Marjan Budihna

Radiotherapy, combined with simulataneous 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/m 2 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/m 2 . 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 radiotherpy fared better than patients treated by radiotherapy alone.

Postoperative concomitant irradiation and chemotherapy with mitomycin C and bleomycin for advanced head-and-neck carcinoma.

PURPOSE In a prospective randomized clinical study, simultaneous postoperative application of irradiation (RT), mitomycin C, and bleomycin was tested in a group of patients with operable advanced head-and-neck carcinoma. It was expected that the planned combined postoperative therapy would reduce the number of locoregional recurrences and prolong survival. METHODS AND MATERIALS A total of 114 eligible patients with Stage III or IV squamous cell head-and-neck carcinoma were randomized to receive postoperative RT alone (Group 1) or RT combined with simultaneous mitomycin C and bleomycin (Group 2). Patients were stratified according to the stage and site of the primary tumor and the presence or absence of high-risk prognostic factors. Primary surgical treatment was performed with curative intent in all patients. Patients in both groups were postoperatively irradiated to the total dose of 56-70 Gy. Chemotherapy included mitomycin C 15 mg/m(2) after 10 Gy and 5 mg of bleomycin twice a week during RT to the planned total dose of 70 mg. RESULTS At 2 years, patients in the radiochemotherapy group had better locoregional control (86%) than those in the RT alone group (69%; p = 0.037). Disease-free survival and overall survival was also better in the radiochemotherapy group compared with the RT-alone group (76% vs. 60%, p = 0.099; and 74% vs. 64%, p = 0.036, respectively). Patients who benefited from chemotherapy were those with high-risk factors. CONCLUSION The results of the present study indicate that concomitant postoperative radiochemotherapy with mitomycin C and bleomycin improves locoregional control and survival in patients with advanced head-and-neck carcinoma. The patients who benefited from chemotherapy were those with high-risk factors.

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.

The effect of pilocarpine and biperiden on salivary secretion during and after radiotherapy in head and neck cancer patients

PURPOSE The influence of parasympathicomimetic pilocarpine and anticholinergic biperiden on salivation in patients irradiated for malignant tumors of the head and neck region was assessed in a prospectively designed clinical study. METHODS AND MATERIALS Sixty-nine patients, irradiated for head and neck cancer with salivary glands included in the irradiation fields, were randomly assigned into three groups (A, B, and C). Group A consisted of patients receiving pilocarpine, group B of those who were receiving biperiden during radiotherapy and pilocarpine for 6 weeks after its completion, while group C comprised patients not receiving any xerostomy prevention therapy during or after radiotherapy. The quantity of secreted unstimulated saliva was measured before the beginning of radiotherapy, after 30 Gy of irradiation, on completed irradiation, and 3, 6, and 12 months after completion of radiotherapy. RESULTS Saliva secretion has been found to be the least affected by irradiation treatment in the group of patients receiving biperiden throughout the course of radiotherapy. Six months after completed irradiation, the differences in the quantity of secreted saliva between groups C and B as well as between groups A and B were statistically significant (P = 0.002 and 0.05 respectively). In patients receiving pilocarpine during radiotherapy, and those in the control group, further decrease in saliva secretion was observed. One year after completed therapy, the quantity of secreted saliva could only be measured in the patients receiving biperiden during radiotherapy: it amounted to 16% of the average quantity of saliva secreted before the beginning of irradiation. CONCLUSION It seems that the inhibition of saliva production during irradiation treatment and the stimulation after completed radiotherapy may contribute to the preservation of salivary gland function after therapy.

Cathepsin D in tissue and serum of patients with squamous cell carcinoma of the head and neck

