组和对照组各25例。对照组采用体外常规放疗联合近距离腔内治疗,研究组采用体外三维适形调强放疗联合近距离腔内放疗。观察两组病人术后近期疗效及远期并发症的相关指标,采用Kaplan-Meier法进行生存分析,Log-rank法比较生存时间。结果两组间治疗有效率、1年内复发率差异无统计学意义(P0.05)。研究组平均复发时间长于对照组(P0.05),Ⅰ~Ⅱ级急性直肠反应、Ⅰ级急性膀胱反应和Ⅱ级晚期膀胱反应的发生率均显著低于对照组(P0.05)。两组复发生存曲线差异有统计学意义(χ~2=5.393,P=0.020)。结论体外三维适形调强放疗联合近距离腔内放疗与体外常规放疗联合近距离腔内治疗相比,对Ⅱb~Ⅲb期子宫颈残端癌疗效无明显差异,但其并发症减少,短期复发率低,生存率较高,仍具有较大优势。     

Vacuum Application Increases Therapeutic Safety and Allows Intensified Local Radiation Treatment of Malignant Soft-Tissue Tumors

Purpose: In order to simplify and improve outcome of radiation therapy and final defect coverage in patients suffering from invasive soft-tissue tumors, brachytherapy and application of V.A.C.uum-assisted closure (V.A.C.^®) were combined with delaying flap incision. Patients and Methods: Two patients were excised as radically as possible and brachytherapy tubes were implanted directly on the tumor bed. At the same time, flaps for later defect coverage were preconditioned by circumcision. Brachytherapy and external- beam irradiation were performed directly on the vacuum sponge followed by subsequent defect coverage with the preconditioned flaps. Results: Excision significantly reduced tumor masses in both patients; in one case sensible and motor function of the involved extremity was clearly improved. V.A.C.^® coverage allowed repeated brachytherapy and external-beam applications following exact placing of plastic tubes and FLABs on the tumor bed. Sequential irradiation had no effect on neighboring flap tissues, which healed without impairment following transposition. Conclusion: Combination of V.A.C.^® and brachytherapy can effectively replace circumstantial and laborious IORT (intraoperative radiotherapy) procedures. Exact placement of tubes on the tumor bed without subsequent tissue coverage is conserving preconditioned flap tissues, which are transposed for final defect coverage at the end of radiotherapy. However, by circumventing radiation exposure of these tissues, a possible later irradiation sequence can be performed without endangering defect-covering flaps.     

Impact of MLC leaf width on the quality of the dose distribution in partial breast irradiation

Partial-breast irradiation (PBI) aims to limit the target volume for radiotherapy in women with early breast cancer after partial mastectomy to the region at highest risk of local recurrence, the tumor bed. Multileaf collimators are used to achieve conformal radiation beam portals required for PBI. Narrower leaf widths are generally assumed to allow more conformal shaping of beam portals around irregularly shaped target volumes. The aim was to compare 5-mm and 10-mm leaf widths for patients previously treated using PBI and assess subsequent planning target volume (PTV) coverage and organ at risk (OAR) doses for 16 patients. Several plans (5-mm leaf width or 10-mm leaf width) were generated for each patient using the original treated plan as the basis for attempts at further optimization. Alternating between different leaf widths found no significant difference in terms of overall PTV coverage and OAR doses between treatment plans. Optimization of the original treated plan allowed a small decrease in ipsilateral breast dose, which was offset by a lower PTV minimum. No significant dosimetric difference was found to support an advantage of 5-mm over 10-mm leaf width in this setting.     

Intraoperative Strahlentherapie (IORT) in der Behandlung des Mammakarzinoms – eine neue therapeutische Alternative im Rahmen der brusterhaltenden Therapie? Stellenwert und Zukunftsperspektiven. Erfahrungsbericht aus dem European Institute of Oncology (EIO), Mailand

