Adult Onset Still's Disease and Radiotherapy treatment for breast cancer: Case report about management of this rare association and literature review.

AIM: This manuscript focuses on the first experience in literature of a patient with a complicated Adult Onset Still's Disease-related heart failure who thereafter underwent adjuvant radiotherapy for left breast cancer. BACKGROUND: AOSD is a rare autoimmune inflammation-related disease, in which life-threatening pulmonary and cardiac complications can occur. In literature, AOSD is often associated with cancer, as paraneoplastic syndrome, but there are few data about primary AOSD and management of oncological therapies. MATERIALS AND METHODS: A patient who needed adjuvant breast cancer radiotherapy underwent tumour board evaluation to define feasibility of an RT in a patient with of a history of a heart life-threatening complication 2 years before AOSD. Results of the review were discussed by a multidisciplinary panel of experts that chose the type of surgery, radiotherapy and monitoring of patient. RESULTS: Literature review confirmed association of AOSD with BC in some pts and uniqueness of this treatment management experience. Patient underwent RT according to schedule of 40.05/2.67 Gy/fx on residual left breast and 10/2 Gy/fx on tumour bed with the gating technique. The panel chose to keep immunosuppressive therapy with anakinra. No complications were observed at clinical, ECG and laboratory examinations. Maximum toxicity was G2 skin. At first follow up AOSD signs of flare were negative. CONCLUSION: In conclusion, when oncological treatments, especially radiotherapy, are mandatory for AOSD pts, multidisciplinary management and tailored monitoring are necessary to avoid acute adverse effects and allow pts to complete therapies.

Shoulder girdle impairment in breast cancer survivors: the role of range of motion as predictive factor for dose distribution and clinical outcome.

BACKGROUND: Pain and functional impairment of the ipsilateral shoulder girdle in patients who underwent surgery and radiotherapy for breast cancer (BC) is a late complication reported in the literature. We analyze a correlation with dosimetric parameters and propose an algorithm for sparing strategies. METHODS: A total of 111 patients treated for BC were included in this observational analysis during follow-up protocol visits. Exclusion criteria were the presence of moderate or severe arthrosis history and/or rheumatologic diseases. All the patients had complete physical and multidimensional examinations during joint (physiatrist and radiotherapy oncology) follow-up visits. A scapula-humeral articulation (SHA) standardized contouring was performed retrospectively on Eclipse® treatment plans. A possible correlation between patients' characteristics, radiotherapy, and dosimetry analysis and functional impairment was investigated at statistical analysis. Results of analysis were summarized into a proposal of algorithm for sparing SHA. RESULTS: A total of 111 patients were selected during follow-up visits. Mean age of patients was 60 years (range 41-85 years). A total of 103 patients (93%) underwent conservative surgery, with 110 patients (99%) undergoing axilla surgery as well. Fifty-two patients (46.8%) presented a reduction of range of motion (ROM) abduction on the treated side at the observational analysis. Mean ROM abduction reduction was 13°06' (range 0°-100°). Disability of the Arm, Shoulder and Hand questionnaire (DASH) score results were excellent in 79 patients (71.2%), discrete in 15 patients (13.5%), good in 15 patients (13.5%), and sufficient in 2 patients (1.8%). Median EQD2 Dmax at SHA was 18 Gy (range 0.22-51.9 Gy) and median EQD2 mean dose at SHA was 2 Gy (range 0.04-24.32 Gy). Univariate analysis showed a linear correlation between DASH score and ROM of abduction of treated side (ρ=-0.7), ROM of abduction and ROM of flexion in ipsilateral arm (ρ=0.8), or ROM of abduction and ROM of flexion in contralateral arm (ρ=0.8). A statistically significant difference in ROM abduction between the 2 arms was found at χ2 test (P<0.05 at χ2 confidence interval = 95%). Cox linear regression analysis showed ROM abduction on treated arm as a predictive factor of DASH score (P<0.0001). Age (P<0.05), DASH score (P=0.006), and ROM abduction on treated arm (P=0.005) were found as independent predictive factors of mean dose at multivariate analysis. A mean dose higher than 7 Gy and ROM abduction reduction more than 30° were related to DASH score level reduction. CONCLUSIONS: This hypothesis-generating study introduces an algorithm to be validated for management of sparing SHA and improving quality of survivorship. ROM evaluation after surgery, early physiotherapy, standard contouring, and planning adaptation represent possible indications to preserve shoulder impairment. Further prospective studies are needed to discriminate impairment of surgery and radiotherapy in order to personalized therapeutic plan programs.

Intensified adjuvant treatment of prostate carcinoma: feasibility analysis of a phase I/II trial.

