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.

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.

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.

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.

[Role of palliative and symptomatic radiotherapy in bone metastasis]. / Il ruolo della radioterapia palliativa e sintomatica delle metastasi ossee.

INTRODUCTION: The presence of bone metastases is a common event in the natural history of nearly all neoplasms which often affects the patient's quality of life greatly. Bone metastases may cause pain and pathologic fractures, or even a cord compression syndrome with severe neurologic symptoms. We tried to assess the optimal irradiation schedule for these patients and to discuss the use of radiopharmaceuticals. MATERIALS AND METHODS: We reviewed the literature focusing on studies investigating the efficacy of hypofractionated radiotherapy for bone metastases. We also addressed the problem of treating multiple skeletal lesions with half-body irradiation and radionuclides. RESULTS: External beam irradiation achieves pain palliation in more than 75% of patients with bone metastases, even with hypofractionation down to a single-dose administration. The results of exclusive radiotherapy in the cord compression syndrome depend on a prompt diagnosis, patient presentation and the intrinsic radiosensitivity of tumor cells. Palsy can always be avoided in these patients. Half-body irradiation can achieve complete pain relief in over 20% of patients and decrease pain markedly in the remaining cases with only a single-dose fraction (6-10 Gy), within 48 hours of irradiation and with little side-effects. Better results in terms of pain relief (80% complete responses) and duration of palliation come from fractionated half-body irradiation (up to 17.5 Gy in 7 fractions), which however has a more delayed response (1-2 weeks) and higher toxicity. The use of radiopharmaceuticals has been recently reevaluated after the introduction of new nuclides: results are similar to those of external beam irradiation (up to 80% responses), but cost and hematologic toxicity are both high. Radiopharmaceuticals can be used within an integrated treatment with external beam irradiation, chemotherapy and biphosphonates. DISCUSSION: The efficacy of external beam irradiation in the palliation of bone metastasis-related symptoms is confirmed by this literature review, even with short treatments and single-dose administrations. This is important for both patient expectations and the necessity for improved resource allocation with reference to the territorial distribution and waiting lists of radiotherapy centers. Finally, as for the role of radiopharmaceuticals, the best nuclides are not widely used yet for the high cost of the treatment, even though they provide similar results to external beam irradiation. The issue of their efficacy in combination with antiblastic drugs and/or external beam irradiation remains open and will be clarified only with further randomized clinical trials.

[Radiation treatment of early stage supraglottic cancer]. / Le traitement radiothérapique des tumeurs sus-glottiques au stade initial.

The management of early-stage squamous cell carcinoma (SCC) of the supraglottic larynx is still controversial. Supraglottic laryngectomy as well as irradiation alone is correlated with good oncological and functional results. In order to evaluate the results and prognostic factors influencing the successful using radiotherapy (RT), the authors performed a retrospective study of 100 consecutive T1-T2 N0 M0 cases of SCC of the supraglottic larynx, treated at a single institution between 1983 and 1992. RT was delivered with 60Co or 6 MeV photons through two lateral parallel opposed portals encompassing the primary laryngeal tumor and the upper and mid-neck nodes (Robbins' levels II, III and V). Supraclavicular nodes (level IV) were electively irradiated in 54 patients with T2 N0 tumors only, using an anterior field with midline block. Sixty-three patients received conventional fractionation (2 Gy/fraction, once-a-day, five times a week), while 37 patients were irradiated according to a twice-a-day fractionation regimen (1.5 Gy/fraction, twice a day with six-hour interval, five days a week). The median total tumor dose delivered was 67 Gy. A multivariate analysis showed that performance status, tumor grade and fractionation modality were the only statistically significant variables influencing disease-free survival. Acute and late radiation reactions were relatively low. This retrospective study confirms that conservative management of T1-T2 N0 supraglottic cancer using RT can achieve good cure rates with the possibility of larynx preservation for the majority of the patients. The decision between different conservative treatment modalities may be influenced by several factors correlated to the patient's conditions, tumor characteristics, but especially treatment modalities.

