Marco Orsatti

Adjuvant androgen deprivation impacts late rectal toxicity after conformal radiotherapy of prostate carcinoma

To evaluate whether androgen deprivation impacts late rectal toxicity in patients with localised prostate carcinoma treated with three-dimensional conformal radiotherapy. One hundred and eighty-two consecutive patients treated with 3DCRT between 1995 and 1999 at our Institution and with at least 12 months follow-up were analysed. three-dimensional conformal radiotherapy consisted in 70–76 Gy delivered with a conformal 3-field arrangement to the prostate±seminal vesicles. As part of treatment, 117 patients (64%) received neo-adjuvant and concomitant androgen deprivation while 88 (48.4%) patients were continued on androgen deprivation at the end of three-dimensional conformal radiotherapy as well. Late rectal toxicity was graded according to the RTOG morbidity scoring scale. Median follow up is 25.8 (range: 12–70.2 months). The 2-year actuarial likelihood of grade 2–4 rectal toxicity was 21.8±3.2%. A multivariate analysis identified the use of adjuvant androgen deprivation (P=0.0196) along with the dose to the posterior wall of the rectum on the central axis (P=0.0055) and the grade of acute rectal toxicity (P=0.0172) as independent predictors of grade 2–4 late rectal toxicity. The 2-year estimates of grade 2–4 late rectal toxicity for patients receiving or not adjuvant hormonal treatment were 30.3±5.2% and 14.1±3.8%, respectively. Rectal tolerance is reduced in presence of adjuvant androgen deprivation.

Randomized study comparing chemotherapy plus radiotherapy versus radiotherapy alone in FIGO stage IIB-III cervical carcinoma

Between January 1989 and December 1991, 64 patients with advanced cervical carcinoma FIGO stage IIb-III were randomized to receive radiotherapy (RT) alone or the sequential combination of chemotherapy (CT) and RT. RT consisted of external RT (40 Gy fractionated over 4 weeks) + brachytherapy (40 Gy to point A) + an additional boost to the parameters (15–20 Gy) in arm RT; CT consisted of cisplatin 60 mg/m2 i.v. day 1 q 15 days administered for 2 cycles before the start of RT and for 4 cycles after the end of radiation treatment in CT + RT arm. Among the 58 evaluable patients objective response rate was as follows: in RT arm, CR in 40.7% of patients, PR in 40.7%, and SD in 18.6%; in CT+RT arm, CR in 42% of patients, PR in 35.5%, and SD in 22.5%. The median duration of response was 12 months (range: 3–38 + months). At a median follow-up of 36 months survival (S) and progression-free survival (PFS) were 83% and 72.4% in RT arm, 72% and 59.3% in CT + RT arm, respectively. No significant difference was observed between the 2 treatment arms, neither in terms of objective response nor in terms of S and PFS. Both treatments were generally well tolerated. In our experience the addition of chemotherapy to standard radiotherapy does not enhance morbidity and does not interfere with the correct delivery of the planned treatment. However, results of this combined modality regimen remain unsatisfactory, since no improvement in pelvic control and survival of patients with advanced cervical carcinoma was observed.

Alternating chemo-radiotherapy in bladder cancer: A conservative approach

PURPOSE The aim of this Phase II study was to determine a bladder-sparing treatment in patients with invasive bladder cancer, allowing a better quality of life. Objectives were to test toxicity and disease-free and overall survival of patients given an alternated chemo-radiotherapy definitive treatment. METHODS AND MATERIALS Seventy-six patients with bladder cancer Stage T1G3 through T4 N0 M0 were entered in the same chemotherapy regimen (Cisplatin 20 mg/mq and 5-Fluorouracil 200 mg/mq daily for 5 days) alternated with different radiotherapy scheduling, the first 18 patients received two cycles of 20 Gy/10 fractions/12 days each; the second group of 58 patients received two cycles of 25 Gy/10 fractions/12 days each (the last 21 patients received Methotrexate 40 mg/mq instead of 5-Fluorouracil). RESULTS A clinical complete response was observed in 57 patients (81%), partial response in 7 patients (10%), and a nonresponse in 6 patients (9%). At a median follow-up of 45 months, 33 patients (47%) were alive and free of tumor. The 6-year overall survival and progression-free survival was 42% and 40%, respectively. Systemic side effects were mild, while a moderate or severe local toxicity was observed in 14 patients and 13 patients (about 20%), respectively. CONCLUSION Our conservative combination treatment allowed bladder-sparing in a high rate of patients and resulted in a survival comparable to that reported after radical cystectomy.

