Consolidative active scanning proton therapy for mediastinal lymphoma: selection criteria, treatment implementation and clinical feasibility.

AIMS: Proton therapy (PT) represents an advanced form of radiotherapy with unique physical properties which could be of great advantage in reducing long-term radiation morbidity for cancer survivors. Here, we aim to describe the whole process leading to the clinical implementation of consolidative active scanning proton therapy treatment (PT) for mediastinal lymphoma. METHODS: The process included administrative, technical and clinical issues. Authorization of PT is required in all cases as mediastinal lymphoma is currently not on the list of diseases reimbursable by the Italian National Health Service. Technically, active scanning PT treatment for mediastinal lymphoma is complex, due to the interaction between actively scanned protons and the usually irregular and large volumes to be irradiated, the nearby healthy tissues and the target motion caused by breathing. A road map to implement the technical procedures was prepared. The clinical selection of patients was of utmost importance and took into account both patient and tumor characteristics. RESULTS: The first mediastinal lymphoma was treated at our PT center in 2018, four years after the start of the clinical activities. The treatment technique implementation included mechanical deep inspiration breath-hold simulation computed tomography (CT), clinical target volume (CTV)-based multifield optimization planning and plan robustness analysis. The ultimate authorization rate was 93%. In 4 cases a proton-photon plan comparison was required. Between May 2018 and February, 2021, 14 patients were treated with consolidative PT. The main clinical reasons for choosing PT over photons was a bulky disease in 8 patients (57%), patient's age in 11 patients (78%) and the proximity of the lymphoma to cardiac structures in 10 patients (71%). With a median follow-up of 15 months (range, 1-33 months) all patients but one (out-of-field relapse) are without evidence of disease, all are alive and no late toxicities were observed during the follow-up period. CONCLUSIONS: The clinical implementation of consolidative active scanning PT for mediastinal lymphoma required specific technical procedures and a prolonged experience with PT treatments. An accurate selection of patients for which PT could be of advantage in comparison with photons is mandatory.

Radiation-induced acute dysphagia : Prospective observational study on 42 head and neck cancer patients.

PURPOSE: Acute toxicity in head and neck (H&N) cancer patients treated with definitive radiotherapy (RT) has a crucial role in compliance to treatments. The aim of this study was to correlate doses to swallowing-associated structures and acute dysphagia. METHODS: We prospectively analyzed 42 H&N cancer patients treated with RT. Dysphagia (grade ≥ 3) and indication for percutaneous endoscopic gastrostomy (PEG) insertion were classified as acute toxicity. Ten swallowing-related structures were considered for the dosimetric analysis. The correlation between clinical information and the dose absorbed by the contoured structures was analyzed. Multivariate logistic regression method using resampling methods (bootstrapping) was applied to select model order and parameters for normal tissue complication probability (NTCP) modelling. RESULTS: A strong multiple correlation between dosimetric parameters was found. A two-variable model was suggested as the optimal order by bootstrap method. The optimal model (Rs = 0.452, p < 0.001) includes V45 of the cervical esophagus (odds ratio [OR] = 1.016) and Dmean of the cricopharyngeal muscle (OR = 1.057). The model area under the curve was 0.82 (95% confidence interval 0.69-0.95). CONCLUSION: Our results suggested that the absorbed dose to the cricopharyngeal muscle and cervical esophagus might play a relevant role in the development of acute RT-related dysphagia.

Dosimetric and NTCP advantages of robust proton therapy over robust VMAT for Stage III NSCLC in the immunotherapy era.

