Oral complications of head and neck radiotherapy: prevalence and management.

AIM: The aim of the study was to evaluate the short-term and long-term toxicity caused by radiation treatment in the head and neck with the technique of intensity-modulated radiotherapy (IMRT). METHODS: We selected 20 patients, 18 men and 2 women aged between 21 and 71 years, undergoing radiation therapy (IMRT) in head and neck. Patients were visited during radiotherapy and followed for six months after the end of the therapy. We assessed the presence of: mucositis, xerostomia, dysgeusia, dysphagia, pain, trismus and, in the case of late-onset complications, radiation cavities. RESULTS: Acute toxicity: in 20 patients, 18 reported mucositis, 19 xerostomia, 17, dysgeusia, 15 dysphagia, 18 had pain and 3 patients had trismus. Tardive toxicity: in 14 patients, 5 reported mucositis, 11 xerostomia, 6 dysgeusia, 2 dysphagia, 3 had pain, 4 trismus and in 4 patients were found radiation cavities. CONCLUSION: Acute complications with higher prevalence were xerostomia (19 of 20 patients), dysgeusia of 2nd grade (11 patients of 20), mucositis of 1st grade and pain of 1st grade (10 patients of 20). Among the late complications it was noted a maintenance of the high prevalence of xerostomia (11 patients of 14) and an increase in prevalence of trismus (4 patients of 14) against a reduction of all other complications. The presence of radiation cavities in 4 patients of 14 was also recorded.

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

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

In vivo EBT radiochromic film dosimetry of electron beam for Total Skin Electron Therapy (TSET).

EBT radiochromic films were used to determine skin-dose maps for patients undergone Total Skin Electron Therapy (TSET). Gafchromic EBT radiochromic film is one of the newest radiation-induced auto-developing photon and electron-beam analysis films available for therapeutic radiation dosimetry in radiotherapy applications. EBT films can be particularly useful in TSET; due to patient morphology, underdosed regions typically occur, and the radiochromic film represents a suitable candidate for monitoring them. In this study, TSET was applied to treat cutaneous T-cell lymphoma. The technique for TSET was implemented by using an electron beam with a nominal energy of 6MeV. The patient was treated in a standing position using dual angled fields in order to obtain the greatest dose uniformity along the patient's longitudinal axis. The electron beam energy was degraded by a PMMA filter. The in vivo dose distribution was determined through the use of EBT films, as well as of thermoluminescent dosimeters for comparison (TLDs). EBT results showed a reasonable agreement with TLDs data.

Dosimetric, mechanical, and geometric verification of conformal dynamic arc treatment.

A conformal dynamic arc (CD-arc) technique has been implemented at the S. Giovanni Calibita-Fatebenefratelli Hospital Radiotherapy Center. This technique is performed by rotational beams and a dynamic multileaf collimator (DMLC): during the treatment delivery the gantry rotates and the field shape, formed by the DMLC changes continuously. The aim of this study was to perform dosimetric, mechanical, and geometric verification to ensure that the dose calculated by a commercial treatment planning system and administered to the patient was correct, before and during the clinical use of this technique. Absolute dose values, at the isocenter and at other points placed in dose heterogeneity zone, have been verified with an ionization chamber in a solid homogeneous phantom. In uniform dose regions measured dose values resulted in agreements with the calculated doses within 2%. Isodose distributions have also been determined by radiographic films and compared with those predicted by the planning system. Distance to agreement between calculated and measured isodoses in dose gradient zone was within 2 mm. In conclusion, our results demonstrated the feasibility and the accuracy of the CD-arc technique for achieving highly conformal dose distributions. Up till now 20 patients have been treated with CD-arc therapy.

Head and neck cancer: new trends in research and clinical practice.

Head and neck cancer represents an interesting subject of research in the third millennium. Apart from basic research (molecular biology, genic therapies etc.) which it shares with other neoplasms, a number of studies are in progress in the field of clinical research. In particular trials of combined radiation and chemotherapy with one or several drugs are being carried out and they will certainly provide definitive results in the field of clinical application. Further acquisitions will be provided by the studies on non conventional dose fractionation and the application of intensity modulated radiotherapy. Finally, the first studies on chemoprevention in patients with malignant or precancerous lesions of the head and neck will be soon concluded.

The impact of the new organization on the management of breast cancer.

The radical change in the health care service now going on for some years requires the commitment of medical specialists, as well as the acquisition of an adequate knowledge of the economic implications associated to the therapeutic choice. Among primary objectives of health care management in the field of breast cancer, the best cost-effective strategy and the rationalization and standardization of diagnostic and therapeutic approaches, should be identified. Problems related to breast cancer are examined for effective, efficient and economic optimization.

Preoperative chemoradiation with cisplatin and 5-fluorouracil for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, sphincter preservation.