Aspartic proteinase cathepsin D (CD) is believed to be associated with proteolytic processes leading to local invasion and seeding of tumour cells. To estimate a potential prognostic value of cathepsin D in squamous cell carcinoma of the head and neck, its total concentration was measured immunoradiometrically (ELSA-CATH-D kit, CIS bio international) in cytosols of tumour and adjacent normal tissue samples from 111 patients; in 42/111 patients, the CD concentration was determined in serum samples obtained at diagnosis (serum no. 1) and after the therapy (serum no. 2) from each of these patients. Sera of 15 healthy volunteers served as controls. A significantly elevated concentration of CD was measured in tumour cytosols as compared to normal tissue cytosols (31.1 versus 12.6 pmol/mgp, P < 0.0001) and in cytosols of normal laryngeal tissue than of the oral cavity or pharynx (13.3 versus 11.2 pmol/mgp, P = 0.03). The higher CD tumour concentration correlated with the age of the patients (< or =60 versus >60 years, 28.8 versus 32.8 pmol/mgp, P = 0.045) and histopathological tumour grade (G1+2 versus G3, 32.6 versus 24.4 pmol/mgp, P = 0.02). In serum samples, a lower concentration of CD was measured in the control group than in the patients (3.6 versus 4.1 pmol/mls, P = 0.045) and in serum no. 1 than in serum no. 2 (4.1 versus 5.1 pmol/ mls. P = 0.05). The CD concentration in sera obtained at diagnosis was stage-dependent (S(I-III) versus S(IV), 3.9 versus 4.7 pmol/ mls. P = 0.09); there was a trend towards lower CD concentrations with an increasing time delay in serum no. 2 sampling (Rs = -0.20, P = 0.21). No correlation was observed between cytosolic and serum concentrations of CD. We conclude that our results confirm a specific role of CD in the process of invasion and metastasis of squamous cell carcinoma of the head and neck, which might also be of prognostic value in this particular cancer type.

Carcinoma of the nasopharynx: Results of radiation treatment and some prognostic factors

Seventy-four patients treated for squamous cell carcinoma (SCC) of the nasopharynx were evaluated for the 5-year survival rate. The influence of stage, age, histological differentiation, total tumour dose and irradiation treatment technique (continuous vs. split-course) upon the survival was evaluated in 64 patients (palliations and histologically unclassified SCC were excluded). The 5-year survival rate in the whole group was 28/74 (38%), and in the group without palliations and unclassified SCC 26/64 (41%). The 5-year survival of patients with T1 carcinoma was better (8/9 = 89%) than of patients with T2 (4/14 = 29%), T3 (7/17 = 41%) and T4 (7/24 = 29%) carcinoma. In the group of 55 patients with T2, T3 and T4 carcinoma, those up to 50 years old had better survival (11/21 = 52%) than patients older than 50 years (7/34 = 21%) (p less than 0.01), patients treated with the tumour dose greater than 65 Gy had better survival (16/38 = 42%) than those treated with 50-65 Gy (2/17 = 12%) (p less than 0.05), and patients older than 50 years, with poorly differentiated carcinoma had better survival (7/20 = 35%) than those of the same age, with well-differentiated carcinoma (0/14 = 0%) (p less than 0.005). The split-course irradiation technique did not improved the 5-year survival rate, although on average the total tumour dose in this type of treatment was for 7.9 Gy higher than in the continuous irradiation.

Prognostic value of some tumor markers in unresectable stage IV oropharyngeal carcinoma patients treated with concomitant radiochemotherapy

Abstract Background. The aim of the study was to investigate how the expression of tumor markers p21, p27, p53, cyclin D1, EGFR, Ki-67, and CD31 influenced the outcome of advanced inoperable oropharyngeal carcinoma patients, treated with concomitant radiochemotherapy. Patients and methods. The pretreatment biopsy specimens of 74 consecutive patients with inoperable stage IV oropharyngeal squamous cell carcinoma treated with concomitant radiochemotherapy were in retrospective study processed by immunochemistry for p21, p27, p53, cyclin D1, EGFR, Ki-67, and CD31. Disease-free survival (DFS) was assessed according to the expression of tumor markers. Results. Patients with a high expression of p21 (≥10%), p27 (>50%), Ki-67 (>50%), CD31 (>130 vessels/mm2) and low expression of p53 (<10%), cyclin D1 (<10%) and EGFR (<10%) (favorable levels - FL) had better DFS than patients with a low expression of p21 (<10%), p27 (≤50%), Ki-67 (≤50%), CD31 (<130 vessels/mm2) and high expression of p53 (≥10%), cyclin D1 (≥10%) and EGFR (≥10%) (unfavorable levels - UL). However, statistical significance in survival between FL and UL was achieved only for p27 and cyclin D1. DFS significantly decreased with an increasing number of markers with an unfavorable level per tumor (1–4 vs. 5–7) (78% vs. 32%, respectively; p = 0.004). The number of markers per tumor with UL of expression retained prognostic significance also in multivariate analysis. Conclusions. Statistical significance in survival between FL and UL emerged only for p27 and cyclin D1. The number of markers per tumor with UL of expression was an independent prognostic factor for an adverse outcome.

