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Introduction. Transarterial chemoembolization is the first-line treatment in unresectable hepatocellular carcinoma. There is no standard treatment after transarterial chemoembolization failure. We report the case of a patient with advanced hepatocellular carcinoma who showed a complete response and a long cancer control with hypofractionated stereotactic radiotherapy after transarterial chemoembolization failure. Case Presentation. A 70-year-old Caucasian woman was treated with transarterial chemoembolization for advanced hepatocellular, but no cancer control was obtained. A hypofractionated stereotactic radiotherapy was planned delivering 40 Gy in 5 fractions. A dramatic reduction in alpha-fetoprotein was observed. Contrast-enhanced ultrasonography at 1 and 2 months showed large necrotic areas. Computerised tomography scan showed a 90% objective tumour response, then a complete remission at 3 and 6 months after treatment, respectively. Status of patient remained unchanged for 2 years. Conclusions. Hypofractionated stereotactic radiotherapy can improve survival and prognosis of unresectable hepatocellular carcinoma patient.

To select among breast cancer patients and according to breast volume size those who may benefit from 3D conformal radiotherapy after conservative surgery applied with prone-position technique. Thirty-eight patients with early-stage breast cancer were grouped according to the target volume (TV) measured in the supine position: small (≤400 mL), medium (400-700 mL), and large (≥700 ml). An ad-hoc designed and built device was used for prone set-up to displace the contralateral breast away from the tangential field borders. All patients underwent treatment planning computed tomography in both the supine and prone positions. Dosimetric data to explore dose distribution and volume of normal tissue irradiated were calculated for each patient in both positions. Homogeneity index, hot spot areas, the maximum dose, and the lung constraints were significantly reduced in the prone position (p < 0.05). The maximum heart distance and the V(5Gy) did not vary consistently in the 2 positions (p = 0.06 and p = 0.7, respectively). The number of necessary monitor units was significantly higher in the supine position (312 vs. 232, p < 0.0001). The subgroups analysis pointed out the advantage in lung sparing in all TV groups (small, medium and large) for all the evaluated dosimetric constraints (central lung distance, maximum lung distance, and V(5Gy), p < 0.0001). In the small TV group, a dose reduction in nontarget areas of 22% in the prone position was detected (p = 0.056); in the medium and high TV groups, the difference was of about -10% (p = NS). The decrease in hot spot areas in nontarget tissues was 73%, 47%, and 80% for small, medium, and large TVs in the prone position, respectively. Although prone breast radiotherapy is normally proposed in patients with breasts of large dimensions, this study gives evidence of dosimetric benefit in all patient subgroups irrespective of breast volume size., (Copyright © 2012. Published by Elsevier Inc.)

Purpose: To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors., Patients and Methods: Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18-24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20-30 Gy. The median follow-up was 12 months (range, 1-48)., Results: The overall 3-year actuarial local progression-free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a high single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008)., Conclusion: High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: To assess the pattern of failures in patients with FIGO stage IIIc(1)-IIIc(2) endometrial cancer., Patients and Methods: Data were retrospectively analyzed for 34 patients with this malignancy who underwent extra-fascial total hysterectomy, bilateral salpingo-oophorectomy and pelvic/para-aortic node dissection. Postoperative treatment consisted of radiotherapy in 5 patients, 6 cycles of chemotherapy in 9, and 3-4 cycles of chemotherapy followed by radiotherapy in 20. The median follow-up of survivors was 33 months (range, 6 to 133 months)., Results: Tumour relapsed in 14 out of 34 patients (41.2%). Median time to recurrence was 17 months (range, 9.5-42 months). Vaginal recurrence developed in 2 patients (5.9%), distant recurrence in 5 (14.7%), pelvic node recurrence in 3 (8.8%) and para-aortic recurrence in 7 (20.6%). Two patients had multiple sites of recurrence. Distant failure occurred in 11.1% of the patients who received 6 cycles of chemotherapy versus 20.0% of those who had 3-4 cycles of chemotherapy followed by radiotherapy. Five-year overall survival was 60.5%, and, in particular, it was 62.5% for stage IIIc(1) and 57.0% for stage IIIc(2)., Conclusion: FIGO stage IIIc(1)-IIIc(2) endometrial cancer relapses in approximately 40% of cases, and distant sites and para-aortic nodes represent the most common sites of failure.

Aim: To assess the relationship between the timing of radiotherapy and the risk of local failure in patients with endometrioid-type endometrial cancer who had undergone surgery and adjuvant external pelvic radiotherapy (with or without brachytherapy), but not chemotherapy., Patients and Methods: One hundred and seventy seven patients were analyzed in this study. The median follow-up of the survivors was 72 months., Results: Radiotherapy was delivered after a median time of 14.6 weeks from surgery and the median overall treatment time was 6.4 weeks. The tumor relapsed in 32 (18.1%) patients after a median time of 21 months. The local recurrence (vaginal or central pelvic) occurred in 11 patients. The local recurrence rate was associated with tumor grade (p=0.02), myometrial invasion (p=0.046), FIGO stage (p=0.003), pathological node status (p=0.037) and time interval from surgery to radiotherapy using 9 weeks as the cut-off value (p=0.046), but not with the overall treatment time. All the local relapses occurred in patients who received adjuvant irradiation after an interval from surgery >9 weeks., Conclusion: The time interval from surgery to radiotherapy might affect the local recurrence rate in patients not receiving chemotherapy. Every possible effort should be made to start radiotherapy within 9 weeks, when radiotherapy only is deemed necessary as adjuvant treatment.

