Rupert Bartsch, Wien Ute Berndt, Halle Serban-Dan Costa, Magdeburg Peter Dall, Lüneburg Peter Dubsky, Wien Florian Fitzal, Wien Alexander Gaiger, Wien Oleg Gluz, Mönchengladbach Volker Hanf, Fürth Kerstin Hermelink, München Reinhard Horvat, Wien Jens Huober, Ulm Wolfgang Janni, Ulm Walter Jonat, Kiel Michael Knauer, St. Gallen Rolf Kreienberg, Ulm Christiane Kuhl, Bonn Annette Lebeau, Hamburg Cornelia Liedtke, Lübeck Sibylle Loibl, Neu-Isenburg Helmut Madjar, Wiesbaden Christian Marth, Innsbruck Volker Möbus, Frankfurt/M. Ulrike Nitz, Mönchengladbach Angelo Paradiso, Bari Richard Pötter, Wien Kurt Possinger, Berlin Rita Schmutzler, Köln Andreas Schneeweiss, Heidelberg Christian Singer, Wien Isabell Witzel, Hamburg Rachel Würstlein, München Christoph Zielinski, Wien Editors-in-Chief

Background: Intraoperative radiotherapy during breast-conserving surgery is being studied as an alternative to 6 weeks of external beam radiotherapy (EBRT) for low-risk women; it can be delivered using electrons (intraoperative electron radiotherapy, IOERT) or 50-kV X-rays. Materials and Methods: We analyzed both single institutional and randomized studies involving single-fraction IOERT treatments. Rates for ipsilateral breast tumor recurrences, disease-specific survival, and overall survival were obtained. Results: IOERT had true 5-year recurrence rates of < 1.5% for ASTRO (American Society for Radiation Oncology) and ESTRO (European Society for Therapeutic Radiology and Oncology) suitable women, or for low-risk women as defined by the ELIOT trial. Women with ductal carcinoma in situ eligible for breast-conserving therapy, older women that currently receive no EBRT, and younger women with favorable biology are additional potential candidates. Conclusion: ASTRO suitable and ESTRO good women for accelerated partial breast irradiation are low-risk groups. Higher-risk women with favorable biology might also be suitable candidates for IOERT, providing the tumor biology can be determined prior to surgery. For intraoperative radiotherapy using 50-kV X-rays, follow-up was too short to assess the effectiveness of the treatment.

143 Background: We report the results of a single-institution phase II trial of accelerated partial breast irradiation (APBI) using a single dose of intraoperative electron radiotherapy (IOERT) in patients with low-risk early-stage breast cancer. Methods: From July 2006 to December 2009, 226 patients suitable for BCT were enrolled in a phase II trial with IOERT as radical treatment immediately after surgical resection. All patients had biopsy-proven cancer. After the surgeon temporarily re-approximated the excision cavity, a dose of 21 Gy using IOERT was delivered to the tumor bed with a margin of 2 cm laterally. Results: No acute reactions were reported after irradiation. Three patients experienced a transient edema. In 7 others a haematoma was observed. No cases of liponecrosis were observed. With a mean follow-up of 49 months (range 31-66 months), only one case of local recurrence has been reported. The observed toxicity was considered acceptable. As to cosmetic results, at 6 months after the end of IORT, 71/226 patients (31.4.%) had a score of 2 for symmetry and contour (asymmetry exhibited by 1/3 or less of volume breast), while 19/226 (8.4%) had a score 3 (asymmetry greater than 1/3 of breast volume). These findings remained unchanged at the following examinations. No breast oedema, discoloration at site or scar prominence were observed. Conclusions: IOERT offers the advantage of an excellent delineation of the tumor bed under visual control and high sparing of normal tissue, including the skin. IOERT delivers a very high biologically dose at the time of the surgery, when residual tumor cells are more rapidly proliferating. IOERT is insensitive to chemotherapy sequencing since all of the radiation is given during the surgery. The absolute recurrence rate of 0.4% and the recurrence rate per year of 0.2% of the present study are very encouraging. APBI using a single dose of IOERT can be delivered safely in women with early, low-risk breast cancer. A longer follow-up is needed to ascertain its efficacy compared to that of the current standard treatment of whole breast irradiation.

