Giampaolo Biti

Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: eight-year update of an Italian prospective randomized study.

PURPOSE To compare the effectiveness of chemotherapy (CHT) with extended-field radiotherapy (RT) in the treatment of early-stage Hodgkins disease (ESHD), we report an 8-year updated analysis of a study in which treatment with six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) CHT was randomly compared with extended-field RT. PATIENTS AND METHODS From August 1979 to December 1982, 89 adult patients with pathologic stage I-IIA Hodgkins disease (HD) were randomly allocated to receive either RT with mantle field followed by periaortic irradiation (n = 45) or six monthly courses of MOPP CHT (n = 44). RESULTS All patients in the RT arm and 40 of 44 in the CHT arm achieved complete remission. Twelve relapses occurred in each group. Eight patients treated with MOPP and two of the RT arm died of HD. Three other patients of the CHT group died because of a second cancer. With a median follow-up greater than 8 years, the overall survival rate is significantly higher in the RT than in the CHT group (93% v 56%; P less than .001), whereas the rates of freedom from progression and relapse-free survival (RFS) were similar in the two groups (76% v 64% and 70% v 71%, respectively). Of the 12 patients relapsing after RT, 11 (92%) achieved a second CR, compared with only six of the 12 (50%) in the MOPP group. Analysis of the response rate to salvage treatments showed that the type of relapse in the MOPP group was a prognostic indicator for the achievement of a second CR, whereas in the RT group, a second CR was obtained regardless of the characteristics of the relapses. At 80 months, the probability of survival of relapsing patients calculated from time of relapse was 85% and 15% in the RT and CHT groups, respectively (P = .02). CONCLUSION We conclude that RT alone is the treatment of choice for adult patients with ESHD with favorable prognostic factors.

UTERINE SARCOMA: TWENTY-SEVEN YEARS OF EXPERIENCE

PURPOSE A correlation of treatment for uterine sarcoma with outcome, prognostic importance of pathology, and clinical parameters. PATIENTS AND METHODS One hundred forty-one patients (median age: 56 years, range: 19-85 years) with a histologically verified uterine sarcoma were identified from a database compiled at the Royal Marsden Hospital and the University of Florence between 1974 and 2001. Seventy-two patients had leiomyosarcoma, 42 had mixed müllerian tumors, 22 had endometrial stromal sarcoma, 1 hemangiopericytoma, 1 rhabdomyosarcoma, and 3 patients had unspecified sarcoma. According to FIGO classification, Stage I, II, III, and IV tumors were identified in 71, 13, 31, and 26 patients, respectively. RESULTS At the time of analysis, 73.7% of patients were dead, and 26.3% were alive with a median survival of 2 years from initial diagnosis. Univariate analysis for cause-specific survival demonstrated statistical significance for histology (p = 0.02), grade (p = 0.003), stage (p = 0.007), and age (p = 0.02). Multivariate analysis demonstrated significant prognostic values for stage (p = 0.02) and histology (p = 0.05) only. Postoperative radiotherapy with a total dose higher than 50 Gy seems to be significant (p = 0.001) in reducing local recurrence. CONCLUSIONS Our data favor treatment for Stages I, II, and III of uterine sarcoma with radical surgery plus radical dose irradiation comprising both external beam radiotherapy and brachytherapy.

Accelerated Partial Breast Irradiation With IMRT: New Technical Approach and Interim Analysis of Acute Toxicity in a Phase III Randomized Clinical Trial

PURPOSE To evaluate with a randomized clinical trial the possibility of treating the index quadrant with external intensity-modulated radiotherapy (IMRT) in a selected group of patients with early-stage breast cancer and to analyze the acute toxicity. METHODS AND MATERIALS From September 2005, a randomized Phase III clinical trial has been conducted to compare conventional (tangential field) fractionated whole breast treatment (Arm A) with accelerated partial breast irradiation plus intensity-modulated radiotherapy (Arm B). For intensity-modulated radiotherapy, the clinical target volume was drawn with a uniform 1-cm margin around the surgical clips in three dimensions. The ipsilateral and contralateral breast, ipsilateral and contralateral lung, heart, and spinal cord were contoured as organs at risk. All the regions of interest were contoured according to the International Commission on Radiation Units and Measurements reports 50 and 62 recommendations. RESULTS In September 2008, 259 patients were randomized and treated. The mean clinical target volume in Arm B was 44 cm(3) and the mean planning target volume was 123 cm(3). The mean value of the ratio between the planning target volume and the ipsilateral breast volume was 21%. The rate of Grade 1 and Grade 2 acute skin toxicity was 22% and 19% in Arm A (Radiation Therapy Oncology Group scale), respectively. The tolerance in Arm B was excellent with only 5% Grade 1 and 0.8% Grade 2 acute skin toxicity. The planning constraints were fully satisfied in most patients. In a very few cases, this was not possible because of very unfavorable anatomy. Quality assurance procedures were performed according to our internal quality assurance protocol, with excellent results. CONCLUSION In the present preliminary analysis, we have demonstrated that accelerated partial breast irradiation is feasible, with very low acute toxicity.