AIMS: To assess the robustness and to define the dosimetric and NTCP advantages of pencil-beam-scanning proton therapy (PBSPT) compared with VMAT for unresectable Stage III non-small lung cancer (NSCLC) in the immunotherapy era. MATERIAL AND METHODS: 10 patients were re-planned with VMAT and PBSPT using: 1) ITV-based robust optimization with 0.5 cm setup uncertainties and (for PBSPT) 3.5 % range uncertainties on free-breathing CT 2) CTV-based RO including all 4DCTs anatomies. Target coverage (TC), organs at risk dose and TC robustness (TCR), set at V95%, were compared. The NTCP risk for radiation pneumonitis (RP), 24-month mortality (24MM), G2 + acute esophageal toxicity (ET), the dose to the immune system (EDIC) and the left anterior descending (LAD) coronary artery V15 < 10 % were registered. Wilcoxon test was used. RESULTS: Both PBSPT methods improved TC and TCR (p < 0.01). The mean lung dose and lung V20 were lower with PBSPT (p < 0.01). Median mean heart dose reduction with PBSPT was 8 Gy (p < 0.001). PT lowered median LAD V15 (p = 0.004). ΔNTCP > 5 % with PBSPT was observed for two patients for RP and for five patients for 24 MM. ΔNTCP for ≥ G2 ET was not in favor of PBSPT for all patients. PBSPT halved median EDIC (4.9/5.1 Gy for ITV/CTV-based VMAT vs 2.3 Gy for both ITV/CTV-based PBSPT, p < 0.01). CONCLUSIONS: PBSPT is a robust approach with significant dosimetric and NTCP advantages over VMAT; the EDIC reduction could allow for a better integration with immunotherapy. A clinical benefit for a subset of NSCLC patients is expected.

Immunotherapy in HER2-positive breast cancer: state of the art and future perspectives.

Breast cancer (BC) is a complex disease with primary or acquired incurability characteristics in a significant part of patients. Immunotherapeutical agents represent an emerging option for breast cancer treatment, including the human epidermal growth factor 2 positive (HER2+) subtype. The immune system holds the ability to spontaneously implement a defensive response against HER2+ BC cells through complex mechanisms which can be exploited to modulate this response for obtaining a clinical benefit. Initial immune system modulating strategies consisted mostly in vaccine therapies, which are still being investigated and improved. However, the entrance of trastuzumab into the scenery of HER2+ BC treatment was the real game changing event, which embodied a dominant immune-mediated mechanism. More recently, the advent of the immune checkpoint inhibitors has caused a new paradigm shift for immuno-oncology, with promising initial results also for HER2+ BC. Breast cancer has been traditionally considered poorly immunogenic, being characterized by relatively low tumor mutation burden (TMB). Nevertheless, recent evidence has revealed high tumor infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in a considerable proportion of HER2+ BC patients. This may translate into a higher potential to elicit anti-cancer response and, therefore, wider possibilities for the use and implementation of immunotherapy in this subset of BC patients. We are herein presenting and critically discussing the most representative evidence concerning immunotherapy in HER2+ BC cancer, both singularly and in combination with therapeutic agents acting throughout HER2-block, immune checkpoint inhibition and anti-cancer vaccines. The reader will be also provided with hints concerning potential future projection of the most promising immutherapeutic agents and approaches for the disease of interest.

Targeting immune response with therapeutic vaccines in premalignant lesions and cervical cancer: hope or reality from clinical studies.

Human papillomavirus (HPV) is widely known as a cause of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN). HPVs related to cancer express two main oncogenes, i.e. E6 and E7, considered as tumorigenic genes; their integration into the host genome results in the abnormal regulation of cell cycle control. Due to their peculiarities, these oncogenes represent an excellent target for cancer immunotherapy. In this work the authors highlight the potential use of therapeutic vaccines as safe and effective pharmacological tools in cervical disease, focusing on vaccines that have reached the clinical trial phase. Many therapeutic HPV vaccines have been tested in clinical trials with promising results. Adoptive T-cell therapy showed clinical activity in a phase II trial involving advanced CC patients. A phase II randomized trial showed clinical activity of a nucleic acid-based vaccine in HPV16 or HPV18 positive CIN. Several trials involving peptide-protein-based vaccines and live-vector based vaccines demonstrated that these approaches are effective in CIN as well as in advanced CC patients. HPV therapeutic vaccines must be regarded as a therapeutic option in cervical disease. The synergic combination of HPV therapeutic vaccines with radiotherapy, chemotherapy, immunomodulators or immune checkpoint inhibitors opens a new and interesting scenario in this disease.

In vivo cell kinetics in head and neck squamous cell carcinomas predicts local control and helps guide radiotherapy regimen.

