Multimodal management of stages III-IVa malignant thymoma.

PURPOSE: The optimal therapy for locally advanced malignant thymoma is controversial. We review our experience with a multimodal approach in 63 consecutive cases. PATIENTS AND METHODS: Forty-three patients had stage III and 20 stage IVa disease. Surgery with radical intent was initially performed in 30 cases, while 33 cases not amenable to radical surgery underwent neoadjuvant treatment (radiotherapy in 8 and chemotherapy in 25) before surgical reassessment. All patients, whether or not surgically resected, received radiation therapy. RESULTS: Radical resection (RR) was performed in 20 patients ab initio (all stage III) and in 12 patients after neoadjuvant treatment (eight stage III and four stage IVa). With the addition of patients radically operated with neoadjuvant treatment, the radical resection rate increased from 46 to 65% in stage III patients, and from 0 to 20% in those with stage IVa disease, respectively. Radical surgery was associated with longer progression free survival and overall survival according to both univariate analysis ( P< 0.001 and P<0.01, respectively) and multivariate analysis after adjustment for age, gender, histology and disease stage ( P<0.001 and <0.02, respectively). Progression free survival (median 56.9 months) was slightly lower in patients undergoing radical surgery after neoadjuvant approaches than in those radically resected ab initio (median not achieved), but overall survival (median not achieved) was similar in both groups. Subtotal surgical resection promoted complete response to subsequent radiation therapy. This condition significantly correlated with a better outcome. CONCLUSIONS: Complete surgical resection is an independent prognostic parameter in locally advanced thymoma treated with a multimodal approach. Preoperative treatment to increase the complete resection rate could improve the overall survival of these patients.

CT-MRI image fusion for delineation of volumes in three-dimensional conformal radiation therapy in the treatment of localized prostate cancer.

The objective of this study was to assess the utility of CT-MRI image fusion software and compare both prostate volume and localization with CT and MRI studies. We evaluated the differences in clinical volumes in patients undergoing three-dimensional conformal radiation therapy for localized prostate cancer. After several tests performed to ensure the quality of image fusion software, eight patients suffering from prostate adenocarcinoma were submitted to CT and MRI studies in the treatment position within an immobilization device before the start of radiotherapy. The clinical target volume (CTV) (prostate plus seminal vesicles) was delineated on CT and MRI studies and image fusion was obtained from the superimposition of anatomical fiducial markers. A comparison of dose-volume histograms relative to CTV, rectum, bladder and femoral heads was performed for both studies. Image fusion showed a mean overestimation of CTV of 34% with CT compared with MRI. Along the anterior-posterior and superior-inferior direction, CTV was a mean 5 mm larger with CT study compared with MRI. The dose-volume histograms resulting from CT and MRI comparison showed that it is possible to spare a mean 10% of rectal volume and approximately 5% of bladder and femoral heads, respectively. This study confirmed an overestimation of CTV with CT images compared with MRI. Because this finding only allows a minimal sparing of organs at risk, considering the organ motion during each radiotherapy session and the excellent outcomes of prostate cancer treatment with CT based target identification, we are still reluctant to reduce the CTV to that identified by MRI.

Timing of radiotherapy in breast cancer conserving treatment.

The optimal timing and sequencing of adjuvant radiotherapy and chemotherapy after breast-conserving surgery for early invasive breast cancer is controversial. Several studies demonstrated that postoperative radiation therapy significantly reduces the incidence of breast recurrences. For patients who do not need systemic treatment, the interval between surgery and the start of radiotherapy should not exceed eight weeks. For node-positive and high-risk patients receiving breast-conserving treatment, adjuvant chemotherapy should be administered prior to radiotherapy, but the delay of radiation should not exceed 20-24 weeks. Side effects and complications of radiotherapy can be expected to increase when chemotherapy is administered concurrently. In particular, antracycline-based chemotherapy regimens increase the damage to heart muscle and coronary arteries: to avoid the risk of ischemic cardiovascular disease, radiotherapy must be performed after the end of systemic treatment.

Basic and clinical research for the new radiotherapy.