Second-line chemotherapy with fotemustine in temozolomide-pretreated patients with relapsing glioblastoma: a single institution experience.

To evaluate efficacy and safety of fotemustine chemotherapy in temozolomide (TMZ) pretreated adults with recurrent glioblastoma multiforme (GBM). Primary endpoint was progression-free survival at 6 months. Twenty-seven patients (median age: 56 years; median Karnofsky performance status at progression: 80) with relapsed glioblastoma multiforme underwent fotemustine as second-line chemotherapy after failure of homogeneous postoperative treatment consisting of conformal radiotherapy (60 Gy in 30 fractions) with concomitant TMZ (75 mg/m2 per day), followed by six courses of TMZ (150–200 mg/m2 for 5 days every 28 days). Patients were assigned to Radiation Therapy Oncology Group recursive partitioning analysis classes for gliomas. After MRI-proven tumor relapse or progression, all patients underwent chemotherapy with fotemustine, given intravenously 100 mg/m2 every week for 3 consecutive weeks (induction phase) and then every 3 weeks (maintenance phase). Adequate liver, renal, and bone marrow functions were required. Toxicity grading was based on the National Cancer Institutes Common Toxicity Criteria (version 2.0). Response to treatment was assessed on MacDonald criteria. According to an intention-to-treat-analysis, data on all enrolled patients were included in statistical analysis. Eight partial responses (29.6%) and five cases of stable disease (18.5%) were observed. Median time to progression was 5.7 months. Progression-free survival at 6 months was 48.15%. Median survival from the beginning of fotemustine chemotherapy was 9.1 months. Median survival from diagnosis of glioblastoma was 21.2 months. Toxicity was manageable and mainly hematological (grade 3 thrombocytopenia: three cases; grade 4 leukopenia: one case). Fotemustine has shown therapeutic efficacy as single-drug second-line chemotherapy in treatment of TMZ pretreated patients.

Association Between Genetic Polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT Genes and Radiosensitivity in Breast Cancer Patients

PURPOSE Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion). METHODS AND MATERIALS Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. RESULTS Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR=53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR=38.26; 95% CI, 1.19-1232.52). CONCLUSIONS To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic polymorphisms may be promising candidates for predicting acute radiosensitivity, but further studies are necessary to confirm our findings.

Classical Hodgkin’s lymphoma in adults: guidelines of the Italian Society of Hematology, the Italian Society of Experimental Hematology, and the Italian Group for Bone Marrow Transplantation on initial work-up, management, and follow-up

During the last decades, survival of patients treated for classical Hodgkin’s lymphoma (HL) has improved substantially, and the overall cure rate for this neoplasm is about 80–85% at present. This article provides practice guidelines for the initial workup, therapy and follow-up of classical Hodgkin’s lymphoma. Extensive recommendations are given to prospectively limit the risk of therapy-related gonadic damage and to preserve fertility. The Italian Society of Hematology (SIE), the Italian Society of Experimental Haematology (SIES) and the Italian Group for Bone Marrow Transplantation (GITMO) commissioned a project to develop practice guidelines for the initial work-up, therapy and follow-up of classical Hodgkin’s lymphoma. Key questions to the clinical evaluation and treatment of this disease were formulated by an Advisory Committee, discussed and approved by an Expert Panel (EP) composed of senior hematologists and one radiotherapist. After a comprehensive and systematic literature review, the EP recommendations were graded according to their supporting evidence. An explicit approach to consensus methodologies was used for evidence interpretation and for producing recommendations in the absence of a strong evidence. The EP decided that the target domain of the guidelines should include only classical Hodgkin’s lymphoma, as defined by the WHO classification, and exclude lymphocyte predominant histology. Distinct recommendations were produced for initial work-up, first-line therapy of early and advanced stage disease, monitoring procedures and salvage therapy, including hemopoietic stem cell transplant. Separate recommendations were formulated for elderly patients. Pre-treatment volumetric CT scan of the neck, thorax, abdomen, and pelvis is mandatory, while FDG-PET is recommended. As to the therapy of early stage disease, a combined modality approach is still recommended with ABVD followed by involved-field radiotherapy; the number of courses of ABVD will depend on the patient risk category (favorable or unfavorable). Full-term chemotherapy with ABVD is recommended in advanced stage disease; adjuvant radiotherapy in patients without initial bulk who achieved a complete remission is not recommended. In the elderly, chemotherapy regimens more intensive than ABVD are not recommended. Early evaluation of response with FDG-PET scan is suggested. Relapsed or refractory patients should receive high-dose chemotherapy and autologous hemopoietic stem cells transplant. Allogeneic transplant is recommended in patients relapsing after autologous transplant. All fertile patients should be informed of the possible effects of therapy on gonadal function and fertility preservation measures should be taken before the initiation of therapy.

