Anna Morra

How Do the ASTRO Consensus Statement Guidelines for the Application of Accelerated Partial Breast Irradiation Fit Intraoperative Radiotherapy? A Retrospective Analysis of Patients Treated at the European Institute of Oncology

PURPOSE To verify how the classification according to the American Society for Therapeutic Radiation Oncology (ASTRO) consensus statement (CS) for the application of accelerated partial breast irradiation (APBI) fits patients treated with intraoperative radiotherapy with electrons (ELIOT) at a single institution. METHODS AND MATERIALS The study included 1,822 patients treated with ELIOT as the sole radiation modality outside of a clinical trial at the European Institute of Oncology after breast-conserving surgery for invasive breast cancer, who were classified into CS groups of suitable, cautionary, and unsuitable. The outcome in terms of ipsilateral breast recurrence, regional node relapse, distant metastases, progression free-survival, cause-specific survival, and overall survival were assessed. RESULTS All the 1,822 cases except for 25 could be classified according to ASTRO CS: 294 patients met the criteria for inclusion into the suitable group, 691 patients into the cautionary group, and 812 patients into the unsuitable group. The 5-year rate of ipsilateral breast recurrence for suitable, cautionary, and unsuitable groups were 1.5%, 4.4%, and 8.8%, respectively (p = 0.0003). Whereas the regional node relapse showed no difference, the rate of distant metastases was significantly different in the unsuitable group compared with the suitable and cautionary groups, having a significant impact on survival. CONCLUSION In the context of patients treated with ELIOT, the ASTRO guidelines identify well the groups for whom APBI might be considered as an effective alternative to whole breast radiotherapy and also identify groups for whom APBI is not indicated.

PRELIMINARY RESULTS OF ELECTRON INTRAOPERATIVE THERAPY BOOST AND HYPOFRACTIONATED EXTERNAL BEAM RADIOTHERAPY AFTER BREAST-CONSERVING SURGERY IN PREMENOPAUSAL WOMEN

PURPOSE To report the acute and preliminary data on late toxicity of a pilot study of boost with electron intraoperative therapy followed by hypofractionated external beam radiotherapy (HEBRT) of the whole breast. METHODS AND MATERIALS Between June 2004 and March 2007, 211 women with a diagnosis of early-stage breast cancer were treated with breast-conserving surgery. During surgery, an electron intraoperative therapy boost of 12 Gy was administered to the tumor bed. Adjuvant local treatment was completed with HEBRT, consisting of a course of 13 daily fractions of 2.85 Gy to the whole breast to a total dose of 37.05 Gy. Acute toxicity of the breast was evaluated at the end of HEBRT and at 1 month of follow-up. Late toxicity was recorded at 6 and 12 months of follow-up. RESULTS We report the data from 204 patients. The maximal acute skin toxicity was observed at the end of HEBRT (182 patients evaluable) with 7 (3.8%) Grade 3, 52 (28.6%) Grade 2, 123 (67.6%) Grade 1, and no Grade 0 or Grade 4 cases. A total of 108 patients were evaluated for late toxicity. The recorded late skin toxicity was Grade 4 in 1 patient (0.9%), Grade 3 in 1 patient, and Grade 2 or less in 106 patients (98.2%). CONCLUSIONS The results of this study have shown that electron intraoperative therapy followed by HEBRT allows for the delivery of a high dose to the tumor bed and an adequate dose to the whole breast. This treatment is feasible, compliance is high, and the rate of acute toxicity and the preliminary data on chronic toxicity seem acceptable.