Basic research has allowed the full knowledge of the underlying mechanisms of the use of radiotherapy in cancer treatment. However, in spite of the crop of radiobiological studies, the impact on clinical research in last years has been relatively little. Within the recent research in man, studies on altered dose fractionations, combined radiation and chemotherapy together with the development of sophisticated technology have allowed the use of new methods of radiotherapy while those existing have been optimized.

Topical role of brachytherapy: economic and organizational aspects.

Brachytherapy for the recent technological advances, represents a fundamental "therapeutic step" in a multidisciplinary approach based on surgery, external beam radiotherapy and chemotherapy, if necessary. The various professionals involved, each within their personal skills, participate in the formulation of a correct therapeutic program. The widespread use of high dose rate brachytherapy leads to consider that the machines should be supplied to major radiotherapy centers only, because the procedure requires the combination with external beam radiotherapy.

Brachytherapy and local control.

Locoregional control of primary tumor is fundamental to cure since only in one third of patients the onset of distant metastases is the major cause of therapeutic failure. Thus recently, all therapeutic approaches aimed at the enhancement of locoregional control have been considered with growing interest. More particularly, brachytherapy alone or in combined modality therapy as an important option in the local treatment of various malignant tumors, has been widely used; this being related to the now available information on dose-rate, remote after-loading procedures, the new, safe and handy radionuclides and computerized dosimetry systems which allow a more accurate and rapid dose calculation. These advances have led to a wider application of brachytherapy. Together with the classical indications for head and neck and cervical tumors, brachytherapy plays now a well-established role in the treatment of breast, brain, gastrointestinal, genitourinary, soft tissue lung and eye tumors.

Combined modality therapy for laryngeal and hypopharyngeal cancer.

In recent years, the improvement in results in terms of survival in the treatment of laryngeal and hypopharyngeal cancer at the same stage has been rather poor. Therefore, oncologists have tried to improve the quality of life through a decrease in morbidity while not decreasing the treatment efficacy. In particular, the objective was to preserve with noninvasive procedures the anatomy and function of the larynx and hypopharynx while not affecting the possible cure. The refinement on diagnostic, surgical and anesthetic procedures, the potential of modern radiotherapy, the acquisition of new knowledge in medical oncology have allowed the planning of combined modality therapy protocols aimed at organ preservation in many patients. Concurrent radiation and chemotherapy in patients with locally advanced disease is a clinical problem still under study. Results of some phase I and III studies have shown the efficacy of radiochemotherapy, at times with a non negligible toxicity involving healthy tissues, but with a real effective improvement in survival and organ preservation in laryngeal and hypopharyngeal cancer.

Quality control in radiotherapy.

Results achieved in radiotherapy have progressively improved in the course of years for the steady technological advances which allowed to exploit at best the available equipment and to create new devices, as well as for the better radiobiological knowledge. However, the need is felt for recommendations defining a set of principles to ensure the minimum acceptable standards. In Italy, a quality assurance system in radiotherapy should be applicable to the over 90 centers now operating with about 170 high energy units, 600 radiotherapists, 200 physicists and 600 technicians who treat over 100,000 patients per year. General requirements of this system and its organization are analyzed based on the various international scientific reports, formalized in a report of the national scientific societies of various European countries gathered in Bruxelles in October 1994. This report has been absorbed and edited in Italian by the Italian Association of Radiation Oncology (AIRO).

Results of a low aggressivity chemotherapy regimen (CVP/CEB) in elderly Hodgkin's disease patients.