Unlabelled: The aim of this study was to assess the pattern of failure and the outcome of endometrial cancer patients and to analyze the variables predictive of the risk of local, distant and retroperitoneal lymph node disease recurrence., Patients and Methods: The authors assessed 511 patients who underwent primary surgery. The median follow-up of survivors was 74 months. Peritoneal, hematogenous and lymph node recurrences outside retroperitoneal area were considered as distant failures., Results: Tumor relapsed in 83 (16.2%) patients. Median time to recurrence was 18.5 months (range, 3-129 months). The relapse was local in 13 cases, distant in 37, retroperitoneal in 22, and involved both distant and other sites in 11. Logistic regression showed that cervical involvement was the only independent predictor of local recurrence. Tumor grade, lymph-vascular space involvement (LVSI) and myometrial invasion were independent predictors of distant failure. Lymph node status and tumor grade were independent predictors of retroperitoneal recurrence. Five- and 10-year overall survival rates were 87.1% and 79.5%, respectively. Patient age, lymph node status, cervical involvement, tumor grade, LVSI and myometrial invasion were independent prognostic variables for overall survival., Conclusion: Cervical involvement was an independent predictor of local recurrence, LVSI and myometrial invasion were independent predictors of distant failure, lymph node status was an independent predictor of retroperitoneal relapse, and tumor grade was an independent predictor of both distant and retroperitoneal recurrence. The identification of risk factors for different patterns of failure can be useful in better tailoring adjuvant treatment.

Extra-fascial total hysterectomy and bilateral salpingo-oophorectomy with or without lymph node dissection is the initial treatment for endometrial cancer. Unresolved scientific controversy exists regarding the selection of patients who may benefit from lymphadenectomy, the magnitude of such benefit, and the role of adjuvant therapy. External pelvic irradiation has been shown to reduce loco-regional recurrences without improving survival. Meta-analyses of randomized trials indicate that external pelvic irradiation offers a significant benefit in terms of survival only in high-risk disease (i.e. stage Ic grade 3). Intermediate risk patients (i.e. stage Ib grade 3 disease), therefore, may be treated with adjuvant intravaginal brachytherapy alone to avoid the risk of side effects associated with pelvic irradiation. Overall, patients with clinically early endometrial cancer develop relapses in less than 20% of cases, mostly at distant sites. Randomized trials comparing adjuvant external pelvic irradiation versus adjuvant chemotherapy have shown conflicting clinical results. Chemotherapy seems to prevent or delay distant spread more than radiotherapy, while radiotherapy appears to prevent or delay local relapses more than chemotherapy, although these trends fail to achieve statistical significance. Recent evidence from a randomized trial indicates that sequential external pelvic irradiation with or without brachytherapy and platinum-based chemotherapy result in significantly better progression-free survival than radiotherapy alone in patients with high-risk endometrial cancer. Reliable surgical/pathological variables predictive of high risk of distant failure may be used to identify a subset of patients suitable for randomized trials of adjuvant chemotherapy with or without external irradiation., (2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To report tumor local control after treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) to extracranial metastatic sites., Methods and Materials: A total of 126 metastases in 103 patients were treated with SD-IGRT to prescription doses of 18-24 Gy (median, 24 Gy) between 2004 and 2007., Results: The overall actuarial local relapse-free survival (LRFS) rate was 64% at a median follow-up of 18 months (range, 2-45 months). The median time to failure was 9.6 months (range, 1-23 months). On univariate analysis, LRFS was significantly correlated with prescription dose (p = 0.029). Stratification by dose into high (23 to 24 Gy), intermediate (21 to 22 Gy), and low (18 to 20 Gy) dose levels revealed highly significant differences in LRFS between high (82%) and low doses (25%) (p < 0.0001). Overall, histology had no significant effect on LRFS (p = 0.16). Renal cell histology displayed a profound dose-response effect, with 80% LRFS at the high dose level (23 to 24 Gy) vs. 37% with low doses (≤22 Gy) (p = 0.04). However, for patients who received the high dose level, histology was not a statistically significant predictor of LRFS (p = 0.90). Target organ (bone vs. lymph node vs. soft tissues) (p = 0.5) and planning target volume size (p = 0.55) were not found to be associated with long-term LRFS probability. Multivariate Cox regression analysis confirmed prescription dose to be a significant predictor of LRFS (p = 0.003)., Conclusion: High-dose SD-IGRT is a noninvasive procedure resulting in high probability of local tumor control. Single-dose IGRT may be effectively used to locally control metastatic deposits regardless of histology and target organ, provided sufficiently high doses (> 22 Gy) of radiation are delivered., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: To assess the predictive and prognostic values of pretreatment platelet and hemoglobin levels in patients with locally advanced cervical cancer who underwent neoadjuvant chemotherapy followed by radical hysterectomy., Methods: The authors retrospectively assessed 140 patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB2-IIB cervical cancer who underwent chemosurgical treatment., Results: Median pretreatment platelet and hemoglobin levels were 272,000/μL and 12.5 g/dL, respectively. Fourteen patients achieved a pathologically complete response, and 26 had an optimal partial response, with an optimal pathological response rate of 28.6%. By univariate analysis, optimal pathological response rate was associated with well/moderately differentiated grade (P = 0.02) and platinum-/paclitaxel-based chemotherapy regimen (P = 0.04), but not with platelet and hemoglobin levels. Multiple logistic regression confirmed that tumor grade (odds ratio, 2.827; 95% confidence interval [95% CI], 1.250-6.397; P = 0.01) and chemotherapy regimen (odds ratio, 5.416; 95% CI, 1.459-20.110; P = 0.01) were independent predictors of optimal pathological response. Five-year recurrence-free survival and 5-year overall survival were 66 % and 73%, respectively. By log-rank test, recurrence-free survival and overall survival were associated with pathological response (P = 0.0002 and P = 0.001), lymph node status, (P = 0.008 and P = 0.002), lymphovascular space status (P = 0.005 and P = 0.003), and parametrial and/or surgical margin status (P = 0.004 and P = 0.001), but not with platelet and hemoglobin levels. On multivariate analysis, pathological response (hazard ratio [HR], 7.999; 95% CI, 1.916-33.394; and HR, 6.007; 95% CI, 1.426-25.307) and parametrial and/or surgical margin status (HR, 2.061; 95%CI, 1.047-4.058; and HR, 2.561; 95% CI, 1.244-5.271) were independent prognostic variables of recurrence-free survival and overall survival., Conclusions: The achievement of an optimal pathological response is the strongest independent prognostic variable for patients with cervical cancer treated with neoadjuvant chemotherapy and radical hysterectomy, whereas pretreatment platelet and hemoglobin levels seem to be neither predictive of response to chemotherapy nor prognostic of long-term outcome.

