Vladimir Svoboda

Local control of carcinoma of the tonsil by radiation therapy: An analysis of patterns of fractionation in nine institutions

PURPOSE To investigate the importance to outcome of treatment for squamous cell carcinomas of the tonsillar fossa, of dose per fraction, overall treatment duration, and total dose. METHODS AND MATERIALS A collaborative retrospective study was undertaken in nine centers that used widely different dose-fractionation patterns for external beam radiation therapy. RESULTS There were 676 eligible cases treated only with photon beams during the years 1976-1985. The probability of local control (of the tonsillar fossa primary) was influenced by both T-stage and N-stage. Significant treatment parameters were total dose and overall treatment duration, but not dose per fraction. Over the range of about 40 to 90% and for a constant overall treatment duration, local tumor control probability increased by nearly 2% for each 1 Gy increase in total dose. For a constant total dose there was a decrease in the probability of local control associated with prolongation of overall treatment duration, presumed to result from accelerated regrowth of surviving tumor clonogens during the course of treatment. If it is assumed that accelerated regrowth occurred at a constant rate and began within 9 days of the start of treatment, an average of 0.53 Gy extra dose per days extension of treatment would be required to maintain a constant probability of local control. Correspondingly, the probability of local control from a constant dose would be lowered by an average of at least 1% for each days extension of treatment duration. However, the data are slightly more consistent with an average delay of as long as 30 days before onset of accelerated repopulation, with a consequent increase to an average of 0.73 Gy per day for the value of the compensatory dose. The alpha/beta ratio for this tumor is high enough that the effect of fraction size on the probability of local control can be ignored; a precise estimate is not possible because the best value for beta was close to zero. After accounting for the significant variables studied (treatment time, T-stage, N-stage), the dose-response curves for tumor control were still shallow, suggesting that there are additional causes for heterogeneity of responses among these tumors. CONCLUSIONS Total dose is important to treatment outcome: After accounting for other treatment variables, there is about a 2% per Gy increase in probability of tumor control over the ranges of control commonly achieved. Overall treatment duration is important. There is at least a 1% per day decrease in tumor control probability if delivery of a constant total dose is prolonged, requiring a compensatory increase in dose by 0.5-0.7 Gy per day to achieve a constant rate of tumor control. Fraction size is not, of itself, an important factor in the response of primary carcinoma of the tonsil. If a tumor has demonstrated a capacity for metastatic spread to lymph nodes, a higher total dose should be considered to achieve control rates at the primary site equivalent to those in node negative patients. Even after accounting for variables such as tumor stage, total dose, and overall treatment duration, there is sufficient heterogeneity in other undocumented determinants of tumor control to cause the tumor control probability curve to be a shallow function of dose.

Late normal tissue sequelae from radiation therapy for carcinoma of the tonsil: Patterns of fractionation study of radiobiology

PURPOSE To evaluate the influence of dose fractionation and other factors on the development of late complications in mandibular bone, muscle, and mucosa of the oral cavity after external beam radiation therapy for carcinoma of the tonsil. METHODS AND MATERIALS A retrospective analysis was made of the results in 676 patients treated with a spectrum of fractionation regimens in nine centers during the years 1976-1985. Only severe (Grades 3-4) late complications were analyzed. RESULTS With more than 5 years follow-up, it was found that total dose was a factor for all three types of complications, but that in other respects, the radiobiology of late-(> 3 months) developing mucosal ulcerations was different from that for mandibular necrosis and muscle injury. Dose per fraction was a significant factor for bone and muscle (estimated alpha/beta values of 0.85 Gy and 3.1 Gy, respectively). By contrast, mucosa showed no influence on response from change in fraction size over the range of approximately 1.0-3.5 Gy. Complications in bone and muscle were not related to overall treatment duration, whereas there was a significant inverse relationship for mucosa breakdown. The rate of development of complications was fastest in mucosa and slowest in bone. The appearance of complications by 4 years after treatment was about 80% of those developing by 8 years in the mucosa, 66% in muscle, and about 50% in bone. The high alpha/beta ratio, inverse relationship with overall treatment duration, and faster development of mucosal complications suggests that they may develop as a consequence of earlier mucosal injury. As anticipated, adequate retrospective analysis of acute complications could not be made even when objective criteria such as weight loss, unplanned delays in completing treatment, or hospitalization during treatment were the measures. Field size was a significant factor for mandible complications, but not for muscle or mucosa. CONCLUSION The radiobiological characteristics of bone and muscle were those characteristic of other late-responding tissues, whereas late sequelae in mucosa had radiobiological parameters similar to those for acute responses. Field size was a significant factor for bone complications but not for others.