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.

The predictive role of flow cytometry-derived tumor potential doubling time (Tpot) in radiotherapy: open questions and future perspectives.

Measurement of tumor-cell kinetic parameters, following in vivo administration of thymidine analogues and bivariate flow cytometry, allows quantitative cell kinetic determinations in a clinically relevant time-scale, potentially useful for selection of individual radiotherapy schedules. Among the dynamic cell kinetic parameters that can be measured using the in vivo method, the tumor potential doubling time (Tpot), defined as the time to double the number of proliferating tumor cells in the absence of cell loss, has been postulated to be a predictor of a tumor's proliferative capability, thus representing a potential predictive factor of local control after irradiation. So far, published data have shown the safety and feasibility of the technique, even in multicenter studies, and demonstrated a wide range of parameter values in many tumor sites. With only a few exceptions the hypothesis that Tpot is an independent prognostic indicator cannot be considered proven yet. We review the major controversial issues and open questions, mainly in the area of data production and analysis, that must be resolved before the predictive role of Tpot is unequivocally defined. The future of radiotherapy predictive assays lies in the development of multiparametric studies, accounting for multiple factors of radiation response, which may prove of greater prognostic significance than any single parameter approach based only on cell kinetics.

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 patient's conditions, tumor characteristics, treatment modalities, and also economic costs.

Accelerated radiation therapy for locally advanced squamous cell carcinomas of the oral cavity and oropharynx selected according to tumor cell kinetics--a phase II multicenter study.

PURPOSE: A Phase II multicenter trial testing an accelerated regimen of radiotherapy in locally advanced and inoperable cancers of the head and neck, in patients selected on the basis of 5-bromo-2-deoxyuridine/DNA flow cytometry-derived tumor potential doubling time (Tpot). METHODS AND MATERIALS: From September 1992 to September 1993, 23 patients consecutively diagnosed to have locally advanced, inoperable carcinomas of the oral cavity and the oropharynx, with Tpot of < or = 5 days, received an accelerated radiotherapy regimen (AF) based on a modification of the concomitant boost technique: 2 Gy/fraction once a day, delivered 5 days a week up to 26 Gy, followed by 2 Gy/fraction twice a day, with a 6-h interval, one of the two fractions being delivered as a concomitant boost to reduced fields, up to 66 Gy total dose (off-cord reduction at 46 Gy), shortening the overall treatment time to 4.5 weeks. A contemporary control group of 46 patients with Tpot of >5 days or unknown was treated with conventional fractionation (CF): 2 Gy/fraction once a day, 5 days a week, up to 66 Gy in 6.5 weeks, with fields shrinkage after 46 Gy. RESULTS: All patients completed the accelerated regimen according to protocol and in the prescribed overall treatment time. Immediate tolerance was fairly good: 65% of the patients in the AF group experienced Grade 3 mucositis vs. 45% in the CF group (p = n.s.). Symptoms related to mucosal reactions seemed to persist longer in AF than in CF patients. The crude proportion of mild (Grades 1 and 2) late effects on skin (p < 0.01) and salivary glands (p < 0.05) was higher in AF than in CF patients, although these reactions did not exceed the limits of tolerance. Three patients in the AF and 1 in the CF arm experienced a late Grade 4 bone complication. Actuarial estimates of severe (Grades 3 and 4) late complications showed a 2-year hazard of 33.3% in the AF arm and 49.7% in CF (p = NS). The actuarial 2-year local control rate of the AF patients was 49.4%, while actuarial 2-year overall survival for the same patients was 43.5%. CONCLUSION: The results suggested that this accelerated regimen is worth testing in a controlled randomized trial to compare different accelerated schedules. Our findings also confirmed the 5-bromo-2-deoxyuridine/DNA flow cytometry technique as a suitable method of evaluating tumor cell kinetics in multicenter clinical studies, on condition that all measurements are carried out by one most experienced laboratory.

