Vittorio Donato

MACOP-B and involved field radiation therapy is an effective therapy for primary mediastinal large B-cell lymphoma with sclerosis

PURPOSE To evaluate the clinical features of presentation and the response to two different third-generation regimens (F-MACHOP and MACOP-B) of primary mediastinal large B-cell lymphoma (MLBCL), a recently defined distinct clinicopathological entity of non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS Thirty-seven consecutive patients with MLBCL, eight male and 29 female (F/M ratio 1:3.5) with a median age of 35 years, were enrolled in the present study. Thirty-five (94.5%) patients presented disease confined to thorax, with chest symptoms of a rapidly enlarging mass in the mediastinum in 70% and superior vena cava syndrome (SCVS) in 43% of these patients. The first 10 patients received F-MACHOP and the succeeding 27 patients MACOP-B chemotherapy, associated in 24 (88.8%) with involved field radiation therapy (IFRT). 67Gallium scan was routinely performed pre- and post-IFRT in 18 patients. RESULTS All 37 patients were assessable for response: 10 of 10 (100%) in the F-MACHOP and 26 of 27 (96.3%) in the MACOP-B group achieved overall responses (CR + PR). Three of 24 (12.5%) patients in PR after chemotherapy obtained CR after IFRT. Persistent Gallium avidity was observed in 16 patients after chemotherapy and in only four patients after IFRT. Thus far, four of the 10 F-MACHOP and two of the 26 MACOP-B responders have presented disease progression. The probability of progression-free survival (PFS) was 91% and 60% (P < 0.02) while overall survival (OS) was 93% and 70% (P = n.s.) at a mean follow-up of 27 and 52 months in the MACOP-B + IFRT and F-MACHOP groups, respectively. CONCLUSION MACOP-B + IFRT has proved to be a highly effective and less toxic therapeutic approach for primary MLBCL and appears to be superior to other third-generation chemotherapy regimens.

PROGNOSTIC IMPLICATION OF CLINICAL AND PATHOLOGIC FEATURES IN PATIENTS WITH GLIOBLASTOMA MULTIFORME TREATED WITH CONCOMITANT RADIATION PLUS TEMOZOLOMIDE

Aims and background Glioblastoma multiforme is the most common and most malignant primary brain tumor in adults. The current standard of care for glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy plus temozolomide, given concomitantly with and after radiotherapy. This report is a prospective observational study of 43 cases treated in the Department of Radiotherapy, University of Rome La Sapienza, Italy. We examine the relationship between pathologic features and objective response rate in adult patients treated with concomitant radiation plus temozolomide to identify clinical, neuroradiologic, pathologic, and molecular factors with prognostic significance. Methods Forty-three consecutive patients (24 males and 19 females), ages 15-77 years (median, 57) with newly diagnosed glioblastoma multiforme, were included in this trial between 2002 and 2004 at our department. All patients were treated with surgery (complete resection in 81%, incomplete in 19%) followed by concurrent temozolomide (75 mg/m2/day) and radiotherapy (median tumor dose, 60 Gy), followed by temozolomide, 200 mg/m2/day for 5 consecutive days every 28 days. Neurologic evaluations were performed monthly and cranial magnetic resonance bimonthly. We analyzed age, clinical manifestations at diagnosis, seizures, Karnofsky performance score, tumor location, extent of resection, proliferation index (Ki-67 expression), p53, platelet-derived growth factor and epidermal growth factor receptor immunohistochemical expression as prognostic factors in the patients. The Kaplan-Meier statistical method and logrank test were used to assess correlation with survival. Results Fourteen patients (32%) manifested clinical and neuroradiographic evidence of tumor progression within 6 months of surgery. In contrast, 5 patients (12%) showed no disease progression for 18 months from the beginning of treatment. Median overall survival was 19 months. Multivariate analysis revealed that an age of 60 years or older (P <0.03), a postoperative performance score ≤70 (P = 0.04), the nontotal tumor resection (P = 0.03), tumor size >4 cm (P = 0.01) and proliferation index overexpression (P = 0.001) were associated with the worst prognosis. p53, PDGF and EGFR overexpression were not significant prognostic factors associated with survival. Conclusions The results suggest that analysis of prognostic markers in glioblastoma multiforme is complex. In addition to previously recognized prognostic variables such as age and Karnofsky performance score, tumor size, total resection and proliferation index overexpression were identified as predictors of survival in a series of patients with glioblastoma multiforme.

