Andrea Bolner

Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial.

PURPOSE To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. METHODS AND MATERIALS Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week). RESULTS No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. CONCLUSIONS The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.

Cisplatin, hyperthermia, and radiation (trimodal therapy) in patients with locally advanced head and neck tumors: A phase I–II study

PURPOSE Hyperthermia is now being widely used to treat clinical malignancies especially combined with radiotherapy and more rarely with chemotherapy. The combination of heat, radiation, and chemotherapy (trimodality) can lead to potent interaction. The present Phase I-II study was conducted to evaluate the feasibility and acute toxicity of a combination of cisplatin, hyperthermia, and irradiation in the treatment of superficial cervical nodal metastases from head and neck cancer. METHODS AND MATERIALS Eighteen patients with measurable neck metastases from previously untreated squamous cell head and neck tumors were entered into the trial. Therapy consisted of a conventional irradiation (total dose 70 Gy, 2 Gy five times a week) combined with a weekly administration of 20 mg/m2 iv of cisplatin and a total of two sessions of local external microwave hyperthermia (desired temperature of 42.5 degrees C for 30 min). RESULTS Feasibility of the treatment was demonstrated. Acute local toxicity was mild; no thermal blisters or ulcerations were reported and only two patients experienced local pain during hyperthermia. Cutaneous toxicity appeared greater than in our previous studies with irradiation plus hyperthermia and irradiation plus cisplatin. Systemic toxicity was moderate with major toxic effects observed in three patients (World Health Organization (WHO) grade 3 anaemia). Even though it was not an aim of the study to evaluate the nodal response, we observed a complete response rate of 72.2% (95% confidence interval 51-93.4%), 16.6% of partial response and 11.1% of no change. CONCLUSION The study confirms the feasibility of the combination of cisplatin, heat, and radiation with an acceptable toxicity profile. The trimodal therapy deserves further evaluation as a way to enhance the efficacy of irradiation in the treatment of nodal metastases from head and neck tumors.

Phase I study of gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer

PURPOSE Although the use of radical transurethral resection followed by concurrent radiochemotherapy leads to a similar survival rate to that achieved after cystectomy, the number of long-term survivors is low in both cases. An improvement may be obtained by adding a new drug, such as gemcitabine, which is active in bladder cancer and acts as a radiosensitizer. However, because gemcitabine may be very toxic when associated with radiotherapy, we designed this dose-finding study in an attempt to find the dose that can be safely added to radiotherapy and concurrent cisplatin in patients treated with transurethral resection for infiltrating bladder cancer. PATIENTS AND METHODS After undergoing macroscopically complete transurethral resections for transitional carcinoma of the bladder, patients staged pT2 or higher and without distant metastases concurrently received 54 Gy of fractionated radiotherapy over 6 weeks with cisplatin (100 mg/m(2) q.3 w), starting on Day 1 of radiotherapy. Concomitant gemcitabine was administered on Days 1, 8, and 15 q.3 w for 2 cycles at a dose of 200 mg/m(2), escalated to 500 mg/m(2), with a 100 mg/m(2) increase at each dose level. The maximum tolerated dose was defined as the dose of gemcitabine associated with dose-limiting toxic effects (febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 or 4 enteric toxicity, or Grade 4 nonhematologic toxicity) in 33% of the patients treated at that dose level. Six to 8 weeks after completing the therapy, the patients underwent cystoscopic reevaluation with multiple biopsies of the initial tumor site. RESULTS Of our consecutive series of 16 patients, 5 received a gemcitabine dose of 200 mg/m(2)/week, 3 a dose of 300 mg/m(2)/week, 3 a dose of 400 mg/m(2)/week, and 5 a dose of 500 mg/m(2)/week for 6 weeks. No dose-limiting toxicity was observed at doses of up to 400 mg/m(2)/week. At the dose 500 mg/m(2)/week, 1 patient experienced an intestinal perforation that recovered after surgery, and another suddenly died after developing Grade 3 untreated diarrhea in the last treatment week. All of the 15 evaluable patients were microscopically disease free at the cystoscopic reevaluation; furthermore, the posttreatment computed tomography scans did not reveal any distant metastases. CONCLUSIONS After transurethral resection for the conservative treatment of infiltrating bladder cancer, gemcitabine doses of up to 400 mg/m(2)/week seem to be safe in combination with cisplatin and radiotherapy in organ-sparing management. On the basis of the promising results of this Phase I study, we are currently conducting a Phase II trial to verify the possible improvement in local control resulting from the addition of gemcitabine.

