Laura Cella

Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors

PURPOSE To assess the potential influence of improved dose distribution with proton beams compared to conventional or intensity-modulated (IM) X-ray beams on the incidence of treatment-induced secondary cancers in pediatric oncology. METHODS AND MATERIALS Two children, one with a parameningeal rhabdomyosarcoma (RMS) and a second with a medulloblastoma, were used as models for the purpose of this study. After defining the target and critical structures, treatment plans were calculated and optimized, four for the RMS case (conventional X-ray, IM X-rays, protons, and IM protons) and three for the irradiation of the spinal axis in medulloblastoma (conventional X-ray, IM X-rays, protons). Secondary cancer incidence was estimated using a model based on Publication No. 60 of the International Commission on Radiologic Protection. This model allowed estimation of absolute risks of secondary cancer for each treatment plan based on dose-volume distributions for the nontarget organs. RESULTS Proton beams reduced the expected incidence of radiation-induced secondary cancers for the RMS patient by a factor of >or=2 and for the medulloblastoma case by a factor of 8 to 15 when compared with either IM or conventional X-ray plans. CONCLUSIONS The potential for a significant reduction in secondary cancers with pediatric cancers after using proton beams (forward planned or IM) in the treatment of RMS and MBD in children and adolescents represents an additional argument supporting the development of proton therapy for most radiotherapy indications in pediatric oncology.

Optimizing radiotherapy of orbital and paraorbital tumors: intensity-modulated X-ray beams vs. intensity-modulated proton beams

PURPOSE This study presents a dosimetric optimization effort aiming to compare intensity-modulated (IM) X-rays and IM protons in 4 different orbital and paraorbital tumors. These are most challenging targets for standard radiotherapy due to their close relationship with the eyes and related structures. METHODS AND MATERIALS A primary orbital lymphoma, an optic nerve meningioma, a sphenoidal ridge meningioma protruding into the orbit, and a pediatric parameningeal paraorbital rhabdomyosarcoma were selected for the purpose of this study. Planning target volumes (PTVs) and organs at risk (OAR) were defined in each patient CT data set for each tumor site. IM X-ray and IM proton three-dimensional treatment plans were implemented. The following total tumor doses were prescribed: 30 Gy for the orbital lymphoma, 54 Gy for both meningiomas, and 50.4 Gy for the rhabdomyosarcoma case. Dose-volume histograms (DVHs) were obtained for all targets and OAR with both treatment techniques. DVHs were used to predict normal tissue complication probabilities (NTCPs) for the OAR in the vicinity of the tumor. RESULTS The PTV coverage was optimal and equally homogeneous with both IM X-rays and IM proton plans in the 4 tumor sites. DVHs for most OAR were better with IM proton beams especially in the low- to mid-dose range region. The integral nontarget dose was lower with IM protons in every case (factor ranging from 1.5 to 1.9). However, predicted NTCPs (for severe late effects) were equally low for both treatment techniques in every tumor site. CONCLUSION Although IM proton plans optimally decreased the dose to the OAR in all tumor sites, both optimized X-ray and proton beams equally succeeded to reduce severe-toxicity prediction risks to less than 5% while optimally treating the PTV.

Potential role of intensity modulated proton beams in prostate cancer radiotherapy

PURPOSE The present study was undertaken to assess the potential benefit of intensity modulated (IM) proton beams in optimizing the dose distribution to safely escalate the tumor dose in prostate cancer radiotherapy. METHODS AND MATERIALS Four treatment plans were compared in a prostate cancer patient aiming to deliver 81 Gy to the target: 1) conformal 18 MV X-rays, 6-fields; 2) 214 MeV protons, 2-fields; 3) IM 15 MV X-rays, 5-fields; and 4) 177-200 Mev IM protons, 5-fields as in Plan 3. In addition, IM methods were used to further escalate the tumor dose to 99 Gy. Dose-volume histograms (DVH) were used to physically compare the treatment plans. DVH data were also used to obtain normal tissue complication probabilities (NTCP) for the rectum, bladder, femoral heads, and tumor control probabilities. RESULTS Although the planning target volume dose distribution was satisfactory with the four treatment plans, the homogeneity was slightly reduced in both X-ray plans (IM and standard) and the low-to-medium doses delivered to all organs at risk, and other normal tissues were significantly reduced by both proton plans. For a prescribed dose of 81 Gy, only the IM X-ray and IM proton plans both succeeded in predicting an acceptably low NTCP for the rectum (<5%, Grade 3). The integral nontarget dose was significantly reduced with IM proton beams (i.e., 3.1, 1.3, and 1.7 times less than Plans 1, 2, and 3, respectively). When escalating the dose to 99 Gy, no additional improvement between IM protons and IM X-ray beams was observed. CONCLUSION Both IM X-ray and proton beams were able to optimize the dose distribution and comply with the goal of delivering the highest dose to the target while reducing the risk of severe morbidity to acceptable levels. The main advantage compared to IM X-rays was that IM protons succeeded in significantly reducing the low-to-medium dose to the nontarget tissues and achieved a small improvement in planning target volume (PTV) dose heterogeneity.