The aim of this study is to propose and validate an original new class of solutions for three-dimensional conformal radiation therapy (3DCRT) treatment planning for non-small cell lung cancer (NSCLC) according to the different patterns of disease presentation (on the basis of tumor location and volume) and to explore beams arrangement (planar or no-planar solutions) to respect dose constraints to the lung parenchyma. Benchmarks matched to validate the new approach are interuser reproducibility and saving on planning time. Tumor location was explored and specific categories created according to the tumor volume and location. Therefore, by applying planar and no-planar 3D plans, we searched for an optimization of the beams arrangement for each category. Dose-volume histograms (DVHs) were analyzed and a plan comparison performed. Results were then validated (class solution planning confirmation) by applying the same strategy to another group of patients. This has been realized at two dose levels (50.4 and 59.4 Gy). Fifty-nine patients were enrolled in this dosimetric study. In the first 27 patients ("exploratory sample") three main planning target volume location categories were identified according to the pattern of the disease presentation: (1) centrally located; (2) peripheral T and mediastinal N (P+N); and (3) superior sulcus. Original class solutions were proposed for each location category. On the next 32 patients ("validation sample"), the treatment planning started directly with the recommended approach. Mean V(20 Gy) value was 18.8% (SD +/- 7.25); mean V(30 Gy):12% (SD +/- 4.05); and mean lung dose: 11.6 Gy (SD +/- 5.77). No differences between the two total dose level groups were observed. These results suggest a simple and reproducible tool for treatment planning in NSCLC, allowing interuser reproducibility and cutting down on planning time., (2010 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Aim: To review a tailored treatment with concurrent chemoradiotherapy (CT/RT) or neoadjuvant chemotherapy (NACT) followed by radical hysterectomy in locally advanced cervical cancer., Patients and Methods: One hundred and four patients were treated with a tailored therapeutic approach. CT/RT was the standard treatment for patients with stage Ib2-IIb disease aged more than 70 years, or with high surgical risk, as well as for those with stage III-IV disease. NACT followed by radical hysterectomy was the treatment of choice for patients with stage Ib(2)-IIb disease, maximum age of 70 years and good performance status., Results: For the 61 women who underwent CT/RT, 5-year disease-free (DFS) survival and 5-year overall survival (OS) were 62% and 71%, respectively. Patient outcome was associated with the clinical response to CT/RT (complete responders versus others: 5-year DFS, 81% versus 19%, p<0.001; 5-year OS, 84% versus 37%, p=0.001). For the 43 women who underwent NACT, 5-year DFS and 5-year OS were 66% and 75%, respectively. Patient outcome was associated with the pathological response to chemotherapy (optimal responders versus others: 5-year DFS, 89% versus 62%, p=0.03; 5-year OS, 90% versus 72%, p=0.05)., Conclusion: Tailored treatments obtained satisfactory clinical outcomes in locally advanced cervical cancer. Optimal pathological response to NACT has been found to be a surrogate endpoint of OS. The identification of biological variables able to predict response to NACT is strongly warranted for an accurate selection of patients who may really benefit from chemosurgical treatment.