PURPOSE: To perform a preliminary feasibility acute and late toxicity evaluation of an intensified and modulated adjuvant treatment in prostate cancer (PCa) patients after radical prostatectomy. MATERIAL AND METHODS: A phase I/II has been designed. Eligible patients were 79 years old or younger, with an ECOG of 0-2, previously untreated, histologically proven prostate adenocarcinoma with no distant metastases, pT2-4 N0-1, and with at least one of the following risk factors: capsular perforation, positive surgical margins, and seminal vesicle invasion. All patients received a minimum dose on tumor bed of 64.8 Gy, or higher dose (70.2 Gy; 85.4%), according to the pathological stage, pelvic lymph nodes irradiation (57.7%), and/or hormonal therapy (69.1%). RESULTS: 123 patients were enrolled and completed the planned treatment, with good tolerance. Median follow-up was 50.6 months. Grade 3 acute toxicity was only 2.4% and 3.3% for genitourinary (GU) and gastrointestinal (GI) tract, respectively. No patient had late grade 3 GI toxicity, and the GU grade 3 toxicity incidence was 5.8% at 5 years. 5-year BDSF was 90.2%. CONCLUSIONS: A modulated and intensified adjuvant treatment in PCa was feasible in this trial. A further period of observation can provide a complete assessment of late toxicity and confirm the BDSF positive results.

Long-term analysis of gemcitabine-based chemoradiation after surgical resection for pancreatic adenocarcinoma.

PURPOSE: To evaluate the efficacy in terms of local control (LC) of 24 h infusion of gemcitabine plus radiotherapy after surgery for pancreatic cancer. METHODS: Weekly gemcitabine (100 mg/m(2)) was provided as a 24-hour infusion during the course of radiotherapy (50.4 Gy to the tumor, 39.6 Gy to the nodes). Patients subsequently received five cycles of gemcitabine monochemotherapy (1,000 mg/m(2) 1, 8, q21). The primary end point of the study was to achieve a 2-year LC rate of ≥80 % with type I and II errors of 5 and 20 %. The study was designed to accrue a maximum sample size of 35 patients. Secondary end points were toxicity evaluation, metastasis-free survival (MFS), and overall survival (OS). RESULTS: Data of 35 patients were available. Most of the patients (n = 27; 77.1 %) had duodeno-cephalo-pancreatectomy, 5 (14.3 %) distal pancreatectomy, and 3 (8.6 %) total pancreatectomy. The pathological stages were T1-T2 (n = 7; 20.0 %), T3-T4 (n = 28; 80.0 %), N0 (n = 17; 48.6 %), and N1 (n = 18; 51.4 %). Thirty patients (85.7 %) completed chemoradiation. Twenty-three patients (65.7 %) received further sequential chemotherapy. Acute toxicity was acceptable. No late toxicity occurred. The median follow-up period was 64 (range 24-118) months, and 2-year crude rate of LC was 83 (median not reached). Median MFS and OS were 26.5 and 22.5 months, respectively. CONCLUSIONS: The rate of LC met the main goal of the study. The regimen resulted in a high LC rate but failed to show a benefit in terms of OS or MFS, thus suggesting the need for a more intensified multimodal approach.

Intensity-modulated radiotherapy with simultaneous integrated boost to dominant intraprostatic lesion: preliminary report on toxicity.

OBJECTIVES: To evaluate the feasibility of intensity-modulated radiotherapy with simultaneous integrated boost to the dominant intraprostatic lesion for definitive treatment of prostate cancer. MATERIALS AND METHODS: Patients were deemed eligible for the study if they had histologically proven stage cT2-T3 N0M0 prostate adenocarcinoma. In addition <20% risk of lymph nodal involvement according to Roach formula, was required for enrollment. Patients were treated with intensity-modulated radiotherapy with simultaneous integrated boost technique to the dominant intraprostatic lesion defined by magnetic resonance imaging. The prescribed dose to the prostate and seminal vesicles was 72 Gy (1.8 Gy per fraction). The dose delivered to the intraprostatic lesion received was 80 Gy (2 Gy per fraction). Acute gastrointestinal (GI) and genitourinary (GU) toxicity was evaluated weekly during treatment, and at 1 and 3 months thereafter. Late GI and GU toxicity was evaluated by Kaplan Meier method. RESULTS: Forty patients were deemed evaluable. Acute and late GI and GU toxicity were evaluated in all patients. Two patients (5%) developed acute grade 3 GI toxicity and 1 patient (2.5%) developed acute grade 3 GU toxicity. No grade 4 acute GI or GU toxicity occurred. With a median follow-up of 19 months (interquartile range, 15 to 26 mo), the 2-year actuarial cumulative incidence of grade ≥2 rectal toxicity was 9.5%. The 2-year actuarial cumulative incidence of grade ≥2 urinary toxicity was 13.3%. CONCLUSIONS: Treatment related acute toxicity was low in our cohort. Prolonged observation with a larger series of patients is necessary to evaluate late toxicity and local control.