Association between single nucleotide polymorphisms in the XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck cancer

PURPOSE Individual variability in radiosensitivity is large in cancer patients. Single nucleotide polymorphisms (SNPs) in genes involved in DNA repair and in protection against reactive oxygen species (ROS) could be responsible for such cases of radiosensitivity. We investigated the association between the occurrence of acute reactions in 101 patients with squamous cell carcinoma of the head and neck (SCCHN) after radiotherapy (RT) and five genetic polymorphisms: XRCC1 c.1196A>G, XRCC3 c.722C>T, RAD51 (c.-3429G>C, c.-3392G>T), and GSTP1 c.313A>G. MATERIALS AND METHODS Genetic polymorphisms were detected by high resolution melting analysis (HRMA). The development of acute reactions (oral mucositis, skin erythema and dysphagia) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for biologically effective dose (BED). RESULTS Development of grade ≥2 mucositis was increased in all patients (chemo-radiotherapy and radiotherapy alone) with XRCC1-399Gln allele (HR=1.72). The likelihood of developing grade ≥2 dysphagia was higher in carriers of RAD51 c.-3429 CC/GC genotypes (HR=4.00). The presence of at least one SNP or the co-presence of both SNPs in XRCC1 p.Gln399Arg /RAD51 c.-3429 G>C status were associated to higher likelihood of occurrence of acute toxicities (HR=2.03). CONCLUSIONS Our findings showed an association between genetic polymorphisms, XRCC1 c.1196A>G and RAD51 c.-3429 G>C, and the development of radiation-induced toxicities in SCCHN patients.

Patterns of care and survival in a retrospective analysis of 1059 patients with glioblastoma multiforme treated between 2002 and 2007: a multicenter study by the Central Nervous System Study Group of Airo (italian Association of Radiation Oncology).

OBJECTIVETo investigate the pattern of care and outcomes for newly diagnosed glioblastoma in Italy and compare our results with the previous Italian Patterns of Care study to determine whether significant changes occurred in clinical practice during the past 10 years. METHODSClinical, pathological, therapeutic, and survival data regarding 1059 patients treated in 18 radiotherapy centers between 2002 and 2007 were collected and retrospectively reviewed. RESULTSMost patients underwent both computed tomography and magnetic resonance imaging either preoperatively (62.7%) or postoperatively (35.5%). Only 123 patients (11.6%) underwent a biopsy. Radiochemotherapy with temozolomide was the most frequent adjuvant treatment (70.7%). Most patients (88.2%) received 3-dimensional conformal radiotherapy. Median survival was 9.5 months. Two- and 5-year survival rates were 24.8% and 3.9%, respectively. Multivariate analysis showed the statistical significance of age, postoperative Karnofsky Performance Status scale score, surgical extent, use of 3-dimensional conformal radiotherapy, and use of chemotherapy. Use of a more aggressive approach was associated with longer survival in elderly patients. Comparing our results with those of the subgroup of patients included in our previous study who were treated between 1997 and 2001, relevant differences were found: more frequent use of magnetic resonance imaging, surgical removal more common than biopsy, and widespread use of 3-dimensional conformal radiotherapy + temozolomide. Furthermore, a significant improvement in terms of survival was noted (P < .001). CONCLUSIONChanges in the care of glioblastoma over the past few years are documented. Prognosis of glioblastoma patients has slightly but significantly improved with a small but noteworthy number of relatively long-term survivors.