Long-term results of conventional radiotherapy versus accelerated hyperfractionated radiotherapy versus concomitant radiotherapy and chemotherapy in locoregionally advanced carcinoma of the oropharynx

Aims and Background To compare conventional fractionation (CF) radiation therapy (RT), arm A, versus a split-course accelerated hyperfractionated schedule (S-AHF), arm B, versus CFRT plus concomitant chemotherapy (CT), arm C, in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx. Methods and Study Design Between January 1993 and June 1998, 192 previously untreated patients with stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were enrolled in a multicenter randomized phase III trial (ORO 93-01). In arms A and C, 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks. In arm B, the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day, five days a week, with a planned two-week split at 38.4 Gy. In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil (CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v. on days 1 to 4 every 28 days). Results No statistically significant difference was found in five-year overall survival (P = 0.39): 21% for arm A, 21% for arm B, and 40% for arm C. Similarly, there was no statistically significant difference in terms of five-year relapse-free survival: 15% for arm A, 17% for arm B, and 36% for arm C. There was a slight trend towards better five-year locoregional control (P = 0.07) for the combined arm: patients without locoregional relapse were 48% in arm C, 21% in arm A and 18% in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined (P = 0.02; arm A+B 20%; arm C 48%). Distant metastases were fairly balanced in the three arms (A: 14; B: 9; C: 11), with a tendency towards more frequent isolated distant metastasis development in arm C (8 of 11 [72%] versus 7 of 23 [30%] in arms A+B). Five-year second-tumor-free survival was 85%. The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption (five lung, two esophagus, two oral cavity, one larynx, one pancreas, one hepatocarcinoma, one myeloma). Arm C showed slightly more G3+ late side effects involving subcutaneous tissues and mucosa, although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient. The occurrence of persistent G3 xerostomia was comparable in the three treatment arms. Conclusions The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance, but combined treatment almost doubled the five-year overall survival, relapse-free survival and locoregional control rate. Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy. The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death.

Impact of Residual Setup Error on Parotid Gland Dose in Intensity-Modulated Radiation herapy with or without Planning Organ-at-Risk Margin