BACKGROUND: Hodgkin's disease (HD) after the age of 65 years is uncommon and there are no published data on chemotherapy regimens devised for elderly HD patients. PATIENTS AND METHODS: From 1990 to 1993, 25 elderly HD patients were treated with the CVP/CEB regimen: chlorambucil 6 mg/sqm p.o. days 1 through 7, vinblastine 6 mg/sqm i.v. on day 1, procarbazine 100 mg/sqm p.o. days 1 through 7, prednisone 30 mg/sqm p.o. days 1 through 7, cyclophosphamide 500 mg./sqm i.v. day 15, etoposide 70 mg/sqm i.v. day 15, bleomycin 10 mg/sqm i.v. day 15. Each course was repeated every 4 weeks. Stage I and II patients were treated with 3 courses followed by involved field radiotherapy, while more advanced stage patients received 6 courses and radiotherapy was limited to bulky areas. The results of the CVP/CEB regimen are retrospectively compared to those of 74 elderly patients treated between 1982 and 1989 and subdivided into the following 2 groups: 32 patients treated according to the same therapy used at that time in younger patients, and 42 patients given alternative low aggressivity or palliative treatment. RESULTS: CVP/CEB is a well-tolerated regimen, with only 1 (4%) toxic death and 2 (8%) protocol violations/interruptions. The CVP/CEB complete remission rate (73%) compares favorably with our previous groups of patients, mainly because of the lower toxic death rate. However, the CVP/CEB relapse-free survival rate is lower than that of patients treated with more aggressive conventional regimens (47% vs. 77%, p < 0.02). The CVP/CEB overall survival and event-free survival rates are 55% and 32%, respectively, and they are not statistically different from those of patients treated before 1990. CONCLUSIONS: CVP/CEB is a well-tolerated low toxicity regimen with a high CR rate. The relapse rate is high and event-free survival is comparable to that of patients treated conventionally. Our results suggest the need for individualized treatment criteria for older patients with HD.

[High-dose-rate brachytherapy. The indications, technic and preliminary results]. / La brachiterapia ad alto rateo di dose. Indicazioni, tecnica e risultati preliminari.

The authors report their experience of high dose brachytherapy technique (HDR), relative to the first period of work, especially regarding treatment indications and preliminary clinical results. Twenty eight patients were examined, 12 of them with esophageal carcinoma, 7 biliary tract carcinoma, 6 skin of the face and 3 head and neck carcinoma. HDR brachytherapy was the first treatment in 20 cases; the other 8 cases were recurrences after previous irradiation. The HDR treatment had a curative purpose in 15 patients and was palliative in the other 13. Brachytherapy doses ranged from 20 to 30 Gy for curative treatments, with 4-8 fractions; 1 fraction was used for palliative radiotherapy, with doses from 5 to 10 Gy. The results were satisfactory. Local control was achieved in 5/6 patients affected with cholangiocarcinoma of the biliary tract and in 6/6 patients with skin neoplasia. In esophageal cancer, 9/12 patients treated with palliative, disobstructive purpose, showed dysphagia remission in 89% of the cases; the remission was maintained in 7 patients (78%), with 9 months median follow-up. HDR brachytherapy was then proved, during this first period of clinical application, as a valid and safe therapeutic method. It also allowed to extend the application field of brachytherapy, with new indications, as in esophageal neoplasias and biliary tract carcinomas.

The cost of hyperthermia: nine years experience at the Radiation Therapy Department of the Turin University.

BACKGROUND: In this paper the authors try to quantify the expenditure for the equipment, staff, treatment per patient and research, sustained at the Radiation Therapy Department of the University of Turin for the treatment of cancer with hyperthermia, METHODS: Two hyperthermic computerized devices are available: the SAPIC SVO3 multifrequencies system (915, 434 and 2-30 MHz) for external hyperthermia, and the SACEM system. working only with the frequency of 915 MHz, for interstitial and intracavitary heating. From September 1983 to December 1991, 408 patients have been treated with hyperthermia, for a total number of treated sites of 483; 2960 heating sessions were performed, with a average of six sessions per patient. RESULTS: The overall cost of our "hyperthermia project" was about 2,000,000,000 Italian liras; the equipment cost was estimated at 1,258,650,000 Liras (839,100 US$), and the cost per treatment and per heat session at about 3,985,200 (2676 US$) and 664,200 liras (443 US$), respectively. The cost of the research program can be estimated in 175,000,000 liras (116,666 US$). The National Health System provides for a partial reimbursement of 2,000,000 liras (1,333 US$) for each course of hyperthermia. Taking into account the mean expected life expectancy and increasing purchases for replacement of equipment, these costs increase 10% each year. As regards the cost-benefit problem, using the Rees formula it varies from 1112 US$ when hyperthermia is used as elective treatment to 3380 US$ when hyperthermia is used as palliative treatment. CONCLUSIONS: Hyperthermia is, in our experience, an expensive therapy.