Although the evidence for the benefit of adding temozolomide (TMZ) to radiotherapy (RT) is limited to glioblastoma patients, there is currently a trend toward treating anaplastic astrocytomas (AAs) with combined RT + TMZ. The aim of the present study was to describe the patterns of care of patients affected by AA and, particularly, to compare the outcome of patients treated exclusively with RT with those treated with RT + TMZ. Data of 295 newly diagnosed AAs treated with postoperative RT ± TMZ in the period from 2002 to 2007 were reviewed. More than 75% of patients underwent a surgical removal. All the patients had postoperative RT; 86.1% of them were treated with 3D-conformal RT (3D-CRT). Sixty-seven percent of the entire group received postoperative chemotherapy with TMZ (n = 198). One-hundred sixty-six patients received both concomitant and sequential TMZ. Prescription of postoperative TMZ increased in the most recent period (2005-2007). One- and 4-year survival rates were 70.2% and 28.6%, respectively. No statistically significant improvement in survival was observed with the addition of TMZ to RT (P = .59). Multivariate analysis showed the statistical significance of age, presence of seizures, Recursive Partitioning Analysis classes I-III, extent of surgical removal, and 3D-CRT. Changes in the care of AA over the past years are documented. Currently there is not evidence to justify the addition of TMZ to postoperative RT for patients with newly diagnosed AA outside a clinical trial. Results of prospective and randomized trials are needed.

Background We report the results of a single-institution, phase II trial of accelerated partial breast irradiation (APBI) using a single dose of intraoperative electron radiation therapy (IOERT) in patients with low-risk early stage breast cancer. Methods and Materials A cohort of 226 patients with low-risk, early stage breast cancer were treated with local excision and axillary management (sentinel node biopsy with or without axillary node dissection). After the surgeon temporarily reapproximated the excision cavity, a dose of 21 Gy using IOERT was delivered to the tumor bed, with a margin of 2 cm laterally. Results With a mean follow-up of 46 months (range, 28-63 months), only 1 case of local recurrence was reported. The observed toxicity was considered acceptable. Conclusions APBI using a single dose of IOERT can be delivered safely in women with early, low-risk breast cancer in carefully selected patients. A longer follow-up is needed to ascertain its efficacy compared to that of the current standard treatment of whole-breast irradiation.

To the Editor: In the paper by Alongi et al.1 the hope and concerns of the Italian radiation oncologist when reirradiation is needed are accurately investigated. Novel techniques have made it possible to treat patients affected by recurrences or primary tumors at previously irradiated sites, but when retreating a tumor the radiation oncologists does not refrain from delivering an effective dose even if it could be dangerous to the patient in terms of late effects. Combined treatment with hyperthermia (HT) allows administering a lower radiation dose and achieving the same radiobiological effects and better outcomes, particularly in terms of acute and late toxicity. Dr Van Der Zee et al., from Erasmus Medical Center, Rotterdam, reviewed 21 published clinical studies on 974 patients with recurrent breast cancer after previous irradiation who were treated with HT and radiotherapy (RT). The rate of complete responses following reirradiation and HT in these patients was 61%, compared to only 32% after RT alone. The authors also reviewed their clinical experience in treating patients who had recurrent breast cancer after previous irradiation2. They stated that, “in 74% of our patients with recurrent breast cancer treated with a reirradiation scheme of 8 fractions of 4 Gy in 4 weeks, combined with 4 or 8 HT treatments, a complete response is achieved, approximately twice as high as the complete remission (CR) rate following the same reirradiation alone. The CR rate in tumors smaller than 30 mm is 80-90%, for larger tumors it is 65%. HT appears beneficial for patients with microscopic residual tumor as well.” Dr Moros et al., from the Department of Radiation Oncology of the University of Arkansas, reviewed the results of 2 consecutive clinical studies using simultaneous HT and radiation therapy to treat 119 breast cancer patients3. The 2 trials (60 cases) included breast cancer patients who recurred after prior therapies, including RT. The authors concluded that, “the product of radiation dose and total thermal dose was highly correlated with complete response.” Dr Jones, from the Radiation Oncology Department of Duke University, North Carolina, in a recent review on breast cancer4 stated that, “the tremendous progress that has occurred in the role of HT for the treatment of breast cancer, has garnered broad interest at the national level, and the impact of these data led the National Comprehensive Cancer Network (NCCN) to include HT in the 2007 Breast Cancer Guidelines for recurrent breast cancer. In summary, there is a strong biological rationale for the use of HT in breast cancer, and this has been proven in clinical trials to enhance treatment outcome.” This author published a randomized trial where 109 patients with superficial tumors (chest wall recurrence of breast cancer, head and neck tumors, melanoma and other tumors) were randomly assigned to receive RT alone or RT plus superficial HT; the complete response rate was 66.1% in the HT arm and 42.3% in the no-HT arm5. Dr Ott from the Radiation Oncology Department of Erlangen (Germany), based on previous clinical experiences, designed a phase II study for rectal cancer recurrences in previously irradiated sites by using an RT course of 45 Gy in 25 fractions combined with regional HT6. This trial, supported by the German Hyperthermia Study Group and the Atzelsberg Circle, has been approved by the German Krebs Liga. In conclusion, considering these data and the important role of HT in the battle against cancer7, we suggest that among the emerging possibilities in reirradiating patients also hyperthermia combined with lower doses of RT should be considered.