PURPOSE: To determine whether pretherapy cell kinetics can predict local control for patients affected by head and neck squamous cell carcinomas (HN-SCCs) to be treated by primary radiotherapy and, moreover, guide to a choice between conventional and accelerated radiotherapy. PATIENTS AND METHODS: Between 1989 and 1993, 83 patients with stage II to IV HN-SCC entered the study. Multiple primary tumor biopsies were obtained 6 hours after in vivo infusion of bromodeoxyuridine (BrdUrd). In vivo S-phase fraction labeling index (LI), duration of S phase (Ts), and potential doubling time (Tpot) were obtained by analysis of multivariate flow-cytometric data. Between April 1989 and January 1991, 49 patients were treated by conventional radiotherapy (70 Gy in 35 fractions over 7 weeks), whereas, afterwards, 34 patients entered an accelerated radiotherapy regimen with the concomitant boost technique (75 Gy in 40 fractions over 6 weeks). RESULTS: Univariate analysis showed that, among patients treated by conventional radiotherapy, local control probability was affected by tumor stage (P = .02), Tpot (P < .001), and LI (P = .04). Similarly, among patients treated with accelerated radiotherapy, we found that local control probability was related to tumor stage (P = .03) and primary tumor site (P = .05). For the subgroup of patients with tumors characterized by fast growth (Tpot < or = 5 days), accelerated radiotherapy gave a better local control rate than conventional radiotherapy (P = .02). Cox multivariate analysis of the total number of patients showed that the only significant independent prognostic factors related to local control were tumor stage (P = .002) and Tpot (P = .004). Moreover, when the Cox analysis was restricted to the subgroup of patients treated with conventional radiotherapy, Tpot was the most significant factor to predict local outcome (P < .01). CONCLUSION: Pretreatment tumor Tpot appears to be an important independent prognostic factor for local control of HN-SCC treated by primary radiotherapy.

Chemoradiotherapy as an alternative to radiotherapy alone in fast proliferating head and neck squamous cell carcinomas.

The aim of this pilot study was to explore the prognostic relevance of cell kinetics parameters on the local control of patients affected by head and neck squamous cell carcinoma (HN-SCC), randomly assigned to receive either alternating chemoradiotherapy or partly accelerated radiotherapy. Between 1992 and 1995, 40 patients with HN-SCC at stages III and IV entered the study. Multiple primary tumor biopsies were obtained 6 h after in vivo infusion of bromodeoxyuridine, an analogue of thymidine that is incorporated in DNA-synthesizing cells. In vivo S-phase fraction labeling index (LI), duration of S-phase (TS), and potential doubling time (Tpot) were obtained by analysis of the flow cytometric content of bromodeoxyuridine and DNA. Twenty patients were treated by alternating chemotherapy and conventional radiotherapy (arm A), whereas 20 other matching patients received partly accelerated radiotherapy alone (arm B). Univariate local control analysis showed that LI, TS, and Tpot were not prognostically significant in either arm. However, local control probability at 2 years for fast growing tumors, characterized by a LI of 9%, was higher for patients treated with alternating chemoradiotherapy than it was for those treated with partly accelerated radiotherapy alone (68 versus 39%). Conversely, local control probabilities for slow proliferating tumors (LI, <9%) treated in the two arms were similar. These results suggest a potential role for alternating chemotherapy and radiotherapy in HN-SCC patients with fast growing tumors.

The Shape of Parotid DVH Predicts the Entity of Gland Deformation During IMRT for Head and Neck Cancers.

The Jacobian of the deformation field of the registration between images taken during Radiotherapy is a measure of compression/expansion of the voxels within an organ. The Jacobian mean value was applied to investigate possible correlations between parotid deformation and anatomical, clinical and dosimetric parameters. Data of 84 patients were analyzed. Parotid deformation was evaluated through Jacobian maps of images taken at the start and at the end of the treatment. Several clinical, geometrical and dosimetric factors were considered. Correlation between Jacobian mean value and these parameters was assessed through Spearman's test. Univariate and multivariate logistic analyses were performed by considering as the end point the first quartile value of the Jacobian mean value. Parotid dose volume histograms were stratified according to gland deformation, assessing the most predictive dose-volume combination. At multivariate analysis, age (p = 0.02), overlap between tumor volume and parotid gland (p = 0.0006) and the parotid volume receiving more than 10 Gy (p = 0.02) were found as the best independent predictors, by considering Jacobian mean value fist quartile, the parotid volume receiving more than 10 Gy and 40 Gy were found as the most predictive dosimetric parameters. Parotid glands were divided in three different sub-groups (bad-, medium- and good dose volume histogram). The risk to have Jacobian means value lower than first quartile was 39.6% versus 19.6% versus 11.3% in these three groups. By including in the multivariate analysis this "dose volume grouping" parameter, age and bad dose volume histogram were found as the most predictive parameters for large shrinkage. The pattern of parotid deformation may be well predicted by some pre-treatment variables; a bad dose volume histogram seems the most important predictor.

