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Esophageal cancer ranks sixth among the causes of death from cancer worldwide. Patients undergoing surgery have a median survival ranging from 13 to 19 months; 2-year survival rates range from 35 to 42 percent, and 5-year survival rates from 15 to 24 percent. In particular, the 3 year survival (= SVV) is about 26%, with a median survival of 17 months. An interesting point is that about 20-25% of the patients has only locoregional involvement as pattern of failure. At least two randomized studies reported about the combined use of radiotherapy and chemotherapy as sensibilization. They assessed that patients treated with chemoradiation had a longer median survival compared to patients receiving radiation therapy alone, both in early and advanced stages. Moreover radiochemotherapy seems able of achieving high rates of downstaging and of increasing overall and disease-free survival.

Dose and volume and their correlation with the development of pulmonary toxicity are among the most widely studied and validated factors in radiotherapy. Most common treatment planning systems allow prompt assessment of Vdose and Mean Lung Dose (MLD). The former represents the percentage of normal lung parenchyma receiving a dose equal to or higher than the established threshold dose; the latter corresponds to the mean dose delivered to the normal lung parenchyma. Most important studies reported on the subject and threhold values recommended for Vdose and MLD are analyzed. The monitoring system of late toxicity used by the authors is presented.

Abstract. Radiotherapy was the standard treatment for patients with locally advanced non-small cell lung cancer until the mid 1990s. Chemotherapy was added in order to improve outcome, and during the last decade sequential, concurrent or mixed modalities have been extensively explored and discussed. Goals of neoadjuvant chemoradiation are resecability and downstaging. Recent published experiences evidenced that neoadjuvant chemoradiotherapy is feasible if delivered with low total dose and limited volume; pathological downstaging to stage 0-I could be a reasonable surrogate end-point for overall and disease free survival and for distant metastasis.

The treatment of choice of patients with locally advanced non-small cell lung cancer is radiotherapy combined or not with chemotherapy. Only 30% of lung cancer patients are operable for cure at diagnosis. Consequently the knowledge of the radiobiological basis and of clinical outcomes achieved with radiation therapy is of the utmost importance. Total dose, fractionation, concomitant chemotherapy are the main factors to be examined. In order to improve local control several attempts are reported in the literature. They concern: changes in fractionation and total dose; the use of radiosensitizers and radioprotectors; combined chemoradiation and molecular therapies.

In the last decades, many attempts were made to optimize the biological effect of RT in the treatment of pancreatic carcinoma. The use of combined radiotherapy and chemotherapy was certainly successful, with the most promising results achieved with the combination of several drugs with RT or with innovative modalities of administration of concomitant chemotherapy. A dose effect in resected tumors seems suggested by some studies; while the use of high doses in inoperable tumors did not result in significant advantages in terms of response and outcome, a significant correlation between dose and toxicity was observed. Altered fractionations were not studied systematically, though an accelerated-hypofractionated (30 Gy in 10 fractions) treatment is indicated as feasible in combination with concomitant chemotherapy with results similar to those achieved with conventional fractionations and a markedly shorter duration. Based on the small improvements recorded in the treatment of these tumors, the evaluation of newer treatment modalities seems justified.

The case of a patient undergoing quadrantectomy of lower quandrants of the right breast and ipsilateral axillary lymph node dissection for breast cancer followed by adjuvant radiotherapy is discussed. The stage of the disease and prognostic factors are analyzed for prognosis. Comorbidities ruled out chemotherapy. Radiation therapy was planned followed by clinicoinstrumental controls. After the second control ipsilateral costal bone metastases were observed; radiation therapy for palliation was prescribed.

Prognosis for non-small cell lung cancer (NSCLC) patients who have locally advanced unresectable disease is poor for persistent thoracic disease and development of distant metastasis. In view of the poor rate of local control following conventional radiation therapy, there is a great need for methods to improve its efficacy. Three-dimensional conformal radiation therapy (3DCRT) is a high precision radiotherapy able to deliver higher doses with smaller doses to the surrounding normal tissues. However, the real problem is: "what do I want to treat?" This question is addressed based on the clinical and biological target volume definition. Selection of the CTV is therefore basically the clinical compromise between the most radical possible CTV and the critical normal tissue tolerance. The clinical target volume includes the GTV plus a margin to encompass subclinical or microscopic malignant disease immediately adjacent to it. Standard radiation therapy consists of a dose of 40 Gy to the entire mediastinum, supraclavicular fossa, and ipsilateral hilum, even if there is no evidence of disease in these areas. Despite the high risk of nodal spread in lung cancer, the benefit of additional elective nodal irradiation (ENI) is not proven while it seems to significantly increase the rate of radiation morbidity. Several studies have been published where ENI was systematically omitted. The main arguments for omitting ENI and the principal clinical experiences, are discussed.