External beam radiotherapy plus 24-hour continuous infusion of gemcitabine in unresectable pancreatic carcinoma: long-term results of a phase II study.

PURPOSE: To evaluate the efficacy of gemcitabine-based chemoradiation (CT-RT) in treating patients (pts) affected by locally advanced pancreatic cancers (LAPC). METHODS AND MATERIALS: Weekly gemcitabine (100 mg/m(2)) was given as a 24-hour infusion during the course of three-dimensional radiotherapy (50.4 Gy to the tumor, 39.6 Gy to the nodes). After CT-RT, pts received five cycles of sequential chemotherapy with gemcitabine (1000 mg/m(2); 1, 8, q21). Response rate was assessed according to World Health Organization criteria 6 weeks after the end of CT-RT. Local control (LC), time to progression (TTP), metastases-free survival (MFS), and overall survival (OS) were analyzed by the Kaplan Meier method. RESULTS: Forty pts (male/female 22/18; median age 62 years, range, 36-76) were treated from 2000 to 2005. The majority had T4 tumour (n = 34, 85%), six pts (15%) had T3 tumour. Sixteen pts (40%) were node positive at diagnosis. Grade 3-4 acute toxicity was observed in 21 pts (52.5%). Thirty pts (75%) completed the treatment schedule. A clinical response was achieved in 12 pts (30%). With a median follow-up of 76 months (range, 32-98), 2-year LC was 39.6% (median, 12 months), 2-year TTP was 18.4% (median, 10 months), and 2-year MFS was 29.7% (median, 10 months). Two-year OS (25%; median, 15.5 months) compared with our previous study on 5-fluorouracil-based CT-RT (2.8%) was significantly improved (p <0.001). CONCLUSIONS: Gemcitabine CT-RT seems correlated with improved outcomes. Healthier patients who are likely to complete the treatment schedule may benefit most from this therapy.

Chemoradiation with concomitant boost followed by radical surgery in locally advanced cervical cancer: a dose-escalation study.

OBJECTIVE: Aim of this study is to evaluate the feasibility of an accelerated fractionation radiotherapy by concomitant boost in locally advanced cervical cancer patients, to explore the maximum tolerated dose (MTD) of radiation through a dose-escalation scheme, and to verify if increasing the radiation dose would result in a higher rate of pathologic complete response. METHODS: During the first and the last week of treatment, a combination of cisplatin (20 mg/mq/d, IV, days 1-4) and 5-fluorouracil (1 g/mq/d, continuous venous infusion, days 1-4) was administered. The dose escalation of external radiotherapy was delivered on the primary tumor, using the concomitant boost technique (CB, 90 cGy per fraction), delivering 3 different dose levels: (1) 1 weekly boost for a total dose of 4320 cGy; (2) 2 weekly boosts, total dose 4680 cGy; (3) 3 weekly boosts, total dose of 5040 cGy. RESULTS: Eighteen patients were submitted to a radiochemotherapeutic schedule of 3960 cGy in 22 fractions on pelvic lymph nodal stations. The MTD of radiation was not reached, being the only toxicities registered neutropenia G3 (n = 4), thrombocytopenia G3 (n = 1), stomatitis G3 (n = 1), diarrhea G3 (n = 2) easily managed. Six weeks after the end of radiochemotherapy, 17 patients were submitted to radical surgery, and are therefore evaluable for pathologic response. Among them, 15 complete remissions (88.2%, including 3 microscopical partial response), 1 partial response (5.9%), and 1 progression (5.9%) have been observed. CONCLUSIONS: These results demonstrate, even if in a small study, that this regimen of concurrent chemoradiation followed by radical surgery is well tolerated.

Squamous cell carcinoma antigen in follow-up of cervical cancer treated with radiotherapy: evaluation of cost-effectiveness.

