Paolo Antognoni

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSE The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy. MATERIALS AND METHODS Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis. RESULTS From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16). CONCLUSIONS The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

Conservative management of T1-T2N0 supraglottic cancer: A retrospective study

PURPOSE Evaluate the results of conservative management of early-stage supraglottic cancer. PATIENTS AND METHODS A retrospective analysis of 166 consecutive T1-T2N0 cases of squamous cell carcinoma of the supraglottic larynx, treated conservatively between 1983 and 1992, was performed. Sixty-six patients received conservative surgery (CS), whereas 100 patients received definitive radiation therapy (RT). Surgical procedures included horizontal supraglottic laryngectomy in 38 patients, extended supraglottic laryngectomy in 16 patients, and reconstructive laryngectomy with cricohyoidopexy in 12 patients. Elective bilateral neck dissection was always performed. Radiotherapy was delivered with 60Co or 6 MV photons to the primary laryngeal tumor and the upper and mid neck nodes (level II and III), whereas supraclavicular nodes (level IV) were electively irradiated only in 54 patients with T2N0 tumors. Fifty-two patients received conventional fractionation, whereas 31 patients were irradiated according to a twice-a-day fractionation regimen. The median total tumor dose was 67 Gy (range, 64 to 72 Gy). RESULTS The 5-year overall survival of the whole series was 72.7% +/- 4.5. In patients treated with CS, the 5-year disease-free survival was 88.4% +/- 4.5 versus 76.4% +/- 6.1 for patients who received RT. Salvage surgery was effective in rescuing 2 of 3 CS failures and 12 of 25 RT failures. The overall incidence of secondary tumors (11%) and distant metastases (5%) was relatively low, although together they account for 15% of all deaths. Complications of CS were significantly correlated to the extent of surgical procedure. A multivariate analysis performed in the RT group showed that performance status, tumor grade, and fractionation regimen significantly influenced disease-free survival. CONCLUSION Conservative management of T1-T2N0 supraglottic cancer, either by CS or RT, can achieve good cure rates with larynx preservation for the majority of the patients (82% overall; 95% in the CS group and 72% in the RT group). The decision between different conservative treatment modalities may be influenced by the patients conditions, tumor characteristics, treatment modalities, and also economic costs.

ARCON: accelerated radiotherapy with carbogen and nicotinamide in head and neck squamous cell carcinomas. The experience of the Co-operative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer (EORTC)☆

BACKGROUND Since there is increasing evidence that both acute (perfusion-limited) and chronic (diffusion-limited) hypoxia, and tumor repopulation may prejudice the outcome of radiotherapy, the combination of carbogen (95% oxygen-5% carbon dioxide) and nicotinamide with accelerated radiotherapy (ARCON) should reduce the impact of these factors of radioresistance. AIM This clinical study was aimed at determining the feasibility, as well as the qualitative and quantitative toxic effects of a therapeutic approach based on ARCON, and assessing the tumor response rates that can be achieved with this regime in patients with locally advanced tumors of the head and neck. METHODS A phase I/II study conducted between 1993 and 1996 by the Co-operative Group of Radiotherapy of the EORTC included three consecutive steps: accelerated fractionation (AF) combined with carbogen (11 analyzable patients), AF combined with the daily administration of nicotinamide (n=10), and AF with both carbogen and nicotinamide (n=17). Radiotherapy was based on an accelerated regime (72 Gy in 5.5 weeks). Nicotinamide was delivered 90 min before the first irradiation session, at a daily dose of 6 g. Carbogen breathing started 5 min before irradiation and lasted throughout the entire radiotherapy sessions. RESULTS No significant difference in loco-regional toxicity was found among the three study steps, when carbogen and nicotinamide, either alone or in combination, were combined with AF. The feasibility of the ARCON protocol, as proposed in the present EORTC study, appears to be significantly impaired when nicotinamide is added, at a daily dose of 6 g, to AF and carbogen, in an unselected group of patients. More than 20% of patients experienced grade 2 or 3 emesis. It also demonstrates, in unselected groups of patients, no significant difference in tumor response and local control when carbogen and nicotinamide, either alone or in combination, are added to accelerated radiotherapy. The percentages of objective response at 2 months were 81, 70 and 87%, respectively. CONCLUSION Future ARCON trials should target selected head and neck tumor localizations and stages, and a lower nicotinamide dose is needed to reduce severe upper gastro-intestinal toxicity.