Postoperative radiotherapy for head and neck squamous cell carcinomas: feasibility of a biphasic accelerated treatment schedule.

PURPOSE: It has been suggested that postoperative tumor cell proliferation may influence the outcome of advanced head and neck squamous cell carcinomas treated by surgery and postoperative radiotherapy. This Phase I pilot study was undertaken to determine the feasibility of a biphasic accelerated radiotherapy regimen with early and late concomitant boost delivery for postoperative treatment of patients with advanced head and neck cancers. METHODS AND MATERIALS: From April 1993 to April 1994, 29 patients with advanced head and neck cancers were enrolled in this study after they underwent complete surgical resection. The basic radiation course delivered a median dose of 49 Gy in 25 fractions over 5 weeks at 1.8-2 Gy/fraction. The concomitant boost was delivered to the high-risk areas as a second daily fraction during the first (1.4 Gy/fraction) and fifth weeks (1.6 Gy/fraction). The total dose to the high-risk areas was 64 Gy in 35 fractions over 5 weeks. RESULTS: Twenty-seven patients (93%) completed the treatment without interruptions. Only two patients experienced severe acute toxicity requiring treatment breaks of 6 and 8 days, respectively. All patients developed confluent mucositis; in 69% of the cases it covered >50% of the treated surface. No patient developed Grade 5 (ulceration/bleeding) mucosal reaction. Mucositis required a median time of 7 weeks for complete healing (range 3-43). Two patients developed transient bone exposure. The median weight loss was 5.5% of pretreatment body weight (range 1.2-17.1%), and four patients required nutritional assistance with nasogastric feeding tube. CONCLUSION: The results of this study show that this biphasic acceleration regimen is feasible with acceptable acute toxicity.

Evidence of cell kinetics as predictive factor of response to radiotherapy alone or chemoradiotherapy in patients with advanced head and neck cancer.

PURPOSE: The aim of this study was to investigate the potential clinical relevance of cell kinetics parameters to the locoregional control (LRC) and overall survival of patients affected by head and neck squamous cell carcinoma (HN-SCC) treated by conventional radiotherapy, partly accelerated radiotherapy, or alternating chemoradiotherapy. METHODS AND MATERIALS: Between January 1993 and June 1996,115 patients with HN-SCC at Stage III and IV entered the study. Multiple primary tumor biopsies were obtained 6 h after in vivo infusion of bromodeoxyuridine (BrdUrd), an analogue of thymidine that is incorporated in DNA-synthesizing cells. In vivo S-phase fraction labeling index (LI), duration of S-phase (Ts), and potential doubling time (Tpot) were obtained by analysis of the flow cytometric content of BrdUrd and DNA. Eighty-two patients were randomly assigned to receive either alternating chemoradiotherapy or partly accelerated radiotherapy, whereas 33 other matching patients received conventional radiotherapy. RESULTS: Univariate LRC analysis showed that LI value was a prognostically significant factor, independent of type of therapy. Multivariate analysis failed to show cell kinetics parameters as statistically significant factors affecting LRC probability and overall survival. However, subgroup analysis showed that LRC probability at 4 years for fast proliferating tumors characterized by a LI >/= 8% was significantly better for patients treated either with alternating chemoradiotherapy or partly accelerated radiotherapy than it was for those treated with conventional radiotherapy. Conversely, LRC probability for slow proliferating tumors (LI < 8%) treated with the three treatment modalities was similar. CONCLUSIONS: These results showed that, independent of type of treatment, pretreatment cell kinetics provided only a weak prognostic role of outcome in HN-SCC. However, this report raises the hypothesis that fast growing HN-SCC may be more likely to benefit from intensified therapy, as given in this series. Cell kinetics parameters studied by the in vivo BrdUrd/flow cytometry method might be considered predictive factors of response, providing information on which type of treatment may be selected according to tumor proliferation rate.

Potential doubling time in head and neck tumors treated by primary radiotherapy: preliminary evidence for a prognostic significance in local control.