[Radiotherapy of cutaneous cervical-facial carcinomas]. / La radioterapia dei carcinomi cutanei cervico-facciali.

The main goal of therapy for epithelial skin cancer is cure with the best functional and cosmetic outcome. Both surgery and radiotherapy give similar results for early stage lesions with 5-year local control rates ranging from 85% to 95%. Remarkable technological progress has been made yielding well defined indications to radiotherapy as a single treatment or in the context of a multidisciplinary approach. Selection of treatment should be tailored considering anatomic site, surface conformation, size, histology, grading and characteristics of tumours (new occurrence, relapse), number of localizations, age and medical conditions of the single patient. Surgery, guided by intraoperative control of resection margins, is undoubtedly the therapy of choice for most of early stage lesions. Radiation therapy plays an important role in specific anatomic situations in which the functional or cosmetic result is better than for a surgical modality, electively for the treatment of multiple lesions and for large deep- infiltrating carcinomas that generally are not suitable to excision. Exclusive radiotherapy is also indicated as rescue treatment of surgical relapses no more amenable to reexcision as well as for palliation of advanced cases, mainly for elderly or medically compromised patients. Postoperative irradiation should be considered for macro or microscopic residual disease. Merkel cell or adnexal carcinomas and for highly recurrent lesions after repeated surgery. Treatment results and complications of radiotherapy are discussed, emphasizing high local control rates and good functional and cosmetic outcomes. The main irradiation techniques referred to specific anatomic sites are also presented.

Role of postoperative radiation therapy in the management of early stage primary gastric non-Hodgkin's lymphomas: a retrospective analysis.

BACKGROUND: Clinical approaches to early primary gastric non-Hodgkin's lymphomas have not yet been clearly defined, and the role of postoperative radiotherapy remains a matter of discussion. METHODS: Twenty-seven patients with early primary gastric non-Hodgkin's lymphoma were observed from December 1978 to December 1990 at our Institution. They were staged according to Musshoff and Schmidt-Volmer (19) as I E (n = 16), II E 1 (n = 7) and II E 2 (n = 4). All of them underwent local combined treatment, consisting of surgery and postoperative radiotherapy; chemotherapy was also administered to 10 patients, mainly with the CHOP regimen, for 4-6 cycles before radiotherapy. Irradiation was delivered using 10 MV photons from a linear accelerator. Large abdominal fields were employed in 21 cases with daily fractions of 1.5-2 Gy up to a median total dose of 30 Gy (range: 27-36 Gy). Six patients were irradiated only on the surgical bed up to 40.5 Gy (range: 39-40.5 Gy). RESULTS: The 5-year overall and disease-free survivals were respectively 92.4% and 89.8%. The main known prognostic indicators, stage of disease, type of surgery as well as age and sex, were not found to be statistically significant in our series. No clear difference emerged between patients sequentially treated with the combination surgery-chemotherapy-radiotherapy and those who did not receive adjuvant chemotherapy. Two patients recurred at distant sites, but no local failure was seen during the follow-up. CONCLUSIONS: Although no firm conclusion can be drawn, our experience, in agreement with recent published reports, points out that the use of postoperative radiotherapy is associated not only to favorable results in terms of local control and survival, but also, and moreover, to a negligible incidence of side effects and sequelae. However, in the absence of multi-institutional prospective randomized studies, whose activation is nowadays strongly warranted, the exact role of adjuvant therapies remains a matter of discussion, and the optimal treatment of early primary gastric non-Hodgkin's lymphoma still depends on individual experience and the physician's philosophy.

Postoperative radiation therapy for adult soft tissue sarcomas: a retrospective study.