Introduction: We report the results of a phase II trial exploring the efficacy and the feasibility of combination of gemcitabine and cisplatin concurrent with radiotherapy followed by surgery in patients with stage III non-small cell lung cancer., Methods: Patients with histocytologically confirmed non-small cell lung cancer were treated with cisplatin 80 mg/sqm/wk of 1 and 4 or 20 mg/sqm/d of weeks 1 and 4 and weekly gemcitabine at 300 to 350 mg/m2 plus involved field radiotherapy. A 3D-conformal radiotherapy was delivered up to 50.4 Gy, with daily fractionation of 1.8 Gy. After clinical, radiologic, and pneumological reassessment, patients who reentered criteria for resectability were operated., Results: The stage at diagnosis was IIIA-N2 in 29 patients and IIIB-T4N0-2 for vascular direct infiltration for the remaining 21. Fifteen patients (30%) experienced acute grade 3 to 4 hematological toxicity, whereas acute grade 3 esophageal toxicity was recorded in three patients (6%). One patient developed a grade 4 pulmonary toxicity (2%). Clinical response was 40 (80%) partial response, one (2%) stable disease, and nine (18%) progressive disease. Thirty-six patients (72%) underwent surgery. Final pathology showed a downstaging to stage 0 to I in 25 cases (50%). Median overall survival for all patients was 21.8 months, with a 3-year survival of 40.2%., Conclusions: The results of this phase II trial confirm the feasibility and the efficacy of concurrent chemoradiotherapy followed by surgery.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The main treatment for localized gastrointestinal stromal tumors is surgical resection. These tumors respond poorly to conventional cytotoxic chemotherapy agents and to radiotherapy. Imatinib mesylate, a small-molecule kinase inhibitor, has proved useful in the treatment of recurrent or metastatic GISTs and is now being tested in the adjuvant and neoadjuvant setting. The role of radiotherapy in the management of patients with GIST is currently restricted to symptomatic palliation. We present the case of a 54-year-old man affected by rectal GIST extending to the anal canal, with constipation, hematochezia, and anal pain. He received imatinib, 400 mg orally per day, for a week before and during radiation therapy. Irradiation was delivered to the gross tumor volume by 3D conformal therapy. The planned total dose was 50.4 Gy in fractions of 1.8 Gy daily. We observed a partial clinical response 3 weeks after the end of combination treatment. The patient then underwent a sphincter-saving surgical procedure. There was no perioperative morbidity and a complete pathological response was obtained. At the present time, the role of radiotherapy in the management of patients with GIST is restricted to symptomatic palliation. The introduction of molecularly targeted therapy combined with radiation therapy could improve the outcomes for patients diagnosed with GIST.

Objective: To quantify differences between the alternative methods of F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)-based delineation of the gross tumor volume in patients with head and neck cancer., Materials and Methods: Twelve patients with locally-advanced head and neck carcinomas were studied. The reference gross tumor volume (GTVref) was established by a radiation oncologist, along with a neuroradiologist, using the computed tomography-simulation and diagnostic magnetic resonance imaging data. With the GTVref obscured, a second radiation oncologist and a nuclear medicine physician determined the following contours: (1) high FDG uptake based on visual inspection (GTVvis), (2) the contour derived from the 50% maximum standardized uptake value (SUV) threshold (GTV50), (3) the contour derived from a 2.5 SUV absolute threshold (GTV2.5), and (4) the contours derived from an iterative segmentation algorithm (GTViter). These volumes were compared with the GTVref using a signed-ranks test with the exact reference distribution., Results: The average GTVref was 75.5 mL (median 72.8 mL, range 22.2-138.4 mL). The average GTVvis was 57.6 (median 55.4 mL, range 12-115.8 mL). Overall, a 21% reduction in volume size was observed with GTVvis versus GTVref. When the signed-ranks test with the exact reference distribution was applied, the difference was not statistically significant (P = 0.32). The average GTV2.5 was 60 mL (median 64.5, range 8.8-90.3 mL). The differences between GTV2.5 and GTVref were not statistically significant (P = 0.35). The use of GTV50 and GTViter produced significantly smaller volumes with respect to GTVref (P < 0.005)., Conclusions: PET-based tumor volumes are strongly affected by the choice of threshold level. Quantitatively, GTVs derived from visual inspection of the region of high FDG uptake do not significantly differ from GTVref in this cohort of patients. The inclusion of alternative FDG-PET segmentation data, other than visual inspection, may reduce target volumes significantly.

