Inoperable oropharyngeal carcinoma treated with concomitant irradiation, mitomycin C and bleomycin - long term results.

Patients with inoperable head and neck tumors were treated concomitantly with radiochemotherapy with mitomycin C and bleomycin in our prospective randomized clinical trial (1991- 1993). For the subgroup of patients with oropharyngeal carcinoma the results with radiochemotherapy were significantly superior to irradiation alone. Such scheme of treatment was then adopted as standard method. Here we present the long-term results and dose- response relationships in patients with inoperable oropharyngeal carcinoma treated by the same radiochemotherapy scheme till 1997. Ninety-five patients with stage III and IV inoperable oropharyngeal squamous cell carcinoma were treated with curative intent, concomitantly with supra-voltage irradiation 2 Gy/day 5 times weekly to 60-73 Gy, bleomycin 5 mg 2 times weekly and. one application of mitomycin C 15 mg/m(2) after 10 Gy. Logistic dose- response curve was calculated. Median follow-up was 85 months. The loco-regional control, disease- free survival and overall survival at 5 years were 55%, 51% and 32% (95% CI: 44-67%, 41-62%, 22-42%), respectively. The probability of new primary malignancy at 5 years was 23%. In multivariate analysis performance status, biological equivalent dose, dose of bleomycin, and stage were identified as independent prognostic factors for loco-regional control, disease-free, and overall survival. Th gamma-value of dose response curve was 2.86. The outcome of the disease was directly proportional to intensity of irradiation and chemotherapy. It appears that in our concomitant radiochemotherapy MiC increased radioresponsiveness of the tumor by its effect on hypoxic fraction.

Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report.

PURPOSE: To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone. METHODS AND MATERIALS: Between March 1991 and December 1993, 64 patients with inoperable head and neck carcinoma (41 with oropharyngeal site) were randomized to radiotherapy alone (group A) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin (group B). In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66-70 Gy. The planned concomitant treatment in group B was: bleomycin 5 units twice a week i.m., total dose 70 units, mitomycin C 15 mg/m2 i.v. after delivery of 10 Gy, and 10 mg/m2 i.v. on the last day of radiotherapy. To enhance the effect of these two drugs, patients received also nicotinamide, chlorpromazine, and dicoumarol. Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma, the study was closed and such patients were after December 1993 routinely treated with the combined therapy (as in arm B). Until October 1996, we treated and followed up 48 such consecutive patients. RESULTS: Median follow-up of our study patients is 42 months. Complete remission (CR) rate in group A was 31% and in group B 59% (p = 0.04); disease-free survival (DFS) in group A was 8% and in group B 37% (P = 0.01); and overall survival (OS) was 7% in group A and 26% in group B (p = 0.08). CR rate for patients with oropharyngeal carcinoma was 29% in group A (N = 21) and 75% in group B (N = 20) (p = 0.007); DFS in group A was 10% and in group B 48% (p = 0.001); and the OS was 10% in group A and 38% in group B (p = 0.019). In patients with inoperable oropharyngeal carcinoma treated after December 1993, complete remission was achieved in 32/48 (67%, 95% CI: 52%-80%). DFS at the median follow-up of 14 months was 60% (95% CI 43-77%) and OS 58% (95% CI 42-74%). CONCLUSION: From the results of our study it seems that the concomitant treatment significantly improves CR rate, DFS, and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone.

Clinical thermoradiotherapy: the influence of some prognostic parameters on recurrence-free survival.

