Hassan K. Awwad

Intercapillary distance measurement as an indicator of hypoxia in carcinoma of the cervix uteri

The mean tumor intercapillary distance (ICD) was measured in 44 patients in Stages IIB and III carcinoma of the cervix uteri using a histo-chemical procedure for staining capillary endothelial cells. A mean ICD of 304 +/- 30 microns was obtained, which was independent of the clinical stage and histological grade of differentiation. For each tumor, the proportion of ICDs greater than an arbitrarily chosen value of 300 microns (approximately twice the maximum oxygen diffusion range) was calculated using the normal frequency distribution statistics. The mean ICD and this proportion decreased progressively during the course of external beam pelvic irradiation up to a dose of 4000 cGy. The mean ICD was greater in patients who suffered local recurrence within two years than in patients whose tumors remained controlled. This applied to pre-treatment values and measurements performed after the delivery of 2000 and 4000 cGy. The proportion of ICDs greater than 300 microns showed a similar trend. No significant correlation was found between the hemoglobin concentration at time of presentation and either the mean ICD, or the probability of local control. It is proposed that ICD measurement may be a useful tool to identify subgroups of tumors where hypoxia can interfere with the effectiveness of radiotherapy.

Postoperative radiotherapy of carcinoma in bilharzial bladder: Improved disease free survival through improving local control

Abstract Two hundred thirty-six patients with T 3 bladder cancer who survived radical surgery and proved to have P 3a , P 3b , or P 4a tumors were randomized in two phases into three groups: (a) no further treatment (83 patients (b) postoperative radiotherapy multiple daily fractionation (MDF), using 3 daily fractions of 1.25 Gy each, with 3 hr between fractions, up to a total dose of 37.5 Gy in 12 days (75 patients); and (c) postoperative radiotherapy conventional fractionation (CF), for a total dose of 50 Gy/5 weeks (78 patients). The tolerance of the patients to postoperative radiotherapy was quite acceptable, with equal acute reactions in MDF and CF groups. The 5-year disease-free survival (DFS) rates amounted to 49 and 44% in MDF and CF postoperative radiotherapy groups, respectively, compared to 25% in the cystectomy-alone group. The 5-year local control rates were 87% and 93% for those treated with multiple daily fractionation and conventional fractionation while it was 50% in the surgery-alone group. The therapeutic benefit of postoperative irradiation was consistent for all tumor types, histological grades, and pathological stages for both the disease-free survival and local control. Patients with nodal metastases demonstrated lower recurrence rates in the postoperative radiotherapy groups, but this was not associated with improved disease-free survival. Multivariate analysis using the Cox Model confirmed these results. The independent prognostic factors affecting both disease-free survival and local control were the addition of postoperative radiotherapy, the nodal status, the pathological stage, and the tumor grade. Late complications of radiotherapy in the skin, small intestine, rectum, and the anastomotic site of the urinary division were lower with MDF than with conventional fractionation.

Pre-operative irradiation of T3-carcinoma in Bilharzial bladder: A comparison between hyperfractionation and conventional fractionation☆

Abstract The present report deals with a prospective randomized study investigating the value of pre-operative telecobalt irradiation in the management of T 3-carcinoma in Bilharzial bladder. A total pre-operative dose of 4000 rad was split into 2 equal courses with a gap of 1 week. Two dose-time regimens were compared: split-course conventional fractionation, 200 rad/day (SC) and hyperfractionation (HF). In the latter, the daily dose amounted to 1000 rad and was divided into 17 hourly acute fractions, 60 rad each. The SC and HF regimens produced equivalent local tissue reactions. Hyperfractionation, however, was associated with a somewhat higher incidence of radiation sickness. Both regimens resulted in an increase of the 2-year disease-free survival rate from 19 ± 10% (316) to 53 ± 9% (1732) without added surgical hazard; both HF and SC appeared to be equally effective. An appreciable post-irradiation tumor shrinkage was noted in the majority of patients; this is consistent with a rapid tumor cell turnover rate. Moreover the likelihood of long term local tumor control seemed to be greater in the more rapidly shrinking tumors. This is proposed to be linked to a more extensive reoxygenation process. No correlation was obtained between the quantitative scoring of the cytohistological radiation effect and the outcome of treatment.

