Stefano Luzi

Analysis of intraprostatic failures in patients treated with hormonal therapy and radiotherapy: implications for conformal therapy planning

PURPOSE Conformal therapy of prostate cancer is based on high-dose irradiation to the entire prostate gland. The aim of this study was to analyze the pattern of intraprostatic recurrence in patients undergoing external beam radiotherapy (EBRT) at a dose of 65-70 Gy to evaluate whether conventional radiotherapy doses are adequate to control microscopic disease outside the primary tumor and therefore whether high-dose irradiation can be exclusively focused on the macroscopic disease. METHODS AND MATERIALS The clinical and radiologic reports of 118 patients with prostate cancer undergoing EBRT (64.8-70.2 Gy) combined with hormonal therapy were evaluated. In all patients, before and after therapy, the size and site of the primary neoplasm within the prostate were assessed by clinical examination and imaging studies. RESULTS With a median follow-up of 45 months (range 14-119), the 5-year actuarial local control rate was 83.9%. Twelve patients had an intraprostatic recurrence, with the appearance of a new nodule (in 5 patients with a complete response after therapy) or increased nodular size compared with the minimal size (in the 7 other patients). In all patients, on the basis of a semiquantitative evaluation of the site of recurrence, this was shown to originate within the initial tumor volume. CONCLUSION The results of this analysis seem to confirm some histologic findings observed in patients undergoing prostatectomy for local recurrence after radiotherapy that suggest that local recurrence usually originates in the primary tumor rather than in focal prostatic intraepithelial neoplasia. This observation might justify the application of conformal therapy procedures aimed at identifying the gross tumor volume, in the phase of boost, exclusively with the primary tumor.

COMBINED MODALITY TREATMENT IN UNRESECTABLE EXTRAHEPATIC BILIARY CARCINOMA

PURPOSE Cancers of the extrahepatic biliary tract are rare. Surgical resection is considered the standard treatment, but is rarely feasible. Several reports of combined modality therapy, including external beam radiation, often combined with chemotherapy and intraluminal brachytherapy, have been published. The purpose of this study was to evaluate the effect of chemoradiation plus intraluminal brachytherapy on response, local control, survival, and symptom relief in patients with unresectable or residual extrahepatic biliary carcinoma. METHODS AND MATERIALS From February 1991 to December 1997, 20 patients (14 male, 6 female; mean age 61 +/- 12 years; median follow-up 71 months) with unresectable (16 patients) or residual (4 patients), nonmetastatic extrahepatic bile tumors (common bile duct, 8; gallbladder, 1; Klatskin, 11) received external beam radiation (39.6-50.4 Gy); in 19 patients, 5-fluorouracil (96-h continuous infusion, days 1-4 at 1,000 mg/m(2)/day) was also administered. Twelve patients received a boost by intraluminal brachytherapy using (192)Ir wires of 30-50 Gy, prescribed 1 cm from the source axis. RESULTS During external beam radiotherapy, 8 patients (40%) developed grade 1-2 gastrointestinal toxicity. Four patients treated with external-beam plus intraluminal brachytherapy had a clinical response (2 partial, 2 complete) after treatment. For the total patient group, the median survival and time to local progression was 21.2 and 33.1 months, respectively. Distant metastasis occurred in 10 (50%) patients. Two patients who received external beam radiation plus intraluminal brachytherapy developed late duodenal ulceration. Two patients with unresectable disease survived more than 5 years. CONCLUSION Our data suggest that chemoradiation plus intraluminal brachytherapy was relatively well-tolerated, and resulted in reasonable local control and median survival. Further follow-up and additional research is needed to determine the ultimate efficacy of this regimen. New chemoradiation combinations and/or new treatment strategies (neoadjuvant chemoradiation) may contribute, in the future, to improve these results.

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

ObjectivesTo evaluate the feasibility of intensity-modulated radiotherapy with simultaneous integrated boost to the dominant intraprostatic lesion for definitive treatment of prostate cancer. Materials and MethodsPatients 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. ResultsForty 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%. ConclusionsTreatment 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.