Long-term side effects and cosmetic outcome in a pool of breast cancer patients treated with intraoperative radiotherapy with electrons as sole treatment

AIMS To evaluate late toxicity and cosmetic outcome after intraoperative radiotherapy using electrons (ELIOT) as sole treatment modality in early breast cancer patients. METHODS A total of 119 patients selected randomly among 1200 cases was analyzed. Late toxicities were documented using the LENT-SOMA scoring system, cosmesis was evaluated with the Harvard scale, and a numeric rating scale was used to assess symptoms. RESULTS After a median follow-up of 71 months, grade II fibrosis was observed in 38 patients (31.9%) and grade III fibrosis in 7 patients (5.9%). Postoperative complications (12.6%) did not correlate with late toxicity. Physicians and patients scored cosmesis as excellent or good in 84% and 77.3% of the cases, respectively. Patient satisfaction was higher than 90%. CONCLUSIONS In the study, ELIOT gives low and acceptable long-term toxicity. A longer follow-up and a larger number of patients are needed to confirm these promising results.

Hyperfractionated Radiotherapy in Locally Advanced Nasopharyngeal Cancer

Background:Despite numerous randomized trials suggesting a benefit of unconventional fractionation in locally advanced head and neck cancer, the role of this approach in nasopharyngeal carcinoma is debatable. Based on the current clinical experience, the authors introduced hyperfractionated irradiation in the treatment of locally advanced head and neck cancer, including nasopharyngeal tumors. The preliminary results of this treatment approach in nasopharyngeal cancer patients are presented, with special focus on the pattern of failure and toxicity.Patients and Methods:43 patients with nasopharyngeal cancer (stage II–IV, TNM 1997) underwent hyperfractionated irradiation. In 34 cases, radiotherapy was preceded by a median of three cycles of cisplatin-based induction chemotherapy. Irradiation was delivered using a shrinking-field technique up to a total dose of 74.4 Gy in 62 fractions of 1.2 Gy twice daily (minimum 6-h interval)/5 days/week.Results:Acute toxicity of hyperfractionated radiotherapy was significant but tolerable. Mucositis proved the most common side effect (grade 3: 24 patients, grade 4: three patients). Severe late toxicity was not observed. 30 of 34 patients (88%) responded to induction chemotherapy. At 6 weeks after completion of radiotherapy, complete response was seen in 35 patients (81%), partial response in five (12%), stable disease in one, and progressive disease in two. After a median follow-up of 32 months, 18 patients (41%) developed progressive disease. Primary tumor progression was observed in three patients, and seven patients each showed regional lymph node progression and distant metastases. In one case both regional lymph node progression and distant metastases were diagnosed. The 2-year progression-free survival and overall survival rates were 58% and 84%, respectively.Conclusion:Hyperfractionated radiotherapy seems a feasible and active regimen in locally advanced nasopharyngeal carcinoma. Accompanying acute and late toxicity is acceptable and does not compromise delivery of the planned irradiation dose. This regimen is associated with a high local control rate; relatively high nodal and distant failure, however, call for further treatment modifications, e. g., optimization of irradiation technique and/or dose escalation as well as improved systemic therapies.Hintergrund:Obwohl zahlreiche randomisierte Studien zugunsten unkonventioneller Fraktionierungsschemata bei lokal fortgeschrittenenen Kopf-Hals-Tumoren sprechen, ist der Stellenwert dieses Vorgehens beim Nasopharynxkarzinom umstritten. Auf der Basis gängiger klinischer Erfahrung führten die Autoren die hyperfraktionierte Bestrahlung in die Therapie lokal fortgeschrittener Kopf-Hals-Tumoren, einschließlich Nasopharynxkarzinome, ein. Erste Ergebnisse dieses Therapieansatzes bei Patienten mit Nasopharynxkarzinom werden vorgestellt und insbesondere Grenzen des Verfahrens und seine Toxizität diskutiert.Patienten und Methodik:43 Patienten mit Nasopharynxkarzinom (Stadium II–IV, TNM 1997) erhielten eine hyperfraktionierte Strahlentherapie. In 34 Fällen gingen der Bestrahlung im Mittel drei Zyklen einer Cisplatin-basierten Induktionschemotherapie voraus. Die Strahlentherapie wurde im Rahmen einer „Shrinking-Field-Technik“ bis zu einer Gesamtdosis von 74,4 Gy in 62 Fraktionen mit 2× täglich 1,2 Gy (Minimum 6-h-Interval) an 5 Tagen pro Woche durchgeführt.Ergebnisse:Die Akuttoxizität der hyperfraktionierten Strahlentherapie war bedeutend, aber tolerabel. Häufigste Nebenwirkung war die Mukositis (Grad 3: 24 Patienten, Grad 4: drei Patienten). Schwerwiegende Spättoxizitäten wurden nicht festgestellt. 30 von 34 Patienten (88%) sprachen auf die Induktionschemotherapie an. 6 Wochen nach Abschluss der Strahlentherapie, wurde eine komplette Remission bei 35 Patienten (81%) beobachtet, partielles Ansprechen bei fünf (12%), Krankheitsstillstand bei einem und Fortschreiten der Erkrankung bei zwei Patienten. Nach im Median 32 Monaten Follow-up zeigte sich bei 18 Patienten (41%) eine Progression der Erkrankung. Fortschreiten des Primärtumors wurde bei drei Patienten beobachtet, und sieben Patienten wiesen entweder Befall der regionalen Lymphknoten oder Fernmetastasen auf. In einem Fall wurden sowohl Befall der regionalen Lymphknoten als auch Fernmetastasen diagnostiziert. Das progressionsfreie Überleben und Gesamtüberleben nach 2 Jahren waren 58% bzw. 84%.Schlussfolgerung:Die hyperfraktionierte Strahlentherapie scheint bei lokal fortgeschrittenem Nasopharynxarzinom praktikabel und wirksam zu sein. Die auftretende Akut- und Spättoxizität ist akzeptabel und gefährdet die Verabreichung der geplanten Strahlungsdosis nicht. Dieses Vorgehen führt zu einer hohen lokalen Kontrolle; allerdings verlangt das relativ hohe regionale und systemische Therapieversagen weitere Modifikationen, z. B. die Optimierung der Bestrahlungstechnik und/oder Dosisekalation sowie verbesserte systemische Therapien.