ARCON: accelerated radiotherapy with carbogen and nicotinamide in non small cell lung cancer: a phase I/II study by the EORTC

BACKGROUND Non small cell lung cancers (NSCLC) are rapidly proliferating tumours, which are characterized by the presence of extensive hypoxic components, especially in patients with advanced loco-regional disease. Previous studies suggest a deleterious impact of acute (perfusion-limited) hypoxia on the outcome of radiotherapy for these tumours. AIM This pilot study was aimed at determining the feasibility and tumour response rates that can be achieved with an ARCON regime in patients with locally advanced, staged IIIA or B, NSCLC tumours. METHODS The phase I/II study included three steps: accelerated fractionation (AF) combined with carbogen (ten analysable patients), AF together with the daily administration of nicotinamide (n = 11 ) and AF with both carbon and nicotinamide (n = 14). Radiotherapy was based on a large daily dose per fraction (2.75 Gy up to 55 Gy in 4 weeks). Nicotinamide was administered at a dose of 6 g per patient per treatment day and carbogen was inhaled for 5 min before and during radiotherapy. RESULTS The incidence of grade 3 + acute toxicity during the irradiation did not exceed 10%, neither in the lung parenchyma nor in the mediastinum. No significant difference was found in loco-regional, radio-induced toxicity among the three study steps. Although a similar fraction of patients showed grade 2 or 3 emesis in all the steps, of the 25 patients entered in the two Nicotinamide containing steps 10 (40%) developed grade 2 or greater reactions which significantly detracted from their quality of life. There was no significant difference in tumour clearance rate among the three steps. The percentage of objective responses at 2 months was 60, 54 and 57% in steps 1, 2 and 3, respectively. CONCLUSION The feasibility of this ARCON protocol, using 2.75 Gy doses per fraction over 4 weeks, is good as regards radiotherapy-related side effects but it appears necessary in future to reduce the dose of Nicotinamide to reduce the incidence of nausea and vomiting. There was no significant difference in time to progression among the three study steps.

Biological predictors of response to radiotherapy in head and neck cancer: recent advances and emerging perspectives.

The study of new biological parameters has received considerable attention in radiotherapy during the last decade due to their potential value in predicting treatment response in squamous cell carcinoma of the head and neck (SCC-HN) and the foreseen possibility of selecting altered fractionation radiotherapy for the individual patient. Although there are established clinical parameters in SCC-HN patients that relate to radiation response (extent of disease, hemoglobin level), recent advances with direct measurement of tumor oxygenation, inherent radiosensitivity and proliferation rate have increased the promise of individualization of treatment strategy according to these radiobiologically based parameters. Molecular research has now identified a host of new biological parameters with potential predictive utility; oncogenes, tumor suppressor genes, cell-cycle control genes, apoptosis genes and angiogenesis genes have been extensively studied and correlated with radiation response. Moreover, study of the epidermal growth factor receptor signal-transduction system as a possible response modulator has recently fostered molecular strategies which employ blockade of the receptor to down-regulate tumor growth. This article briefly reviews and analyzes the main controversial issues and drawbacks that hinder the general use of biological parameters for predicting tumor response to radiotherapy. It highlights the future perspectives of radiotherapy predictive assay research and the need to shift from single-parameter analysis to multiparametric studies which take into account several potential predictors that together are involved in different biological and clinical pathways.

Laryngeal long-term morbidity after supraglottic laryngectomy and postoperative radiation therapy.

PURPOSE This study was performed to investigate factors associated with laryngeal morbidity when postoperative radiation therapy (RT) is added to supraglottic laryngectomy. MATERIALS AND METHODS From 1980 to 1994, 56 patients affected with T1 to 4 N0 to 2c supraglottic squamous cell carcinoma selected for standard (59%) or extended (41%) supraglottic laryngectomy at 2 different institutions were retrospectively analyzed. Most of the patients (91%) also underwent neck dissection. Approximately 80% of the patients had stage T4 primary lesions or N2 neck disease. Postoperative RT was added for presumed microscopic disease at the primary site (13 patients), regional nodes (23 patients), or both (20 patients). Median delivered doses to the larynx and to the neck were 50 Gy (range, 40 to 64 Gy) and 46 Gy (range, 40 to 64 Gy), respectively. Median follow-up for living patients is 11 years (range, 2.8 to 16.9 years). Laryngeal complication was defined as the appearance of grade 2 or higher toxicity according to the European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG) scoring systems. RESULTS Two- and 5-year actuarial locoregional control rates were 85+/-5% and 83+/-5%, respectively. Thirty patients (54%) developed laryngeal complications. However, just one patient experienced grade 4 laryngeal oedema requiring permanent tracheostomy. Estimated actuarial survival without laryngeal complications were 50+/-7%, 43+/-7%, and 39+/-7% at 2, 5, and 10 years, respectively. At univariate analysis, treated volumes (P = .03) and total dose to the larynx (P = .03) were significantly associated with local toxicity. A trend was observed also for the maximum dose to the neck (P = .06) and dose per fraction (P = .09). A multivariate Cox proportional hazards model showed total dose to the larynx to be the only independent predictor of toxicity (P = .03). The hazard ratio of laryngeal toxicity was 2.2 (95% confidence interval: 1.1/4.6), for a total dose to the larynx greater than 50 Gy. CONCLUSION After supraglottic laryngectomy, postoperative RT to the neck does not affect local morbidity, but careful RT treatment planning is necessary to avoid delivering a total dose to the larynx greater than 50 Gy.

