Umberto Ricardi

Stereotactic body radiation therapy for early stage non-small cell lung cancer: Results of a prospective trial

Patients affected with early stage (IA-IB) non-small cell lung cancer (NSCLC), deemed medically inoperable, are usually treated by conventional 3D-CRT, with poor results in terms of local tumour control and survival. Hypofractionated stereotactic body radiation therapy (SBRT) appears to be a valid alternative option, with high rates of local control and promising survival rates according to recent reported series. We herein report the final results of a prospective phase II trial of SBRT in 62 stage I NSCLC patients, homogeneously treated with three fractions of 15Gy each, given every other day during a 1 week time, up to a total dose of 45Gy; dose was prescribed to the 80%-isodose encompassing planning target volume. Patients were immobilized in a dedicated stereotactic body frame; margins around gross tumour volume were 5mm in the axial plane and 10mm in the longitudinal direction. Median age was 73.7 years. A pathologic confirmation of NSCLC was obtained in 64.5% of patients. Forty-three patients had stage IA and 19 stage IB disease. The majority of patients did not experience any toxicity; mild skin reactions, fatigue, dyspnea/cough or transient thoracic pain were recorded in approximately 10% of patients. With a median follow-up time of 28 months, 2 patients experienced an isolated local relapse, 4 an isolated nodal relapse and 15 a systemic failure. At 3 years, local control rate was 87.8%, cancer-specific survival 72.5%, overall survival 57.1%, with 8 out of 20 non-cancer related deaths. In multivariate analysis, tumour volume was associated with a better outcome. In our series, SBRT was well tolerated and confirmed its efficacy, with local control and survival rates globally superior to those reported using conventional radiotherapy. A longer follow-up is needed in order to establish a correct comparison with surgical series, and to fully ascertain a potential negative impact of SBRT on comorbidities of such a fragile patients population.

Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

E. Zucca1, C. Copie-Bergman2, U. Ricardi3, C. Thieblemont4, M. Raderer5 & M. Ladetto6, on behalf of the ESMO Guidelines Working Group* Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; APHP, Groupe Henri Mondor-Albert Chenevier, Département de Pathologie, Créteil, France; Department of Oncology, Radiation Oncology Unit, University of Turin, Turin, Italy; Department of Hematology, APHP-Saint-Louis Hospital, University Paris-Diderot, Paris, France; Department of Internal Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Division of Hematology, Department of Experimental Medicine and Oncology, University of Turin, San Giovanni Battista Hospital, Turin, Italy

Modern Radiation Therapy for Nodal Non-Hodgkin Lymphoma—Target Definition and Dose Guidelines From the International Lymphoma Radiation Oncology Group

Radiation therapy (RT) is the most effective single modality for local control of non-Hodgkin lymphoma (NHL) and is an important component of therapy for many patients. Many of the historic concepts of dose and volume have recently been challenged by the advent of modern imaging and RT planning tools. The International Lymphoma Radiation Oncology Group (ILROG) has developed these guidelines after multinational meetings and analysis of available evidence. The guidelines represent an agreed consensus view of the ILROG steering committee on the use of RT in NHL in the modern era. The roles of reduced volume and reduced doses are addressed, integrating modern imaging with 3-dimensional planning and advanced techniques of RT delivery. In the modern era, in which combined-modality treatment with systemic therapy is appropriate, the previously applied extended-field and involved-field RT techniques that targeted nodal regions have now been replaced by limiting the RT to smaller volumes based solely on detectable nodal involvement at presentation. A new concept, involved-site RT, defines the clinical target volume. For indolent NHL, often treated with RT alone, larger fields should be considered. Newer treatment techniques, including intensity modulated RT, breath holding, image guided RT, and 4-dimensional imaging, should be implemented, and their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control.

An Individual Patient Data Metaanalysis of Outcomes and Prognostic Factors After Treatment of Oligometastatic Non-Small-Cell Lung Cancer.