AIMS AND BACKGROUND Our previous survey showed that the patterns of postoperative radiotherapy (PORT) for head and neck cancer (HNC) in Italy might be suboptimal. A prospective observational study was therefore designed to evaluate this issue in greater detail. METHODS All radiotherapy centers involved in the HNC Working Group of the Italian Radiation Oncology Association were asked to enter into the study all patients treated with PORT during a 6-month period. RESULTS A total of 200 patients were accrued by 24 centers from December 2008 to May 2009. Larynx (38%) and oral cavity (34%) were the most common primary sites. The median time between surgery and the start of radiotherapy was 69 days (range, 25-215 days). Seventy-nine percent of cases with no evidence of risk factors for local recurrence were treated with high-dose radiotherapy to the primary site. In about 75% of cases the pN0 neck was included in the target volume. Concomitant chemotherapy was delivered to about 60% of patients with major risk factors and 21% of patients with no risk factors. CONCLUSIONS Three issues emerged from our study as potential targets for future investigations: the impact on clinical outcome of the interval between surgery and the start of PORT; factors driving radiation oncologists to overtreat volumes at low risk of recurrence; and problems associated with the delivery of concomitant chemotherapy.

PURPOSE:To evaluate the therapeutic effect of delivering regional hyperthermia (HT) plus chemoradiotherapy (CRT) in patients suffering from locally advanced unresectable pancreatic cancer (LAPC).METHODS:Between January 2000 and December 2008, 68 patients affected by primary (56/68) or recurrent (12/68) LAPC were treated either with CRT alone or CRT plus HT. Radiotherapy (RT) consisted of 3D conformal irradiation of tumor and regional lymph nodes (dose ranged from 30 Gy/10 fractions to 66 Gy/33 fractions). Chemotherapy (CT) consisted of gemcitabine (GEM) alone or in association with either oxaliplatin, cisplatin, or 5-FU. HT was delivered twice a week, concomitant with RT.RESULTS:In the current study, 60 of the original 68 patients were included. Median overall survival (OS) was 15 months in the HT group versus 11 months in the control group (log-rank test: p = 0.025). HT did not increase CRT toxicity.CONCLUSION:HT can be added safely to CRT in LAPC, thus, resulting in slightly prolonged survival in certain cases.

For patients affected by intermediate- and high-risk prostate cancer, a single local therapy is not enough, and a more aggressive treatment, such as androgen suppression therapy (AST) and pelvic irradiation, is indicated. Biochemical disease-free survival (bDFS) and overall survival (OS) improve in intermediate- and high-risk prostate cancer using radiotherapy (RT) combined with AST as compared with the RT alone.Hyperthermia (HT), combined with RT for the treatment of prostate cancer with intermediate- and high-risk, has been defined as "promising". In the development of new strategies, the reduction of short and long-term treatment related toxicity is of primary importance. Quality of Life (QoL) has been previously investigated and the authors concluded that HT does not negatively impact QoL in patients treated with radiation and HT. The use of HT in treating advanced prostate cancer has been reported by many centres; several studies suggest the feasibility of HT added to conventional RT.In intermediate- and high-risk prostate cancer, the combination of RT plus a long-term androgen suppression provides good results in terms of OS and QoL. HT, improving the anti-cancer effects of irradiation, as demonstrated by experimental in vitro and in vivo studies, could increase the outcome in the treatment of locally advanced prostate tumours without adding toxicity. A randomised phase III trial comparing RT-AST combined treatment plus/minus HT is needed to demonstrate the efficacy of HT.