Hodgkin’s lymphoma emerging radiation treatment techniques: trade-offs between late radio-induced toxicities and secondary malignant neoplasms

BackgroundPurpose of this study is to explore the trade-offs between radio-induced toxicities and second malignant neoplasm (SMN) induction risk of different emerging radiotherapy techniques for Hodgkin’s lymphoma (HL) through a comprehensive dosimetric analysis on a representative clinical model.MethodsThree different planning target volume (PTVi) scenarios of a female patient with supradiaphragmatic HL were used as models for the purpose of this study. Five treatment radiation techniques were simulated: an anterior-posterior parallel-opposed (AP-PA), a forward intensity modulated (FIMRT), an inverse intensity modulated (IMRT), a Tomotherapy (TOMO), a proton (PRO) technique. A radiation dose of 30 Gy or CGE was prescribed. Dose-volume histograms of PTVs and organs-at-risk (OARs) were calculated and related to available dose-volume constraints. SMN risk for breasts, thyroid, and lungs was estimated through the Organ Equivalent Dose model considering cell repopulation and inhomogeneous organ doses.ResultsWith similar level of PTVi coverage, IMRT, TOMO and PRO plans generally reduced the OARs’ dose and accordingly the related radio-induced toxicities. However, only TOMO and PRO plans were compliant with all constraints in all scenarios. For the IMRT and TOMO plans an increased risk of development of breast, and lung SMN compared with AP-PA and FIMRT techniques was estimated. Only PRO plans seemed to reduce the risk of predicted SMN compared with AP-PA technique.ConclusionsOur model–based study supports the use of advanced RT techniques to successfully spare OARs and to reduce the risk of radio-induced toxicities in HL patients. However, the estimated increase of SMNs’ risk inherent to TOMO and IMRT techniques should be carefully considered in the evaluation of a risk-adapted therapeutic strategy.

Short course radiation therapy for elderly cancer patients.: Evidences from the literature review

The choice of the appropriate treatment strategy for elderly cancer patients may be a difficult challenge. Radiation therapy is commonly offered to these patients, but treatment duration may represent a limiting factor, as many patients cannot tolerate a conventional course of radiotherapy (RT) due to age-related medical or logistic problems. Hypofractionated RT may represent a very convenient choice, but it entails an increased risk of late toxicity occurrence. We made a literature review to define the possible role of hypofractionated RT for elderly cancer patients. As expected, we found out that short irradiation schedules are more commonly employed for treatments with palliative aims but a more widespread use of these regimes is still controversial. The lack of prospective trials tailored for these patients makes even more difficult to tailor the choice of treatment on standardised treatment guidelines. Nevertheless our review highlights that for several tumour types RT can be scheduled conveniently and effectively in order to achieve local disease control and/or symptom relief with the least discomfort and treatment-related morbidity for elderly patients.

Modeling the risk of radiation-induced lung fibrosis: Irradiated heart tissue is as important as irradiated lung

PURPOSE We used normal tissue complication probability (NTCP) modeling to explore the impact of heart irradiation on radiation-induced lung fibrosis (RILF). MATERIALS AND METHODS We retrospectively reviewed for RILF 148 consecutive Hodgkin lymphoma (HL) patients treated with sequential chemo-radiotherapy (CHT-RT). Left, right, total lung and heart dose-volume and dose-mass parameters along with clinical, disease and treatment-related characteristics were analyzed. NTCP modeling by multivariate logistic regression analysis using bootstrapping was performed. Models were evaluated by Spearman Rs coefficient and ROC area. RESULTS At a median time of 13months, 18 out of 115 analyzable patients (15.6%) developed RILF after treatment. A three-variable predictive model resulted to be optimal for RILF. The two models most frequently selected by bootstrap included increasing age and mass of heart receiving >30Gy as common predictors, in combination with left lung V5 (Rs=0.35, AUC=0.78), or alternatively, the lungs near maximum dose D2% (Rs=0.38, AUC=0.80). CONCLUSION CHT-RT may cause lung injury in a small, but significant fraction of HL patients. Our results suggest that aging along with both heart and lung irradiation plays a fundamental role in the risk of developing RILF.