PURPOSE: The squamous cell carcinoma (SCC) antigen is still considered the most accurate serologic tumor marker in cervical carcinoma. We assessed the contribution of the SCC assay to the detection of recurrences in patients treated with radiotherapy. METHODS AND MATERIALS: The pattern of recurrence and follow-up data were prospectively recorded for 135 patients. Of the 135 patients, 103 (76.3%) had primary cervical carcinoma and 32 (23.7%) had already experienced disease recurrence that had been successfully treated with surgery (n = 2), surgery plus radiotherapy (n = 2), radiotherapy (n = 5), or concomitant chemoradiotherapy (n = 23). The follow-up evaluations (chest X-ray, abdominopelvic magnetic resonance imaging, gynecologic examination with colposcopy, Papanicolaou smear, and SCC assay) were performed at 6-month intervals; the evaluation was done earlier if recurrent disease was suspected. The median follow-up time was 29 months (range, 6-131). The SCC serum levels were assayed, and a cost analysis was done. RESULTS: A total of 481 SCC determinations were performed. Of the 135 patients, 43 (31.8%) experienced disease recurrence. The SCC levels were higher in those with recurrent disease than in the disease-free patients. Elevation of SCC was documented in 34 (79.1% sensitivity) of 43 recurrences before symptoms appeared. Of the 38 patients with serum SCC elevation, 34 developed a recurrence (positive predictive value, 89.5%). Of the 97 patients with negative SCC serum levels, 88 had negative findings at the clinicoradiologic evaluation (negative predictive value, 90.7%). A simplified approach (SCC plus gynecologic examination) was evaluated. Compared with the complete follow-up program, the rate of missed recurrence was 2.2%. The total projected cost per patient for 5 years of follow-up for the simplified procedure was approximately 12.2-fold lower than the standard approach. CONCLUSIONS: Our results have shown that a simplified diagnostic approach, including the SCC assay and gynecologic examination, can detect a high rate of recurrence from cervical cancer, with a very favorable cost-effective profile.

Chemoradiation and brachytherapy in biliary tract carcinoma: long-term results.

PURPOSE: To evaluate long-term effects of chemoradiation and intraluminal brachytherapy in terms of local control, disease-free survival, overall survival, and symptom relief in patients with unresectable or residual extrahepatic biliary carcinoma. METHODS AND MATERIALS: Twenty-two patients with unresectable (17 patients) or residual (5 patients) nonmetastatic extrahepatic bile tumors received external beam radiation therapy (39.6-50.4 Gy) between 1991 and 1997. In 21 patients, 5-fluorouracil (96-h continuous infusion, Days 1-4, 1,000 mg/m2/day) was administered. Twelve patients received a boost of intraluminal brachytherapy with 192Ir wires (30-50 Gy) 1 cm from the source axis. RESULTS: During external beam radiotherapy, 10 patients (45.4%) developed Grade 1 to 2 gastrointestinal toxicity. In patients with unresectable tumor who could be evaluated, the clinical response was 28.6% (4 of 14). Two patients showed complete response. In all 22 patients, median durations of local control, disease-free survival, and overall survival were 44.5 months, 16.3 months, and 23.0 months, respectively. Two patients who received external beam radiation therapy and intraluminal brachytherapy developed late duodenal ulceration. In patients with unresectable tumors, median survival was 13.0 months and 22.0 months in those treated with and without brachytherapy, with 16.7% and no 5-year survival, respectively (p=0.607). Overall 5-year survival was 18.0%: 40% and 11.7% in patients treated with partial resection and in those with unresectable tumor, respectively (p=0.135). CONCLUSION: This study confirmed the role of concurrent chemoradiation in advanced biliary carcinoma; the role of intraluminal brachytherapy boost remains to be further analyzed in larger clinical trials.

Impact of dose and volume on subcutaneous fibrosis.

The multifactorial genesis of radiation-induced fibrosis makes a general outline of the occurence of this late toxicity fairly unpredictable. Scientific knowledge about dose fractionation, irradiated volume, total time, conformation procedures including IMRT can help provide better treatments. Chemical and physical therapies aimed at the removal of fibrosis are still limited or under study. The system of monitoring late toxicity used by the authors is presented.

Concurrent 5-fluorouracil, mitomycin C and radiation with or without brachytherapy in recurrent cervical cancer: a scoring system to predict clinical response and outcome.