Concomitant radiotherapy and daily low-dose carboplatin in locally advanced, unresectable head and neck cancer. Definitive results of a phase I-II study.

The combination of daily low-dose carboplatin and radiotherapy was studied in 55 patients with inoperable head and neck cancer. All patients were planned to receive 70 Gy plus carboplatin i.v. daily, 45-60 min before radiotherapy. A starting schedule of 30 mg/m2 on days 1 through 5, weeks 1, 3, 5 and 7 was administered to 17 patients; an escalating daily dose, up to 55 mg/m2, was given to 38 additional patients. Up to a daily dose of 45 mg/m2, only 4.4% of the patients developed grade 3 leukopenia; on the contrary, grade 3 and 4 leukopenia was seen in 62.5% of patients receiving 50 mg/m2 or more. Mucositis was the major nonhaematologic toxicity and seemed to be dose-dependent. At the end of the loco-regional treatment there were 33 (61.1%) CR and 17 PR; the most effective total carboplatin dose seemed to be 40-45 mg/m2. After surgical salvage the number of CRs increased to 37 (68.5%). One- and 2-year loco-regional control rates were 64% and 53% respectively. One- and 2-year actuarial survival rates were 71% and 53% respectively; the corresponding rates of disease-free survival were 60% and 43%. There was a strong correlation nodal status and both survival and disease-free survival.

Probability of cure in elderly Hodgkin's disease patients.

BACKGROUND: Elderly Hodgkin's disease patients have a poor prognosis. The question arises whether these patients need aggressive treatment or a palliative strategy. So far, as a consequence of the scarcity of trials designed for them, useful information can be obtained only by retrospective analyses. METHODS: We retrospectively studied clinical data from 567 patients recorded from 1982 to 1989 in the Piemonte Hodgkin's Disease Register (PHDR). The 65 patients over 65 years of age were compared to younger ones. We analyzed the role of disease independently of confounding variables, mainly inadequacy of staging and/or treatment, comorbidity and toxicity. RESULTS: In the elderly comorbidity was as high as 35%. Forty elderly patients (60%) entered a suboptimal plan with a low degree of aggressivity, which was different from the usual PHDR protocol. Elderly patients also had a high proportion of subsequent protocol interruptions (25%). Chemotherapy dose intensity was negatively affected by advanced age (p < 0.01 after both 3 and 6 courses of chemotherapy). Toxic deaths were significantly higher in elderly patients than in younger ones (14% vs 1%; p < 0.05). CR rates, overall survival (OS), disease-specific survival (DSS) and event free survival (EFS) were all significantly influenced by age (p < 0.01). Relapse-free survival (RFS) in patients achieving CR did not differ according to age class (77% vs 60%; p = ns). RFS was better in elderly patients entering the PHDR protocols than in those following an alternative plan (75% vs 54%; p = 0.04); however, elderly patients treated according to PHDR guidelines showed a higher incidence of toxic deaths than those treated less aggressively (23% vs 8%). The two groups had similar EFS (36% vs 24%; p = ns). CONCLUSIONS: Elderly patients who achieve CR can have good RFS and cure is possible, but the toxic cost of conventional strategies is unacceptable and selected strategies still must be found.

Vestibular apparatus disorders after external radiation therapy for head and neck cancers.

External irradiation of different head and neck cancers may involve parts of the ear. The vestibular function of 25 patients in which the inner ear was comprised in the irradiated volume was investigated by electronystagmography (ENG). Doses administered to the vestibular system ranged between 2800 and 5120 cGy. Five patients suffered subjective vertigo or dizziness. Eleven patients (three out of five with vertigo) showed vestibular abnormalities to ENG (44% of the total). Altered responses to specific tests were as follow: six patients to the bithermal caloric stimulation, two to the pendular-sinusoidal test and the other three to both of them. Patients were evaluated 3 and 6 months after the ending of the radiation therapy course. At the first evaluation, abnormalities to caloric test were noted in three patients (12%) and to sinusoidal rotatory test in one patient (4%). At the second evaluation, rates of abnormal response increased to 36% and 20%, respectively. Vestibular disorders seemed to be scantly related to the total radiation dose. Data of literature are discussed in order to identify possible implications on treatment planning.