Thirty-one patients with loco-regional advanced tumors accessible for local thermoradiotherapy were treated at the Institute of Oncology in Ljubljana, between 1989-1993. There were six primary inoperable and 25 recurrent or residual tumors after previous radiotherapy. In 13 patients treatment consisted of combined interstitial water hyperthermia and brachyradiotherapy, in 5 patients combination of interstitial hyperthermia and percutaneous radiotherapy was used, and percutaneous microwave hyperthermia with percutaneous irradiation was employed in remaining 13 patients. Complete response (CR) was achieved in 17/31 (55%) of all treated patients. Among various tumoral and therapeutic parameters tested significant influence on complete response rate was found for tumor volume (p = 0.047), minimum intratumoral temperature (p = 0.004), time interval between hyperthermia and radiotherapy (p = 0.02), and fraction-size of immediate radiotherapy (p = 0.002). More than one hyperthermia treatment and total tumor dose of irradiation > 45 Gy did not significantly improve local control rate in our patients. For all 31 patients treated with thermoradiotherapy 3-year recurrence-free survival (RFS) of 41% was achieved. For the group of 9 patients in whom the interval between hyperthermia and irradiation exceeded 1 hour, RFS of 18% compared to 53% for 22 patients treated with "synchronous" thermoradiotherapy was achieved, however the difference between the groups was not significant (log rank p = 0.17). In 25 patients in whom minimum intratumoral temperature (Tmin50) exceeded 42.5 degrees C significant difference in RFS between the subgroups of 19 patients treated synchronously and 6 patients in whom time interval between the two modalities was longer than 1 hour, i.e. 65% vs. 25% respectively, was found (log rank p = 0.048). However, most favorable RFS of 81% was achieved in the subgroup of 15 patients in whom good hyperthermia treatment (Tmin50 > or = 42.5 degrees C) was followed by an immediate irradiation using fraction size > or = 3 Gy (p = 0.015). Treatment related toxicity was acceptable and did not correlate with response rate. Our conclusion is that thermoradiotherapy is more effective when somewhat larger fraction-size of radiotherapy than conventional, i.e. 3-5 Gy, are employed in synchronous combination of both treatment modalities.

Early glottic cancer: the influence of primary treatment on voice preservation.

PURPOSE: Retrospective analysis was performed to assess the influence of primary surgical or irradiation treatment on local control, survival, and final preservation of larynx in comparable groups of patients with T1N0 and T2N0 glottic cancer. METHODS AND MATERIALS: Two hundred sixty-three previously untreated patients with invasive squamous cell carcinoma of the glottis (187T1 and 76T2) were treated with primary radiotherapy (159T1 and 60T2) or primary surgery (28T1 and 16T2) between January 1976 and December 1990, at the University of Ljubljana, Slovenia. Conventional one daily fraction of 2 Gy to doses of 60-74 Gy (median: 65 Gy) were used in 98% of primarily irradiated patients through out the observed period. To enable better comparison between the two treatment groups, primarily irradiated patients were retrospectively stratified by the criteria of suitability for primary voice-sparing operation. Several host, tumor, and treatment parameters were analyzed. RESULTS: Only the stage of the disease significantly influenced both 10-year recurrence-free and disease-specific survival regardless primary treatment modality (p = 0.0002). In all primary irradiated patients local control was significantly better for those with overall treatment time of less than 48 days (p = 0.007). In patients suitable for voice-sparing operation, local control of primarily operated patients was similar to that of patients primarily irradiated with shorter overall treatment time, which was 93 and 88% for T1 and 67 and 64% for T2 tumors, respectively. Ultimate local control in primary surgery and radiotherapy group was 96 and 96% for T1 and 89 and 88% for T2 tumors, respectively. Equal larynx preservation of 100% in T1 and 90% in T2 patients was achieved in finally cured primarily operated patients and those patients primarily irradiated with a shorter overall treatment time. If treatment time was longer than 48 days, significantly worse final larynx preservation of 84% in T1 and 75% in T2 patients was observed (p = 0.003). In patients unsuitable for voice sparing operation, 87% of T1 and 50% of T2 patients in primary radiotherapy group finally had their larynx preserved. CONCLUSION: Stratification based on criteria of possibility for initial voice-sparing operation is important when comparing primary surgery with primary radiotherapy treatment in early glottic cancer. The detrimental effect of prolonged treatment time of irradiation resulted not only in inferior local control rate but also in worse final larynx preservation.