PURPOSE: To evaluate the impact of preoperative external radiation therapy intensified by systemic chemotherapy including bolus cisplatin (c-DDP) and 4-day infusional 5-fluorouracil (PLAFUR-4) on tumor response and sphincter preservation in patients with extraperitoneal T3 rectal cancer with acceptable toxicity, and to compare the results to our previous experience with bolus mitomycin c (MMC) and 4-day infusion 5-FU (FUMIR). METHODS AND MATERIALS: Between October 1995 and March 1998, 40 consecutive patients with resectable extraperitoneal adenocarcinoma of the rectum were treated with preoperative chemoradiation: slow infusion i.v. c-DDP, 60 mg/m2, day 1 and 29 plus 24-h continuous infusion i.v. 5-fluorouracil (5-FU) 1000 mg/m2, days 1-4 and 29-32, and concurrent external beam radiotherapy (45 Gy whole pelvis followed by 5.4 Gy boost). All but 3 patients had T3 disease. Surgery was performed 6-8 weeks after the end of chemoradiation. RESULTS: No patient had Grade 4 acute toxicity. Grade 3 hematological toxicity was observed only in 2 (5%) patients. No patient had major gastrointestinal, skin, or urological acute toxicity. All patients had radical surgery. There was no perioperative mortality; perioperative morbidity rate was 12%. Overall, 23% (9 of 40) of patients had a complete pathological response and 10% (4 of 40) of patients had rare isolated residual cancer cells (Tmic). Comparing the stage at the diagnostic workup with the pathological stage, tumor downstaging was observed in 27 (68%) patients; nodal status downstaging was detected in 24 (60%) patients. Thirty-four (85%) patients had a sphincter-saving surgical procedure. In 4 of 10 (40%) patients who were definitive candidates for an abdominoperineal resection (APR), the sphincter was preserved, as it was in 13 of 13 (100%) probable candidates. Lengthening of the distance between the anorectal ring and the lower pole of the tumor > or =20 mm was observed in 9 (23%) patients. None of the patients had soilage after the sphincter-saving procedure. In our previous experience with FUMIR the complete pathological response was 9%, the sphincter-saving surgical procedure was performed in 66% cases, and the Grade 3+ toxicity was observed in 13% of patients. CONCLUSIONS: The addition of c-DDP to 5-FU (PLAFUR-4) in a neoadjuvant radiochemotherapy schedule improved the pathological response rate in comparison with our previous experience. Toxicity was low indeed, thus we commenced another study adding one more day of 5-FU infusion (PLAFUR-5) to further improve our results.

[Supportive therapy in oncology]. / Le terapie di supporto in oncologia.

The current trend towards a more intensive cancer treatment is possible thanks to the availability of a really important and effective supportive care. It is our opinion that it would be essential for the junior staff in oncology, for the practitioners, but also for the knowledge of anyone contributing in different ways to give the cancer treatment, to have reference points to give also the best supportive care. With this aim we thought to start a study, in Italy, to investigate, first, which is the supportive care used in the most common acute toxicities during or immediately after cancer therapy. We decided to begin with a survey addressed to hematologists, medical oncologists, radiotherapists; 105 centers were contacted. In order to have a high number of people able to answer to different clinical questions we decided to use Internet to communicate with participating centers without moving people. The final goal of the project is to formulate guidelines in supportive care, but also to promote the use of Internet as much as possible in the medical world with the aim to make easier every kind of communication and exchange of information.

Supportive care in radiotherapy: a review.

The normal tissue tolerance and the related early side effects represent the main constraint on the total radiation dose which can be administered to the target volume. The most common disorders during radiotherapy or chemo-radiotherapy are summarized in this review. Since in the recent years great advances have been made towards the improvement of acute tolerance, practically every adverse symptoms can be controlled or lowered with an adequate treatment. Some suggestions are reported in order to prevent or lower the degree and the incidence of major complications, specifically mucositis-related symptoms like stomatitis, diarrhea, cystitis. Possibly, a multicenter effort is to be made in order to optimize the quality of supportive care for irradiated patients in all radiation therapy centers.

Chemoradiotherapy with carboplatin in continuous infusion in the locoregional control of advanced head and neck cancer.

Because of the difficulty to achieve and maintain locoregional control in head and neck cancer, many clinical trials were focused on the addition of chemotherapy to locoregional treatments in advanced head and neck cancer patients. In particular, concomitant chemoradiotherapy resulted in high response rate and improved local control, sometimes with increased toxicity. In the effort to improve local control a phase II study on chemoradiotherapy with carboplatin in prolonged continuous infusion for 14 days (420 mg/m2 total dose) during standard radiotherapy, was performed. 45 patients were evaluable for response: CR 62.5% (global response 96%). After a mean follow-up of 48 months 9/28 patients with CR were still alive with no evidence of disease; two additional patients were alive but with locoregional disease. As for deceased patients, one died from non-tumor related causes, 13 from locoregional disease and 2 for metastatic disease. If the entire population of Crs is analyzed, it is observed that 13 patients (46.5% of CRs and 29% of the entire series) maintained a durable locoregional control. In most patients recurrence was detectable both in the primary tumor and in the neck.