Aggressive treatment of intrathoracic recurrences of thymoma.

Between 1974 and 1988, 21 patients with intrathoracic recurrences of thymoma received radiotherapy with radical intent; surgery was always attempted when considered feasible: 11 patients were partially (6 cases) or totally (5 cases) resected before irradiation, while in the other 10 radiotherapy was the only treatment. In 7 cases the recurrence was confined to the anterior mediastinum, 9 had pleural nodules without mediastinal lesions and 5 had both mediastinal and pleural lesions. Mediastinal recurrences were treated by opposed parallel mediastinal fields with 2/3 of the dose delivered through the anterior port: doses ranged between 38 and 44 Gy; a boost of 10-16 Gy was given in patients not radically resected. Pleural nodules were treated with a variety of techniques according to the extent of the lesions. The 7-year survival of the whole group was 70%; 5 patients died: 4 with intrathoracic progression and one with distant metastases. The survival was 74% in the 11 patients having received surgery, either radical or subtotal, and 65% in the 10 patients treated with radiotherapy alone: the difference is not significant. Patients with Karnofsky index greater than 70 had a significantly better survival (100%, versus 28%, p = 0.0015). This is a selected series of patients presenting recurrences still amenable to a radical treatment either by surgery and radiotherapy or by radiotherapy alone: the results confirm that an aggressive approach is warranted in patients in good general conditions with recurrences confined to the mediastinum and/or 1 hemithorax.

Daily low-dose carboplatin and standard radiotherapy in unresectable head and neck and lung cancers: a pilot study.

A total of 14 patients with locally advanced and unresectable head and neck (SCCHN) or non small cell lung cancer were treated with a definitive course of radiation therapy with conventional fractionation and 30 mg/m2 carboplatin (CBDCA) given daily as an i.v. infusion during the 1st, 3rd, 5th and 7th weeks of the combined treatment. The planned tumor dose of at least 7000 cGy was reached in all SCCHN patients except 1 (6600 cGy). The 2 NSCLC patients received 6320 and 5980 cGy, respectively. The planned total CBDCA-dose of 600 mg/m2 was administered in all patients. No treatment delays were required in 10 patients. Interruptions for severe mucositis or myelosuppression occurred in 4 patients (28.6%), but in no case did the delay exceed 1 week. Complete response was obtained in 8 patients (57.1%); 7 of the 12 with SCCHN and 1 of the 2 with NSCLC. The other 6 patients achieved a partial response. Granulocytopenia of WHO grade 3 occurred in 1 patient; apart from vomiting and mucositis, toxicities above grade 2 were not observed.

Hyperthermia alone in the treatment of recurrences of malignant tumors. Experience with 60 lesions.

Localized hyperthermia alone has been used for the treatment of cancer recurrences in which previous conventional therapies have failed. Since 1983 and 1988, 57 patients with 60 lesions have been heated by means of a microwave and radiofrequency system. Treatment protocol provided 45 minutes of heating at the intratumor temperature of at least 42 degrees C, twice a week, for a total number of six, eight, or ten heating sessions. Invasive intratumor thermometry was performed for all lesions. Complete response (CR) was obtained in ten cases (16.6%) and partial response (PR) in 14 (23.4%). Higher rates of CR were observed in the chest wall (38.5%) compared with the head and neck area (11.4%), trunk (10%), and limbs (none). Adenocarcinoma was the most responsive histologic type (40%). Squamous cells carcinoma had 7.7% CR. The only case of undifferentiated carcinoma showed CR; there were none on five sarcomas. Long-term local control (24 months) was approximately 7%. The multivariate analysis showed the statistical significance of the histologic variety (adenocarcinoma versus others, P less than 0.0001). Side effects and complications of the treatment were minimal.