PURPOSE: The aim of the study was to determine preliminarily whether cell kinetic parameters evaluated using in vivo infusion of bromodeoxyuridine (BrdUrd) and flow cytometry, play a role as prognostic factors of loco-regional control in squamous cell head and neck carcinoma treated with radiotherapy. METHODS AND MATERIALS: Between April 1989 and December 1991, 42 patients with unresectable Stage II-IV squamous cell carcinoma of the oral cavity, pharynx or larynx were given an infusion of BrdUrd solution prior to primary tumor biopsy sampling at 4-6 hr later. The simultaneous labeling S-phase fraction (LI) and duration (Ts) as well as the estimated potential doubling time (Tpot) were measured using flow cytometric analysis of BrdUrd and DNA content. Twenty-six patients received standard radiotherapy (70 Gy/35 fractions/7 weeks) whereas 15 patients were treated with the concomitant boost technique (75 Gy/40 fractions/6 weeks). RESULTS: A complete set of flow cytometric data was available for 31 patients. The median value of LI, Ts, and Tpot were 9%, 9 hr and 5 days, respectively. Univariate analysis among the patients treated homogeneously by standard radiotherapy, indicated that local control was affected by Tpot value (p = 0.02). When the same analysis was performed for the patients treated with either standard radiotherapy or concomitant boost regimen, we found a p = 0.04. Thus, patients with a tumor Tpot value < or = 5 days had a significantly lower three-year local control than patients with Tpot > 5 days. Log-rank test univariate analysis showed, in addition, that nodal status was the strongest prognostic factor of local control (p = 0.005). Age, tumor stage, tumor site, performance status, grading, radiotherapy regimen, DNA ploidy and LI value were, instead, not significantly related to loco-regional control. Finally, when comparing the type of radiotherapy for tumors with Tpot < or = 5 days, we found a trend toward a better local control after concomitant boost regimen, with respect to standard regimen (p = 0.06). CONCLUSION: The present preliminary results suggest that Tpot could play a role as additional prognostic factor influencing the disease outcome in head and neck carcinoma treated by radiotherapy.

Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control.

PURPOSE: This retrospective study was conducted to review the results of treatment and to identify prognostic factors for local and regional control in a population of 378 patients with nasopharyngeal carcinomas treated in a single institution by radiation therapy alone. METHODS AND MATERIAL: All patients were treated at The University of Texas M. D. Anderson Cancer Center between 1954 and 1992 following a consistent treatment philosophy but with evolving technique. There were 286 males and 92 females with a median age of 52 years (range: 16-86 years). The majority of the patients were Caucasian (282 patients, 75%). Thirty-two patients (8%) had one or more cranial nerve deficits. Three-fourths of the patients presented with AJCC Stage IV disease (T4, N0-3, 118 patients; T1-3, N2-3 164 patients). Histologically, 193 tumors (51%) were squamous cell carcinomas, 154 (41%) lymphoepitheliomas, and 31 (8%) unclassified carcinomas. Average total dose varied with T-stage and ranged from 60.2 to 72.0 Gy. Median follow-up time was 10 years. RESULTS: For the entire population the 5-, 10-, and 20-year actuarial survival rates were 48, 34, and 18%, respectively, with 184 patients (49%) dying of nasopharyngeal cancer. Actuarial control rates at 5, 10, and 20 years were 71, 66, and 66% for the primary site and 84, 83, and 83% for the neck. A total of 100 patients (26%) had local failures and 51 patients (13%) had regional failures with a median time to recurrence of 8.2 months and 13 months, respectively. Advanced T-stage, squamous histology, and presence of cranial nerve deficits were poor prognostic factors for local control in both univariate and multivariate analyses. N-stage and tumor histology were significant factors for neck control. Treatment year, total dose within the ranges used, and duration of treatment did not have any significant effect on local or regional control. The actuarial incidence of Grade 3-5 late complications was 16, 19, and 29% at 5, 10, and 20 years, respectively. Twelve patients (3%) died of treatment-related complications; all but one fatal complication occurred before 1971 and the other in 1976. CONCLUSIONS: This study shows very good long-term local and regional control rates for nasopharyngeal carcinomas after definitive radiotherapy and establishes a benchmark for newer treatment strategies. Improvements in treatment technique over the years have dramatically reduced the frequency of severe late complications. Patients with advanced stage tumors and differentiated squamous histology have a relatively poor prognosis when treated with conventional radiotherapy and are candidates for dose escalation or combined modality studies.

Chemotherapy alternated with radiotherapy in the treatment of advanced head and neck carcinoma: predictive factors of outcome.