BACKGROUND: External beam radiation therapy (EBRT) represents an integral component of breast-conserving treatment. In published series it has been demonstrated that the external boost can be replaced by intraoperative radiotherapy (IORT) where irradiation at a single dose from 10 up to 15 Gy was safely delivered directly to the tumor bed. PATIENTS AND METHODS: At the European Institute of Oncology, Milan, we initiated a dose escalation study to investigate the feasibility of applying single doses of IORT from 10 Gy up to 22 Gy. A portable IORT equipment with different electron energies was used. From July to December 1999, a total of 65 patients with T1-2 (max. 2.5 cm) No-1 breast cancer, median age 58 years (range 33-80 years) was treated. Ten patients received 10 Gy, eight patients were treated with an IORT of 15 Gy, eight received 17 Gy, six had 19 Gy, and 33 were treated with 21-22 Gy. Patients with 10 and 15 Gy received an additional EBRT of 44 and 40 Gy, respectively. In all other patients IORT was the sole radiation treatment. RESULTS: No acute side effects or intermediate untoward effects after a follow-up from three to nine months related to IORT were observed. CONCLUSIONS: Since the applicator can be safely placed under the control of the surgeon and radiotherapist IORT has the potential of accurately treating the tumor bed. Skin and subcutaneous tissue are not irradiated thus decreasing the potential risk of fibrosis and eventually obtaining a better cosmesis. With IORT single doses of 22 Gy being equivalent to a 60 Gy EBRT can safely be delivered. Even so the average time of operation was prolonged by around 20 minutes IORT application ultimately improves the quality of life of the patients in shortening overall treatment. Long-term follow-up is necessary to demonstrate whether large single doses of IORT might have the potential of sufficient local tumor control without major side effects. As a future perspective a randomized trial comparing EBRT with IORT as sole treatment will be performed.     

DEGRO practical guidelines: radiotherapy of breast cancer I

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.     

Anatomic Variations Due to Radical Prostatectomy

BACKGROUND AND PURPOSE: A quantitative estimate of the impact of prostatectomy on pelvic anatomy is unavailable, even if it would be an important prerequisite for a precise definition of clinical target volume (CTV) in post-prostatectomy radiotherapy. The purpose of this study was to investigate the impact of prostatectomy on the definition of CTV, on the position of bladder and rectum and their implications for three-dimensional conformal radiotherapy (3-D CRT). PATIENTS AND METHODS: Six patients eligible for radical retropubic prostatectomy were considered. Each patient underwent a planning CT between 1 week and 1 month before surgery (CTpre), and then CT was repeated in the same positioning 1-2 months after surgery (CTpost). For each patient the CT(pre/post) scans were matched; rectum, bladder and CTV were contoured on both CT scans for each patient by one observer. Two different CTVs were contoured: CTV1: prostate + seminal vesicles in CTpre; prostate + seminal vesicles surgical bed in CTpost; CTV2: prostate in CTpre; prostate surgical bed in CT(post). After image registration, the contours of rectum, bladder and CTV1/2 drawn on CTpost were transferred on CTpre. The corresponding planning target volumes (PTVs) were generated, and for each PTV, a conformal four field technique using 18-MV X-rays was planned. The volumes of CTV1, CTV2, PTV1, PTV2, rectum and bladder pre- and post-surgery were compared. Differences in 3-D position of these structures before and after surgery were analyzed by beam's eye view (BEV) images. Pre- and post-surgery dose-volume histograms (DVHs) of rectum and bladder were compared together with the fraction of rectum/bladder receiving at least 95% of the ICRU dose (V95), the treated volume (TV, body included in the 95% isodose) and the irradiated volume (IV, body included in the 50% isodose). RESULTS: For both CTV1 and CTV2, the volumes were significantly reduced after prostatectomy (average reduction around 30 cm3 for both; range 0-60 cm3). This reduction was mainly due to a more caudal definition of the cranial edge of CTV after prostatectomy (average difference for CTV2: 1.5 cm; range 0-2.5 cm). Concerning the bladder, a systematic posterior shift of the bladder base (average: 1.5 cm) was found and was correlated with a significant reduction of V95 for bladder (around 10 cm3; p = 0.03). V95 of the rectum, TV and IV also resulted to be significantly lower after surgery. The average reduction of V95 for the rectum was relatively small (2.5 cm3 of rectal wall). CONCLUSION: The impact of prostatectomy on CTV definition is high. A significant reduction of CTV, PTV, TV and IV may be expected after surgery with a consequent reduction of the portions of rectum/bladder irradiated with adjuvant radiotherapy.     