INTRODUCTION/BACKGROUND An individual patient data metaanalysis was performed to determine clinical outcomes, and to propose a risk stratification system, related to the comprehensive treatment of patients with oligometastatic NSCLC. MATERIALS AND METHODS After a systematic review of the literature, data were obtained on 757 NSCLC patients with 1 to 5 synchronous or metachronous metastases treated with surgical metastectomy, stereotactic radiotherapy/radiosurgery, or radical external-beam radiotherapy, and curative treatment of the primary lung cancer, from hospitals worldwide. Factors predictive of overall survival (OS) and progression-free survival were evaluated using Cox regression. Risk groups were defined using recursive partitioning analysis (RPA). Analyses were conducted on training and validating sets (two-thirds and one-third of patients, respectively). RESULTS Median OS was 26 months, 1-year OS 70.2%, and 5-year OS 29.4%. Surgery was the most commonly used treatment for the primary tumor (635 patients [83.9%]) and metastases (339 patients [62.3%]). Factors predictive of OS were: synchronous versus metachronous metastases (P < .001), N-stage (P = .002), and adenocarcinoma histology (P = .036); the model remained predictive in the validation set (c-statistic = 0.682). In RPA, 3 risk groups were identified: low-risk, metachronous metastases (5-year OS, 47.8%); intermediate risk, synchronous metastases and N0 disease (5-year OS, 36.2%); and high risk, synchronous metastases and N1/N2 disease (5-year OS, 13.8%). CONCLUSION Significant OS differences were observed in oligometastatic patients stratified according to type of metastatic presentation, and N status. Long-term survival is common in selected patients with metachronous oligometastases. We propose this risk classification scheme be used in guiding selection of patients for clinical trials of ablative treatment.

First-Line Treatment for Primary Testicular Diffuse Large B-Cell Lymphoma With Rituximab-CHOP, CNS Prophylaxis, and Contralateral Testis Irradiation: Final Results of an International Phase II Trial

PURPOSE Primary testicular lymphoma (PTL) has poor prognosis with failures in contralateral testis, CNS, and extranodal sites. To prevent these events, we designed an international phase II trial (International Extranodal Lymphoma Study Group 10 [IELSG-10]) that addressed feasibility and activity of conventional chemoimmunotherapy associated with CNS prophylaxis and contralateral testis irradiation. The trial was conducted by the IELSG and the Italian Lymphoma Foundation. PATIENTS AND METHODS Fifty-three patients (age 22 to 79 years) with untreated stage I or II PTL were treated with six to eight courses of rituximab added to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days (R-CHOP21); four doses of intrathecal methotrexate (IT-MTX) and radiotherapy (RT) to the contralateral testis (30 Gy) for all patients and to regional lymph nodes (30 to 36 Gy) for stage II disease. RESULTS All patients received R-CHOP21, 50 received CNS prophylaxis, and 47 received testicular RT. With a median follow-up of 65 months, 5-year progression-free survival and overall survival rates were 74% (95% CI, 59% to 84%) and 85% (95% CI, 71% to 92%), respectively. Ten patients relapsed or progressed: two in lymph nodes, five in extranodal organs, and three in the CNS. The 5-year cumulative incidence of CNS relapse was 6% (95% CI, 0% to 12%). No contralateral testis relapses occurred. Ten patients died: lymphoma (n = 6), secondary leukemia (n = 2), heart failure (n = 1), and gastric cancer (n = 1). Grade 3 to 4 toxicities were neutropenia, 28%; infections, 4%; and neurologic, 13%. No deaths occurred as a result of toxicity. CONCLUSION This international prospective trial shows that combined treatment with R-CHOP21, IT-MTX, and testicular RT was associated with a good outcome in patients with PTL. RT avoided contralateral testis relapses, but CNS prophylaxis deserves further investigation.

Stereotactic body radiation therapy for lung metastases

INTRODUCTION Stereotactic body radiation therapy (SBRT) has an emerging role in patients affected with pulmonary metastases. Purpose of this study was to evaluate efficacy and tolerability of SBRT in a cohort of patients treated between 2003 and 2009 at our institution. METHODS A total of 61 patients with oligometastatic lung tumors (single pulmonary nodules in 73.7%) were included in the study. SBRT was performed with a stereotactic body frame and a 3D-conformal technique. Fifty-one patients received 26 Gy in 1 fraction, 22 a dose of 45 Gy in 3 fractions and 3 a dose of 36 Gy in 4 fractions. Primary tumor was lung cancer in 45.7% of patients, colorectal cancer in 21.3% and a variety of other origins in 33%. The primary endpoint was local control, secondary endpoints were survival and toxicity. RESULTS After a median follow-up interval of 20.4 months, local control rates at 2 and 3 years were 89% and 83.5%, overall survival 66.5% and 52.5%, cancer-specific survival 75.4% and 67%, progression-free survival 32.4% and 22.3%. Tumor volume was significantly associated to survival, with highest rates in patients with single small tumors. Median survival time was 42.8 months, while median progression-free survival time was 11.9 months. Toxicity profiles were good, with just one case of grade III toxicity (pneumonitis). CONCLUSION This study shows that SBRT is an effective and safe local treatment option for patients with lung metastases. Definitive results are strictly correlated to clinical selection of patients.

SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease

BACKGROUND We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). METHODS Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. RESULTS Patients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 ± 0.02 vs 0.88 ± 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 ± 0.023 event-free and overall survival. CONCLUSIONS Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.

Pediatric medulloblastoma: toxicity of current treatment and potential role of protontherapy.

Post-operative craniospinal irradiation and systemic chemotherapy are both necessary in the treatment of pediatric medulloblastoma. Late toxicity is a major problem in long term survivors and significantly affects their quality of life. We have systematically reviewed the literature to examine data on late toxicity, specifically focusing on: endocrine function, growth and bone development, neurocognitive development, second cancers, ototoxicity, gynecological toxicity and health of the offspring, cardiac toxicity and pulmonary toxicity. In this paper, we describe qualitatively the kind of detected side effects and, whenever possible, try to assess their incidence and the relative role of craniospinal irradiation (as opposed to other treatments and to the disease itself) in producing them. Subsequently we examine the possible approach to reduce unwanted effects from craniospinal irradiation to target and non-target tissues and we consider briefly the role of hyperfractionation, tomotherapy and IMRT. We describe the characteristics of protontherapy and its potential for non-target tissues toxicity reduction reviewing the existing physical and dosimetric studies and the (still very limited) clinical experiences. Finally we propose intensity modulated spot scanning protontherapy with multiportal simultaneous optimization (IMPT) as a possible tool for dose distribution optimization within different areas of CNS and potential reduction of target tissues toxicity.

Role of radiation therapy in locally advanced thymoma

The records of all patients treated for thymoma in the Department of Radiotherapy of the University of Torino between 1970 and 1988 were reviewed. There were 77 patients in stage III or IVa (59 in stage III and 18 in stage IVa); 74 patients were operated upon before radiotherapy and 3 had a pre-operative irradiation followed by surgery and post-operative boost. Complete resection was possible in 55.9% of cases with stage III and in none with stage IVa. Subtotal resection was done in 35.6% of patients in stage III and 83.3% in stage IVa. 8 patients had only a biopsy: 5 in stage III (8.5%) and 3 in stage IVa (16.6%). Post-operative radiation doses ranged between 39.6 and 46 Gy to the whole mediastinum followed by a 10-16 Gy boost on smaller fields in cases presenting residual disease after surgery. The pre-operative dose was 30 Gy followed by a post-operative boost of 16-24 Gy. Conventional fraction sizes of 1.8-2 Gy were always used. The 10 years survival rate was 58.3%. There was a significant difference between stage III (70.9%) and stage IVa (26.3%) (p less than 0.0004). Survival of patients in stage III was not significantly affected by the type of surgery. No significant difference in survival or recurrence rate was observed in patients with different histologies and in patients with or without myasthenia. Thoracic relapses occurred in 15.2% of patients in stage III and in 50% of patients in stage IVa (p less than 0.01). Only 7 relapses (9.1%) were within the limits of the radiation field.(ABSTRACT TRUNCATED AT 250 WORDS)

Incidence, survival and prevalence of myeloid malignancies in Europe

BACKGROUND The Surveillance of Rare Cancers in Europe (RARECARE) project aims at increasing knowledge of rare cancers in Europe. This manuscript describes the epidemiology of myeloid malignancies (MMs), taking into account the morphological characterisation of these tumours. METHODS We used data gathered by RARECARE on cancer patients diagnosed from 1995 to 2002 and archived in 64 European population-based cancer registries, followed up to 31st December 2003 or later. RESULTS The overall annual crude incidence of MMs was 8.6 per 100,000. Acute myeloid leukaemia (AML) and myeloproliferative neoplasms (MPN) were most common, with incidence rates of 3.7 and 3.1 per 100,000 year respectively, followed by 1.8 for myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MD/MPN) and 0.1 for histiocytic and dendritic cell neoplasms (HDCN). The 5-year relative survival rate ranged from 18% for chronic myelomonocytic leukaemia, 19% for AML, 29% for MDS and 44% for chronic myeloid leukaemia to relatively favourable rates for MPN (62%) and HDCN (83%). Total number of new cases of MMs in the EU27 is estimated at 43,000 annually, total number of prevalent cases (1st January 2008) at 189,000 cases. CONCLUSION MMs form a large variety of rare entities with specific characteristics. Collection of detailed information (immunophenotype, genetic abnormalities, molecular data and clinical data) and an up-to-date classification system is essential for their surveillance, especially now that more and more targeted therapies are being introduced.