Hypofractionated radiotherapy with simultaneous integrated boost (SIB) plus temozolomide in good prognosis patients with glioblastoma: a multicenter phase II study by the Brain Study Group of the Italian Association of Radiation Oncology (AIRO).

INTRODUCTION: A multicenter phase II study for assessing the efficacy and the toxicity of hypofractionated radiotherapy with SIB plus temozolomide in patients with glioblastoma was carried out by the Brain Study Group of the Italian Association of Radiation Oncology. METHODS: Twenty-four patients with newly diagnosed glioblastoma belonging to Recursive Partitioning Analysis classes III and IV were enrolled. The prescribed dose was 52.5 Gy in 15 fractions of 3.5 Gy and 67.5 in 15 fractions of 4.5 Gy to the SIB volume. Dose constraints for the hypofractionated schedule were provided. Radiotherapy was associated with concomitant and sequential temozolomide. RESULTS: Median overall survival (OS) was 15.1 months, while median progression-free survival (PFS) was 8.6 months. Actuarial OS at 12 months was 65.6% ± 0.09, whereas actuarial PFS at 12 months was 41.2% ± 0.10. Status of methylation of MGMT promoter resulted to be a significant prognostic factor for OS. Radiotherapy-related acute toxicity was not relevant. Three patients (12.5%) had G3 myelotoxicity that required temozolomide temporary interruption or dose reduction during the chemotherapy. However, chemotherapy was not definitely discontinued for toxicity in any case. One patient out of 24 (4.2%) developed radionecrosis that required surgical resection with no evidence of disease in the surgical specimen. CONCLUSIONS: This trial confirms that hypofractionated radiotherapy with SIB and association with temozolomide may be a reasonable and feasible option for good prognosis patients with GBM.

Intensity-modulated radiation therapy with simultaneous integrated boost combined with concurrent chemotherapy for the treatment of anal cancer patients: 4-year results of a consecutive case series.

PURPOSE: To report the 4-year outcomes of a consecutive series of anal cancer patients treated with concurrent chemo-radiation delivered with intensity-modulated radiotherapy (IMRT), employing a simultaneous integrated boost (SIB) approach. METHODS: A consecutive series of 54 patients was enrolled between 2007 and 2013. Treatment schedule consisted of 50.4 Gy/28 fractions (1.8 Gy daily) to the gross tumor volume, while the elective nodal volumes were prescribed 42 Gy/28 fractions (1.5 Gy/daily) for patients having a cT2N0 disease. Patients with cT3-T4/N0-N3 tumors were prescribed 54 (T3) or 60 (T4) Gy/30 fractions (1.8-2 Gy daily) to the gross tumor volume; gross nodal volumes were prescribed 50.4 Gy/30 fr (1.68 Gy daily) if sized ≤ 3 cm or 54 Gy/30 fr (1.8 Gy daily) if > 3 cm; elective nodal regions were given 45 Gy/30 fractions (1.5 Gy daily). Chemotherapy was administered concurrently according to the Nigro's regimen. Primary endpoint was colostomy-free survival (CFS). Secondary endpoints were local control (LC), disease-free survival (DFS), cancer-specific survival (CSS), overall survival (OS), and toxicity profile. RESULTS: Median follow up was 32.6 months (range 12-84). The actuarial probability of being alive at 4 years without a colostomy (CFS) was 68.9% (95% CI: 50.3%-84.7%). Actuarial 4-year OS, CSS, DFS, and LC were 77.7% (95% CI: 60.7-88.1%), 81.5% (95% CI: 64%-91%), 65.5% (95% CI: 47.7%-78.5%), and 84.6% (95% CI: 71.6%-92%). Actuarial 4-year metastasis-free survival was 74.4% (95% CI: 55.5%-86.2%). Maximum detected acute toxicities were as follows: dermatologic -G3: 13%; GI-G3: 8%; GU-G3: 2%; anemia-G3: 2%; neutropenia-G3:11%; G4: 2%; thrombocytopenia- G3:2%. Four-year G2 chronic toxicity rates were 2.5% (95% CI: 3.6-16.4) for GU, 14.4% (95% CI: 7.1-28) for GI, 3.9% (95% CI: 1%-14.5%) for skin, and 4.2% (95% CI: 1.1-15.9) for genitalia. CONCLUSIONS: Our study shows the feasibility of IMRT in the combined modality treatment of anal cancer, with comparable results to the literature with respect to LC, sphincter preservation and survival. Acute toxicity is lower if compared to series employing standard techniques. Our results support the use of IMRT on a routine basis for the treatment of anal cancer.

Bilateral breast radiation delivered with static angle tomotherapy (TomoDirect): clinical feasibility and dosimetric results of a single patient.