AIMS AND PURPOSE: This is a prospective, phase II study aimed to evaluate the effect of concurrent 5-fluorouracil, mitomycin C, and radiation with or without brachytherapy on the clinical outcome of a series of recurrent cervical cancer patients and to determine the prognostic impact of a subset of factors. METHODS: Thirty-three patients with locally recurrent, non-metastatic cervical cancer received external beam radiation (4-week split course: 23.4 + 23.4 Gy) plus two courses of concomitant chemotherapy (5-fluorouracil, 96-h continuous infusion, days 1-4, 1 g/m2/day; mitomycin C, 10 mg/m2, bolus i.v., day 1). Twelve patients with vaginal recurrence (36.4%) underwent endocavitary low-dose rate brachytherapy boost (20-25 Gy); 11 patients with lateral pelvic recurrence (33.3%) received external beam radiation boost (14-20 Gy). RESULTS: Fourteen complete responses (42.4%), 7 partial responses (21.2%), 5 disease stabilizations (15.1%) and 7 progressions (21.2%) were obtained. After a median follow-up of 34 months (range, 6-127), overall actuarial 3-year survival, progression-free survival and local progression-free survival were 59.7%, 48.1% and 51.7%, respectively. Patients with vaginal recurrence of less than 4 cm and negative lymph nodes proved to respond best to the treatment. Two patients (6.1%) experienced hematologic grade 3 toxicity. One patient had grade 3 intestinal toxicity (3.0%). No patient had major skin or urological acute toxicity. Severe late toxicity was infrequent. Three patients had prolonged leukopenia (9.0%). Four patients showed severe vaginal stenosis (12.1%). A clinical score of 0 to 1 was assigned to each patient on the basis of the absence (score = 0) or presence (score = 1) of any of the following prognostic factors: time between surgery and recurrence shorter than 12 months, pelvic wall site of recurrence, positive lymph nodes, hemoglobin < 11 g/dL. Using this system, it was clear that patients with a low total score had a significantly better outcome (clinical remission, 51% of patients with a score < or = 2 vs 12% of patients with a score > 2, P = 0.06), local control of the disease (65% vs 20% after 3 years, P = 0.001,) and overall survival (75% vs 30% after 3 years, P = 0.032). CONCLUSIONS: Our data suggest that this combined modality therapy was relatively well tolerated and resulted in reasonable local control and survival. The scoring system proved to be helpful to identify patients with the greatest chance of benefiting from the treatment. Further studies are probably needed to salvage the other patients, whose prognosis remains severe.

Concurrent 5-fluorouracil, mitomycin C and radiation, with or without brachytherapy, in recurrent endometrial cancer: a scoring system to predict clinical response and outcome.

AIMS AND BACKGROUND: This prospective, phase II study aimed to test the efficacy of concurrent 5-fluorouracil, mitomycin C and radiation, with or without brachytherapy, on the clinical outcome of a series of recurrent endometrial cancer patients and to determine the prognostic impact of a subset of factors. METHODS: Thirty patients with locally recurrent, nonmetastatic endometrial cancer received external beam radiation (4-week split course: 23.4 + 23.4 Gy) plus two courses of concomitant chemotherapy (5-fluorouracil, 96-h continous infusion, days 1-4; 1 g/m2/day; mitomycin C, 10 mg/m2, bolus iv, day 1). Nineteen patients (63.3%) underwent endocavitary, low-dose brachytherapy boost (20-25 Gy); eight patients (26.7%) received external beam radiation boost (14-20 Gy). RESULTS: Eleven complete responses (36.7%), 11 partial responses (36.7%), 6 disease stabilizations (20.0%) and 2 progressions (6.6%) were observed. After a median follow-up of 27 months (range, 1-108), overall actuarial 3-year survival, progression-free survival and local progression-free survival were 46.8%, 35.2% and 41.2%, respectively. Two patients (6.7%) experienced hematological grade 3 toxicity. Two patients (6.7%) had grade 3 intestinal toxicity. Severe late toxicity was infrequent, only 3 patients showing severe vaginal stenosis (10.0%). A clinical score of 0 to 1 was assigned to each patient on the basis of the absence (score = 0) or presence (score = 1) of any of the following prognostic factors: time between surgery and recurrence shorter than 12 months, pelvic wall site of recurrence, positive lymph nodes, hemoglobin < 11 g/dL. With this device, it was clear that patients with a low score had a significantly better outcome (clinical remission: 77.2% of patients with a score < 2 vs 25.0% of patients with a score > or = 2, P = 0.009), better local control of the disease (50.2% vs. 0 at 3 years, P = 0.014,) and better overall survival (65.8% vs 0 at 3 years, P = 0.003). CONCLUSIONS: Our data suggest that this combined modality therapy was relatively well tolerated and resulted in reasonable local control and survival. The scoring system proved to be helpful in identifying patients with the best chance of benefiting from the treatment.

Biological optimization of the dose in prostate cancer.