Oral Vinorelbine and Cisplatin as Induction Chemotherapy and Concomitant Chemo-Radiotherapy in Stage III Non-small Cell Lung Cancer: Final Results of an International Phase II Trial

Introduction: Cisplatin in combination with vinorelbine has reported an optimal activity/tolerance ratio when used in combination with radiotherapy in locally advanced unresectable non-small cell lung cancer. The currently available oral formulation of vinorelbine should be easier to use assuming a similar activity profile. An international phase II trial with vinorelbine oral and cisplatin as induction followed by oral vinorelbine and cisplatin with concomitant radiotherapy was implemented to evaluate the efficacy in terms of objective response (OR) following this combination as primary end point and duration or response, progression-free survival, overall survival, and safety as secondary endpoints. Material and Methods: The study included patients between 18 and 75 years, with histologically proven untreated locally advanced inoperable stage IIIA/IIIB (supraclavicular lymph nodes and pleural effusion excluded) non-small cell lung cancer, adequate bone marrow, hepatic and renal function, Karnofsky performance status ≥80%. Patients were treated with oral vinorelbine 60 mg/m2 day 1,8 cycle 1 and 80 mg/m2 day 1,8 cycle 2 (if no grade 3-4 toxicity) and cisplatin 80 mg/m2 day 1 every 3 weeks for 2 cycles as induction. Patients without progression received oral vinorelbine 40 mg/m2 day 1, 8 and cisplatin 80 mg/m2 day 1 every 3 weeks for 2 more cycles with radiotherapy 66 Gy in 6.5 weeks. Results: Patient and disease characteristics (n = 54) included: median age 57 years; female sex 24%; stage IIIA 48% and IIIB 52%; Squamous carcinoma 59%, Karnofsky performance status 100% (range, 80-100%) 50%, patients ≥5% weight loss at baseline 7%. Relative dose intensities of oral vinorelbine/cisplatin were 86%/93% and 97%/98% at induction and in combination with radiotherapy, respectively. Forty-one patients (76%) increased oral vinorelbine from 60 to 80 mg/m2 day during induction (reasons for nonescalation: hematological 7 patients, nonhematological 2 patients, error 4 patients). After two cycles of chemotherapy induction, the OR intent-to-treat in the 54 patients was 37%. Toxicities during induction were as follows: Neutropenia G3-4 (28%), Febrile Neutropenia (7%), nausea G3 (11%), vomiting G3-4 (9%), anorexia G3 (4%), diarrhea G4 (2%), constipation G3 (2%). Forty-seven out of 54 (87%) patients received concomitant chemo-radiotherapy. Median radiotherapy delivered dose was 66 Gy. Tolerance: 9% G3 Neutropenia; 4% G3 dysphagia/radiation; 2% G3 radiation dermatitis. Late pulmonary fibrosis was reported in one patient (1.8%). One month after completion of chemo-radiotherapy, the overall OR intent-to-treat in the 54 patients was 54% (95% CI: 40-67%). With a median follow-up of 37 months (95% CI: 34-41) the median progression-free survival and overall survival were: 12.5 (95% CI: 9.6-16.4) and 23.4 (95% CI: 17.6-29.8) months, respectively. Conclusion: Oral vinorelbine in combination with cisplatin is an effective combination in stage IIIA/IIIB patients. The excellent tolerance profile allowed to complete concomitant chemo-radiotherapy in 87% of patients. Oral vinorelbine in combination with cisplatin is a new and promising option that facilitates the administration of concomitant chemo-radiotherapy with high rates of treatment completion.

MOPP chemotherapy versus extended-field radiotherapy in the management of pathological stages I-IIA Hodgkin's disease.

In order to assess whether mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy (CT), which is less expensive and more easily available than radiotherapy (RT), is at least as effective as RT in terms of cure rate and has less iatrogenic damage, 89 consecutive patients with Hodgkins disease (HD) (pathological stage I-IIA) were randomly allocated to receive mantle plus lumbar bar RT (36-45 Gy) or CT (six courses of MOPP). Forty-five patients were entered in the RT group and 44 in the CT group. The median follow-up was 60 months. Complete remission (CR) was obtained in all patients in the RT group and in 40 of 44 patients in the CT group. Overall survival (OS) and disease-free survival (DFS) were, respectively, 87.2% and 72.7% in the CT group and 93.5% and 74% in the RT group. Survival probability of relapsing patients was 76% for the patients in the RT group and 45% in the CT group. Treatment-related complications were more severe in the CT group as compared with the RT group.