Mammography findings following electron intraoperative radiotherapy or external radiotherapy for breast cancer treatment

Radiotherapy following breast cancer conserving surgery decreases the risks of local recurrence. Because 85% of breast cancers relapse in or around the surgical bed there has been some debate on the need for irradiating the whole breast. Electron intraoperative radiotherapy (ELIOT) has been used as a viable alternative for conventional external radiotherapy (RT). While the former requires a single dose of 21 Gy in the tumoral bed, the latter requires 5-6 weeks of irradiation with a total dose of 50 Gy and a boost of 10 Gy that irradiates the surgical bed. Herein, we investigated whether any significant differences exist between the mammography findings obtained from patients submitted to one of the two techniques. Two groups of 30 patients each were included in this study. All patients had mammographies taken at 12 and 24 months after finishing treatment. The mammography findings evaluated were: cutaneous thickening (>2 mm), architectural distortion secondary to fibrosis, edema, calcifications (both benign and malignant), and fat necrosis. For all variables studied, there was no statistical difference between the two groups. This indicates that the mammography findings obtained in either 12- or 24-month follow-up periods after breast cancer conserving surgery are similar, regardless of which of the two radiotherapy techniques (ELIOT or RT) is employed as a treatment for breast cancer.     

Accelerated partial breast irradiation: a dosimetric comparison of three different techniques

PURPOSE: We report the first single-institutional dosimetric comparison of patients treated with three forms of accelerated partial breast irradiation: interstitial HDR brachytherapy, the MammoSite balloon apparatus, and 3D conformal external beam quadrant irradiation (3D-CRT). METHODS: A retrospective dosimetric comparison of interstitial HDR brachytherapy, MammoSite balloon brachytherapy, and 3D-CRT was performed. Thirty patients including 10 from each treatment technique were included for a dosimetric comparison of the dose received by the ipsilateral breast, PTV, heart, and ipsilateral lung. Interstitial patients were treated with 4 Gy in 8 fractions to 32 Gy, and the MammoSite patients were treated with 3.4 Gy in 10 fractions to 34 Gy. 3D-CRT patients were treated with 3.85 Gy in 10 fractions to 38.5 Gy using multiple isocentric beams. The CT images from simulation or implant evaluation were transferred into our 3D treatment planning software. The lumpectomy cavities were outlined for every patient, except the MammoSite patients, where the cavity was defined by the balloon edge. The PTV was constructed as a uniform expansion of 1.5 cm for all interstitial HDR patients, 1.0 cm for the MammoSite patients, and a 1.0 cm expansion in addition to the CTV expansion of 1.0 cm (n=2), and 1.5 cm (n=8) for the 3D-CRT patients. The CTV expansion for 3D-CRT and the PTV expansion for the brachytherapy patients were limited to the chest wall and skin. Normal structures including both ipsilateral lung and breast and heart for left-sided lesions were outlined. The lumpectomy cavity was subtracted from the PTV and normal breast tissue for evaluation. To evaluate dose to the ipsilateral breast and lung, PTV, and heart, a dose-volume histogram (DVH) analysis was performed. All histograms were normalized to the volume of the structure (i.e., expressed as percent volume). RESULTS: The average percentage of the breast receiving 100% and 50% of the prescribed dose (PD) was higher in the 3D-CRT group (24% and 48%, respectively) compared with the MammoSite (5% and 18%, respectively) and interstitial patients (10% and 26%, respectively). Improved coverage of the PTV was noted in the 3D-CRT plans compared with the MammoSite and interstitial HDR plans. With the interstitial HDR technique, 58% of the PTV received 100% of the PD compared with 76% with MammoSite and 100% with 3D-CRT techniques. The percentage of the PTV receiving 90% of the PD was 68%, 91%, and 100% for the interstitial HDR, MammoSite, and 3D-CRT patients, respectively. The ipsilateral lung V20 was slightly higher for 3D-CRT at 5% compared with 0% for both brachytherapy techniques. CONCLUSION: In those treated with 3D-CRT, coverage of the PTV was better with 3D-CRT but varied with the definition used. At the coverage at 90% of the PD, no difference was observed between 3D-CRT and MammoSite (which were both better than interstitial). 3D-CRT resulted in better coverage of the PTV compared with MammoSite or interstitial brachytherapy techniques. Better PTV coverage with 3D-CRT came at the cost of a higher integral dose to the remaining normal breast. Dosimetrically, the best partial breast irradiation technique appears to depend on the clinical situation. Of the brachytherapy techniques, MammoSite appears to be superior in PTV coverage. When comparing MammoSite vs. 3D-CRT PTV coverage at 90% of the PD, the difference was not significantly different.     