CTV definition in exclusive or adjuvant radiation therapy of pancreatic carcinoma is essentially based on the opinion of "expert" authors and on the knowledge of lymphatic pathways. The subject has been widely debated. Radiotherapy treatments of the entire upper abdomen (liver and pancreatic region), pancreas and lymph node stations, to volumes focused on macroscopic tumor only, have been proposed. Carcinoma of exocrine pancreas is characterized by the frequent, early appearance of metastasis via the lymphatic route. Most commonly involved lymph node stations include those of the celiac trunk, superior mesenteric, peripancreatic, lumboaortic lymph nodes, those of the hepatic portal (the latter in particular for pancreatic head tumors) and of the hilum of spleen (the latter in particular for pancreatic tail tumors). The possible multicentricity of pancreatic carcinoma, most likely due to intraductal spread, should lead to the inclusion in the CTV of the entire pancreatic parenchyma. This should be considered also for the frequent perineural intra- or extrapancreatic spread of pancreatic carcinoma present also in small tumors (T1). In extrapancreatic spread the retropancreatic adipose tissue should be included in the CTV at least at the GTV level. At the present state of knowledge, in the absence of pattern of failure analysis and of comparison of different treatment approaches, in terms of the definition of volumes of interest, CTV definitions which include lymphatic drainage stations, most part of pancreatic parenchyma and retropancreatic adipose tissue seem justified especially in treatments for cure. In palliation, the CTV may be limited to the GTV and the adipose tissue behind it.

Colorectal carcinoma ranks second in incidence after lung cancer in males and breast carcinoma in females. Within the clinical research on this tumor, new molecules of antineoplastic agents and new combined modality treatments have been introduced. From the examination of ongoing protocols some trends can be identified: the interest in immunotherapy and genetic therapy, frequently tested in combination with chemotherapy; the effort at the optimization of the administration of antineoplastic agents in the most common sites of metastatic lesions by hepatic or intraperitoneal infusion; the trend to a more aggressive treatment of metastastatic lesions with hyperthermia and cryoablation as well with the combination of systemic therapy and surgery. As far as radiotherapy is concerned, the main goals of clinical research seem represented by the need to optimize combined modality therapy in T3-4 rectal carcinoma both in terms of pre- and postoperative radiotherapy timing as well as of the combination with adjuvant chemotherapy. There is a growing interest in new drugs which in the future may replace the conventional 5-fluorouracil in concurrent chemoradiation.

To-date, the therapeutic standards, defined by randomized studies for carcinoma of the exocrine pancreas are disappointing. Obviously, there is much interest in the improvement of these results based on the evidence of additional clinical trials. To identify some trends in the clinical research in this field, some characteristics of 31 ongoing trials, described in the web site of the National Cancer Institute were examined. 28/31 trials are coordinated by Centers of the U.S.A. and 3/31 trials specifically concern symptom palliation. Excluding the latter, 4 trials enroll patients with operable neoplasms, 8 with inoperable tumors, 4 with metastatic neoplasm and 12 involve both latter categories. Four of the 5 phase I or I-II studies concern concomitant radiochemotherapy of inoperable neoplasms; the 16 phase II studies and the 7 phase III studies involve the use of different combined modality therapies in all patient categories. Overall, 18 trials test innovative treatment modalities (new drugs, immunotherapy, monoclonal antibodies). Eight trials include the evaluation of the quality of life between endpoints. Based on this assessment of some of the ongoing clinical trials, hopefully, there will be: 1. a greater interest in the prospective therapies for this neoplasm, especially at the European level, considering the high incidence of this disease; 2. more careful attention to the possibility of downstaging of locally advanced neoplasms considering the present, proven possibility to achieve better clinical responses in pancreatic carcinoma; 3. a more widespread interest in the establishment of parameters for the quality of life, considering the frequently "palliative" intent of available therapies.

The organizational optimization in radiotherapy tends to a correct balance of quality of service and containment of health care expenditure; this goal is necessarily correlated with the real potentialities available to each center while considering the possible clinical benefits for the patient. In lung cancer, outcomes achieved with radiation therapy are encouraging in terms of local control and survival when treatment is performed with the available modern technology whose costs from an exclusively economic analysis are shown to be still quite high. In an assessment focused on clinical outcomes, better local control, higher survival and improved quality of life represent tangible benefits: this has a positive impact on community costs and may represent a high priority goal for health care providers, yielding a benefit that can be quantified with the most recent analyses of health care economy.