Concomitant radiotherapy with protracted 5-fluorouracil infusion in locally advanced carcinoma of the pancreas: a phase II study.

Aims and Background To evaluate the efficacy of combined radiation therapy and continuous infusion of 5-fluorouracil in patients with locally advanced carcinoma of the pancreas. Methods Between January 1992 and June 1999, 31 patients with locally advanced adenocarcinoma of the pancreas were treated in our Institute. In 20 patients, the tumor (65%) was located in the head of the pancreas and in 11 (35%) in the body or tail; 13 cases also showed involved nodes. Radiation therapy consisted in a median dose of 63 Gy in 33-36 fractions applied to the tumor and regional lymph nodes. Chemotherapy with 5-fluorouracil in continuous infusion, 250 mg/m2 daily, was administered in the first and fifth week of the radiation therapy. Thereafter, 22 patients received 3-10 cycles of adjuvant chemotherapy with same doses. Median follow-up of the series was 20 months. The toxicity of the treatment was scored according to WHO criteria. All patients underwent nutritional assessment at the time of radiochemotherapy. Results The median overall survival was 15.2 months (range, 4-42). At restaging, 17 cases (55%) showed no change and 14 (45%) a partial remission. At the end of radiochemotherapy in 8 (26%) of the cases there was indication for pancreatectomy, which was executed in 4 patients. At the time of the study, 2 patients (6.4%) were surgically proven disease free. Eleven of the 13 cases (85%) presenting involved nodes showed that the enlarged lymph nodes had disappeared. Nineteen patients (61%) are alive with clinical evidence of disease and 2 cases are alive with liver metastases; 8 patients (26%) died for disease. In 74% of cases there was complete pain control. Tolerance to the regimen was good. Nutritional assistance was evaluated and was found to be correlated to survival. Conclusions The results of the series confirm a good tolerance with low acute toxicity. Tumor down-staging and resectability rates were high, together with prolonged survival and a good quality of life.

Patterns of CT lung injury and toxicity after stereotactic radiotherapy delivered with helical tomotherapy in early stage medically inoperable NSCLC

OBJECTIVE To evaluate toxicity and patterns of radiologic lung injury on CT images after hypofractionated image-guided stereotactic body radiotherapy (SBRT) delivered with helical tomotherapy (HT) in medically early stage inoperable non-small-cell lung cancer (NSCLC). METHODS 28 elderly patients (31 lesions) with compromised pulmonary reserve were deemed inoperable and enrolled to undergo SBRT. Patterns of lung injury based on CT appearance were assessed at baseline and during follow up. Acute (6 months or less) and late (more than 6 months) events were classified as radiation pneumonitis and radiation fibrosis (RF), respectively. RESULTS After a median follow-up of 12 months (range, 4-20 months), 31 and 25 lesions were examined for acute and late injuries, respectively. Among the former group, 25 (80.6%) patients showed no radiological changes. The CT appearance of RF revealed modified conventional, mass-like and scar-like patterns in three, four and three lesions, respectively. No evidence of late lung injury was demonstrated in 15 lesions. Five patients developed clinical pneumonitis (four patients, grade 2 and one patient, grade 3, respectively), and none of whom had CT findings at 3 months post-treatment. No instance of symptomatic RF was detected. The tumour response rate was 84% (complete response + partial response). Local control was 83% at 1 year. CONCLUSION Our findings show that HT-SBRT can be considered an effective treatment with a mild toxicity profile in medically inoperable patients with early stage NSCLC. No specific pattern of lung injury was demonstrated. ADVANCES IN KNOWLEDGE Our study is among the few showing that HT-SBRT represents a safe and effective option in patients with early stage medically inoperable NSCLC, and that it is not associated with a specific pattern of lung injury.

Moderately Escalated Hypofractionated (Chemo) Radiotherapy Delivered with Helical Intensity-Modulated Technique in Stage III Unresectable Non-Small Cell Lung Cancer.