Interstitial brachytherapy for pancreatic cancer: Report of seven cases treated with 125I and a review of the literature

Since 1975, seven groups of investigators have reported clinical results of interstitial brachytherapy (IBT) for pancreatic cancer. The reports are comprised of data from 254 patients, 21 of whom died in the postoperative period for an overall operative mortality rate of 8.7%. Operative mortality rate range from 0% to 32% in individual reports. Most patients have been treated with 125I, although 25 patients were treated with 198Au seeds. Most investigators report combining IBT with external beam radiation therapy (EBRT) +/- adjuvant chemotherapy. In general, IBT has been associated with considerable morbidity. Median patient survival time has not exceeded 15 months. This report describes an additional seven patients with locally unresectable pancreatic cancer, without distant metastases, treated primarily with 60 to 100 Gy matched peripheral dose (MPD) by 125I IBT. One patient died postoperatively of a pulmonary embolus. Four of the remaining six patients were also treated with modest doses (10.5 to 30 Gy) of EBRT late in the course of the disease for local tumor progression. One developed a pancreaticocutaneous fistula, and one developed exacerbation of pre-existing diabetes mellitus. The median patient survival time from the date of IBT was 7 months (range: 0 to 21 months). One patient is alive without clinical evidence of cancer 9 months after IBT.

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.

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.

Is chemoradiation feasible in elderly patients

Cancer in the elderly is becoming an increasing public health problem. Nevertheless, several authors have noted the relative lack of information regarding the treatment of cancer in the elderly. The aim of this study was to determine the tolerance of concomitant chemoradiation in patients age ≥ 75 years with anorectal carcinoma.

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.

Prognostic significance of anemia and role of erythropoietin in radiation therapy.

Anemia represents a common finding in cancer patients, especially at an advanced stage. Anemia has an impact on the quality of life and at the same time seems to markedly limit the disease control that can be achieved with radiotherapy. The results of a series of clinical studies published in the last decade allow some general observations: 1. the administration of erythropoietin, especially if associated to ferrous sulfate is able to increase hemoglobulin levels in cancer patients undergoing radiation therapy (combined with concomitant chemotherapy); 2. erythropoietin stimulation of hemoglobin in anemia decreases the need for blood transfusion in cancer patients; 3. tumor response to radiation therapy appears to be enhanced by erythropoietin-induced hemoglobulin increase. Further clinical studies are required for assessment of indications, identification of optimal administration modalities, cost-analysis of this promising therapy for patients undergoing radiation therapy.

COST- AND TIME-SPARING SIMPLIFIED CONFORMAL THERAPY FOR PROSTATE CANCER: IS IT FEASIBLE?

PURPOSE It was hypothesized that using a simplified technique of volumes profiles determination (STVPD) based on CT data sets (correlate and projection) would increase the target dose without increasing the bladder and rectal dose obtained by conventional simulation techniques. To test this hypothesis, patients referred for radical radiation treatment for prostate carcinoma were prospectively evaluated by performing treatment planning using standard simulation, with (SSB) and without corner blocks (SSWB), STVPD, and 3D beams eye view. METHODS AND MATERIALS Twenty-one patients with prostate carcinoma (stage B: 7; stage C: 14) underwent four treatment planning procedures where the field arrangement was defined by standard simulation (SSB and SSWB), STVPD, and 3D beams eye view (BEV) with a four field (10 MV photons) box technique. Dose-volume histograms (DVHs) for the planning target volume (PTV), bladder, and rectum (relatives to the four techniques) were generated for all patients and compared; average percentage dose to the bladder and rectum were also calculated. RESULTS STVPD and 3D BEV treated an increased percentage of PTV at 95% isodose level, in comparison to standard simulation (with and without blocks). No statistically significant differences were found between the two techniques. A significant reduction of irradiated bladder volume was found between 3D BEV and STVPD versus simulation with and without blocks (mean percentage dose: 77.3%, 81.8%, 93.5%, and 92.6% respectively). No marked differences were recorded in rectal irradiation (mean percentage dose: 53.1%, 53.7%, 51.9%, and 50.2% respectively). Time required for treatment planning (excluding CT scan and definitive simulation) was less than 15 minutes for STVPD and more than 120 minutes for 3D BEV. CONCLUSION Our results confirm the inadequacy of standard simulation. It is possible, with conformal therapy, to increase the dose to the PTV, decreasing the irradiated volume of the bladder. The absence of sparing effect in the rectum is discussed. Using a box technique, STVPD can be used routinely to define the PTV in patients with prostate cancer, reducing the time required for treatment planning, with dosimetric results similar to those of 3D BEV.