One of the principal therapeutic options in unresectable carcinoma of exocrine pancreas is concomitant radiochemotherapy. However, in current scientific literature cost analyses of this therapeutic modality are lacking. A payer-oriented cost-effectiveness analysis of concomitant radiochemotherapy was carried out. Outcomes and differences in costs relatively to two different therapeutic strategies were compared retrospectively: biliary drainage + observation (group 1); biliary drainage + concomitant radiochemotherapy (group 2). Cost-effectiveness was assessed based on the analysis of incremental cost of benefit in terms of survival in group 2. As incremental cost of group 2 was considered that of radiochemotherapy, costs of diagnosis and staging being similar in the two groups. The unit of measurement used was $/Lys (LYS = years of life saved). For estimates of cost-effectiveness in different clinical situations, a sensitivity analysis was carried out. The incremental cost of standard concomitant radiochemotherapy was shown to be $4,755. Incremental costs relatively to the situations of minimum and maximum treatment were shown to be $4,410 and $8,375, respectively. Median survival was 4.5 and 10 months in group 1 and 2 respectively (logrank: p = 0.0046). The benefit in terms of survival achieved by concomitant radiochemotherapy was shown to be 5.5 months equal to 0.46 years. Therefore, in the standard situation, the treatment cost-effectiveness can be estimated in: $4,755/0.46 years = $10,337/LYS, that is, the cost of a year of life saved was shown to be $10,337. Results of sensitivity analysis showed that cost-effectiveness can be estimated in the range $7,603 and $25,379/LYS. In conclusion, concomitant radiochemotherapy in patients with unresectable pancreatic carcinoma is able to improve the quality of life through the relief of related symptoms as well as median survival (10 vs 4.5 months). Costs of these benefits, even if considering better survival only, based on this analysis, were shown to be acceptable.

Local recurrence affects approximately 50% of patients undergoing surgery for pancreatic adenocarcinoma. To lower the incidence of locoregional recurrence, the combination with surgery of adjuvant radiotherapy has been proposed. The latter is based on external radiotherapy (ERT), intraoperative radiotherapy (IORT) or their combination. To evaluate the impact on local control and survival, results achieved in a a group of patients undergoing surgical resection and combined adjuvant radiotherapy, are analyzed. 17 patients with adenocarcinoma of the exocrine pancreas were treated with a therapeutic protocol based on pancreatectomy and intraoperative radiotherapy (IORT) to the tumor bed (10 Gy) followed by postoperative radiotherapy (50 Gy); 9 patients underwent also preoperative radiotherapy (5 Gy) to the pancreas and liver. With a median follow-up of 45 months, in 3 patients (17.6%) local recurrence was observed while 12 patients (70.6%) showed liver metastases or peritoneal spread. Median survival was 17.5 months and actuarial survival at 2 and 5 years was 41.2% and 11.2%, respectively. As compared to a moderate local control, the prognosis of patients undergoing surgical resection remained disappointing. Thus, the effort of improving results with new therapeutic modalities as preoperative radiochemotherapy and adjuvant chemotherapy, seems justified.

Better local control in locally advanced IIIA-B non small cell lung cancer, not considered for surgery, can be achieved through therapy intensification with non conventional fractionation of radiation dose, concomitant boost to the tumor volume, conformal therapy and combined modality therapy. All these procedures tend to produce an improved response, which, if stable in time, may also improve local control and survival. The reported experiences define a positive and encouraging trend on which new guidelines for a more suitable definition of standard therapies for the disease can be modulated.

Organ preservation as protection of the patient's quality of life in the modern approach to oncology, is a primary objective together with local control and survival. This objective can be attained through the optimization of therapeutic procedures and an interdisciplinary approach directed towards the best result of combined modality therapy. There are districts and organs where preservation is already well-established in terms of results to be achieved (breast, gastrointestinal apparatus, head-neck, prostate, bladder, soft tissue sarcoma, eye tumors). For other sites of disease, as carcinomas of the lung, still at present, systematization of a therapeutic program including organ preservation among its objectives to ensure an acceptable quality of life, is necessary. First trends towards this direction, in diseases not treatable with surgery alone, consider combined radiotherapy with or without surgery for better control without increased toxicity. Monitoring of the quality of life together with the already standardized parameters of local control and survival used in the evaluation of results, is desirable in these patients.