Chemotherapy versus radiotherapy in the management of ovarian cancer patients with pathological complete response or minimal residual disease at second look

The management of patients with epithelial ovarian cancer with no or minimal residual disease at second-look laparotomy after aggressive surgery and platinum-based chemotherapy has not been definitively established. We report the results of a randomized study comparing three more courses of the same chemotherapy inducing the response (21 patients) with whole-abdomen radiotherapy (20 patients). Thirty-eight patients responded to first-line chemotherapy and three had stabilization of disease. In eight patients tumor debulking was performed at second-look laparotomy. No severe toxic effects were noted in both arms. Bowel obstruction occurred in one patient treated with radiotherapy. At a median follow-up of 22 months, 11 of 20 patients in the radiotherapy arm and 6 of 21 in the chemotherapy arm progressed and 9 and 3 patients died, respectively. Although the number of randomized patients is small we stopped the trial because of the survival and progression-free survival advantage of chemotherapy-treated patients.

High-Risk Early-Stage Ovarian Cancer Randomized Clinical Trial Comparing Cisplatin Plus Cyclophosphamide versus Whole Abdominal Radiotherapy

From 1985 to 1989 70 patients with high-risk FIGO Stage I-II ovarian carcinoma entered a randomized trial comparing chemotherapy (CT: cisplatin 50 mg/m2 + cyclophosphamide 600 mg/nr day 1 every 28 days for 6 courses) versus whole abdominal radiotherapy (WAR) given according to the open-field technique (43.2 Gy/24 fractions to the pelvis and 30.2 Gy to the upper abdomen). Protocol violations occurred in 8 patients randomized to WAR who received CT because of their own and/or physicians decision. Since protocol compliance was poor and accrual low the study was prematurely closed. Treatment-related toxicity for patients receiving CT was mild and tolerable, consisting chiefly of controllable grade 3 emesis (71%). Grade 3–4 diarrhea was experienced by 28% of patients treated with WAR: severe enteritis requiring hospitalization was observed in 2 patients. Late bowel obstruction requiring surgery was observed in I patient. At a median follow-up of 60 months, 21 patients died and 23 relapsed. Five-year survival was 71% and 53% (p =.16), while relapse- free survival was 14% and 50% (p =.07) for CT and WAR, respectively. Although no firm conclusion can be drawn from the present study, a short-term CT. including cisplatin, appears a safe treatment in comparison to WAR.

Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in patients undergoing radiotherapy for head and neck tumour: results from a double-blind placebo-controlled trial

Fluconazole is recommended in the prophylaxis of oropharyngeal candidiasis (OPC) in patients undergoing radiotherapy for head-neck tumours; however, the actual effectiveness of fluconazole in this setting remains unclear. Adult patients with cervico-cephalic carcinoma submitted to radical or adjuvant radiotherapy were randomized to 100 mg fluconazole (n = 138) or matched placebo (n = 132) oral suspension once daily from the sixth session of radiotherapy up to the end of treatment. The final analysis of the investigation showed a higher rate of the OPC outbreak-free survival in the fluconazole compared with placebo (P = 0.008 in the log-rank test). The mean time (95% CI) to OPC outbreak was 56 (53-59) days in the fluconazole group and 47 (43-51) days with placebo. The mean duration of radiotherapy was 43.5 and 39.9 days, respectively in the two groups (P = 0.027). Adverse effects were reported in 70.3% of patients in the fluconazole group and in 67.4% with placebo. The results showed prophylaxis with fluconazole given in irradiated patients with head-neck tumours significantly reduces the rate and the time to development of OPC compared with placebo.