Purpose:To estimate the dosimetric impact of residual setup errors on parotid sparing in head-and-neck (H&N) intensity-modulated treatments and to evaluate the effect of employing an PRV (planning organ-at-risk volume) margin for the parotid gland.Patients and Methods:Ten patients treated for H&N cancer were considered. A nine-beam intensity-modulated radiotherapy (IMRT) was planned for each patient. A second optimization was performed prescribing dose constraint to the PRV of the parotid gland. Systematic setup errors of 2 mm, 3 mm, and 5 mm were simulated. The dose-volume histograms of the shifted and reference plans were compared with regard to mean parotid gland dose (MPD), normal-tissue complication probability (NTCP), and coverage of the clinical target volume (V95% and equivalent uniform dose [EUD]); the sensitivity of parotid sparing on setup error was evaluated with a probability-based approach.Results:MPD increased by 3.4%/mm and 3.0%/mm for displacements in the craniocaudal and lateral direction and by 0.7%/ mm for displacements in the anterior-posterior direction. The probability to irradiate the parotid with a mean dose > 30 Gy was > 50%, for setup errors in cranial and lateral direction and < 10% in the anterior-posterior direction. The addition of a PRV margin improved parotid sparing, with a relative reduction in NTCP of 14%. The PRV margin compensates for setup errors of 3 mm and 5 mm (MPD ≤ 30 Gy in 87% and 60% of cases), without affecting clinical target volume coverage (V95% and EUD variations < 1% and < 1 Gy).Conclusion:The parotid gland is more sensitive to craniocaudal and lateral displacements. A setup error of 2 mm guarantees an MPD ≤ 30 Gy in most cases, without adding a PRV margin. If greater displacements are expected/accepted, an adequate PRV margin could be used to meet the clinical parotid gland constraint of 30 Gy, without affecting target volume coverage.Ziel:Abschätzung der dosimetrischen Konsequenzen des Positionierungsfehlers auf die Parotisschonung durch IMRT bei Kopf- Hals-Tumoren und Quantifizierung des Effekts der Verwendung eines PRV-(Planning organ at Risk Volume-)Sicherheitsabstands um die Parotis.Patienten und Methodik:Die CT-Datensätze von 10 Patienten mit Kopf-Hals-Tumoren wurden untersucht. Für jeden Patienten wurde ein intensitätsmodulierter Bestrahlungsplan mit neun primären Einstrahlrichtungen generiert. Ein zweiter Plan wurde unter Verwendung eines PRV erzeugt. Für beide Pläne wurden systematische Positionierungsfehler von 2 mm, 3 mm und 5 mm simuliert. Die DVHs der verschobenen und der Referenzpläne wurden hinsichtlich mittlerer Parotisdosis (MPD), Normalgewebskomplikationswahrscheinlichkeit (NTCP) und Dosisabdeckung des klinischen Zielvolumens (Parameter: V95% und EUD) evaluiert. Die Empfindlichkeit der Parotisdosis auf den Positionierungsfehler wurde mit einem probabilistischen Ansatz untersucht.Ergebnisse:Durch Positionierungsfehler erhöht sich die MPD um 3,4%/mm und 3,0%/mm für Verschiebungen in kraniokaudaler und lateraler Richtung sowie um 0,7%/mm für Verschiebungen in anterior-posteriorer Richtung. Die Wahrscheinlichkeit, die Parotis mit einer mittleren Dosis von > 30 Gy zu belasten, war > 50% für Positionierungsfehler in kranialer und lateraler Richtung and < 10% in anterior-posteriorer Richtung. Die Verwendung eines PRV-Sicherheitsabstands verbesserte die Parotisschonung mit einer Verringerung der NTCP um 14%. Der PRV-Sicherheitsabstand kompensiert Positionierungsfehler von 3 mm und 5 mm (MPD ≤ 30 Gy in 87% bzw. 60% der Fälle), ohne relevante Beeinflussung des klinischen Zielvolumens (Variation von V95% und EUD um < 1% bzw. < 1 Gy).Schlussfolgerung:Die Parotisdosis ist sensitiver auf kraniokaudale und laterale Positionierungsfehler als auf anteriorposteriore. Wird der Positionierungsfehler kleiner als 2 mm gehalten, kann eine MPD ≤ 30 Gy meist ohne PRV-Sicherheitsabstand gewährleistet werden. Ist mit größeren Positionierungsfehlern zu rechnen, kann ein PRV-Sicherheitsabstand helfen, die Dosisvorgaben (MPD höchstens 30 Gy) für die Parotis einzuhalten, ohne wesentlich die Zielvolumenabdeckung zu beeinflussen.

Hyperfractionated radiation in combination with local hyperthermia in the treatment of advanced squamous cell carcinoma of the head and neck: a phase I–II study

Twenty-seven patients with cervical metastases from squamous cell head and neck tumours were treated with hyperfractionated XRT (total dose 69.60-76.80 Gy, 1.2 Gy b.i.d. five times a week) combined with a total of two to six sessions of superficial external HT. Acute local toxicity was mild; as major acute side effects, only one ulceration was recorded. No severe late side effects were observed. Late toxicity was similar to that observed in our previous studies with the combination of heat and radiation. Nodal complete response was observed in 77% of patients, partial response was observed in 15% of patients and no change was observed in 8% of patients. Five-year actuarial nodal control was 64.5 +/- 19% and 5-year actuarial survival was 24 +/- 10%. The treatment of nodal metastases from head and neck tumours with the combination of HT and hyperfractionated XRT is feasible with an acceptable acute and late toxicity profile.