Purpose: To predict acute Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) and Subjective Objective Signs Management and Analysis/Late Effect of Normal Tissue (SOMA/LENT) toxicities of the lower gastrointestinal (LGI) syndrome in patients with prostate cancer undergoing three-dimensional conformal radiotherapy using a tool (nomogram) that takes into account clinical and dosimetric variables that proved to be significant in the Italian Association for Radiation Oncology (AIRO) Group on Prostate Cancer (AIROPROS) 0102 trial., Methods and Materials: Acute rectal toxicity was scored in 1,132 patients by using both the RTOG/EORTC scoring system and a 10-item self-assessed questionnaire. Correlation between clinical variables/dose-volume histogram constraints and rectal toxicity was investigated by means of multivariate logistic analyses. Multivariate logistic analyses results were used to create nomograms predicting the symptoms of acute LGI syndrome., Results: Mean rectal dose was a strong predictor of Grade 2-3 RTOG/EORTC acute LGI toxicity (p = 0.0004; odds ratio (OR) = 1.035), together with hemorrhoids (p = 0.02; OR = 1.51), use of anticoagulants/antiaggregants (p = 0.02; OR = 0.63), and androgen deprivation (AD) (p = 0.04; OR = 0.65). Diabetes (p = 0.34; OR = 1.28) and pelvic node irradiation (p = 0.11; OR = 1.56) were significant variables to adjust toxicity prediction. Bleeding was related to hemorrhoids (p = 0.02; OR = 173), AD (p = 0.17; OR = 0.67), and mean rectal dose (p = 0.009; OR = 1.024). Stool frequency was related to seminal vesicle irradiation (p = 0.07; OR = 6.46), AD administered for more than 3 months (p = 0.002; OR = 0.32), and the percent volume of rectum receiving more than 60 Gy (V60Gy) V60 (p = 0.02; OR = 1.02). Severe fecal incontinence depended on seminal vesicle irradiation (p = 0.14; OR = 4.5) and V70 (p = 0.033; OR = 1.029)., Conclusions: To the best of our knowledge, this work presents the first set of nomograms available in the literature specific to symptoms of LGI syndrome and provides clinicians with a tailored probability of the specific outcome. Validation of the tool is in progress.

Purpose: To assess the pattern of local failure using (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans after radiotherapy (RT) in non-small-cell lung cancer (NSCLC) patients treated with definitive RT whose gross tumor volumes (GTVs) were defined with the aid of pre-RT PET data., Method and Materials: The data from 26 patients treated with involved-field RT who had local failure and a post-RT PET scan were analyzed. The patterns of failure were visually scored and defined as follows: (1) within the GTV/planning target volume (PTV); (2) within the GTV, PTV, and outward; (3) within the PTV and outward; and (4) outside the PTV. Local failure was also evaluated as originating from nodal areas vs. the primary tumor., Results: We analyzed 34 lesions. All 26 patients had recurrence originating from their primary tumor. Of the 34 lesions, 8 (24%) were in nodal areas, 5 of which (63%) were marginal or geographic misses compared with only 1 (4%) of the 26 primary recurrences (p = 0.001). Of the eight primary tumors that had received a dose of <60 Gy, six (75%) had failure within the GTV and two (25%) at the GTV margin. At doses of > or = 60 Gy, 6 (33%) of 18 had failure within the GTV and 11 (61%) at the GTV margin, and 1 (6%) was a marginal miss (p < 0.05)., Conclusion: At lower doses, the pattern of recurrences was mostly within the GTV, suggesting that the dose might have been a factor for tumor control. At greater doses, the treatment failures were mostly at the margin of the GTV. This suggests that visual incorporation of PET data for GTV delineation might be inadequate, and more sophisticated approaches of PET registration should be evaluated.

Purpose: Hypoxia renders tumor cells radioresistant, limiting locoregional control from radiotherapy (RT). Intensity-modulated RT (IMRT) allows for targeting of the gross tumor volume (GTV) and can potentially deliver a greater dose to hypoxic subvolumes (GTV(h)) while sparing normal tissues. A Monte Carlo model has shown that boosting the GTV(h) increases the tumor control probability. This study examined the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomography/computed tomography ((18)F-FMISO PET/CT)-guided IMRT with the goal of maximally escalating the dose to radioresistant hypoxic zones in a cohort of head and neck cancer (HNC) patients., Methods and Materials: (18)F-FMISO was administered intravenously for PET imaging. The CT simulation, fluorodeoxyglucose PET/CT, and (18)F-FMISO PET/CT scans were co-registered using the same immobilization methods. The tumor boundaries were defined by clinical examination and available imaging studies, including fluorodeoxyglucose PET/CT. Regions of elevated (18)F-FMISO uptake within the fluorodeoxyglucose PET/CT GTV were targeted for an IMRT boost. Additional targets and/or normal structures were contoured or transferred to treatment planning to generate (18)F-FMISO PET/CT-guided IMRT plans., Results: The heterogeneous distribution of (18)F-FMISO within the GTV demonstrated variable levels of hypoxia within the tumor. Plans directed at performing (18)F-FMISO PET/CT-guided IMRT for 10 HNC patients achieved 84 Gy to the GTV(h) and 70 Gy to the GTV, without exceeding the normal tissue tolerance. We also attempted to deliver 105 Gy to the GTV(h) for 2 patients and were successful in 1, with normal tissue sparing., Conclusion: It was feasible to dose escalate the GTV(h) to 84 Gy in all 10 patients and in 1 patient to 105 Gy without exceeding the normal tissue tolerance. This information has provided important data for subsequent hypoxia-guided IMRT trials with the goal of further improving locoregional control in HNC patients.

The recent wave of enthusiasm for image guidance in radiation therapy is largely due to the advent of on-line imaging devices. The current narrow definition of image-guided radiotherapy (IGRT), in fact, essentially connotes the use of near real-time imaging during treatment delivery to reduce uncertainties in target position and should therefore be termed IGRT-D. However, a broader (and more appropriate) context of image-guidance should include: (1) detection and diagnosis, (2) delineation of target and organs at risk, (3) determining biological attributes, (4) dose distribution design, (5) dose delivery assurance and (6) deciphering treatment response through imaging i.e. the 6 D's of IGRT. Strategies to advance these areas will be discussed.