Radiotherapy, combined with simultaneous chemotherapy with mitomycin C and bleomycin for inoperable head and neck cancer--preliminary report.

PURPOSE: Prospectively designed randomized clinical study was undertaken to assess the efficacy of simultaneous application of irradiation, Mitomycin C, and Bleomycin in treatment of patients with inoperable head and neck carcinoma. METHODS AND MATERIALS: Between March 1991 and October 1993, 49 patients with inoperable head and neck carcinoma were randomly assigned to receive either radiation therapy alone (group A) or radiotherapy combined with simultaneous application of Mitomycin C and Bleomycin (group B). Patients in both groups were irradiated five times weekly with 2 Gy to the total dose of 66-70 Gy. Chemotherapy regimen included intramuscular application of Bleomycin 5 units twice a week, with the planned dose being 70 units and Mitomycin C 15 mg/m2 applied intravenously after delivery of 9-10 Gy of irradiation. The application of Mitomycin C was planned to be repeated on last day of radiotherapy in the dose of 10 mg/m2. In attempt to enhance the effect of chemotherapeutic drugs, patients in group B received also Nicotinamide, Chlorpromazine, and Dicoumarol. RESULTS: The difference in complete response rate between both treatment groups (24% in group A and 63% in group B) was statistically significant (p = 0.015). The difference in response rate was much more pronounced in patients with oropharyngeal carcinoma only (18% in group A compared to 81% in group B; p = 0.0003), while for all other subgroups added together, there was observed no benefit of multidrug therapy. Median follow-up was 18 months. Disease-free survival of patients in group A (9%) was significantly lower then in group B (48%) (p = 0.001). The difference between both treatment groups was even greater in patients with oropharyngeal carcinoma only: disease-free survival of these patients in group B was 66%, while in group A, all recurred (p = 0.00001). CONCLUSION: From results of our prospective randomized study it seems that the group of patients that received multidrug treatment with Mytomycin C, Bleomycin, Nicotinamide, Chlorpromazine, and Dicoumarol as enhancers of radiotherapy fared better than patients treated by radiotherapy alone.

Preliminary studies of interstitial hyperthermia using hot water.

A hot water interstitial hyperthermia unit was used to heat normal tissue in the thighs of rabbits and pigs. A 4 x 4 array of metal needles or plastic tubes spaced at 10 or 14 mm was implanted. Temperature measurements were made using five-sensor thermocouple probes inserted parallel to the implanted needles or tubes. With a water temperature of 48 degrees C, tissue temperature within the implant exceeded 42.5 degrees C when tube spacing was 14 mm and reached 47 degrees C when the spacing was 10 mm. However, at the lower water temperature of 45.5 degrees C inter-tube spacing was more critical, since the tissue temperature was above 43.5 degrees C for a spacing of 10 mm but below 42.5 degrees C for a spacing of 14 mm. Temperatures observed in vivo tended to be higher than those predicted by computer simulations, in which blood flow was assumed to be greater than that of resting muscle i.e. approximately greater than 0.45 kg m-3 s-1. The results show that an interstitial system using hot water can be a simple and efficient method of inducing hyperthermia.

Hodgkin's disease as a failure of immune regulation: a re-interpretation of the epidemiological findings.

A failure of immune regulation has been often suspected as the basic condition leading to the development of Hodgkin's disease (HD), but the precise nature of this immune defects has not been defined. It is shown here that most of the epidemiological features fit the hypothesis of an increased risk for HD linked to an immune disbalance between a weak immune suppressor activity (ISA), and an enhanced polyclonal B cell activation (PBA). Few infections in childhood and an "untrained" immune system would lead to a weak ISA as the main risk factor among adolescent and young adults in the developed world, while an enhanced PBA due to chronic parasitic infections and malnutrition could explain a relatively high risk for HD among small children in undeveloped countries. The different histologic types of HD may reflect a variable contribution of a weak ISA, or an enhanced PBA under different conditions.