THYROID V30 PREDICTS RADIATION-INDUCED HYPOTHYROIDISM IN PATIENTS TREATED WITH SEQUENTIAL CHEMO-RADIOTHERAPY FOR HODGKIN'S LYMPHOMA

PURPOSE Hypothyroidism (HT) is a frequent late side effect of Hodgkins lymphoma (HL) therapy. The purpose of this study is to determine dose-volume constraints that correlate with functional impairment of the thyroid gland in HL patients treated with three-dimensional radiotherapy. METHODS AND MATERIALS A total of 61 consecutive patients undergoing antiblastic chemotherapy and involved field radiation treatment (median dose, 32 Gy; range, 30-36 Gy) for HL were retrospectively considered. Their median age was 28 years (range, 14-70 years). Blood levels of thyroid-stimulating hormone (TSH), free triiodo-thyronine (FT3), free thyroxine (FT4), and thyroglobulin antibody (ATG) were recorded basally and at different times after the end of therapy. For the thyroid gland, normal tissue complication probability (NTCP), dosimetric parameters, and the percentage of thyroid volume exceeding 10, 20, and 30 Gy (V10, V20, and V30) were calculated in all patients. To evaluate clinical and dosimetric factors possibly associated with HT, univariate and multivariate logistic regression analyses were performed. RESULTS Eight of 61 (13.1%) patients had HT before treatment and were excluded from further evaluation. At a median follow-up of 32 months (range, 6-99 months), 41.5% (22/53) of patients developed HT after treatment. Univariate analyses showed that all dosimetric factors were associated with HT (p < 0.05). On multivariate analysis, the thyroid V30 value was the single independent predictor associated with HT (p = 0.001). This parameter divided the patients into low- vs. high-risk groups: if V30 was ≤ 62.5%, the risk of developing HT was 11.5%, and if V30 was >62.5%, the risk was 70.8% (p < 0.0001). A Cox regression curve stratified by two levels of V30 value was created (odds ratio, 12.6). CONCLUSIONS The thyroid V30 predicts the risk of developing HT after sequential chemo-radiotherapy and defines a useful constraint to consider for more accurate HL treatment planning.

Radioresistance in head and neck squamous cell carcinoma: Biological bases and therapeutic implications.

Head and neck squamous cell carcinoma (HNSCC) is strongly associated with alcohol and tobacco consumption. Lately, the incidence of human papillomavirus (HPV)‐related tumors has shown a significant increase, and HPV‐related tumors show distinctive features if compared with the HPV‐negative counterpart. Locally advanced HNSCC can be treated with concomitant chemoradiotherapy, but early recurrences sometimes occur. Relapses are often related to an intrinsic radioresistance of the tumors. Alterations in intracellular pathways, primarily involved in cell proliferation, apoptosis, and DNA repair, can lead to radioresistance. Preclinical and clinical evidence highlighted that 3 main pathways, including the epidermal growth factor receptor (EGFR), the phosphotidylinositol‐3‐kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and the p53 signaling cascades, play a crucial role in radioresistance development. A future approach may consist in the association of radiotherapy (RT) and selective inhibition of the key pathways involved in radioresistance. Phase I, II, and III clinical trials are currently testing these novel treatment strategies.

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.