Purpose: Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. (18)F-fluoromisonidazole ((18)F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of (18)F-FMISO intratumor distribution using two pretreatment PET scans., Methods and Materials: We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an (18)F-fluorodeoxyglucose study, followed by two (18)F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio >or=1.2. The (18)F-FMISO tracer distributions from the two (18)F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the (18)F-FMISO intensities of the corresponding spatial voxels was derived., Results: A voxel-by-voxel analysis of the (18)F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%., Conclusion: Variability in spatial uptake can occur between repeat (18)F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of (18)F-FMISO-suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before single-time-point (18)F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy.

Aims and Background: To determine whether there is a benefit for biochemical control with adjuvant radiation therapy to the surgical bed following radical prostatectomy in patients with seminal vesicle invasion and pathologically negative pelvic lymph nodes (pT3b-pT4 pN0)., Methods: We retrospectively reviewed the clinical records of radical prostatectomy patients treated between 1995 and 2002. A total of 66 patients with seminal vesicle invasion were identified: 45 of these patients received adjuvant radiation therapy and 21 were observed. Radiation therapy was initiated within 4 months of prostatectomy. Median dose was 66 Gy (range, 60-70 Gy). Median follow-up from the day of surgery was 40.6 months (mean, 41.5; range, 12-99). Biochemical recurrence was defined as the first value > or = 0.2 ng/ml., Results: At two years, the proportion of patients free from biochemical recurrence was 80% in patients who received adjuvant radiation therapy versus 54% for those not given radiation therapy (P = 0.036). Actuarial biochemical recurrence at 5 years was 59% vs 41% for the radiation therapy and no radiation therapy groups, respectively. On univariate Cox regression model, the hazard of biochemical failure was also associated with a detectable (> or = 0.2 ng/ml) postsurgical prostate-specific antigen (P = 0.02) prior to radiation therapy. Pathological T stage (pT3b vs pT4), Gleason score, primary Gleason pattern and positive surgical margins were not significantly associated with biochemical recurrence. The hazard of biochemical failure was around 85% lower in the radiation therapy group than in the observation group (P = 0.002)., Conclusions: Data from the present series suggest that adjuvant radiation therapy for patients with seminal vesicle invasion and undetectable (< or = 0.2 ng/ml) postoperative prostate-specific antigen significantly reduces the likelihood of biochemical failure.

Target volume delineation of lung cancer is well known to be prone to large inter-observer variability. The advent of PET/CT devices, with co-registered functional and anatomical data, has opened new exciting possibilities for target volume definition in radiation oncology. PET/CT imaging is rapidly being embraced by the radiation oncology community as a tool to improve the accuracy of target volume delineation for treatment optimization in NSCLC. Several studies have dealt with the feasibility of incorporating FDG-PET information into contour delineation with the aim to improve overall accuracy and to reduce inter-observer variation. A significant impact of PET-derived contours on treatment planning has been shown in 30-60% of the plans with respect to the CT-only target volume. The most prominent changes in the gross tumour volume (GTV) have been reported in cases with atelectasis and following the incorporation of PET-positive nodes in otherwise CT-insignificant nodal areas. Although inter-observer variability is still present following target volume delineation with PET/CT, it is greatly reduced compared to conventional CT-only contouring. PET/CT may also provide improved therapeutic ratio compared to conventional CT planning. Increased target coverage and often reduced target volumes may potentially result in PET/CT-based planning to yield better tumour control probability through dose escalation, while still complying with dose/volume constrains for normal tissues. Despite these exciting results, more clinical studies need to be performed to better define the role of combined PET/CT in treatment planning for NSCLC.

Several model studies have shown potential clinical advantages with charged particles (protons and light ions) compared with 3D-conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) in many disease sites. The newly developed intensity-modulated proton therapy (IMPT) often yields superior dose distributions to photon IMRT, with the added advantage of a significant reduction in the volume of healthy normal tissues exposed to low-to-medium doses. Initially, the major emphasis in clinical research for proton and light ion therapy was dose escalation for inherently radioresistant tumors, or for lesions adjacent to critical normal structures that constrained the dose that could be safely delivered with conventional x-ray therapy. Since the advent of IMRT the interest in particle therapy has gradually shifted toward protocols aimed at morbidity reduction. Lately the emphasis has mostly been placed on the potential for reduced risk of radiation-induced carcinogenesis with protons. Compared with 3D-CRT, a 2-fold increase has been theoretically estimated with the use of IMRT due to the larger integral volumes. In the pediatric setting, due to a higher inherent susceptibility of tissues, the risk could be significant, and the benefits of protons have been strongly emphasized in the literature. There is a significant expansion of particle therapy facilities around the world. Increasing public awareness of the potential benefits of particle therapy and wider accessibility for patients require that treating physicians stay abreast of the clinical indications of this radiotherapy modality. The article reviews the available literature for various disease sites in which particle therapy has traditionally been considered to offer clinical advantages and to highlight current lines of clinical research. The issue of radiation-induced second malignancies is examined in the light of the controversial epidemiological evidence available. The cost-effectiveness of particle therapy is also discussed., ((c) 2007 American Cancer Society.)