STAGE I SEMINOMA OF THE TESTIS : LONG TERM RESULTS AND TOXICITY WITH ADJUVANT RADIOTHERAPY

Aims and background Pure testicular seminoma has historically been treated with post-orchidectomy radiation therapy with excellent results. Recently, several aspects of the treatment of stage I seminoma have been questioned. We assessed long-term results and toxicity of patients with pure testicular seminoma treated at the Department of Radiation Oncology of S. Chiara Hospital, Trento. Methods From 1953 to 1987, 102 patients with stage I pure testicular seminoma were given megavoltage irradiation with curative intent. All patients had a minimum follow-up of 3 years (maximum 37 years, median 13 years). They received a mean para-aortic/pelvic dose of 33.07 Gy (range 23.70-45.20 Gy) with different doses and fields reflecting the change in techniques over a long period of time. Results The cause-specific actuarial survival at 30 years was 99% and crude survival 67%. One patient had an out-field relapse (inguinal) after a few months and was cured with radiotherapy and chemotherapy. Another patient relapsed with widespared metastases and died after 1 year of progressive disease. Early toxycity was mild and the treatment was well tolerated. Late side effects were reported in 8/102 patients. Conclusion In our series adjuvant radiation therapy resulted in cure rates corresponding to those reported in the literature. The 30-year actuarial survival of 99% was extremely good and the toxicity of the treatment was mild. Post-orchidectomy radiation to the para-aortic and ipsilateral pelvic nodes is a safe and effective method of preventing recurrences and is currently to be considered the treatment of choice in stage I testicular seminoma.

The role of brachytherapy in the management of oropharyngeal carcinomas: the Trento experience.

Aims This study was undertaken to determine the outcome of patients with oropharyngeal cancer treated at the Radiotherapy Department of the Santa Chiara Hospital (Trento, Italy) with brachytherapy alone or combined with external beam radiotherapy (EBRT). Material and methods We retrospectively reviewed the medical records of 87 patients with squamous cell carcinoma of the oropharynx treated by radiation therapy between January 1986 and September 1999. The median age was 59 years and all patients had a minimum follow-up of one year. Tumor locations were 46 tonsillar region, 31 soft palate and 10 base of the tongue. The patients were staged as follows: 41 T1, 35 T2, 11 T3 with 70 N0, 9 N1 and 8 N2. They received either brachytherapy alone (14 patients) or a combination of external beam irradiation and brachytherapy (73 patients) using an afterloading iridium technique in a plastic tube. Results Overall primary tumor control, including salvage surgery, was 81/87 (93%). Control of metastatic cervical adenopathy was as follows: clinical stage N1, 5/9 patients; N2, 2/8 patients. The estimated five-year cause-specific survival and overall survival rates were 81% and 47%, respectively. After interstitial irradiation severe complications were limited to one case of osteoradionecrosis of the mandible and seven cases of mucosal ulcer. Conclusion This study confirms that iridium-192 interstitial implant alone or as a boost after external beam irradiation is a safe and effective therapy in the management of oropharyngeal carcinomas.

Patterns of postoperative radiotherapy for head and neck cancer in Italy: a prospective, observational study by the Head and Neck group of the Italian Association for Radiation Oncology (AIRO)

AIMS AND BACKGROUND Our previous survey showed that the patterns of postoperative radiotherapy (PORT) for head and neck cancer (HNC) in Italy might be suboptimal. A prospective observational study was therefore designed to evaluate this issue in greater detail. METHODS All radiotherapy centers involved in the HNC Working Group of the Italian Radiation Oncology Association were asked to enter into the study all patients treated with PORT during a 6-month period. RESULTS A total of 200 patients were accrued by 24 centers from December 2008 to May 2009. Larynx (38%) and oral cavity (34%) were the most common primary sites. The median time between surgery and the start of radiotherapy was 69 days (range, 25-215 days). Seventy-nine percent of cases with no evidence of risk factors for local recurrence were treated with high-dose radiotherapy to the primary site. In about 75% of cases the pN0 neck was included in the target volume. Concomitant chemotherapy was delivered to about 60% of patients with major risk factors and 21% of patients with no risk factors. CONCLUSIONS Three issues emerged from our study as potential targets for future investigations: the impact on clinical outcome of the interval between surgery and the start of PORT; factors driving radiation oncologists to overtreat volumes at low risk of recurrence; and problems associated with the delivery of concomitant chemotherapy.

Assessment of clinical outcomes and prognostic factors in patients (pts) with non-small cell lung carcinoma (NSCLC) and brain metastases (BM): Results from a single institution.

e20594Background: BM development, which is frequently observed in pts with NSCLC, is usually associated with a poor outcome. Systemic treatments and whole brain radiotherapy (WBRT) are widely used ...