Early results of the EORTC randomized clinical trial on multiple fractions per day (MFD) and misonidazole in advanced head and neck cancer.

From Feb. 1981 to Oct. 1984, a randomized clinical trial was carried out in the EORTC Radiotherapy Group, comparing classical radiotherapy 70 Gy/7 weeks to MFD (3 X 1.6 Gy/day for 10 days, 3 weeks rest, followed by a boost to 67.2 or 72 Gy), with or without Misonidazole (1 g/m2 every irradiation day, total 12 to 14 g/m2) in advanced head and neck cancer (all T3 and T4, all N2, N3 and N1 greater than 3 cm). A total of 523 patients were entered in the study. At the time of analysis (4/85), the median follow-up time was 64 weeks. No significant differences in survival or locoregional control could be demonstrated between the three treatment arms at this time. Whereas early mucosal reactions were heavier in the MFD-arms, no differences in late effects (fibrosis, edema, xerostomy) were found between the three treatment arms. Five patients (all MFD + Misonidazole) died with local complications (edema, necrosis). All five had cancer of the laryngopharynx and 3 of them died from a hemorrhage. Factors affecting prognosis were tumor site, tumor stage, nodal status, and histological differentiation.

The EORTC randomized trial on three fractions per day and misonidazole in advanced head and neck cancer: prognostic factors

In trial no. 22811 on a randomized comparison of multiple fractions per day (MFD), with or without misonidazole, to conventional fractionation in advanced head and neck cancer, a large number (523) of patients was entered in a short period of time. No differences in treatment results were obtained, but the study created an important database, allowing for detailed evaluation of the most important factors influencing prognosis. In univariate analysis, factors significantly influencing survival and locoregional control were: performance status, histological differentiation, tumor site, tumor and nodal staging, and tumoral and nodal volume. In multivariate analysis, significant factors for survival were nodal involvement, tumor stage, performance status, and tumor site. Significant factors for locoregional control were nodal involvement and total tumor burden. This analysis suggests that total tumor burden (volume) should be included in the interpretation of treatment results in head and neck cancer.

The EORTC randomized trial on three fractions per day and misonidazole (trial no. 22811) in advanced head and neck cancer: long-term results and side effects

From 1981 to 1984, a randomized study was done by the EORTC Radiotherapy Group comparing a fractionation schedule with three fractions per day (multiple fractions per day, MFD), with or without misonidazole, to conventional fractionation. The aim of the study was to obtain improved local and regional control and survival by shortening of the treatment time in the first 2 weeks of irradiation. Three fractions of 1.6 Gy/day (4-h interval) were given during 10 irradiation days to a total of 48 Gy. After 3-4-weeks interval, a boost was given to 67.2 or 72 Gy also in three fractions per day. This schedule was compared to an identical arm with misonidazole 1 g/m2/day and a third arm with conventional fractionation (70 Gy in 35 fractions, 7 weeks or 75 Gy in 44 fractions, 9 weeks). A total number of 523 patients was included in the study. Acute mucositis was much heavier in patients treated with three fractions per day (Van den Bogaert et al. Int. J. Radiat. Oncol. Biol. Phys. 8: 1649-1655, 1982). Early results, communicated in 1986 (Van den Bogaert et al. Int. J. Radiat. Oncol. Biol. Phys. 12: 587-591, 1986) showed no differences in treatment outcome between the three treatment arms. Long-term results and data on late effects are now available. Survival at 5 years was 18% (SE 1.9%) and locoregional control was 27% (SE 2.9%). No statistically significant differences could be observed between the three treatment arms.(ABSTRACT TRUNCATED AT 250 WORDS)