We herein report on a case of synchronous bilateral breast cancer patient undergoing adjuvant intensity-modulated whole breast with static angle tomotherapy (TomoDirect). The patient was treated with a hypofractionated schedule employing a simultaneous integrated boost approach. Radiotherapy schedule was 45 Gy/20 fractions (2.25 Gy daily) to the bilateral whole breast and 50 Gy/20 fractions (2.5 Gy daily) to the 2 lumpectomy cavities. Treatment was delivered over 4 weeks. Dosimetric results were robust with consistent target coverage and adequate normal tissue avoidance. Treatment was generally well-tolerated and acute toxicity profile was mild. The present report highlights the promising clinical feasibility of TomoDirect for bilateral breast irradiation.

Palliative radiotherapy for painful bone metastases from solid tumors delivered with static ports of tomotherapy (TomoDirect): feasibility and clinical results.

PURPOSE: To evaluate the feasibility and response to palliative radiotherapy delivered with static ports of tomotherapy--TomoDirect (TD) in patients affected with painful bone metastases from solid tumors. METHODS: A prospective cohort of 130 patients (185 osseous lesions) was treated between 2010 and 2013 with TD. Three fractionation schedules were employed according to clinical decision-making (3 Gy × 10; 4 Gy × 5; 8 Gy × 1). Pain response was investigated at 2 weeks and 2 months (for evaluable patients). The Numeric Rating Scale (NRS-11) was used to assess pain. Response rates to radiotherapy were calculated following the criteria of the International Bone Metastases Consensus Group (IBMCG), accounting for the use of concomitant analgesics (response: complete or partial; non-response: stable pain, pain progression or "other"). Analgesic consumption was recalculated into the daily oral morphine-equivalent dose (OMED). RESULTS: Most of the patients had 1-2 bone metastases (91); those with multiple lesions mostly had a metachronous presentation (60%). Synchronous lesions were mainly approached with multiple plans (63%). Most treatments employed 3-4 fields (77%). Treatment times ranged from 255 to 939 s depending on fractionation, fields, and target lesions number. At 2 weeks, the median self-reported worst pain decreased significantly as median oral morphine-equivalent dose regardless of fractionation used. The response rate according to the IBMCG-based response categories ranged from 45 to 55%. Pain relief duration seems (response at 2 months) slightly inferior with the single fraction approach, with a higher re-treatment rate. At 2 weeks, the median self-reported worst pain and OMED significantly decreased regardless of fractionation (response rate: 49-55%). Pain relief decreased at 2 months, especially for single fraction (higher re-treatment rate). CONCLUSION: TD is a valid option to deliver palliative radiotherapy for painful bone metastases from solid tumors.

Minimizing a tricky situation in breast irradiation with helical tomotherapy.

We report on a patient with breast cancer undergoing adjuvant intensity-modulated whole breast and lymph node irradiation with static angle tomotherapy (TomoDirect), who experienced a traumatic ipsilateral humeral fracture and was able to continue radiotherapy with helical tomotherapy and daily dosimetric monitoring by means of the Planned Adaptive module.

Intensity-modulated and hypofractionated simultaneous integrated boost adjuvant breast radiation employing statics ports of tomotherapy (TomoDirect): a prospective phase II trial.

PURPOSE: To report the 1-year outcomes of a prospective phase II study on hypofractionated whole-breast intensity-modulated radiotherapy (IM-WBRT) with a simultaneous integrated boost (SIB) to the tumor bed delivered with static ports of tomotherapy (TomoDirect) (TD). METHODS: A prospective cohort of 82 patients was enrolled between 2011 and 2012. Treatment schedule consisted of 45 Gy/20 fractions to the whole breast and 50 Gy/20 fractions to the surgical bed delivered concomitantly with TD over 4 weeks. A one-armed optimal two-stage Simon's design was selected to test the hypothesis that treatment modality under investigation would decrease acute skin toxicity over historical data using conventional fractionation and sequential boost. Primary endpoint was acute skin toxicity. Secondary endpoints included late toxicity, cosmesis, quality of life and local control. RESULTS: Median follow-up was 12 months (range 6-18). Maximum detected acute skin toxicity was G0 41 %; G1 53 %; G2 6 %; G3 <1 %. With two G2-G3 acute skin toxicity events in the first stage and four in the second, the study fulfilled the requirements for the definition of the treatment approach under investigation as promising. Late skin toxicity was mild with no >G2 events. Cosmesis was good/excellent in 91 % of patients and fair/poor in 9 %. Quality of life was preserved over time, with the exception of fatigue, which was transiently increased. CONCLUSIONS: Hypofractionated IM-WBRT with a SIB to the tumor bed delivered with TD provides consistent clinical results and it is able to reduce acute skin toxicity rate over conventionally fractionated and sequential boost tomotherapy-based IM-WBRT.