Prognostic factors of choroidal melanoma in Slovenia, 1986—2008

Abstract Introduction Choroidal melanoma is the most common primary malignancy of the eye, which frequently metastasizes. The Cancer Registry of Slovenia reported the incidence of choroid melanoma from 1983 to 2009 as stable, at 7.8 cases/million for men and 7.4/million for women. The aim of the retrospective study was to determinate the prognostic factors of survival for choroidal melanoma patients in Slovenia. Patients and methods From January 1986 to December 2008 we treated 288 patients with malignant choroidal melanoma; 127 patients were treated by brachytherapy with beta rays emitting ruthenium-106 applicators; 161 patients were treated by enucleation. Results Patients with tumours thickness < 7.2 mm and base diameter < 16 mm were treated by brachytherapy and had 5- and 10-year overall mortality 13% and 32%, respectively. In enucleated patients, 5- and 10-year mortality was higher, 46% and 69%, respectively, because their tumours were larger. Thirty patients treated by brachytherapy developed local recurrence. Twenty five of 127 patients treated by brachytherapy and 86 of 161 enucleated patients developed distant metastases. Patients of age ≥ 60 years had significantly lower survival in both treatment modalities. For patients treated by brachytherapy the diameter of the tumour base and treatment time were independent prognostic factors for overall survival, for patients treated by enucleation age and histological type of tumour were independent prognosticators. In first few years after either of treatments, the melanoma specific annual mortality rate increased, especially in older patients, and then slowly decreased. Conclusions It seems that particularly younger patients with early tumours can be cured, whereby preference should be given to eyesight preserving brachytherapy over enucleation.Introduction Choroidal melanoma is the most common primary malignancy of the eye, which frequently metastasizes. The Cancer Registry of Slovenia reported the incidence of choroid melanoma from 1983 to 2009 as stable, at 7.8 cases/million for men and 7.4/million for women. The aim of the retrospective study was to determinate the prognostic factors of survival for choroidal melanoma patients in Slovenia. Patients and methods From January 1986 to December 2008 we treated 288 patients with malignant choroidal melanoma; 127 patients were treated by brachytherapy with beta rays emitting ruthenium-106 applicators; 161 patients were treated by enucleation. Results Patients with tumours thickness < 7.2 mm and base diameter < 16 mm were treated by brachytherapy and had 5- and 10-year overall mortality 13% and 32%, respectively. In enucleated patients, 5- and 10-year mortality was higher, 46% and 69%, respectively, because their tumours were larger. Thirty patients treated by brachytherapy developed local recurrence. Twenty five of 127 patients treated by brachytherapy and 86 of 161 enucleated patients developed distant metastases. Patients of age ≥ 60 years had significantly lower survival in both treatment modalities. For patients treated by brachytherapy the diameter of the tumour base and treatment time were independent prognostic factors for overall survival, for patients treated by enucleation age and histological type of tumour were independent prognosticators. In first few years after either of treatments, the melanoma specific annual mortality rate increased, especially in older patients, and then slowly decreased. Conclusions It seems that particularly younger patients with early tumours can be cured, whereby preference should be given to eyesight preserving brachytherapy over enucleation.

Treatment of carcinoma of the oral cavity with radical and postoperative radiotherapy at the Institute of Oncology Ljubljana, 1990–1995

Summary Aim To evaluate the treatment results of squamous cell carcinoma of the oral cavity treated with radical or postoperative radiotherapy at the Institute of Oncology Ljubljana, in the period 1990–1995. Materials/Methods The medical records of patients were used to collect the data according to the predefined Data Acquisition Protocol. The impact of individual clinical and histopathological factors on the treatment outcome was evaluated by uni- and multivariate analysis. Results Combined therapy was performed in 142 patients, and 93 patients had radiotherapy only. In each of the two subgroups, the performance status of patients was assessed as “poor” in 7% and 30%; the proportion of T1–2 tumours was 53.6% and 16.1%, and the proportion of cN0-stage tumours was 38% and 29%. The 5-year survival without local failure in surgically treated and irradiated only patients was 89% and 30%, without neck failure 85.7% and 50.3%, without any failure 79.1% and 27.5%, and overall survival 43.9% and 11.5%, respectively (all P Conclusions The only independent predictors of survival were performance status and cT stage, whereas the type of therapy impacted only local cure rate. The difference in survival results between the two treatments reflects primarily selection bias which occurred when patients were directed to one of the two treatment options.