PURPOSE: To investigate the impact of pretreatment and treatment-related factors on local-regional control and overall survival rates in advanced (III and IV stage) head and neck cancer patients treated with alternating chemoradiotherapy, a selected group of 115 patients who had PS < or = 1 and received a total dose of radiotherapy (RT) within +/- 5% of that planned, was analyzed. METHODS AND MATERIALS: Patients were planned to receive 4 cycles of chemotherapy (cisplatin and 5-fluorouracil) alternated with radiotherapy (60 Gy/30 fractions). However, mainly due to systemic toxicity, about 30% of the patients received less than 90% of the planned combined chemotherapy total dose (CCTD). Based on differences in treatment planning and delivery, patients were divided into two groups. For living patients, median follow-up is 34 months (range: 24-111 months). RESULTS: At multivariate analysis, RT technique (p = 0.008), N stage (p = 0.010) and CCTD (p = 0.027) were independent predictors of LRC. Compared to each favorable subset (RR = 1), the relative risks of LRC failure were 2.18 (95% CI: 1.21-3.91), 2.23 (95% CI: 1.11-4.50) and 2.23 (95% CI: 1.15-4.31) for patients without improved dose distribution and treatment delivery, with bilateral nodes or nodes greater than 6 cm, and with a CCTD lower than 90%, respectively. Regarding overall survival, only RT treatment was found to be an independent predictor (p = 0.037), with an RR of 1.61 (95% CI: 1.02-2.53) for patients without improved dose distribution and treatment delivery. CONCLUSION: Optimal delivery of RT dose is crucial in patients with advanced head and neck tumors, even if they receive chemotherapy as part of their treatment. This study also suggests that chemotherapy total dose may play a role in patient outcome, but this must be confirmed prospectively.

Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of distant metastasis and survival.

PURPOSE: This retrospective study was conducted to identify the prognostic factors for distant metastasis and survival in a population of 378 patients with nasopharyngeal carcinomas treated by radiation therapy alone. MATERIALS AND METHODS: All patients were treated at the University of Texas M.D. Anderson Cancer Center between 1954 and 1992, following a consistent dose and volume prescription policy. There were 286 males and 92 females. The median age was 52 years (range: 16-86 years). The majority of the patients were white Caucasians (282 patients,75%). Tumors were classified as squamous cell carcinomas (193; 51%), lymphoepitheliomas (154; 41%), or unclassified carcinomas (31, 8%). Three fourths of the patients presented with AJCC Stage IV disease (T4, N0-3, 118 patients; T1-3, N2-3 164 patients). The treatment techniques included opposed lateral fields with or without an anteroposterior or an anterior oblique pairs for dose supplementation to the primary site. Average total doses per T-stage ranged between 60.2 and 72.0 Gy. Median follow-up time was 10 years (range 0.3 to 28.6 years). RESULTS: A total of 103 patients (27%) developed distant metastases at a median time of 8 months (range: 1-90 months). Actuarial rates for distant metastasis were 30%, 32%, 32% at 5, 10, and 20 years, respectively. Actuarial rates for disease specific survival at the same time points were 53%, 45%, and 39% with 184 patients (49%) dying of their nasopharyngeal cancer. Advanced T-stage, N-stage, and non-lymphoepithelioma histology were independent adverse prognostic factors for disease specific survival. Advanced N-stage and low neck disease were independent adverse prognostic factors for distant metastasis with a very high rate of distant metastases for those patients who presented with both adverse factors (relative risk 7.86). On average, patients with distant metastasis lived 5 months after they were diagnosed with metastatic disease (range: 0-172 months), although four patients (4%) survived more than 5 years after diagnosis. CONCLUSIONS: This study demonstrates good long term survival rates after definitive radiotherapy for patients with nasopharyngeal carcinomas. Patients with advanced and lower neck disease have the highest risk of developing distant failures. Such patients can be considered the reference risk group to test the value of adjunctive chemotherapy.

Fitting late rectal bleeding data using different NTCP models: results from an Italian multi-centric study (AIROPROS0101).