Purpose: To evaluate the safety of delivering pre-operative regional hyperthermia (HT) plus an intensified chemo-radiotherapy (CRT) regimen in patients suffering from locally advanced rectal cancer. Methods: Between June 2000 and April 2006, 76 patients with locally advanced (cT3-4 N0/+) rectal adenocarcinoma were treated with HT plus CRT. HT was given once a week, to a total of five treatments, 1 to4 h after radiotherapy (50 Gy with 2-Gy fractions for 5 weeks, plus a 10-Gy boost on the tumour bed, with the same fractionation schedule). Chemotherapy consisted in 5FU 200 mg/m2 continuous infusion throughout the 6 weeks of irradiation and OXA 45 mg/m2 in a weekly bolus. Surgery followed 4 to 6 weeks after the completion of HT plus CRT. Results: HT plus CRT was generally well tolerated. At pathologic examination, there was a pathologic complete response (pCR) (ypT0 ypN0) in 18 out of 76 patients (23.6%), a partial response (PR) in 34/76 ones (44.7%) and a stable disease (SD) in 20/76 (26.3%) ones; 4/76 patients (5.2%) had a progression disease (PD) (distant metastases) at the time of surgery. Good predictors of a longer disease-free survival (DFS) were in order ypN status (log-rank test: p = 0.0008), ypT status (p = 0.002) and pCR (p = 0.03). Conclusion: Preoperative CRT combined with regional HT yielded acceptable toxicity. The rate of pCR was encouraging, although further studies are needed to prove the long-term efficacy of adding HT to CRT.

Aims and background Hyperthermia, the heating of tumors to 41.5–43 °C, could be today considered the fourth pillar of the treatment of cancer. Employed for 20 years in Europe, the USA and Asia, hyperthermia, used in addition to radiotherapy, chemotherapy and surgery, increases both local control and overall survival, restores the chance of the surgery for inoperable tumors and allows a new low-dosage treatment of relapsed cancers previously treated with high radiotherapy dosage without increasing toxicity. Methods Hyperthermia can be either superficial, produced by a microwave generator, or regional, produced by a radiofrequency applicator with multiple antennas, which emanate a deep focalized or interstitial heating. Results The results are confirmed by phase III randomized trials, with level 1 evidence. A review of the international literature on hyperthermia, the experience of the University Hospital of Verona Radiotherapy Department (Italy) and a summary of the Symposium regarding the Evolution of Clinical Hyperthermia plus Radiotherapy during the Twentieth Congress of the French Society of Radiation Oncology (SFRO) are presented. Conclusions Hyperthermia is an important treatment modality in cancer treatment and its results are strongly supported by criteria of evidence-based medicine. Fifteen years of experience of the Radiation Oncology Department in Verona confirms the positive results obtained with international prospective trials, with level 1 evidence. Hyperthermia appears to be the fourth pillar beside surgery, radiotherapy and chemotherapy. Free full text available at www.tumorionline.it

High-grade gliomas (HGG)-glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA)-are still characterized by a dismal prognosis despite recent advances in treatment options (new radiotherapy techniques including IMRT and radiosurgery, new alkylating agents such as Temozolomide [TMZ], molecular targeted drugs). Gold-standard therapy has involved maximum possible resection, followed by adjuvant irradiation plus TMZ followed by maintenance TMZ. TMZ has also proven its efficacy on tumors of oligodendroglial origin. The conventional "5 out of 28 days" schedule of TMZ achieved an overall survival rate at 2 years of 26.5%; in patients with methylation of methylguanine methyltrasnsferase (MGMT) promoter, better results can be achieved but MGMT methylation status determination is feasible only in a few centres. Dose-intensity TMZ schedules have the capability of depleting MGMT in tumor cells, thus promising a better outcome also in non-methylated patients. Alternative schedules, such as the "weekly alternating" or the "21 out of 28 days" ones, have been tried in relapsed patients and recently also in newly diagnosed ones. Sporadic cases of severe bone marrow aplasia with high doses of TMZ have been reported, which required bone marrow transplantation. This chapter tries to find a possible rationale for intensified regimens of TMZ administration and reviews its possible benefits and risks, focusing on results of clinical trials and reported toxicity cases.