Long term rectal function after high-dose prostatecancer radiotherapy: Results from a prospective cohort study

PURPOSE To prospectively evaluate long-term late rectal bleeding (lrb) and faecal incontinence (linc) after high-dose radiotherapy (RT) for prostate cancer in the AIROPROS 0102 population, and to assess clinical/dosimetric risk factors. MATERIALS AND METHODS Questionnaires of 515 patients with G0 baseline incontinence and bleeding scores (follow-up ≥6 years) were analysed. Correlations between lrb/linc and many clinical and dosimetric parameters were investigated by univariate and multivariate logistic analyses. The correlation between lrb/linc and symptoms during the first 3 years after RT was also investigated. RESULTS Of 515 patients lrb G1, G2 and G3 was found in 32 (6.1%), 2 (0.4%) and 3 (0.6%) patients while linc G1, G2 and G3 was detected in 50 (9.7%), 3 (0.6%) and 3 (0.6%), respectively. The prevalence of G2-G3 lrb events was significantly reduced compared to the first 3-years (1% vs 2.7%, p=0.016) ≥G1 lrb was significantly associated with V75 Gy (OR=1.07). In multivariate analysis, ≥G1 linc was associated with V40 Gy (OR=1.015), use of antihypertensive medication (OR=0.38), abdominal surgery before RT (OR=4.7), haemorrhoids (OR=2.6), and G2-G3 acute faecal incontinence (OR=4.4), a nomogram to predict the risk of long-term ≥G1 linc was proposed. Importantly, the prevalence of ≥G1 linc was significantly correlated with the mean incontinence score during the first 3 years after RT (OR=16.3). CONCLUSIONS Long-term (median: 7 years) rectal symptoms are prevalently mild and strongly correlated with moderate/severe events occurring in the first 3 years after RT. Linc was associated with several risk factors.

Endoscopic resection followed by adjuvant radiotherapy for sinonasal intestinal-type adenocarcinoma: Retrospective analysis of 30 consecutive patients.

Intestinal‐type adenocarcinoma (ITAC) is a rare and locally aggressive occupation‐related tumor. Currently, endoscopic‐assisted resection and advances in irradiation modalities (3D conformal radiotherapy/intensity‐modulated radiation therapy [IMRT]) are emerging as an alternative to traditional open surgery and conventional radiotherapy.

Equipment, staffing, and provision of radiotherapy in Lombardy, Italy: Results of three surveys performed between 2012 and 2016

Introduction: Several efforts are being implemented at the European level to measure provision of up-to-date radiation treatments across the continent. Methods: A snapshot survey involving all radiation oncology centers within Lombardy, Italy, was performed in 2012 and repeated in 2014 and 2016, in cooperation with regional governmental officers. Centers were asked to provide detailed information concerning all individual patients being treated on the index day, and to report data on available local resources. Results: We observed an increase in the number of centers and of megavoltage units (MVU) (from 76 to 87, i.e., 8.7 MVU per million inhabitants in 2016). Mean number of MVU per center was 2.5. Average age of MVU increased from 5.3 to 7.5 years and patients on the waiting list also increased. Conformal 3D radiotherapy (RT) treatments decreased from 56% to 42% and were progressively replaced by intensity-modulated RT treatments (from 39% to 49%). Waiting times were overall satisfactory. Radiation oncologists treated on average 152 and radiation therapists 100 RT courses per year. Average reimbursement per course was €4,879 (range €2,476–€8,014). Conclusions: The methodology of snapshot survey proved feasible and provided valuable information about radiation oncology provision and accessibility in Lombardy.

Radiotherapy for head and neck cancer in Lombardy: a survey by the Lombardy Group of the Italian Association for Radiation Oncology.

Aims In 2013, a survey was conducted to analyze the available resources and their use in the radiation treatment of patients with malignancies of the head and neck region in Lombardy, on behalf of the Lombardy group of the Italian Association of Radiation Oncology. Methods A questionnaire was sent to 26 of 34 radiotherapy centers active in the region. Two centers were excluded because they did not treat head and neck cancers (Besta Neurological Institute and Cyberknife center), 4 had started their activity in 2013 or late 2012, and 2 satellite centers had their results included in the main centers response. Items investigated included number of patients with head and neck cancer treated in 2012, general technical issues, and integration with surgery and chemotherapy. Results Twenty-four questionnaires were returned (92% response rate). There was a good consistency on the use of radiotherapy in different settings, whereas integration with chemotherapy showed more heterogeneous data. Treatment techniques were 3D conformal radiotherapy or intensity-modulated radiotherapy with image-guided radiotherapy in most cases and a low rate of treatment-related death was observed. Conclusions This survey provides important data on the use of radiotherapy resources for patients with head and neck cancer in Lombardy. The data offer the opportunity to further investigate issues that could better standardize head and neck cancer treatment and allocate resources across the region.