Prevention of cutaneous damages induced by radiotherapy in breast cancer: an institutional experience.

BACKGROUND AND AIMS A minimal part of patients treated with radiotherapy on the entire breast may present an acute, subacute or chronic cutaneous damage of the healthy tissues involved in the radiation fields. The aim of this retrospective study was to evaluate the most efficient topical hydrating treatment in the prevention of cutaneous radio-induced acute effects in breast cancer. MATERIAL AND METHODS From February 2009 to March 2010, 100 patients affected by breast cancer have been recruited, all of the female sex and with an average age of 47 years. The following topical treatments were compared: Pure vitamin E (Vea lipogel®), Omega-3,6,9 (Quinovit®), Betaglucan, sodium hyaluronate (Neoviderm®), Vitis vinifera A.s-I-M.t-O.dij, (Ixoderm®), natural triglycerides-fitosterols (Xderit®). All enrolled patients were subjected to breast conservative treatment (quadrantectomy with or without homolateral axillary dissection) and without prosthesis positioning, in combination or not with hormonal treatment. Evaluation of the cutaneous acute toxicity was defined according to the RTOG scale either during radiotherapy and during follow-up (3 months after radiation treatment). RESULTS All patients completed the radiotherapy; 62% of patients presented G0-G1 cutaneous toxicity, 28% have developed G2 cutaneous toxicity, 10% have developed G3 toxicity; no patient presented G4 toxicity. Analysis of the data revealed a correlation between the topical treatment used and the incidence of cutaneous toxicity. CONCLUSIONS Of the patients who used the cutaneous hydrating creams--betaglucan, sodium hyaluronate (Neoviderm®) and Vitis vinifera A.s-I-M.t-O.dij (Ixoderm®)--during the radiation treatment, 80% developed G0-G1 toxicity and 20% G2 toxicity. The patients who used the other hydrating creams tested in the study manifested not only G1-G2 toxicity but also some G3 toxicity. Chemotherapeutic treatment with taxanes and/or anthracyclines did not result in an increased breast cutaneous toxicity induced by radiotherapy. The hormone therapy given to patients undergoing radiotherapy did not result in increased breast cutaneous toxicity. Further analysis on a larger number of patients is necessary for definitive results.