Purpose: To assess clinical outcomes and toxicities in patients with stage III unresectable non-small cell lung cancer (NSCLC) treated with a moderately escalated hypofractionated radiotherapy delivered with Helical Intensity-Modulated Technique in combination with sequential or concurrent chemotherapy. Materials and Methods: Sixty-one consecutive patients considered non-progressive after two cycles of induction chemotherapy were treated with a moderately escalated hypofractionated radiation course of 30 daily fractions of 2.25–2.28 Gy each administered in 6 weeks up to a total dose of 67.5–68.4 Gy (range, 64.5–71.3 Gy). Thirty-two received sequential RT after two more cycles (total = 4 cycles) of chemotherapy, while 29 were treated with concurrent chemo-radiation. The target was considered the gross tumor volume and the clinically proven nodal regions, without elective nodal irradiation. Results: With a median follow up of 27 months (range 6–40), 1-year and 2-year OS rate for all patients was 77 and 53%, respectively, with a median survival duration of 18.6 months in the sequential group and 24.1 months in the concomitant group. No Grade ≥4 acute and late toxicity was reported. Acute Grade 3 treatment-related pneumonitis was detected in 10% of patients. Two patients, both receiving the concurrent schedule, developed a Grade 3 acute esophagitis. The overall incidence of late Grade 3 lung toxicity was 5%. No patients experienced a Grade 3 late esophageal toxicity. Conclusion: A moderately hypofractionated radiation course delivered with a Helical Intensity-Modulated Technique is a feasible treatment option for patients with unresectable locally advanced NSCLC receiving chemotherapy (sequentially or concurrently). Hypofractionated radiotherapy with a dedicated technique allows safely dose escalation, minimizing the effect of tumor repopulation that may occur with prolonged treatment time.

Fractionated total body irradiation in allogeneic bone marrow transplantation in leukemia patients: analysis of prognostic factors and results in 136 patients

BACKGROUND AND PURPOSE The results of a single-institution series of patients with chronic and acute leukemias are analyzed with regard to literature-reported predictor variables. MATERIALS AND METHODS Between 1985 and 1994, 136 patients, 82 patients with chronic myeloid leukemia (CML) and 54 with acute leukemia (AL), received a uniform preparatory regimen of fractionated total body irradiation (TBI; 12 Gy in 3 days) plus different chemotherapy regimens before bone marrow transplantation. Eighty-six patients were considered to be in early phase of disease (CML in chronic phase or AL in first complete remission) and 50 in advanced phase (all those beyond first remission or first chronic phase). Ninety-five patients received unmanipulated allogeneic BM, and 41 T-lymphocyte-depleted BM. RESULTS The 5-year overall survival (OS) and disease-free survival (DFS) of the whole series were 43% and 31%, and median survival was 43 and 10 months, respectively. A Cox proportional hazard model identified variables related to overall and disease-free survival. For OS, graft versus host disease (GVHD) was the first independent variable (P < 0.0001), followed by age (P < 0.001), T-depletion (P < 0.01), disease status (P < 0.05) and type of leukemia (P < 0.05). With regard to DFS, only T-depletion (P < 0.0001), disease status (P < 0.01) and GVHD (P < 0.01) resulted predictor factors. Early complications after BMT were reported in 59 patients, TBI-induced delayed toxicity in 9 patients, and 16 patients suffered late complications. CONCLUSIONS Our results confirm the curability of early phase leukemias with standard fractionated TBI-induced Allogeneic bone marrow transplantation (ABMT). With an homogeneous fractionated TBI schedule as employed in our series, T-cell depletion negatively affected the outcome.

Stereotactic body radiation therapy salvage reirradiation of radiorecurrent prostatic carcinoma relapsed in the prostatic bed

A 67-year-old man presented with a slow increase of prostate-specific antigen value after radical prostatectomy and postoperative radiotherapy for prostate cancer. The patient had received 3D conformal radiotherapy to a total dose of 66 Gy in 33 fractions of 2 Gy each on the prostatic bed. Three years later, a macroscopic local failure was diagnosed at the apical region. The patient could not receive androgenic deprivation therapy or other types of treatment owing to comorbid conditions. Thus, stereotactic body radiation therapy with helical image-guided tomotherapy was administered. The total dose was 30 Gy in 5 consecutive fractions of 6 Gy each to the site of the local failure. The treatment was preceded by a transperineal-guided injection of a self-absorbable hydrogel into the prostatic bed, between rectum and bladder, in order to preserve the rectal wall, which already had received significant doses from the first radiation course. Radiation therapy was well-tolerated. After a follow-up period of 6 months, the patient remains healthy, and there has been no further evidence of metastatic spread or recurrence.