BACKGROUND AND PURPOSE: Recent investigations demonstrated a significant correlation between rectal dose-volume patterns and late rectal toxicity. The reduction of the DVH to a value expressing the probability of complication would be suitable. To fit different normal tissue complication probability (NTCP) models to clinical outcome on late rectal bleeding after external beam radiotherapy (RT) for prostate cancer. PATIENTS AND METHODS: Rectal dose-volume histograms of the rectum (DVH) and clinical records of 547 prostate cancer patients (pts) pooled from five institutions previously collected and analyzed were considered. All patients were treated in supine position with 3 or 4-field techniques: 123 patients received an ICRU dose between 64 and 70 Gy, 255 patients between 70 and 74 Gy and 169 patients between 74 and 79.2 Gy; 457/547 patients were treated with conformal RT and 203/547 underwent radical prostatectomy before RT. Minimum follow-up was 18 months. Patients were considered as bleeders if showing grade 2/3 late bleeding (slightly modified RTOG/EORTC scoring system) within 18 months after the end of RT. Four NTCP models were considered: (a) the Lyman model with DVH reduced to the equivalent uniform dose (LEUD, coincident with the classical Lyman-Kutcher-Burman, LKB, model), (b) logistic with DVH reduced to EUD (LOGEUD), (c) Poisson coupled to EUD reduction scheme and (d) relative seriality (RS). The parameters for the different models were fit to the patient data using a maximum likelihood analysis. The 68% confidence intervals (CI) of each parameter were also derived. RESULTS: Forty six out of five hundred and forty seven patients experienced grade 2/3 late bleeding: 38/46 developed rectal bleeding within 18 months and were then considered as bleeders The risk of rectal bleeding can be well calculated with a 'smooth' function of EUD (with a seriality parameter n equal to 0.23 (CI 0.05), best fit result). Using LEUD the relationship between EUD and NTCP can be described with a TD50 of 81.9 Gy (CI 1.8 Gy) and a steepness parameter m of 0.19 (CI 0.01); when using LOGEUD, TD50 is 82.2 Gy and k is 7.85. Best fit parameters for RS are s=0.49, gamma=1.69, TD50=83.1 Gy. Qualitative as well as quantitative comparisons (chi-squared statistics, P=0.005) show that the models fit the observed complication rates very well. The results found in the overall population were substantially confirmed in the subgroup of radically treated patients (LEUD: n=0.24 m=0.14 TD50=75.8 Gy). If considering just the grade 3 bleeders (n=9) the best fit is found in correspondence of a n-value around 0.06, suggesting that for severe bleeding the rectum is more serial. CONCLUSIONS: Different NTCP models fit quite accurately the considered clinical data. The results are consistent with a rectum 'less serial' than previously reported investigations when considering grade 2 bleeding while a more serial behaviour was found for severe bleeding. EUD may be considered as a robust and simple parameter correlated with the risk of late rectal bleeding.

New chemoradiotherapy combinations in head and neck cancer.

Head and neck squamous cell cancer is the sixth most common cancer worldwide. Surgical management is effective as a single modality only for early-stage cancers (30% of patients). Making progress in this cancer is of vital interest. The standard treatment for advanced disease is chemoradiotherapy, with the goal of palliation of symptoms and prolongation of life. Response rates to even the best of regimens are approximately 30-40%, with the median survival period of approximately 6 months. Various approaches to treatment of recurrent disease are under investigation, including new drugs or combinations of drugs, with radiotherapy.

Treatment of nasopharyngeal carcinoma: state of the art and new perspectives (review).

The role of radiotherapy and the current strategies to improve outcome in nasopharyngeal carcinoma are reviewed. Emphasis is on the factors, which may provide a more accurate selection of patients for more aggressive treatments. Clinical data suggest that local failure and distant metastases are separate events. Thus, strategies to optimize one of them are not expected to impact significantly on the other. Patients with advanced T stage disease, cranial nerve palsy, bulky primary lesions and well differentiated tumors may benefit from more local aggressive treatment. These include higher dose radiotherapy throughout conformal 3D radiotherapy and brachytherapy. Altered fractionation schedules and concomitant chemotherapy may also enhance the results obtained by conventional external beam radiotherapy. Patients with advanced neck disease and/or low neck nodes are candidates for additional systemic treatments as well. The role of technical innovations in radiotherapy delivery and that of altered fractionation schedules are unknown, even if results from phase II studies are promising. Regarding chemotherapy, have shown some impact of chemotherapy on outcome. However, additional testing is needed in order to improve the therapeutic index and validate its rationale.

Concomitant administration of two standard regimens of chemotherapy and radiotherapy in advanced squamous carcinoma of the head and neck: a feasibility study.