From technological advances to biological understanding: The main steps toward high-precision RT in breast cancer

Radiotherapy improves local control in breast cancer (BC) patients which increases overall survival in the long term. Improvements in treatment planning and delivery and a greater understanding of BC behaviour have laid the groundwork for high-precision radiotherapy, which is bound to further improve the therapeutic index. Precise identification of target volumes, better coverage and dose homogeneity have had a positive impact on toxicity and local control. The conformity of treatment dose due to three-dimensional radiotherapy and new techniques such as intensity modulated radiotherapy makes it possible to spare surrounding normal tissue. The widespread use of dose-volume constraints and histograms have increased awareness of toxicity. Real time image guidance has improved geometric precision and accuracy, together with the implementation of quality assurance programs. Advances in the precision of radiotherapy is also based on the choice of the appropriate fractionation and approach. Adaptive radiotherapy is not only a technical concept, but is also a biological concept based on the knowledge that different types of BC have distinctive patterns of locoregional spread. A greater understanding of cancer biology helps in choosing the treatment best suited to a particular situation. Biomarkers predictive of response play a crucial role. The combination of radiotherapy with molecular targeted therapies may enhance radiosensitivity, thus increasing the cytotoxic effects and improving treatment response. The appropriateness of an alternative fractionation, partial breast irradiation, dose escalating/de-escalating approaches, the extent of nodal irradiation have been examined for all the BC subtypes. The broadened concept of adaptive radiotherapy is vital to high-precision treatments.

Hyperfractionated radiotherapy in locally advanced nasopharyngeal cancer: An analysis of 43 consecutive patients