Intensity-modulated adjuvant whole breast radiation delivered with static angle tomotherapy (TomoDirect): a prospective case series.

PURPOSE: To report the 2-year outcomes of whole breast intensity-modulated radiotherapy (IMRT) after conserving surgery for early breast cancer (EBC) delivered with static angle tomotherapy (TomoDirect) (TD). METHODS: A prospective cohort of 120 EBC patients underwent whole breast IMRT with TD between 2010 and 2012. Radiation was delivered to a conventionally fractionated whole breast total dose of 50 Gy with TD, followed by a sequential conventionally fractionated tumor bed boost dose of 10-16 Gy with helical tomotherapy (HT). Clinical endpoints include acute and late toxicity, cosmesis, quality of life and local control. RESULTS: Median follow-up was 24 months (range 12-36 months); maximum detected acute skin toxicity was G0 22 %; G1 63 %; G2 12 % and G3 3 %. Predictors of acute dermatitis were as follows: volume of the whole breast minus boost volume receiving 105, 110 and 115 % of prescription dose, whole breast and boost volume, breast thickness and soft tissue thickness. Late skin toxicity was mild with no >G2 events. Cosmesis was good/excellent in 91.7 % of patients and fair/poor in 8.3 %. Quality of life was preserved over time, but for fatigue, transiently increased. CONCLUSION: Adjuvant whole breast IMRT delivered sequentially with both TD and HT provides consistent clinical results. An observed unintended excessive dose outside the tumor bed might increase acute toxicity and eventually affect long-term clinical endpoints. The incorporation of the boost dose within the whole breast phase employing a simultaneous integrated boost (SIB) approach might mitigate this issue.

Combined chemoradiation for head and neck region myxofibrosarcoma of the maxillary sinus.

AIMS AND BACKGROUND: Adult sarcomas of the head and neck region (HNSs) are considered a rare clinicopathological entity. They account for only 2-15% of all adult sarcomas and for less than 1% of all head and neck malignancies. The preferred initial treatment option is wide surgical excision. Whenever surgery is considered infeasible, a frontline combined-modality approach including radiotherapy and chemotherapy might be proposed. We here report on a case of localized sarcoma of the maxillary sinus treated with induction chemotherapy and subsequent intensity-modulated radiation therapy (IMRT), achieving a persistent complete remission status. METHODS: A 66-year-old man was referred to our institution hospital for left-sided facial pain with swollen left cheek and ipsilateral facial palsy. Magnetic resonance imaging showed a mass within the left maxillary sinus extending to the orbital floor and adjacent alveolar bones. Histological examination of the biopsy specimen demonstrated a myxofibrosarcoma. The patient underwent induction chemotherapy with gemcitabine 900 mg/m2 (days 1-8) and taxotere 80 mg/m2 every 3 weeks for 3 cycles and sequential simultaneous integrated boost (SIB) IMRT up to a total dose of 70 Gy/35 fractions to the macroscopic disease with 59.5 Gy/35 fractions to the level IB-II lymph nodes in the left neck. RESULTS: Treatment was well tolerated with mild acute toxicity. Complete remission was achieved at restaging MRI 6 months after the end of the combined modality approach. The patient remains in complete, unmaintained clinical and instrumental complete remission 18 months after treatment, with no late side effects. CONCLUSION: Combination therapy with induction chemotherapy and sequential SIB-IMRT could therefore be a promising modality for head and neck sarcomas, allowing for simultaneous tumor control and normal tissue sparing.

Leptomeningeal metastasis from prostate cancer.

AIMS AND BACKGROUND: Metastatic prostate carcinoma commonly involves bones and extrapelvic lymph nodes, with occasional visceral deposits. Central nervous system involvement is unusual and particularly the occurrence of leptomeningeal metastasis (LM) is extremely rare, with few cases described in the medical literature. The clinical presentation is characterized by multifocal neurological deficit and the prognosis is generally dismal, with survival ranging between 3 and 6 months. We report on a patient affected by LM due to prostate cancer who was treated with a combined-modality approach consisting of sequential chemotherapy and radiotherapy. METHODS: A 70-year-old man was referred to our group for cognitive mental disorder, left-sided frontal headache and nausea; the patient had a previous history of metastatic prostate cancer. LM was diagnosed neuroradiologically with brain MRI and evidence of a detectable level of PSA in the cerebrospinal fluid. He was treated with docetaxel and prednisone for 3 cycles followed by external beam radiotherapy (EBRT) to the whole brain to a total dose of 30 Gy in 10 fractions with a simultaneous integrated boost to the macroscopic disease (total dose of 35 Gy in 10 fractions). No acute toxicity was observed. RESULTS: A substantial clinical response was obtained after EBRT with neurological improvement and radiologically stable disease at post-treatment imaging until 10 weeks after radiation. The patient died of sudden general condition deterioration 3 months after EBRT. CONCLUSION: Since LM derived from prostate cancer is likely to become a more common clinical event, such patients would need to be included in clinical trials evaluating new therapeutic approaches, considering that the current treatment strategies have been shown to be rather ineffective.