Full-Dose Intraoperative Radiotherapy with Electrons in Breast Cancer

PURPOSE: To investigate the feasibility of applying exclusive intraoperative radiation therapy (IORT) after conservative surgery in limited-stage breast carcinoma and to evaluate late effects and cosmetic results after this new conservative treatment. PATIENTS AND METHODS: From October 2000 to November 2002, 47 consecutive patients with unifocal breast carcinoma up to a diameter of 2 cm received conservative surgery followed by IORT with electrons as the sole adjuvant local therapy. Three different dose levels were used: 20 Gy (seven patients), 22 Gy (20 patients), and 24 Gy (20 patients). Patients were evaluated using RTOG/EORTC scale to assess the incidence of late complications. During follow-up, a radiologic assessment with mammography and sonography was periodically performed and any breast-imaging alterations were reported. RESULTS: After a follow-up ranging from 36 to 63 months (median, 48 months), 15 patients developed breast fibrosis (grade 2 in 14 patients, grade 3 in one patient), two patients presented with grade 3 skin changes, one patient developed a clinically relevant fat necrosis, and one patient showed breast edema and pain. Two patients developed contralateral breast cancer and one distant metastases; no local relapses occurred. Asymptomatic findings of fat necrosis were observed at mammography in twelve patients (25.5%), while an hypoechoic area was revealed by sonography in ten patients (21.5%). In four patients (8%), mammographic and sonographic findings suggested malignant lesions and required a rebiopsy to confirm the benign nature of the lesion. CONCLUSION: IORT in breast carcinoma is still an experimental treatment option for select patients with breast cancer and its application should be restricted to prospective trials. Although preliminary data on local control are encouraging, a longer follow-up is needed to confirm the efficacy of IORT in breast cancer and to exclude that severe late complications compromise the cosmetic results or modify the radiologic breast appearance during follow-up increasing the need for additional investigations.     

DEGRO practical guidelines: radiotherapy of breast cancer II

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).     

Intraoperative radiotherapy in early stage breast cancer: potential indications and evidence to date

Following early results of recent studies of intraoperative radiotherapy (IORT) in the adjuvant treatment of patients with early breast cancer, the clinical utility of IORT is a subject of much recent debate within the breast oncology community. This review describes the intraoperative techniques available, the potential indications and the evidence to date pertaining to local control and toxicity. We also discuss any implications for current practice and future research.Adjuvant radiotherapy (RT) following surgery in the treatment of early stage breast cancer delivered with external beam RT (EBRT) permits breast conservation with low rates of in-breast tumour recurrence (IBTR).¹ When IBTR occurs, however, the recurrence is most commonly located in the same quadrant as the index tumour.² Furthermore, pathological examination of mastectomy specimens demonstrates that malignant and/or pre-malignant cells are rarely found >4 cm from the index lesion.³ Such data have given rise to the hypothesis that irradiating only the part of the breast tissue in proximity to the index tumour will be associated with local control rates comparable with those seen after adjuvant whole-breast EBRT. Such partial breast irradiation would also be expected to be associated with less toxicity given the reduced volume of non-target tissue irradiation.Partial breast RT may be delivered by a number of techniques, including EBRT, interstitial brachytherapy and intraoperative RT (IORT).^4,5 The use of IORT has been reported in a range of tumour sites, including the breast, head and neck, lung, limbs (sarcoma), gastrointestinal and genitourinary tracts, and lung.^6–12 For most tumour sites, the premise of IORT is to deliver RT directly and therefore potentially more accurately to the tumour itself or to the tumour bed whilst delivering minimal dose to the surrounding normal tissues. Although not in routine clinical practice, in previous studies of IORT, the IORT has been delivered in combination with EBRT as a “boost” or as the sole RT modality.^6,13In the context of adjuvant treatment for early breast cancer, IORT has most commonly been delivered to the tumour bed after surgical excision of the tumour, and a number of technical approaches have been described. IORT to the breast has been used both to deliver a tumour-bed boost in conjunction with EBRT and as definitive adjuvant RT treatment instead of whole-breast EBRT.^13,14 Until recently, there has been a lack of randomized Phase III trial evidence comparing IORT with EBRT in either setting. This review describes the different IORT techniques available, the potential clinical utility of IORT, the evidence to date and the implications for standard practice and future research.     