From 1977 to 1988, 81 adult patients with localized soft tissue sarcomas at different sites received postoperative external beam radiotherapy (55 Gy median dose) following primary conservative surgery. Sixty were new referrals after primary surgery and 21 were irradiated after excision of recurrent disease. With a median follow-up of 4 years (range: 2-13) the 5-year overall survival (Kaplan-Meier) and local control were 55.5% and 56% respectively, while 5-year disease-free survival is 49%. There were 26 (32%) local relapses and 22 (27%) distant failures. Local recurrence was the sole pattern of failure in 16 patients (20%). Functional and cosmetic results were good to excellent in most cases. In our series local control is the main prognostic variable influencing survival (P less than 0.0001), and its probability seems to show a link with the type of surgical procedure, with a trend (P less than 0.13) in favor of wide total excision. Postoperative radiation therapy represents an acceptable treatment strategy for ASTS, but further improvements are expected from future controlled clinical trials, aiming at the achievement of the definitive cure of these tumors.

[Exclusive radiotherapy of carcinoma of the hypopharynx. Retrospective study of a series of 100 patients]. / La radioterapia esclusiva del carcinoma dell'ipofaringe. Analisi retrospettiva di una casistica di 100 pazienti.

From January 1980 to December 1987, 100 patients with carcinoma of the hypopharynx, staged according to TNM (UICC-1978) criteria, received exclusive radiation therapy at the Radiotherapy Department of the General Hospital of Varese. The median follow-up is 9 months (range: 1-97). Irradiation was delivered with 60Co or with 10 MV photons and tissue-equivalent bolus. Two opposed parallel lateral fields or rotational technique were used, with progressive shrinking of treated volume in order to spare the spinal cord after 45 Gy. Direct fields of electron beams (6-15 MeV) were employed as boosts on the residual nodes. Median total doses: 64.5 Gy to T and N1-3, 45 Gy to N0. A conventional fractionation (2 Gy once a day, 5 times a week) was used in 37 outpatients, while an accelerated hyperfractionated regimen (1.5 Gy twice a day, 5 times a week, with a six hours' interval between each fraction) was employed in 63 inpatients, in order to shorten hospitalization. The five-year overall survival (Kaplan-Meier) of the 100 treated patients is 10%, while the five-year disease-free survival of the 40 patients in complete clinical remission at the end of radiation therapy is 19.8%. The five-year loco-regional control rate after exclusive radiotherapy is 19.1%. Complete remission at the end of treatment seems to represent the only significant prognostic variable affecting survival: five-year overall survival is 32% for the 40 patients achieving complete remission and only 4.4% for the others (p less than 0.05). On the contrary, tumor extension (T class) seems to affect only the two-year local control rate: 35.2% and 10.9% for T1 + T2 and T3 + T4 respectively (p less than 0.1). The main cause of failure after radiation therapy is represented by the lack of control at the primary site (T) alone or associated with regional adenopathies (N). The analysis of isoeffect parameters, according to CRE model, has not shown any evident dose-response relationship for local control. Late effects were observed in 7% of the patients and were similar to those reported in the literature. The occurrence of both distant metastases, 3% in our experience, and secondary tumors (9%) is lower than those previously reported. The present retrospective study strongly reconfirms the inadequacy of exclusive radiation therapy as the sole treatment modality for carcinoma of the hypopharynx and suggests the need of combination therapy (surgery and radiation) as primary treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

[Exclusive radiotherapy of locally advanced carcinoma of the larynx. Analysis of the caseload of Varese (1979-1986)]. / La radioterapia esclusiva dei carcinomi laringei in stadio localmente avanzato. Analisi della casistica di Varese (1979-1986).