Background:Despite numerous randomized trials suggesting a benefit of unconventional fractionation in locally advanced head and neck cancer, the role of this approach in nasopharyngeal carcinoma is debatable. Based on the current clinical experience, the authors introduced hyperfractionated irradiation in the treatment of locally advanced head and neck cancer, including nasopharyngeal tumors. The preliminary results of this treatment approach in nasopharyngeal cancer patients are presented, with special focus on the pattern of failure and toxicity.Patients and Methods:43 patients with nasopharyngeal cancer (stage II–IV, TNM 1997) underwent hyperfractionated irradiation. In 34 cases, radiotherapy was preceded by a median of three cycles of cisplatin-based induction chemotherapy. Irradiation was delivered using a shrinking-field technique up to a total dose of 74.4 Gy in 62 fractions of 1.2 Gy twice daily (minimum 6-h interval)/5 days/week.Results:Acute toxicity of hyperfractionated radiotherapy was significant but tolerable. Mucositis proved the most common side effect (grade 3: 24 patients, grade 4: three patients). Severe late toxicity was not observed. 30 of 34 patients (88%) responded to induction chemotherapy. At 6 weeks after completion of radiotherapy, complete response was seen in 35 patients (81%), partial response in five (12%), stable disease in one, and progressive disease in two. After a median follow-up of 32 months, 18 patients (41%) developed progressive disease. Primary tumor progression was observed in three patients, and seven patients each showed regional lymph node progression and distant metastases. In one case both regional lymph node progression and distant metastases were diagnosed. The 2-year progression-free survival and overall survival rates were 58% and 84%, respectively.Conclusion:Hyperfractionated radiotherapy seems a feasible and active regimen in locally advanced nasopharyngeal carcinoma. Accompanying acute and late toxicity is acceptable and does not compromise delivery of the planned irradiation dose. This regimen is associated with a high local control rate; relatively high nodal and distant failure, however, call for further treatment modifications, e. g., optimization of irradiation technique and/or dose escalation as well as improved systemic therapies.Hintergrund:Obwohl zahlreiche randomisierte Studien zugunsten unkonventioneller Fraktionierungsschemata bei lokal fortgeschrittenenen Kopf-Hals-Tumoren sprechen, ist der Stellenwert dieses Vorgehens beim Nasopharynxkarzinom umstritten. Auf der Basis gängiger klinischer Erfahrung führten die Autoren die hyperfraktionierte Bestrahlung in die Therapie lokal fortgeschrittener Kopf-Hals-Tumoren, einschließlich Nasopharynxkarzinome, ein. Erste Ergebnisse dieses Therapieansatzes bei Patienten mit Nasopharynxkarzinom werden vorgestellt und insbesondere Grenzen des Verfahrens und seine Toxizität diskutiert.Patienten und Methodik:43 Patienten mit Nasopharynxkarzinom (Stadium II–IV, TNM 1997) erhielten eine hyperfraktionierte Strahlentherapie. In 34 Fällen gingen der Bestrahlung im Mittel drei Zyklen einer Cisplatin-basierten Induktionschemotherapie voraus. Die Strahlentherapie wurde im Rahmen einer „Shrinking-Field-Technik“ bis zu einer Gesamtdosis von 74,4 Gy in 62 Fraktionen mit 2× täglich 1,2 Gy (Minimum 6-h-Interval) an 5 Tagen pro Woche durchgeführt.Ergebnisse:Die Akuttoxizität der hyperfraktionierten Strahlentherapie war bedeutend, aber tolerabel. Häufigste Nebenwirkung war die Mukositis (Grad 3: 24 Patienten, Grad 4: drei Patienten). Schwerwiegende Spättoxizitäten wurden nicht festgestellt. 30 von 34 Patienten (88%) sprachen auf die Induktionschemotherapie an. 6 Wochen nach Abschluss der Strahlentherapie, wurde eine komplette Remission bei 35 Patienten (81%) beobachtet, partielles Ansprechen bei fünf (12%), Krankheitsstillstand bei einem und Fortschreiten der Erkrankung bei zwei Patienten. Nach im Median 32 Monaten Follow-up zeigte sich bei 18 Patienten (41%) eine Progression der Erkrankung. Fortschreiten des Primärtumors wurde bei drei Patienten beobachtet, und sieben Patienten wiesen entweder Befall der regionalen Lymphknoten oder Fernmetastasen auf. In einem Fall wurden sowohl Befall der regionalen Lymphknoten als auch Fernmetastasen diagnostiziert. Das progressionsfreie Überleben und Gesamtüberleben nach 2 Jahren waren 58% bzw. 84%.Schlussfolgerung:Die hyperfraktionierte Strahlentherapie scheint bei lokal fortgeschrittenem Nasopharynxarzinom praktikabel und wirksam zu sein. Die auftretende Akut- und Spättoxizität ist akzeptabel und gefährdet die Verabreichung der geplanten Strahlungsdosis nicht. Dieses Vorgehen führt zu einer hohen lokalen Kontrolle; allerdings verlangt das relativ hohe regionale und systemische Therapieversagen weitere Modifikationen, z. B. die Optimierung der Bestrahlungstechnik und/oder Dosisekalation sowie verbesserte systemische Therapien.