Radiotherapy is one of the therapeutic options for nonmetastatic prostate carcinoma. Its outcomes seem superior to simply "wait-and-see" and comparable with those of radical prostatectomy. However, in locally advanced tumors the outcomes are not completely satisfactory. Therefore, in the last decades, numerous studies aimed at the optimization of therapy have been performed. The combination with hormonal therapy and dose escalation have allowed better clinical results. The effect of adjuvant hormonal therapy is well evident especially in phase III studies where the improvement both in biochemical relapse-free survival, cause-specific and overall survival, was documented. As for the effect of dose-escalation, at present, the improvement is limited to the biochemical disease-free survival, when considering the randomized studies. Both strategies seem unnecessary in low-risk patients while the advantages are evident in patients with intermediate-high-risk disease. In case of intermediate risk, dose escalation seems particularly effective while in high risk disease adjuvant hormonal therapy seems more advantageous. The role of dose escalation in this category is discussed, considering that many patients have no more a localized disease. The possibility of further improved clinical outcomes based on the combination of the two strategies is uncertain. Non conventional fractionations and hypofractionation in particular are still under experimentation and their utility has not been established as yet.

5-fluorouracil-based chemoradiation in unresectable pancreatic carcinoma: Phase I-II dose-escalation study.

PURPOSE: A Phase I-II dose-escalation study was performed to evaluate the possible impact of the dose on response, toxicity, pain relief, and outcome in patients with unresectable pancreatic carcinoma. METHODS AND MATERIALS: A total of 50 patients entered the study. The external beam radiotherapy (RT) dose was 39.6 Gy in the first 15 patients, 50.4 Gy in the next 15 patients, and 59.4 Gy in the remaining 20 patients, at five 1.8-Gy fractions weekly. During external beam RT, patients received concurrent continuous infusion of 5-fluorouracil (1000 mg/m(2) on Days 1-4 and 21-24). Patients were evaluated for toxic reactions, local disease control, survival, and pain relief. RESULTS: No treatment-related deaths occurred from acute toxicity. Four patients required a temporary treatment interruption because of acute hematologic (2 patients) or GI (2 patients) toxicity, not correlated with the delivered RT dose. Three patients (6%) developed late toxicity (duodenal ulcer in 2 and duodenal stenosis in 1). All patients who developed late toxicity had received a dose of 59.4 Gy. At univariate analysis, only the RT dose correlated significantly with the incidence of late toxicity (at 2 years, 39.6-50.4 Gy resulted in 0% and 59.4 Gy resulted in 58.2%; p = 0.023). At multivariate analysis, the RT dose also showed a trend with the incidence of late side effects (p = 0.052). Overall, 6 patients had a partial response (12%) and 44 (88%) had no change. The overall response rate was 8.0% (95% confidence interval, 1.5-20.5%). The rate of response was not different in the three groups. In-field locoregional disease progression was seen in 7 patients (14.0%). Distant relapse was documented in 34 patients (68.0%). None of analyzed variables, in particular, the RT dose delivered, showed a statistically significant correlation with objective response, local control, incidence of metastasis, disease-free survival, or overall incidence of pain symptoms after therapy. The whole group median survival was 9 months. The actuarial survival rate at 1, 2, and 3 years was 31.3%, 2.8%, and 0.0%, respectively. None of analyzed parameters correlated significantly with survival at univariate or multivariate analysis. CONCLUSION: In a Phase I-II study, the association of high RT doses with the incidence of severe toxicity in the treatment of unresectable pancreatic carcinoma was confirmed. Furthermore, this dose-escalation study did not document a clearcut correlation, using 5-fluorouracil-based chemoradiation, between the radiation dose and clinical outcome.

High-dose radiotherapy plus prolonged hormone therapy in CT2-3 prostatic carcinoma: is it useful?