The authors analyse a retrospective series of 90 consecutive patients (pts) affected with locally advanced laryngeal carcinoma (T3-4, N0-3--TNM, UICC 1978) who were radically irradiated from November 1979 to December 1986 at the Radiotherapy Department of the General Hospital of Varese. All the patients were treated with 60Co and two opposed parallel lateral fields and progressive shrinkage: 66 with conventional fractionation (2 Gy once a day, 5 times a week), 24 with an accelerated hyperfractionated regimen (1.5 Gy twice a day, 5 times a week). The median total dose delivered to the tumor and clinically involved nodes was 64 Gy (1678 reu, CRE). Median follow-up was 21 months (range: 3-113). The 5-year overall survival (Kaplan-Meier) was 40.5%. The 5-year disease-free survival, for 47 patients in complete remission at the end of radiotherapy, was 51.9% after irradiation alone and 56.7% with salvage surgery. There were no statistically significant differences in survival according to local spread (T3 vs. T4), nodal status (N0 vs. N1-3) and dose fractionation regimen (conventional vs. accelerated hyperfractionated). Isoeffect (CRE) values above 1751 reu obtained a 3-year loco-regional control rate of 65%, while, for isoeffect values under 1600 reu, the 3-year loco-regional control rate was 33.3%. Relevant late sequelae were not observed. Our findings suggest that primary radiotherapy with salvage surgery in reserve could be considered as an effective choice for locally advanced laryngeal carcinoma, at least in selected groups of patients.

[Radiotherapy of rhinopharyngeal carcinoma: analysis of the caseload of Varese (1979-1986)]. / La radioterapia dei carcinomi della rinofaringe: analisi della casistica di Varese (1979-1986).

From December 1979 to December 1986, 100 patients affected with nasopharyngeal carcinoma, staged according to TNM (UICC-1978) criteria received exclusive radiation therapy at the Radiotherapy Department of the General Hospital of Varese. The median follow-up is 36 months (range: 1-114). Irradiation was delivered with 10 MV photons (58 patients) or 60Co (42 patients), with two opposed parallel lateral fields and progressive shrinkage, or rotation technique. Direct fields of electron beams (6-15 MeV) were employed as boosts on the residual nodes. Median total dose: 60 Gy to T, 46 Gy to N0, 62 Gy to N1-3. A conventional fractionation (2 Gy once a day, 5 times a week) was used in 43 patients, while an accelerated hyperfractionated regimen (1.5 Gy twice a day, 5 times a week) was employed in 57 patients. Five-year overall survival (Kaplan-Meier) of the 100 treated patients is 54.9%, while 5-year disease-free survival of the 71 patients in complete clinical remission at the end of radiation therapy is 54.7%. The nodal status represents the most important prognostic variable: 5-year overall survival (100 patients) is 77.7% for N0 patients and 40.8% for N1-3 patients, while 5-year disease-free survival for the 71 patients in clinical remission at the end of radiation therapy is 78.9% and 48.8% for N0 and N1-3 patients respectively. Our findings confirm the high rescue rate (approximately 50%) of irradiation failures by re-irradiation and/or salvage surgery. The analysis of loco-regional recurrences and persistent disease, after radiotherapy, strongly suggests the need for an improvement in loco-regional control rates, by means of a more accurate treatment planning (with CT and MR) and more attention to isoeffect parameters (CRE). The incidence of distant metastases (14%) and difficulties in loco-regional control of advanced disease seem to suggest the use of combined chemo-radiotherapy modalities only for selected groups of patients and exclusively in randomized studies.

[Total skin irradiation with electrons for mycosis fungoides: criteria for the choice of technique and experimental dosimetry]. / Irradiazione cutanea totale con elettroni nella micosi fungoide: criteri per la scelta della tecnica e dosimetria sperimentale.

The initial lesions of mycosis fungoides are confined to the skin at a depth of about 1 cm. Wide fields irradiation with low energy electron beams is therefore the treatment of choice for the first stages of the disease. The authors have analysed the various treatment techniques of total skin electron beam irradiation reported in the literature. Dosimetric and practical features are considered. The angled beams technique seems to fit better the needs of a common Radiation Therapy Department. A treatment system with six pairs of 3 MeV electron beams is described and preliminary dosimetric measurements of a similar system that employs 6 MeV electrons are reported.