Intraoperative radiotherapy with electrons (ELIOT) for early breast cancer: the European Institute of Oncology experience

Partial breast irradiation (PBI) as an alternative to whole breast irradiation (WBI) is an attractive approach tested in several phase II and a few phase III studies, using different modalities of irradiation. Intraoperative radiotherapy (RT) with electrons allows the reduction of a whole course of WBI to a single session during surgery. The European Institute of Oncology (Milan, Italy) conducted a series of investigations aimed proving the safety and the effectiveness of intraoperative RT as a full dose PBI. The single dose of 21 Gy was calculated to be theoretically equivalent to a full course of conventional WBI. This ultimate form of hypofractionation carried some concern regarding the long-term impact on breast parenchyma. Phase I and II studies and a number of off- protocol patients have shown feasibility and good short-term results in both disease control and cosmesis. The results of the ELIOT randomized phase III trial comparing intraoperative RT to conventional WBI are discussed in the context of a worldwide scenario including other four randomized studies and one metanalysis, so far. From the analysis of the available data, the adequate patient selection emerges as mandatory to make intraoperative RT and other PBI modalities a reasonable alternative to conventional WBI. Further investigations are required to fully understand the weight of clinical and histologic variables classically associated with increased risk of local recurrence. In addition, the role of molecular classification in the pattern of recurrence after PBI will be more and more predominant.

Intra-fraction respiratory motion and baseline drift during breast Helical Tomotherapy

BACKGROUND AND PURPOSE To investigate the intra-fraction breast motion during long-lasting treatments of breast cancer with Helical Tomotherapy by means of an optical tracking system. MATERIALS AND METHODS A set of seven radio-transparent passive markers was placed on the thoraco-abdominal surface of twenty breast cancer patients and tracked by an infrared tracking system. A continuous non-invasive monitoring of intra-fraction motion from patient setup verification and correction to the end of radiation delivery was thus obtained. The measured displacements were analysed in terms of cyclic respiratory motion and slow baseline drift. RESULTS The average monitoring time per patient was 15.57min. The breathing amplitude of the chest was less than 2mm, on average, along all anatomical directions. The baseline drift of the body led to more significant setup uncertainties than the respiratory motion. The main intra-fraction baseline drifts were in posterior and inferior directions and occurred within the first eight minutes of monitoring. Considering the intra-fraction motion only, the resultant clinical-to-planning target volume safety margins are highly patient-specific and largely anisotropic. CONCLUSION The non-respiratory motion occurring during prolonged treatments induces notable uncertainties. Non-invasive continuous monitoring of patient setup variations including baseline drifts is recommended in order to minimize dosimetric deviations, which might jeopardize the therapeutic ratio between target coverage and the sparing of organs at risk.

Nonrandomized comparison between concomitant and sequential chemoradiotherapy with anthracyclines in breast cancer.

Purpose To evaluate the tolerance of concomitant administration of anthracycline-based chemotherapy (CHT) and 3-dimensional conformal radiotherapy (RT) after breast-conserving surgery. Methods and Materials Sixty-seven patients, treated with conservative surgery followed by 3-dimensional whole breast RT and concomitant CHT regimens including “Canadian modified” CEF (5-fluorouracil, epirubicin, cyclophosphamide) or AC (doxorubicin, cyclophosphamide) were evaluated for toxicity. They were compared in terms in compliance and acute toxicity with 67 patients irradiated sequentially after having received anthracyclines. Results Acute grade ≥2 skin toxicity was significantly higher in the concomitant group compared to the sequential group, although the incidence of Grade 3 desquamation showed no statistical difference (9% vs. 3%, p = 0.14). Haematological toxicity represented the main cause of treatment discontinuation, reporting higher rate of grade 3-4 leuco-neutropenia in the concomitant group (20.9% vs. 6%, p = 0.01). Mean RT duration was longer in the concomitant group (51 days vs. 45 days) owing to RT breaks. Late toxicity was acceptable. No symptomatic lung and heart events were reported. Radiological lung hyperdensity was detected in 27.7% of the patients in the concomitant group. Post-treatment left ventricular ejection fraction significantly decreased compared with baseline, but cardiac function remained within the normal range, without any difference between left or right-sided RT. Conclusions Although there was more acute grade ≥2 skin toxicity in the concomitant group, the rate of grade 3 dermatitis was lower than expected, suggesting some advantages of 3-D CRT over older techniques. Haematological toxicity exerted a significant impact on both RT and CHT delivery.