Targeted intraoperative radiotherapy tumour bed boost during breast-conserving surgery after neoadjuvant chemotherapy

Introduction

The use of targeted intraoperative radiotherapy (TARGIT-IORT) as a tumour bed boost during breast-conserving surgery (BCS) for breast cancer has been reported since 1998. We present its use in patients undergoing breast conservation following neoadjuvant therapy (NACT).

Method

In this retrospective study involving 116 patients after NACT we compared outcomes of 61 patients who received a tumour bed boost with IORT during lumpectomy versus 55 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Local recurrence-free survival (LRFS), disease-free survival (DFS), distant disease-free survival (DDFS), breast cancer mortality (BCM), non-breast cancer mortality (NBCM) and overall mortality (OS) were compared.

Results

Median follow up was 49 months. The differences in LRFS, DFS and BCM were not statistically significant. The 5?year Kaplan–Meier estimate of OS was significantly better by 15% with IORT: IORT 2 events (96.7%, 95%CI 87.5–99.2), EBRT 9 events (81.7%, 95%CI 67.6–90.1), hazard ratio (HR) 0.19 (0.04–0.87), log rank p = 0.016, mainly due to a reduction of 10.1% in NBCM: IORT 100%, EBRT 89.9% (77.3–95.7), HR (not calculable), log rank p = 0.015. The DDFS was as follows: IORT 3 events (95.1%, 85.5–98.4), EBRT 12 events (69.0%, 49.1–82.4), HR 0.23 (0.06–0.80), log rank p = 0.012.

Conclusion

IORT during lumpectomy after neoadjuvant chemotherapy as a tumour bed boost appears to give results that are not worse than external beam radiotherapy boost. These data give further support to the inclusion of such patients in the TARGIT-B (boost) randomised trial that is testing whether IORT boost is superior to EBRT boost.

     

Breast conservation surgery and interstitial brachytherapy in the management of locally recurrent carcinoma of the breast: the Allegheny General Hospital experience

PURPOSE: To evaluate lumpectomy followed by interstitial brachytherapy as an acceptable salvage therapy for women who have developed localized recurrence of breast cancer after conservation surgery and postoperative external radiotherapy. METHODS AND MATERIALS: Between 1/1998 and 10/2006, 21 patients with T0 or T1 in-breast recurrence of carcinoma were offered interstitial low-dose rate brachytherapy after tumor re-excision as an alternative to salvage mastectomy. All patients had failed lumpectomy followed by standard postoperative external beam radiotherapy (range, 5000-6040cGy) as treatment for the initial breast carcinoma. Seven recurred as ductal carcinoma in situ, 2 as infiltrating lobular carcinoma, and 12 as recurrent invasive carcinoma. The recurrent tumors were excised with final margins of resection free of residual disease per National Surgical Adjuvant Breast and Bowel Project definition. Tumor bed implantation was then carried out with an interstitial technique using (192)Ir with the target volume consisting of the tumor bed plus a minimum 1.0-cm clinical margin. The required minimum dose delivered to the target volume was 4500-5000cGy (range, 4500-5530). RESULTS: Twenty of 21 patients were free of local disease with a median observation time of 40 months (range, 3-69). The single patient who developed a second local recurrence was treated successfully with simple mastectomy. Two patients succumbed to systemic disease at 17 and 24 months after salvage implant therapy. One patient developed a contralateral breast cancer. Cosmetic results defined by the National Surgical Adjuvant Breast and Bowel Project cosmesis scale were acceptable. One patient developed a localized seroma requiring multiple needle aspirations before complete resolution. Two patients developed localized skin breakdown in the tumor bed. One healed after 6 months of conservative treatment. The other healed 9 months later with Grade II cosmesis. This patient also developed a concurrent postoperative wound infection. CONCLUSIONS: Repeat lumpectomy followed by brachytherapy is feasible and may be an acceptable alternative to salvage mastectomy in patients who locally fail conservation breast therapy; however, longer followup and greater patient numbers may be needed to better define the role of salvage brachytherapy.