Prostate carcinoma, with about 190,000 new cases occurring each year (15% of all cancers in men), is the most frequent cancer among men in northern and western Europe. Causes of the disease are essentially unknown, although hormonal factors are involved, and diet may exert an indirect influence; some genes, potentially involved in hereditary prostate cancer (HPC) have been identified. A suspect of prostate cancer may derive from elevated serum prostate-specific antigen (PSA) values and/or a suspicious digital rectal examination (DRE) finding. For a definitive diagnosis, however, a positive prostate biopsy is requested. Treatment strategy is defined according to initial PSA stage, and grade of the disease and age and general conditions of the patient. In localized disease, watchful waiting is indicated as primary option in patients with well or moderately differentiated tumours and a life expectancy <10 years, while radical prostatectomy and radiotherapy (with or without hormone-therapy) could be appropriate choices in the remaining cases. Hormone-therapy is the treatment of choice, combined with radiotherapy, for locally advanced or bulky disease and is effective, but not curative, in 80-85% of the cases of advanced disease. Patients who develop a hormone-refractory prostate cancer disease (HRPC) have to be evaluated for chemotherapy because of the recent demonstration of improved overall survival (2-2.5 months) and quality of life with docetaxel in more than 1,600 cases.

Aims and Background: The National Working Group on Prostate Radiotherapy of AIRO (Associazione Italiana Radioterapia Oncologica, Italian Association of Radiotherapeutic Oncology) was established in March 2001. A retrospective multi-center survey was performed to analyze the patterns of care for prostate cancer patients treated with postoperative radiotherapy following radical prostatectomy in Italy with regard to the year 2000., Materials and Methods: A structured questionnaire was mailed to 47 Italian radiotherapy centers to assess patient accrual in the postoperative setting in the interval comprised between period January-December 2000. Numbers of patients treated for different stages, specific prognostic factors indicating the need for adjuvant radiotherapy, fractionation schedules and prescription doses were acquired as well as other clinically important factors such as radiotherapy timing and the use of hormone therapy. More technical features of the treatment, such as patient positioning, mode of simulation, typical field setup and dose prescription criteria were also included in the questionnaire., Results: The questionnaire was returned by 24 radiotherapy Institutions (51%) with a total number of 470 patients treated postoperatively in the year 2000. An average of about 20 patients were enrolled by each radiotherapy center. The age range was 45-81 years. Radiotherapy was delivered within 6 months of radical prostatectomy in 297 patients (65.4%) (mean, 3.4 months). In 157 (34.6%), the treatment was delivered as a salvage approach for biochemical or micro-macroscopic recurrence. Most of patients had locally advanced stage disease (pT3-pT4) (76%). Unfavorable prognostic factors, such as positive margins, capsular invasion, Gleason pattern score > 7 were present in about 50% of patients., Conclusions: The study confirmed that important risk factors for recurrences are present in a significant percentage of patients treated by radical prostatectomy. The number of patients that would benefit from adjuvant radiotherapy is therefore potentially very large. Future prospective studies should be conducted to assess and to clarify the respective roles of adjuvant and salvage radiotherapy in prostate cancer patients.

Aims and Background: Androgen ablation therapy in conjunction with radiotherapy--neoadjuvant and adjuvant--has consistently been shown to be associated with improved biochemical and local control, whereas controversy still remains as regards its benefit in terms of overall survival. The objective of this study is to determine the impact of androgen ablation in combination to 3D-conformal radiotherapy on late treatment-related toxicity., Methods: 236 patients were treated with 3D-conformal radiotherapy to a total dose ranging from 70 and 78.6 Gy. Fifty-six patients did not receive any form of androgen ablation whereas 176 were given at least 3 months of neoadjuvant androgen ablation. Of these, 64 stayed on androgen ablation for a median time of 6 months post-radiotherapy. Acute toxicity was evaluated weekly during the course of treatment. Late toxicity was assessed at 3-months intervals during the follow-up. Toxicity was scored according to the RTOG criteria., Results: The median follow-up was 24.6 months (range, 12-62). The incidence of late genitourinary toxicity was: 3% G2, 3.5% G3, 0.5% G4. The incidence of late gastrointestinal toxicity was: 12% G2, 2% G3, 1% G4. No association was observed between the use of androgen ablation and late treatment-related toxicity. High-risk patients who continued on androgen ablation long-term were not found to have an increased risk of developing late toxicity with respect to those who never had any form of androgen ablation or those only treated neoadjuvantly., Conclusions: In our experience, the use of androgen ablation does not impact on late toxicity following high dose 3D-conformal radiotherapy for prostate cancer.