High dose-rate microselectron molds in the treatment of skin tumors

PURPOSE The feasibility of high dose rate iridium afterloaded molds in the treatment of skin tumors. METHODS AND MATERIALS Expanded silicone rubber and bronchial applicator tubes were used in the construction of various molds. The number of tubes used and the separation between them depends on the size and area to be treated. Source dwell position and time are set to follow Paterson-Parker rules. Single plane expanded silicone rubber molds between 15 X 15 mm and 60 X 70 mm were used in 120 different sites, and of the others, seven were perspex double molds, two were cylindrical applicators, and one was a partially shielded intranasal applicator. One hundred and thirty lesions of various site and histology were treated in all. After exclusion of treatments that were combined with either external beam or chemotherapy, 106 lesions (76 patients) were evaluated. RESULTS Full response was obtained in all but four basal cell carcinomas. The acute reaction ranged from moist desquamation (27 sites) to erythema only. Follow-up at 5 or more months revealed no changes whatever in 47 sites; 53 showed an excellent cosmetic outcome, although slight changes in pigmentation or minimal atrophy was demonstrable and 6 sites became noticeably atrophic with patchy pigmentation. For 9.6 months of average follow-up time, no recurrences have been observed. CONCLUSION The high-dose-rate iridium-loaded skin applicators offer the possibility of improved therapeutic ratio in the treatment of superficial skin tumors. With the availability of a high-dose-rate afterloader this technique is simple and straightforward.

THE FEASIBILITY OF HIGH-DOSE MULTIPLE DAILY FRACTIONATION AND ITS COMBINATION WITH ANOXIC CELL SENSITIZERS IN THE TREATMENT OF HEAD AND NECK CANCER A pilot study of the Radiotherapy Group of the EORTC (European Organisation for Research on Treatment of Cancer)

From 1978 to the end of 1980, 179 patients with advanced head and neck tumors were accrued in a multicenter pilot study of the EORTC Radiotherapy Group, investigating the feasibility of high dose multiple daily fractionation (MDF) and its combination with misonidazole. The irradiation scheme consisted of three daily fractions of 1.6 Gy (four hour intervals) to a total dose of 48 Gy in two weeks, followed 3 to 4 weeks later by a boost to a total of about 70 Gy in 6 to 7 weeks. Misonidazole was given in daily doses of 1 g/m2 (total 13 or 14 g/m2) to 53 patients, thus sensitizing every radiation session. All patients had large head and neck tumors, with a poor prognosis. Acute reactions were well tolerated. Skin reactions were very moderate; mucosal reactions started at day 10 to 12. All patients had a confluent mucositis that lasted for one to two weeks. When the whole oral cavity was irradiated, reactions lasted somewhat longer. The boost caused no significant symptoms. The radiosensitizer did not modify the reaction pattern. Tumor regression was very impressive, so that palliation was obtained quickly. Nine patients died from treatment related causes. It is difficult to assess local control at this time, but at the time of analysis (August 1981), the actuarial control rate was 48% at 20 months, with misonidazole 57%. This difference, however, is not statistically significant. Survival of the total group is 31% at 20 months. In these patients with a heavy tumor burden the early results were considered a success by all participants. For patients with sufficient follow-up, late reactions can be evaluated. Some edema and fibrosis is seen, but did not exceed a degree which could be expected with single daily fractionation to the same dose. This study demonstrates the possibility of giving highly concentrated treatments to total doses equal to those used in conventional fractionation. For assessment of a possible benefit in local control and ultimate survival, a randomized study is necessary. Such a study is now underway in the EORTC Radiotherapy Group, comparing single daily radiotherapy with multiple daily fractionation with or without misonidazole.

Late results of multiple fractions per day (MFD) with misonidazole in advanced cancer of the head and neck. A pilot study of the EORTC radiotherapy group

In the EORTC Radiotherapy Group, the feasibility of multiple fractions per day (MFD) was tested in a pilot study from 1978 to 1980. Three daily fractions of 1.6 Gy were given (4 h interval) during 2 weeks (total dose 48 Gy), with a boost to about 70 Gy after 3-4 weeks. In 53 of the 179 patients, misonidazole was given on every irradiation day (1 g/m2, total 13-14 g/m2). Data on tolerance and early treatment results were published previously; results with a minimum follow-up period of 3 years are now available. Survival (actuarial is 21% and locoregional tumor control was obtained in 34% of patients; no significant differences were seen between the subregions in the head and neck area. Survival is better in patients treated with misonidazole (probably due to selection), but locoregional control was identical as in patients treated without the sensitizer. In February 1984, 38 patients were alive, 35 without evidence of local tumor (5 after rescue surgery). Metastases were seen in 16% and a second tumor in 7% of patients. Seventeen patients (9%) died of causes, possibly related to treatment; necrosis was observed in 8 (4 with local tumor). Late effects in the long survivors were comparable to what is usually seen after high-dose radiotherapy.