AIMS AND BACKGROUND: Clinical studies published in the last decade have shown the possible improvement in prognosis of patients with prostatic carcinoma undergoing radiation therapy with dose escalation or in combination with hormone therapy. However, in studies on hormone therapy, moderate doses of radiation therapy have been used, whereas in studies with high-dose radiotherapy, hormone therapy usually was not administered. Therefore, it is not clear whether the concomitant use of high doses and prolonged hormone therapy could determine an additional beneficial effect. The aim of the present study was therefore to evaluate the relative prognostic role of different dose levels (< 70 versus > or = 70 Gy) of external beam radiotherapy and of different hormone therapies (neoadjuvant only versus neoadjuvant + adjuvant). METHODS: A total of 426 patients (median age, 71 yrs; range, 51-87 yrs) underwent external beam radiotherapy (70 Gy median dose to prostate volume +/- 45 Gy to pelvic lymph nodes) and neoadjuvant hormone therapy (bicalutamide for 30 days; goserelin, 3.6 mg every 28 days starting two months before radiotherapy and for its entire duration). Dose to the prostate was < 70 Gy in 44.8% of patients and > or = 70 Gy in 55.2%. A total of 244 patients received adjuvant hormonal therapy. The distribution according to the clinical stage was 48.1% T2 and 51.9% T3. The distribution according to the Gleason score was 14.3% grades 2-4, 66.7% grades 5-7 and 19.0% grades 8-10. The distribution according to pretreatment prostate-specific antigen levels (in ng/mL) was 7.0% for 0-4, 29.3% for 4-10, 30.3% for 10-20, and 33.3% for > 20. RESULTS: With a median follow-up of 35 months (range, 1-151), 81 patients (19.0%) showed biochemical recurrence, 17 patients (4.0%) showed local disease progression, and 12 patients (2.8%) showed distant metastases. Overall, 23 patients (5.4%) showed disease progression. Four patients (0.9%) died. At the time of this writing, no patient has died from prostatic carcinoma. At univariate analysis, the radiation dose delivered to the tumor and the administration of adjuvant hormone therapy were shown to be significantly correlated with biochemical disease-free survival. At multivariate analysis, the single parameter significantly correlated with biochemical disease-free survival was the radiation dose delivered to the tumor. In the subset of patients not treated with adjuvant hormone therapy, there was a significant correlation between radiation dose and biochemical disease-free survival at univariate and multivariate analysis. A similar correlation between adjuvant hormone therapy and biochemical disease-free survival was observed in the subset of stage cT3 patients at univariate and multivariate analysis. In patients undergoing combined treatment without adjuvant hormone therapy, a significant correlation was observed between clinical stage and biochemical disease-free survival, at univariate and at multivariate analysis. CONCLUSIONS: The results of the study confirmed the positive impact of radiotherapy doses > 70 Gy and of adjuvant hormone therapy in patients with locally advanced prostatic carcinoma. Owing to the lack of evidence of a correlation between radiation dose and biochemical outcome in patients undergoing prolonged hormone therapy, the role of further dose escalation in patients undergoing combined hormone and radiation therapy is still unclear.

Radiotherapy in cT3 prostatic carcinoma: retrospective comparison between neoadjuvant and adjuvant hormonotherapy.

INTRODUCTION: The aim of this study was to retrospectively compare the clinical outcomes achieved in 2 groups of patients with cT3 prostatic carcinoma undergoing neoadjuvant hormonotherapy and neoadjuvant hormonotherapy plus adjuvant hormonotherapy with external beam radiotherapy. PATIENTS AND METHODS: One hundred patients with cT3N0M0 prostatic carcinoma underwent radiotherapy to pelvic lymph nodes (45 Gy, 1.8 Gy/fraction) with a booster dose (65-70 Gy) to the prostatic cavity. Forty-four patients received neoadjuvant hormonotherapy (goserelin, starting 2 months before radiotherapy and continuing until the end of irradiation); 56 patients received neoadjuvant hormonotherapy plus adjuvant goserelin until disease progression, if present. RESULTS: Patients undergoing adjuvant hormonotherapy as compared to those who received exclusive neoadjuvant therapy showed a higher reduction in PSA level below 1.0 ng/ml (p = 0.0211), a lower incidence of biochemical failures (p = 0.0170), a lower incidence of hematogenous metastases (p = 0.0320) and a trend suggestive of a better disease-free survival (p = 0.0660). At univariate analysis (logrank), Gleason score did not show a significant correlation with any of the end points analyzed. To the contrary, patients with tumor <15 mm showed a better local control (p = 0.0347) and biochemical failure-free survival (p = 0.0102). Furthermore, a trend between initial PSA level and incidence of hematogenous metastases was observed (p = 0.0519). Patients with a posttreatment PSA level <1.0 ng/ml had a lower incidence of metastases (p = 0.0237) and a better survival (p = 0.0178); patients with complete clinical response showed a lower incidence of biochemical failures (p = 0.0469). Radiotherapy doses >70 Gy showed a trend with biochemical failure-free survival (p = 0.0554). At multivariate analysis, a correlation between Gleason score and incidence of metastases (p = 0.0232), and between tumor diameter and local control (p = 0.0178) and biochemical failure-free survival (p = 0.0290) was recorded. CONCLUSIONS: In patients with cT3N0M0 prostate carcinoma, prolonged hormonotherapy was shown to be significantly correlated with biochemical failure-free survival and distant metastasis-free survival. Furthermore, tumor size had a significant impact on biochemical failure-free survival as well as on local control.

Complete response after chemoradiation in ampullary carcinoma: a case report.