Local control in breast cancer: impact on survival.

The role of radiotherapy in breast cancer is examined, based on a review of literature. Its impact on survival is discussed in the framework of a multidisciplinary treatment of the disease.

[Supportive care in oncology]. / Le terapie di supporto in oncologia.

It is extremely important to deliver treatments, both in medical oncology and in radiation oncology, in compliance with the due dose intensity, in order to achieve the best results in terms of clinical response and local control and, often, also in terms of survival. Supportive care is one of the tools for the achievement of this goal, permitting the delivery of aggressive therapies and the improvement of Quality of Life. It is the aim of the Tsonc study to evaluate what the main therapeutic trend is, on the ground of a survey performed in 105 medical oncology, radiation oncology, and haematology centres. For this assessment the WHO/INH and RTOG common toxicity criteria were adopted, even knowing that these score systems had been developed for reporting acute/subacute toxicity and not to choose the therapeutic approach. However, these scales give us the possibility to refer to highly validated systems and provide participants with a common language. Thirty-two items of toxicity were listed, and each item included 2 to 4 degrees of severity so to report supportive care accordingly. The present paper reports the criteria of choice of the scales and symptoms and the schedule of the queries.

Preoperative radiotherapy in the conservative treatment for breast cancer.

Aim of this study was to evaluate the feasibility, therapeutic effectiveness and toxicity of a non conventional radiation therapy (180 cGy twice a day for a total dose of 36 Gy in 2 weeks in the treatment of breast cancer inoperable with conservative surgery as first choice. Ten patients were studied. Results were as follows: complete response: 20%, partial response: 70%; no change: 10%. Acute toxicity was negligible and late toxicity, after a mean 46-month follow-up, was practically absent; the cosmetic result was definitely good. The radiobiology and kinetic features of breast cancer indicate that the potential of accelerated treatment should be further explored, this fractionation being suitable for optimal combined modality treatment with preoperative chemotherapy.

Organ preservation in rectal cancer.

Treatment of distal rectal cancer is aimed at sphincter preservation. Three trials were conducted to this purpose. They differed for T stage selection and therapy. Two of the trials are now completed, while patients are still recruited for the third trial. 21 T2 patients were selected for the first series and treated with local excision plus postoperative radiotherapy. External beam radiotherapy (ERT) was delivered at the dose of 45 Gy. Grade 3-4 (RTOG) acute toxicity was 5%; late toxicity was never observed. Sphincter function was rated as excellent or good in all patients. Sphincter preservation was achieved in 86% of cases. In the T3 FUMIR trial, 83 patients with extraperitoneal rectal cancer (T3) were treated with concomitant mitomycin C (10 mg/m2, day 1) plus 5FU (1000 mg/m2 days 1-4) plus ERT (38Gy). Grade 3-4 acute toxicity (RTOG) was 13%; late toxicity was never observed. Sphincter function was rated excellent or good in 96% of patients; sphincter preservation was achieved in 66% of patients with a lesion at less than 50 mm from the internal anal orifice. In the T3 PLAFUR trial, 19 patients with extraperitoneal rectal cancer (T3) were treated with concomitant cisplatin (60mg/m2, day 1 and 28) plus 5FU (1000 mg/m2 days 1-4 and 28-32) plus ERT (50.4 Gy). Grade 3-4 (RTOG) acute toxicity was 5%; late toxicity was never observed. Sphincter function was rated excellent or good in 93% of patients. Sphincter preservation was achieved in 73.7% of patients; in particular, in 55.6% of those with a lesion at less than 50 mm from the internal anal orifice. Combined modality therapies are showing the ability of sphincter preservation in patients with distal rectal cancer. Ongoing studies will identify the patients who are candidates for this therapeutic approach and the most suitable combined treatment.

Organ preservation with radiochemotherapy in locally advanced bladder cancer.

Bladder cancer is frequent in Western countries and predominantly affects males (ratio: 3:1). In 15-25% of cases there is muscular wall invasion. Treatment of > T1 tumors is radical cystectomy with or without preoperative radiotherapy. In T2 there is 60% survival at 5 years, 40% in T3. Exclusive radiotherapy used to prevent radical cystectomy has lower survival rates in T2 (30-40% at 5 years) as well as in T3 (20% at 5 years). Recently, concomitant radiotherapy and chemotherapy has been introduced again to prevent demolitive surgery. Results are similar or slightly superior than those of surgery alone. In our experience with radiotherapy 180 cGy daily for a total dose of 64 Gy in combination with fluorouracil in locally advanced tumors 40% bladder preservation was achieved.