We report a case of relapsed high-risk non-metastatic medulloblastoma in a 14-year-old boy, which was treated with intensity-modulated radiotherapy (IMRT) and temozolomide (TMZ). At the age of 11, the patient underwent an MRI-confirmed incomplete resection of a fourth-ventricle medulloblastoma, followed by conventional chemotherapy, craniospinal irradiation (55.8 Gy, 1.8 Gy/fraction) and then myeloablative chemotherapy followed by peripheral blood progenitor cell rescue. After 18 months of complete remission following the completion of chemotherapy, MRI showed a 2.5-cm mass in the olfactory notch. The patient underwent IMRT (45 Gy, 1.8 Gy/fraction) with concomitant administration of TMZ (180 mg/m2, 5 days every 21 days), which was well tolerated. After 5 cycles of TMZ, MRI showed complete remission with no evidence of the mass. TMZ was continued for another 5 cycles and then stopped. At 14 months from the completion of IMRT, a new MRI scan showed multiple nodular relapses around the fourth ventricle and the patient is currently treated with oral etoposide.

PURPOSE:We performed a new phase II trial enrolling patients with newly diagnosed high-grade glioma (HGG) to test the efficacy of a weekly alternating temozolomide (TMZ) schedule after surgery and concomitant chemoradiotherapy.METHODS:From January 2005 to January 2007, 34 patients (21 men, 13 women; age range 30-70, mean age 53) were enrolled. There were 32 glioblastoma multiforme and two anaplastic astrocytoma. Each patient after surgery received standard concurrent chemoradiotherapy. After a 4-week break, patients were then to receive 12 cycles of 1-week-on/1-week-off TMZ, with 75 mg/m(2) for the first cycle, 100 mg/m(2) for the second, 125 mg/m(2) for the third, and 150 mg/m(2) from the fourth to the 12th. Hematological toxicity was monitored every week during concomitant chemoradiotherapy and then every 4 weeks.RESULTS:After 12 months from the end of radiotherapy, the overall survival (OS) rate was 59% (20/38), distributed as follows: 60% (18/30) for recursive partitioning analysis (RPA) class 4 patients and 33% (1/3) for RPA class 6 patients; the only RPA class 1 patient was alive and disease free at the time of writing. Median OS was 13 months [95% confidence interval (CI) 11.02-14.98 months]. Hematological toxicity was seen in six patients (18%): grade 1 neutropenia in four, grade 2 thrombocytopenia in one, and grade 4 thrombocytopenia plus grade 1 neutropenia in one. There was one case of opportunistic infection (Pneumocystis carinii pneumonitis).CONCLUSION:The toxicity of the TMZ dose-dense regimen was very low. Results seem to be encouraging for RPA lower classes (patients with good prognostic factors).

Intraoperative ultrasonography (I.US) has been introduced in order to overcome the limits of the preoperative imaging modalities (notably, ultrasonography and computed tomography), both in pancreatic cancer diagnosis and staging. The authors' experience encompasses 32 cases, selected according to the following criteria: lesions that could not be detected both preoperatively and at surgical exploration; lesions detected but not properly characterized, requiring differential diagnosis between cancer and pancreatitis; tumoral lesions with a perspective of radical surgery, in which the preoperative judgment of resectability had to be verified. In the only case of the first group, I.US allowed the identification of a small cancer in a jaundiced patient. In the 11 cases of the second group, I.US-guided fine-needle aspiration biopsy showed three cancers; however, among the other 8 lesions classified as pancreatitis there was one false negative diagnosis (a tumoral mass with liver metastases was demonstrated by computed tomography 6 mo later). Regarding the intraoperative staging of the proven cancers (20 cases of the third group; 4 cases of the first and second groups), I.US changed the planned surgical approach in 9 cases (showing vascular involvement or detecting liver metastases and enlarged lymph nodes not seen preoperatively); in 12 cases it confirmed the possibility of radical surgery. Finally, in the remaining 3 cases, I.US provided dubious information: only vascular dissection during surgery could achieve a correct evaluation, ruling out vascular involvement and thus allowing tumor resection.