Weekly concomitant boost in adjuvant radiotherapy for patients with early breast cancer: preliminary results on feasibility.

AIMS AND BACKGROUND Recent advances in the management of patients with breast cancer are focused toward the reduction of overall treatment time of radiotherapy by delivering a dose biologically equivalent to a standard schedule. The aim of the present study was to evaluate the feasibility and preliminary toxicity of a moderately hypofractionated whole breast irradiation schedule with the addition of a concomitant boost delivered to the tumor bed once-a-week in patients with early breast cancer submitted to conservative surgery. MATERIALS We selected patients with pT1c and pT2 N0/N+ M0 carcinoma of the breast with negative surgical margins. The basic course consisted of 4600 cGy prescribed to the ICRU 50 reference point dose and delivered in 20 fractions, 4 times a week for 5 weeks. Once a week, immediately after whole breast irradiation, a concomitant photon boost of 120 cGy was delivered to the lumpectomy area. Overall, according to the linear-quadratic model, the schedule provides a biologically equivalent dose of 87 Gy for breast tumor (assuming alpha/beta = 4 Gy), of 66 Gy for acute responding normal tissues (assuming alpha/beta = 10 Gy), and 99 Gy for late responding normal tissues (assuming alpha/beta = 3 Gy). Biologically, the schedule compares favorably with the 6-week conventional regimen consisting of 50 Gy, 2 Gy/fraction, followed by a 10 Gy boost (BED(tumor), 90 Gy; BED(acute effects), 72 Gy, and BED(late effects), 100 Gy). RESULTS From November 2004 to April 2007, we tested this radiotherapy schedule in 176 patients. All enrolled patients had achieved a minimum follow-up of 6 months and were considered in detail for the evaluation of feasibility. Three clinical examinations were performed by a group of independent physicians at treatment end, after 1 month and after 6 months. According to the RTOG/EORTC Toxicity Criteria, of the 176 assessable patients at the end of radiotherapy, 58% showed grade 0-1 skin toxicity, 30% grade 2 and 12% grade 3. At one month of follow-up, grade 0 toxicity was observed in 47% of cases, grade 1 in 46% and grade 2 in 7%. At 6 months, late (skin and subcutaneous tissue) toxicity was assessed with the following scores: grade 0 in 68%, grade 1 in 26% and grade 2 in 6% of the patients. At 6 months, cosmesis was excellent, good and fair in 71%, 24% and 5% of patients, respectively. CONCLUSIONS The explored adjuvant schedule planned to intensify the radiotherapy course for patients with early breast cancer by adding a weekly concomitant boost appears to be feasible and provides low local toxicity and excellent to good short-term cosmetic results.

Predictive factors for oropharyngeal mycosis during radiochemotherapy for head and neck carcinoma and consequences on treatment duration. Results of mycosis in radiotherapy (MIR): A prospective longitudinal study

BACKGROUND AND PURPOSE Oropharyngeal mycosis (OPM) is a complication of radiotherapy (RT) treatments for head and neck (H&N) cancer, worsening mucositis and dysphagia, causing treatment interruptions and increasing overall treatment time. Prophylaxis with antifungals is expensive. Better patient selection through the analysis of prognostic factors should improve treatment efficacy and reduce costs. MATERIALS AND METHODS A multicentre, prospective, controlled longitudinal study, with ethics committee approval, examined H&N cancer patients who were candidates for curative treatments with radio-chemotherapy. Patients were divided in groups according to OPM appearance: before the starting of RT (cases), during RT (new cases) and never (no cases). RESULTS Of 410 evaluable patients, 20 were existing cases, 201 new cases and 189 did not report OPM. In our study OPM appears in 42.4% of people >70years and in 58.2% of younger individuals (p=0.0042), and in 68.6% of women versus 50.8% of men (p=0.0069). Mucositis and dysphagia were higher and salivation reduced among people with OPM (p<0.0000). Patients with OPM had longer hospitalization (p=0.0002) and longer (>12days) treatment interruptions (p=0.0288). CONCLUSIONS Patients with OPM had higher toxicity and a greater number of long treatment interruptions. Analyses of prognostic factors can help clinicians understand OPM distribution and select patients with the highest probability of OPM for antifungal prophylaxis.