Dosimetric predictors of asymptomatic heart valvular dysfunction following mediastinal irradiation for Hodgkin’s lymphoma

PURPOSE To identify dose-heart-volume constraints that correlate with the risk of developing asymptomatic valvular defects (VD) in Hodgkins lymphoma (HL) patients treated with three-dimensional radiotherapy (RT). PATIENTS AND METHODS Fifty-six patients undergoing cytotoxic chemotherapy (CHT) and involved-field radiation treatment for HL were retrospectively analyzed. Electro-echocardiography was performed before CHT, after CHT, and after RT. For the entire heart, for right and left ventricle (RV, LV), right and left atrium (RA, LA) percentage of volume exceeding 5-30Gy in increment of 5Gy (V(x)), and dosimetric parameters were calculated using 1.6Gy fraction as reference. To evaluate clinical and dosimetric factors possibly associated with VD, univariate and multivariate logistic regression analyses were performed. RESULTS At a median follow up of 70.5 months, 32.1% of patients developed VD (regurgitation and/or stenosis): 25.0% developed mitral, 5.4% developed aortic, and 14.3% tricuspid VD. In particular the percentage of LA exceeding 25Gy (LA-V(25)) and the percentage of LV exceeding 30Gy (LV-V(30)) correlated with mitral and aortic VD with an odds ratio (OR) of 5.7 (LA-V(25)>63.0% vs. LA-V(25)≤63.0%) and OR of 4.4 (LV-V(30)>25% vs. LV-V(30)≤25%), respectively. RV-V(30) correlated with tricuspid VD (OR=7.2, RV-V(30)>65% vs. RV-V(30)≤65%). CONCLUSION LA-V(25), LV- and RV-V(30) prove to be predictors of asymptomatic alteration of valve functionality.

Radiation therapy in primary orbital lymphoma: a single institution retrospective analysis

BackgroundPrimary orbital lymphoma is a rare disease that accounts for 10% of all orbital tumors. Radiotherapy on the orbital cavity is the treatment of choice for this unusual presentation of localized non-Hodgkins lymphoma (NHL). The aim of this study is to retrospectively evaluate the effectiveness and the toxicity of radiation treatment in patients with primary orbital lymphoma.MethodsForty-seven consecutive patients having primary orbital lymphoma treated in our department between May 1983 and September 2006 were investigated in a retrospective study. Either 60Co γ rays or 6 MV X rays were used to deliver daily fractions of 1.8 or 2.0 Gy, 5 times/week, with total doses ranging from 34.2 to 50 Gy. Forty-three patients had stage IE, three had stage II and one stage IV disease. Thirty-eight patients had marginal zone B-cell lymphoma, 5 diffuse large B cell lymphoma, 3 mantle cell lymphoma and 1 Burkitt lymphoma. Local control (LC), disease free survival (DFS), overall survival (OS) and late side effects were evaluated in all patients.ResultsWith a median follow up of 45 months, LC was obtained in 100% of patients. The estimated 5- and 7-year DFS rates were 75.8% and 55.3%, and the 5- and 7-year OS rates were 88.7% and 79.9% respectively. Acute toxicity was minimal. Late toxicity such as cataract, keratitis, retinopathy and xerophthalmia occurred respectively in 12 (25.5%), 5 (10.6%), 1 (2.1%), and 9 (19.1%) patients.ConclusionRadiotherapy is an effective and at the same time well tolerated treatment for primary orbital lymphoma.

Radiotherapy of large target volumes in Hodgkin's lymphoma: normal tissue sparing capability of forward IMRT versus conventional techniques

BackgroundThis paper analyses normal tissue sparing capability of radiation treatment techniques in Hodgkins lymphoma with large treatment volume.Methods10 patients with supradiaphragmatic Hodgkins lymphoma and planning target volume (PTV) larger than 900 cm3 were evaluated. Two plans were simulated for each patient using 6 MV X-rays: a conventional multi-leaf (MLC) parallel-opposed (AP-PA) plan, and the same plan with additional MLC shaped segments (forward planned intensity modulated radiation therapy, FPIMRT). In order to compare plans, dose-volume histograms (DVHs) of PTV, lungs, heart, spinal cord, breast, and thyroid were analyzed. The Inhomogeneity Coefficient (IC), the PTV receiving 95% of the prescription dose (V95), the normal tissue complication probability (NTCP) and dose-volume parameters for the OARs were determined.Resultsthe PTV coverage was improved (mean V95AP-PA = 95.9 and ICAP-PA = 0.4 vs. V95FPIMRT = 96.8 and ICFPIMRT = 0.31, p ≤ 0.05) by the FPIMRT technique compared to the conventional one. At the same time, NTCPs of lung, spinal cord and thyroid, and the volume of lung and thyroid receiving ≥ 30 Gy resulted significantly reduced when using the FPIMRT technique.ConclusionsThe FPIMRT technique can represent a very useful and, at the same time, simple method for improving PTV conformity while saving critical organs when large fields are needed as in Hodgkins lymphoma.

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.