Problems of a correct approach to radiation therapy of lung cancer are reported. The identification of factors related to the site and function (respiratory motion, critical organs etc) allows systematization of a Quality Assurance procedure in treatment planning and implementation. Already in the diagnostic phase modern technology (CT, MRI) can supply useful information for a more correct staging and consequently for a more suitable treatment, while in the therapeutic phase it helps in the identification of irradiation volumes (simulation), in the use of treatment plans on CT imaging (multislide, 3D), in the use of conformal therapy able to increase the target dose while sparing the critical organs, and in checking correct patient set-up.

Neoplasms of the upper abdomen involve complex problems for radiotherapy. In fact, the anatomical structures are close to each other, lymphatic vessels are numerous and complex, there are organs of low radiation tolerance whose reciprocal position is of difficult assessment and finally there is high visceral mobility due to the diaphragmatic movements. Moreover most organs cannot be identified with the simulator and bone references are of little use. Therefore, treatment of these sites requires the routine application of quality assurance programs, checks of treatment reproducibility, in particular: In a number of clinical settings, CT study of the region (in treatment position) must be included in treatment planning and set-up with simulator and fluoroscopy. Before, during, and after radiotherapy, clinical exams and laboratory tests should be performed to assess the integrity of critical organs.

Pancreatic tumors represent a major field of application of intraoperative radiotherapy (IORT) with electron beams. First clinical studies were carried out principally on unresectable tumors and control of pain was observed in most of them. However, as for prognosis, IORT alone has yielded disappointing results. The use of IORT to boost external beam radiotherapy (ERT) frequently applied in recent trials, has improved local control but not survival rate because of the high incidence of abdominal metastasis. To-date, results of IORT used as an adjuvant to radical surgery have been controversial. As in unresectable tumors, studies have been focused on the combination IORT+ERT, however the intensification of the dose delivered to the tumor bed and the consequent better local control has not resulted in a better prognosis. A more significant contribution of IORT to the treatment of pancreatic tumors may come in the future from the combination of IORT with more effective methods in the control of the abdominal disease ("prophylactic" ERT to the liver or upper abdomen, intra-arterial or intraperitoneal chemotherapy) or from variously timed combinations with ERT (neoadjuvant ERT+IORT).

A series of studies carried out by the Gastrointestinal Tumor Study Group have shown the efficacy of the combination of external beam radiotherapy (ERT) and 5-fluorouracil (5-FU) chemotherapy (CHEM) in unresectable and resectable tumors of the exocrine pancreas. In the former in particular, this method was shown to be superior to ERT alone as well as to polychemotherapy alone. In these studies 5-FU was administered during (concomitant chemotherapy: C-CHEM) or after ERT (adjuvant chemotherapy: A-CHEM). This led several authors to consider this combined treatment as reference standard for pancreatic carcinoma. Its prognosis is still definitely poor because of the difficult local eradication as well as because of the frequent early distant spread, especially at the abdominal level (hepatic and peritoneal). An improvement of present results may stem from the combination of ERT+C-CHEM +/- A-CHEM with methods of dose intensification at the local level (e.g. IORT) concurrently with the use of treatments aiming at a better control of the abdominal spread (e.g. ERT+C-CHEM for prophylaxis of the liver or upper abdomen).

In intraoperative radiation therapy (IORT) a high dose of radiation is delivered to the tumor or to the tumor bed, thus favouring local control with no significant increase in toxicity. At present it is used to deliver a boost dose of radiation for rectal cancer in protocols which include preoperative external beam radiation therapy (ERT). From various experiences carried out in a number of centers, the technical and methodological features of this procedure have been defined also relatively to cost-effectiveness in terms of a longer surgical treatment, involved specialized staff and resources. At the 5th IORT International Congress held in Lyon in September, 1994, of over 70 clinical studies reported, 15 were on rectal cancer with about 700 patients undergoing IORT. The growing interest in the use of this procedure in rectal cancer is explained by the natural history of the disease, burdened with a high rate of local recurrence, and by the possibility of preventing it with high doses of radiation. In primary tumors unresectable for cure and in local recurrence it is evidenced that ERT+surgery+IORT enable an improvement in local control and survival as compared to ERT alone. Results are better when surgery is radical. Several studies deal with the role of preoperative combined concomitant radiochemotherapy which can favour a radical surgery. A sizeable percentage of these patients will present with metastasis, thus adjuvant chemotherapy seems suitable. A role of IORT is envisaged also for resectable high risk tumors, however results should be confirmed by larger clinical series.