Patterns of practice in the radiation therapy management of rectal cancer: survey of the Interregional Group Piedmont, Valle d'Aosta and Liguria of the "Associazione Italiana di Radioterapia Oncologica (AIRO)".

AIMS AND BACKGROUND To report the survey about the main aspects on the use of radiotherapy for the treatment of rectal cancer in Piedmont and Liguria. METHODS AND STUDY DESIGN Sixteen centers (11 from Piedmont and 5 from Liguria) received and answered by email a questionnaire data base about clinical and technical aspects of the treatment of rectal cancer. All data were incorporated in a single data base and analyzed. RESULTS Data regarding 593 patients who received radiotherapy for rectal cancer during the year 2009 were collected and analyzed. Staging consisted in colonoscopy, thoracic and abdominal CT, pelvic MRI and endoscopic ultrasound. PET/CT was employed to complete staging and in the treatment planning in 12/16 centers (75%). Neoadjuvant radiotherapy was employed more frequently than adjuvant radiotherapy (50% vs 36.4%), using typically a total dose of 45 Gy with 1.8 Gy/fraction. Concurrent chemoradiation with 5-fluorouracil or capecitabine was mainly employed in neoadjuvant and adjuvant settings, whereas oxaliplatin alone or in combination with 5-FU or capecitabine and leucovorin was commonly employed as the adjuvant agent. The median interval from neoadjuvant treatment to surgery was 7 weeks after long-course radiotherapy and 8 days after short-course radiotherapy. The pelvic total dose of 45 Gy in the adjuvant setting was the same in all the centers. Doses higher than 45 Gy were employed with a radical intent or in case of positive surgical margins. Hypofractionated regimens (2.5, 3 Gy to a total dose of 35-30 Gy) were used in the palliative setting. No relevant differences were observed in target volume definition and patient setup. Twenty-six patients (4.4%) developed grade 3 acute toxicity. Follow-up was scheduled in a similar way in all the centers. CONCLUSIONS No relevant differences were found among the centers involved in the survey. The approach can help clinicians to address important clinical questions and to improve consistency and homogeneity of treatments.

Abdominopelvic radiotherapy following surgery and chemotherapy in advanced ovarian cancer

Thirty advanced ovarian cancer patients have been treated with sequential multimodality treatment including primary surgery, cisplatin or carboplatin-based polichemotherapy, second-look laparotomy followed by abdominopelvic irradiation (moving strip or open-field technique). Toxicity related to the combined treatment was acceptable: only three patients failed to complete and two patients delayed the prescribed course of radiotherapy because of acute myelosuppression or gastroenteric disturbances. One patient without evidence of disease required laparotomy for bowel obstruction one month after completion of radiotherapy. No other chronic toxicity of clinical significance has been observed. Actuarial three-year survival significantly correlated with residual disease at the start of radiotherapy: no residuum, 100%, microscopic disease, 52%; less than 2 cm macroscopic disease, 27.4% (P less than 0.05), whereas recurrences were less frequent only in the group of pathological complete responders (3/9) compared to patients with limited disease (6/11 with micro and 7/10 with macroscopic residuum). In conclusion radiotherapy following surgery and chemotherapy is not associated to serious morbidity but its value in improving progression-free survival rates has to be tested in randomized trials.