Aims and Background: Until recently radiotherapy of hepatic malignancies has played a limited role due to the well-known limited radiotolerance of the liver. The aim of this paper is to review the available data on the risk of radiation-induced liver disease (RILD) and to define the modern role of radiotherapy in the management of patients with metastatic or primary liver malignancies., Methods: The advent of three-dimensional conformal treatment planning with dose-volume histogram analysis has made the study of partial liver irradiation possible. Limited portions of the liver may withstand high doses of radiation with minimal risk of RILD. Patients with solitary unresectable liver tumors may be treated with high-dose radiotherapy with curative intent. Recently, the feasibility of stereotactically guided treatment techniques with a single fraction or few treatment sessions has been explored in numerous institutions., Results: The radiation tolerance of the whole liver found by several investigations is in the order of approximately 30 Gy, which seriously restricts its clinical application. The role of whole liver irradiation therefore appears of limited benefit in the palliation of patients with multiple liver metastases. The use of three-dimensional conformal techniques has made partial liver irradiation possible to doses in the 70-80 Gy range with conventional fractionation. At least two published series have reported improved local control and survival rates with dose escalation with three-dimensional conformal radiotherapy in patients with unresectable liver metastases. Similar outcomes have been recently reported with single dose (or hypofractionated) stereotactic radiotherapy both in metastatic and primary hepatic malignancies with minimal morbidity. Accurate target delineation and treatment reproducibility are the key to the success of this novel treatment approach, and specific treatment planning techniques and patient setup procedures must be developed to implement it., Conclusions: Stereotactic high-dose radiotherapy is technically feasible for the treatment of inoperable liver malignancies, with the potential of high local control and low morbidity. Definitive evidence on the clinical advantages of this technique over other more established treatments can only be gathered from well-designed clinical studies.

Background and Purpose: The rectum is known to display a dose-volume effect following high-dose 3D-conformal radiotherapy (3D-CRT). The aim of the study is to search for significant dose-volume combinations with the specific treatment technique and patient set-up currently used in our institution., Patients and Methods: We retrospectively analyzed the dose-volume histograms (DVH) of 135 patients with stage T1b-T3b prostate cancer treated consecutively with 3D-CRT between 1996 and 2000 to a total dose of 76 Gy. The median follow-up was 28 months (range 12-62). All late rectal complications were scored using RTOG criteria. Time to late toxicity was assessed using the Kaplan-Meyer method. The association between variables at baseline and > or=2 rectal toxicity was tested using chi(2) test or Fisher's exact test. A multivariate analysis using logistic regression was performed., Results: Late rectal toxicity grade > or=2 was observed in 24 of the 135 patients (17.8%). A 'grey area' of increased risk has been identified. Average DVHs of the bleeding and non-bleeding patients were generated. The area under the percent volume DVH for the rectum of the bleeding patients was significantly higher than that of patients without late rectal toxicity. On multivariate analysis the correlation between the high risk DVHs and late rectal bleeding was confirmed., Conclusions: The present analysis confirms the role of the rectal DVH as a tool to discriminate patients undergoing high-dose 3D-CRT into a low and a high risk of developing late rectal bleeding. Based on our own results and taking into account the data published in the literature, we have been able to establish new dose-volume constraints for treatment planning: if possible, the percentage of rectal volume exposed to 40, 50, 60, 72 and 76 Gy should be limited to 60, 50, 25, 15 and 5%, respectively.

Purpose: To estimate the impact of the uncertainty in contouring the rectum on rectal dose-volume parameters and normal tissue complication probability (NTCP) in a prospective (AIROPROS01-02) investigation about rectal toxicity., Methods and Materials: The participants in a prospective trial (18 observers) were asked to draw the external contour of the rectum of 4 sample patients (3 patients undergoing radical conformal radiotherapy, 1 patient undergoing post-prostatectomy) on CT images (0.5 cm spacing) using a 3D treatment planning system. A previously accepted definition of cranial and caudal borders of the rectum was applied. For each patient, four- and six-field 3D-conformal techniques (70-76 Gy, ICRU dose) were planned and DVH/dose statistics of the rectum were calculated. The impact of interobserver variability on rectal volume, cranial and caudal borders, mean, maximum, and median rectal dose, percentage of rectum receiving more than 40, 45, 50, 55, 60, 65, 70, and 75 Gy (V(40)-V(75)), and NTCP were investigated., Results: Concerning DVHs, 9/18 observers tended to have some systematic deviation. However, deviations from the mean values greater than 5% were found only in 1/9 because of a systematic discrepancy in the caudal limit assessment (mean deviation from the most frequently chosen slice: 8 mm). No other observers showed a mean deviation in the cranial or the caudal limit definition greater than 5.8 mm. For another observer, it was possible to clearly assess the cause of a relatively large systematic deviation for DVH parameters. In both cases, the observers were contacted to avoid these systematic deviations. When considering the remaining 16/18 observers, the average values of SD for V(40)-V(75) ranged between 1% and 4% and were found to be lower (<3%) for the 3 nonoperated patients. The average values of the SD were around 1.5-2 Gy and less than 1.5% for mean/median dose and NTCPs, respectively., Conclusions: Concerning the uncertainty in rectum definition, the collection of rectal dose-volume data in multicenter investigations seems to be feasible after a clear and previously accepted definition of rectum is assessed. However, even with a general agreement on rectum definition, contouring appears to be a quite significant source of uncertainty. A dummy run procedure is useful in identifying possible discrepancies among single observers and in assessing reliable confidence levels on dose-volume constraints because of contouring uncertainty, making the dummy run mandatory in multicenter trials evaluating 3D dose-volume data.