Combined radiochemotherapy for organ preservation in head and neck cancer: review of literature and personal experience.

Combined radiochemotherapy is the most common method aimed at improving the rate of clinical response in advanced head and neck cancer. Complete clinical remission may correspond to a significant percentage in organ and/or function preservation. In 1992 a protocol of concomitant radiochemotherapy with continuous infusion of carboplatin for 14 consecutive days at the daily dose of 30 mg/m2 and concomitant radiotherapy with conventional fractionation (1.8 Gy to a total 65-70Gy) was started. Over a 3-year period, 56 patients with advanced head and neck cancer, were treated. In view of organ preservation, 26 patients of this series, though with considerable extent of the disease at diagnosis, were considered candidates for radical surgery: oral cavity 9 patients; oropharynx 9 patients; larynx/hypopharynx 8 patients. A single patient was stage I (hypopharynx); most patients were stage III (7) and IV (17 = 65%); T4 20%, N3 23%. 17/20 patients (70%) showed complete clinical response, 6 partial clinical response with a single non responder (overall response 95%). A patient underwent total glossectomy followed by local recurrence and another patient underwent pharyngolaryngectomy also followed by recurrence. After a mean follow-up from 22 to 60 months, 9 patients were still free of disease (37.5%). Median duration of complete response was 25.6 months. Overall median survival was 26.7 months: 38 months in responders. 2-year survival of patients with complete response was 59%. As for organ preservation, at present 6 over 18 patients (33%) with tumor of the oral cavity or oropharynx and 3 patients with tumors of larynx/hypopharynx have preserved organ and function. As for complete responders, 54.5% of those with tumors of oral cavity or oropharynx and 50% of those with tumors of larynx/hypopharynx, have preserved anatomy and function after at least 2-year follow-up. To-date, in follow-up controls relevant late toxicity has not been observed, showing that to the positive anatomical result corresponds the functional preservation of single structures.

Quality assurance in radiotherapy of head and neck tumors.

Radiation therapy represents an extensively experimented treatment modality for head and neck tumors. Recent studies have documented a close dependence of clinical results, especially in terms of local control and toxicity, on the radiation therapy quality. Thus the effort to improve the results of conventional radiotherapy has been achieved with the identification of new therapeutic modalities (non conventional fractionation, conformal therapy, fast neutron radiotherapy, concomitant or neoadiuvant chemotherapy) as well as with constant optimization of the accuracy of used procedures. Among them the following should be mentioned: 1) the systematic use of immobilization systems which enable a significant reduction in positioning errors; 2) checks before and during treatment by portal imaging which enable to identify and correct a relevant percentage of inaccuracies; 3) "in vivo" dosimetry which enables an overall assessment of treatment accuracy. The general evolution of the radiobiological knowledge occurred in recent years has introduced into radiotherapy of head and neck tumors new schemes of fractionation and new modalities of combination with other therapeutic procedures. Furthermore, while the widespread use of complex irradiation procedures calls for the urgent need of quality assurance of radiation treatments, this is by all means a mandatory requirement even in the most conventional clinical practice.

Prolonged continuous infusion of carboplatin and concomitant radiotherapy in advanced head and neck cancer. A phase I study.

A Phase I study on conventional radiotherapy and concomitant infusional chemotherapy with carboplatin (CBDCA) was initiated in order to evaluate the toxicity and feasibility of this combined treatment. Twenty-one patients with advanced head and neck carcinoma entered the study: 9 patients (Group A) received a 14-day infusion of 30 mg/m2 of CBDCA daily and 12 (Group B), a 21-day infusion beginning from the first day of radiotherapy. Total doses of 420 and 630 mg/m2 were given to group A and B, respectively. RT total dose ranged from 65 to 70 Gy with standard fractionation (180 cGy/5d/w). Major side effects observed were hematologic and mucosal. In group A grade 3 leukopenia was observed in five patients, grade 3 thrombocytopenia in one, and grade 3 mucositis in 2. In group B hematologic toxicity was severe: grade 3 and 4 leukopenia was seen in 4 and 3 patients, respectively; 3 patients had grade 3 and 2 patients grade 4 thrombocytopenia with a late appearance of nadir. Severe grade 3 mucositis was observed in 6 patients. Nineteen patients were evaluable for tumor response: 7/17 patients with stage III-IV disease achieved a CR and 8 a PR. According to our experience, prolonged infusion with CBDCA during conventional RT courses is feasible, though a certain level of toxicity remains. A 30 mg/m2 daily dose for 21-day infusion is associated with severe hematologic toxicity, while 14-day infusion can be considered the maximum tolerable dose. Whether CBDCA infusion has any advantage over bolus is yet to be confirmed.