BACKGROUND: In advanced squamous cell carcinoma of the head and neck, the superiority of a chemo-radiotherapy combination over radiotherapy alone has been strongly suggested. However, the best modality to combine the two treatments has still to be determinated. A pilot study was designed, testing a combination of two standard chemo- and radiotherapy regimens concomitantly administered. MATERIALS AND METHODS: 26 patients, with unresectable squamous cell carcinoma of the head and neck, were treated with three cycles of chemotherapy (cisplatin 20 mg/m2/day and fluorouracil 200 mg/m2/day as an intravenous bolus, for 5 consecutive days, every 21) simultaneously delivered with radiation (66-70 Gy/33-35 fractions/7 weeks). In order to reduce the mucoseal toxicity. observed in the first 15 patients, 1 week of pause was inserted after the third week of treatment in the subsequent 11 patients. RESULTS: Grade III-IV mucositis was detected in 40% of patients treated without pause after the third week of treatment and in 9% of those treated with. Complete responses were obtained in 13/26 patients (50%) and partial responses in 8/26 (31%). 1 stable disease, 3 early deaths (1 because of toxicity) and 1 lost before being evaluated were considered as treatment failures (19%). CONCLUSIONS: This concomitant chemo-radiotherapy approach showed a good antitumour activity but mucoseal toxicity is too high if no pause is planned during the treatment.

Correlation between immunohistochemical patterns and serum levels of PSA and PSAP in prostatic pathology: evaluation of 198 prostatic fine needle biopsies.

PSA and PSAP were examined in 198 prostatic biopsies and correlated with PSA and PSAP serum levels evaluated before biopsies. In every type of lesion there was no relation between PSA or PSAP serum levels and their expression in biopsy specimens. PSA and PSAP staining was similar in both cancer and benign hyperplasia and lower in dysplasia, atrophy and prostatitis; while serum levels were higher in adenocarcinomas than in other lesions. A significant difference of PSAP serum levels was noted in different Gleason's grading of neoplasia, found neither with PSA serum levels/nor with PSA and PSAP tissue staining.

Gemcitabine, cisplatin, and radiation in advanced, unresectable squamous cell carcinoma of the head and neck: a feasibility study.

Alternating chemoradiotherapy was shown by our institution to be superior to standard radiation in patients with nonsurgical squamous cell carcinoma of the head and neck (SCC-HN). Gemcitabine has shown in vitro and in vivo radiosensitizing properties, synergistic activity with cisplatin, and cytotoxic activity against SCC-HN. Thus, the authors tested the feasibility and antitumoral activity of a modified alternating chemoradiotherapy program that includes gemcitabine. Fourteen patients with stage IV (nine patients) or relapsed after surgery (five patients) unresectable SCC-HN were enrolled. None had previously received chemotherapy or radiotherapy. The treatment plan consisted of cisplatin, 20 mg/m2/day, days 1 to 5, weeks 1 and 5, and gemcitabine 800 mg/m2, day 5, weeks 1, 2, 3, and 5, 6, 7. Radiation was administered during weeks 2, 3, and 4 and 6, 7, and 8 with conventional fractionation up to 60 Gy. At the end of the combined therapy, patients had to receive two additional courses of cisplatin, 20 mg/m2/day, and fluorouracil, 200 mg/m2/day, for 5 days every 21 days. All the patients are evaluable for toxicity and 11 for response. Main grade III-IV toxicities and frequencies were: neutropenia (79%), neutropenia with fever (50%), thrombocytopenia (57%), anemia (35%), mucositis (100%), and cutaneous toxicity (14%). Ten patients (71%) had a weight loss greater than 10%. All but two patients needed hospitalization and tube feeding or parenteral nutrition. The median relative dose intensity of gemcitabine actually delivered was 83%. Two patients died 1 month after the end of treatment before the final evaluation. One patient died of sepsis during the additional cisplatin and fluorouracil courses before response assessment. Ten patients reached a complete response (intention to treat: 71%), and 1 patient had a partial response (9%). At a median follow-up of 34 months, the actuarial 3-year progression-free survival and overall survival are 41% and 63%, respectively. The estimated 3-year locoregional control is 70%. Considering the expected poor prognosis of the enrolled patients, this combined regimen showed an impressive antitumoral activity, but the severity of acute local and hematologic toxicity correlated makes the exportation of this regimen unproposable. However, the activity observed warrants the exploration of different, less toxic, chemo-radiotherapy programs including gemcitabine.