Conservative treatment of anorectal tumors

PurposeTo evaluate the results of interstitial radiotherapy of anorectal tumors.Patients and MethodsFrom 1972 to 1993, one of the authors treated 45 patients by an interstitial implant for anorectal tumors. Of these, 33 patients suffered from primary tumors, 19 from squamous carcinoma, 2 from basaloid carcinoma of the anus and the other 12 from primary adenocarcinoma of the rectum. Of 12 patients treated for local recurrence, 10 had adenocarcinoma and 2 squamous cell carcinoma. Of the 33 patients with primary tumors, 27 received a course of external-beam radiotherapy before the implant. The median follow-up was 35 months.ResultsLocal response depended on the tumor volume treated. All 21 anal tumors showed complete response, 5 patients developed local recurrence and 4 distant metastases; 3 died from their disease. Of 12 rectal adenocarcinomas, 9 responded completely, 4 patients developed local recurrence and 4 distant metastases; 6 died from active disease. In the last group of 12 patients who were treated for recurrent tumors, 7 responded completely. One patient developed local recurrence and 9 distant metastases, only 4 are alive.ConclusionsA combination of external-beam and interstitial radiotherapy is a relatively simple, non-mutilating, but well-tolerated and very effective method of treatment for early carcinoma of the lower rectum and anus.ZusammenfassungZielDie Auswertung der Ergebnisse der interstitiellen Radiotherapie anorektaler Geschwülste.Patienten und MethodeDas Krankengut bestand aus 45 Patienten mit anorektalen Tumoren, die im Zeitraum von 1972 bis 1993 durch interstitielle Implantate behandelt wurden. Von 33 Patienten mit primären Tumoren wurden 19 wegen spinozellulärer, zwei wegen basozellulärer Karzinome des Anus, weitere zwölf wegen Adenokarzinomen des Rektums behandelt. Außerdem wurden zwölf Patienten wegen Lokalrezidiven, davon zehn wegen Adeno- und zwei wegen Spinozellularkarzinomen bestrahlt. Von den 33 Patienten mit primären Tumoren wurden 27 vor dem Implantat mit Teletherapie perkutan bestrahlt. Die mediane Nachbeobachtungszeit betrug 35 Monate.ErgebnisseDer Behandlungserfolg war von der Tumorgröße abhängig. In der Gruppe von 21 Patienten mit Analtumoren, bei der eine komplette Tumorremission erreicht wurde, traten in fünf Fällen Lokalrezidive, in vier Fällen Fernmetastasen auf, drei Patienten sind bisher verstorben. Bei zwölf rektalen Adenokarzinomen wurde neunmal eine komplette Tumorremission erreicht, bei vier Patienten mit Fernmetastastasen. Sechs Patienten verstarben. In der Gruppe von zwölf Patienten, die wegen Lokalrezidiven behandelt wurden, kam es bei sieben zu einer kompletten Remission, bei einem davon entwickelte sich später ein zweites Lokalrezidiv. Es traten neun Fernmetastasen auf, acht Patienten verstarben.SchlußfolgerungDie Kombination der perkutanen Bestrahlung mit interstitiellem Implantat erweist sich als relativ einfache, aber sehr effektive Methode der Behandlung von frühen analen und tiefer liegenden Rektumkarzinomen.

Seventeen years experience with accelerated radiotherapy for carcinoma of the breast

Between 1973 and 1989, one hundred and three women received accelerated radiotherapy to the breast. Fifteen of them had the treatment after local tumor removal; the rest had primary radiotherapy for inoperable cancer. Eleven patients were irradiated twice a day, 83 three times a day, and nine four times a day. The overall time was five days in 52 courses, 7-15 days in 49 courses, and two patients had a longer regime. Actuarial local tumor control was 34.6% at five, and 24.7% at ten years in the whole group, and 25.5% and 14.6%, respectively, in the patients with macroscopical disease. Crude local control in the latter patients was achieved in 24.4% after a five day course, 28.8% after 7 to 11 days course, and 50% after a time of 12 or more days. Crude local control after total dose of less than 40 Gy was 15.8%, after 40-45 Gy, 31.7%, after 45.1-50 Gy, 33.3%, and after more than 50 Gy, 100% (four patients). Sixty patients were evaluable for late damage at 18 months; twenty three of them developed moderate changes. Six suffered severe late damage such as skin leathering or necrosis: three of them were treated for recurrence after previous radiotherapy. The main factor influencing tumor control was not the overall treatment time, but the total dose.