AIMS AND BACKGROUND: The case of a 70-year-old patient with resectable, poorly differentiated adenocarcinoma of the ampulla of Vater is presented. PATIENT AND METHODS: Due to intraoperative hemorrhagic complications, surgical resection was not feasible. The patient was treated with radiochemotherapy consisting of external beam radiotherapy (50.4 Gy; 1.8 Gy/fraction; 5 fractions/week) plus 5-FU (1000 mg/m2/day, continuous i.v. infusion, days 2-5, week 1 and 5 of radiotherapy) and mitomycin C (10 mg/m2 i.v., day 2, week 1 of radiotherapy). RESULTS: At five years' follow-up the patient was in good general condition, without any signs of disease according to CT scan, endoscopic retrograde cholangiopancreatography and tumor marker determination. Multiple random biopsies performed in the ampullary region were negative for tumor growth. CONCLUSIONS: In patients with ampullary carcinoma the use of concurrent chemoradiation should be considered, particularly when surgical resection is unfeasible due to medical contraindications or locally advanced disease.

Lymphatic drainage and CTV in pancreatic carcinoma.

CTV definition in exclusive or adjuvant radiation therapy of pancreatic carcinoma is essentially based on the opinion of "expert" authors and on the knowledge of lymphatic pathways. The subject has been widely debated. Radiotherapy treatments of the entire upper abdomen (liver and pancreatic region), pancreas and lymph node stations, to volumes focused on macroscopic tumor only, have been proposed. Carcinoma of exocrine pancreas is characterized by the frequent, early appearance of metastasis via the lymphatic route. Most commonly involved lymph node stations include those of the celiac trunk, superior mesenteric, peripancreatic, lumboaortic lymph nodes, those of the hepatic portal (the latter in particular for pancreatic head tumors) and of the hilum of spleen (the latter in particular for pancreatic tail tumors). The possible multicentricity of pancreatic carcinoma, most likely due to intraductal spread, should lead to the inclusion in the CTV of the entire pancreatic parenchyma. This should be considered also for the frequent perineural intra- or extrapancreatic spread of pancreatic carcinoma present also in small tumors (T1). In extrapancreatic spread the retropancreatic adipose tissue should be included in the CTV at least at the GTV level. At the present state of knowledge, in the absence of pattern of failure analysis and of comparison of different treatment approaches, in terms of the definition of volumes of interest, CTV definitions which include lymphatic drainage stations, most part of pancreatic parenchyma and retropancreatic adipose tissue seem justified especially in treatments for cure. In palliation, the CTV may be limited to the GTV and the adipose tissue behind it.

Lymphatic drainage and CTV in carcinoma of the prostate.

The prostate lymphatics drain into the periprostatic subcapsular network, from which 3 groups of ducts originate: the ascending ducts from the cranial prostate draining into the external iliac lymph nodes, the lateral ducts running to the hypogastric lymph nodes and the posterior ducts draining from the caudal prostate to the subaortic sacral lymph nodes of the promontory. Internal, external iliac and obturator lymph nodes are the most frequently involved by prostate carcinoma. Metastases to presacral and common iliac lymph nodes are rare. For the limited staging accuracy, present indications for seminal vesicle irradiation and pelvic node prohylactic irradiation are essentially based on risk categories and estimation algorithms; the latter while are widely used in international studies are not free of limitations as stressed since they were introduced. A method to deliver high doses to the tumor while limiting the irradiation of critical organs might be the delivery of a boost to the tumor only. This approach could become increasingly feasible with the diffusion of imaging procedures able to better define tumor extension.

Chemoradiation in cervical carcinoma: a must?

Cervical carcinoma is one of the most frequent gynecological malignancies. Literature shows that while the rate is exceedingly low in systematically screened populations, the incidence remains high because of large populations of at-risk women--particularly in underserved nations and in medically indigent subpopulations of Western nations--who are not screened. Recently, a series of randomized trials has demonstrated the possibility to dramatically improve the prognosis of these patients by using concurrent chemoradiation. In particular, concurrent chemoradiation represents a major treatment option in patients with bulky IB-IIA disease, IIB-IVA disease and resected IB-IIA disease with poor prognostic factors. However, further studies are necessary to optimize treatment schedules and particularly to define the best drug combination to be used during radiation therapy, improve patients selection by the analysis of anatomical (TNM stage) and non-anatomical (tumor oxygenation, genetic markers, tumor angiogenesis) prognostic factors, explore novel treatment strategies, such as use of neoadjuvant chemoradiation in locally advanced tumors, integration of antiangiogenetic therapies in chemoradiation schedules, use of supportive treatments aimed to overcome tumor hypoxia, to evaluate the possibility of 'cure' of locally recurrent tumors by chemoradiation and finally to define the best 'second-line' treatment for patients failing after chemoradiation with or without surgery.