Is the combination of Cetuximab with chemo-radiotherapy regimens worthwhile in the treatment of locally advanced head and neck cancer? A review of current evidence.

The administration of Cetuximab in combination with radiotherapy and chemotherapy has shown clear survival improvements within the locally advanced and the relapsed/metastatic settings respectively. These results have provided the clinical rational for the inclusion of Cetuximab into chemo-radiation regimens. Trials assessing the combination of Cetuximab with induction chemotherapy, concomitant chemo-radiotherapy or both are reviewed. Taken together, their results suggest that the addition of Cetuximab is promising in trials of induction chemotherapy, showing almost uniformly response rates higher than historical controls. In combination with concomitant hyperfractionated radiotherapy and Cisplatin the results of the RTOG 0522 trial do not suggest any benefit. However a positive effect cannot be excluded with other schedules. Although feasibility has been universally suggested, adding Cetuximab implies some toxicity enhancement. Single local and systemic toxicities are more frequent and supposedly the overall treatment intensity is increased. Moreover the drug-specific toxicities are potentially severe and deserve timely recognition and management.

Does TomoDirect 3DCRT represent a suitable option for post-operative whole breast irradiation? A hypothesis-generating pilot study.

BACKGROUND: This study investigates the use of TomoDirect™ 3DCRT for whole breast adjuvant radiotherapy (AWBRT) that represents a very attractive treatment opportunity, mainly for radiotherapy departments without conventional Linacs and only equipped with helical tomotherapy units. METHODS: Plans were created for 17 breast cancer patients using TomoDirect in 3DCRT and IMRT modality and field-in-field 3DCRT planning (FIF) and compared in terms of PTV coverage, overdosage, homogeneity, conformality and dose to OARs. The possibility to define patient-class solutions for TD-3DCRT employment was investigated, correlating OARs dose constraints to patient specific anatomic parameters. RESULTS: TD-3DCRT showed PTV coverage and homogeneity significantly higher than TD-IMRT and FIF. PTV conformality was significantly better for FIF, while no differences were found between TD-3DCRT and TD-IMRT. TD-3DCRT showed mean values of the OARs dosimetric endpoints significantly higher than TD-IMRT; with respect to FIF, TD-3DCRT showed values significantly higher for lung V(20Gy), mean heart dose and V(25Gy), while contralateral lung maximum dose and contralateral breast mean dose resulted significantly lower. The Central Lung Distance (CLD) and the maximal Heart Distance (HD) resulted as useful clinical tools to predict the opportunity to employ TD-3DCRT: positive correlations were found between CLD and both V(20Gy) and mean lung dose and between HD and both V25Gy and the mean heart dose. TD-3DCRT showed a significantly shorter mean beam-on time than TD-IMRT. CONCLUSIONS: The present study showed that TD-3DCRT and TD-IMRT are two feasible and dosimetrically acceptable treatment approach for AWBRT, with an optimal PTV coverage and adequate OARs sparing. Some concerns might be raised in terms of dose to organs at risks if TD-3DCRT is applied to a general population. A correct patients clusterization according to simple quantitative anatomic measures, would help to correctly allocate patients to the appropriate treatment planning strategy in terms of target coverage, but also of normal tissue sparing.

Head and neck region consolidation radiotherapy and prophylactic cranial irradiation with hippocampal avoidance delivered with helical tomotherapy after induction chemotherapy for non-sinonasal neuroendocrine carcinoma of the upper airways.

BACKGROUND: Non-sinonasal neuroendocrine carcinomas (NSNECs) of the head and neck are considered an unfrequent clinico-pathological entity. Combined modality treatment represents an established therapeutic option for undifferentiated forms where distant metastasis is a common pattern of failure. METHODS: We report on a case of NSNEC treated with sequential chemo-radiation consisting of 6 cycles of cisplatin and etoposide followed by loco-regional radiation to the head and neck and simultaneous prophylactic cranial irradiation to prevent from intracranial spread, delivered with helical tomotherapy with the 'hippocampal avoidance' technique in order to reduce neuro-cognitive late effects. RESULTS: One year after the end of the whole combined modality approach, the patient achieved complete remission, with no treatment-related sub-acute and late effects. CONCLUSIONS: The present report highlights the importance of multidisciplinary management for NSNECs of the head and neck, as the possibility to achieve substantial cure rates with mild side effects with modern radiotherapy techniques.