Postoperative radiotherapy of carcinoma in bilharzial bladder using a three-fractions per day regimen

Patients with T3 bladder cancer who survived surgery and proved to have P3a, P3b or P4a tumors were randomized to either no further treatment (61 patients) or postoperative total pelvic irradiation (55 patients). A three-fraction per day regime was adopted with a dose per fraction of 125 cGy and an interval of 3 h between fractions. The total dose amounted to 3750 cGy divided into 30 fractions over 12 days. Patients of the postoperative radiotherapy group were re-randomized to radiotherapy alone or radiotherapy plus misonidazole (MISO) in a daily dose of 1 g/m2 given orally 2 h before the first daily fraction. The 2-year disease-free survival rate in the cystectomy alone group was 33 +/- 6% compared to 65 +/- 6% in the postoperative radiotherapy group. The therapeutic benefit applied to the two cell types, all histological grades and stages and to patients with or without nodal metastases. The benefit of postoperative irradiation was also verified by the Coxs multivariant analysis which adjusts for the relative representation of the important prognostic factors particularly pathological stage and nodal involvement. MISO did not seem to add to the therapeutic gain. No late complications were encountered in the wall of the rectum, small bowel or uretero-intestinal anastomotic sites. This is suggested to be due to the small dose per fraction used. However, early small bowel reactions were dose-limiting.

Cell proliferation of carcinoma in Bilharzial bladder: an autoradiographic study.

The rate of cell production in thirty‐five cases of carcinoma in Bilharzial bladder was evaluated from the labelling index after in vitro incubation with [3H]TdR. Squamous cell carcinoma was the most frequent histological type in this series and had a median LI of 8.0% which corresponds to a potential doubling time of 5.9 days. In squamous cell tumours the LI increased with the histological grade. Transitional cell tumours had a somewhat greater LI.

Studies in dose-time-volume relationships in bladder and tongue radium implants

The clinical results of 26 tongue and 31 bladder radium implants were analysed in terms of proposed dose specification parameters that describe the dose-time-volume relationships of the implant. Tongue cases that recurred within two years were mostly those with a relatively short treatment time and in which a relatively large dose reduction factor had to be applied. The dose-time factor did not differ significantly in the groups of bladder implants having different clinical results. A higher incidence of necrosis was noted in bladder cases. This was associated with a significantly higher mean dose and a somewhat greater degree of dose inhomogeneity. Recurrences were generally linked with greater mean dose, target volume and dose inhomogeneity. These unfavourable dose-volume relationships were frequently associated with poor distribution of needles. The reported experimental and clinical findings pertinent to the differential sparing of normal tissues associated with protraction of continuous irradiation are outlined. In the light of these, it is felt that the results of tongue implants could have been improved by omission of the dose-time adjustment factor for treatment time of 3-10 days without undue risk of necrosis. However, bladder results could have been improved by attainment of a better implantation technique while keeping the treatment time within 6-8 days in view of the lower tolerance.

Cell proliferation in carcinoma in bilharzial bladder: Influence of pre-operative irradiation and clinical implications

Cell proliferation in carcinoma in the bilharzial bladder was studied in 92 patients in terms of the in vitro labeling index (LI), cell density (CD) and labeled cell density (LCD) using the in vitro 3H-Tdr technique. Cell proliferation was much greater in high than in low grade tumors and in deep than in superficial parts of the tumor, but was much less dependent on cell type; transitional cell cancer had the highest activity followed by squamous cell and adenocarcinoma. The probability of local recurrence after cystectomy decreased markedly when the LI exceeded 5.0%. The influence of the following three pre-operative radiotherapy regimens was studied: split-course (SC): the initial course consisted of 20 Gy in 10 treatments with a similar course was given after one week, hyper-fractionation using 17 treatments 0.6 Gy each on two successive days, this 2-day course of 20 Gy was repeated after one week, and concentrated irradiation consisting of two treatments, 6.0 Gy each with a gap of one week. Cystectomy was performed 14-20 days after treatment in all groups. Preoperative irradiation was generally associated with an increased probability of local control. The unfavorable influence of a high pretreatment LI was not noted after pre-operative irradiation. The CD was also reduced in proportion to the pretreatment LI. It is proposed that the response to irradiation was proportional to the initial proliferation activity and hence the prognostic significance of tumor grade and pretreatment LI was masked. Postirradiation tumor volume reduction was a strong predictor of treatment outcome. Concentrated irradiation was the least efficient pre-operative irradiation regimen and was associated with the least tumor volume reduction.

Cancer of the bilharzial bladder

Abstract Cancer of the bladder is a major problem in those parts of the world where bilharziasis is common. Both urinary tract bilharziasis and chronic bacterial cystitis are implicated in the etiology. Most of the tumors are of the squamous type and their clinical behavior is different from that of transitional cell carcinoma. Surgery is the only treatment which confers long-term survival although preoperative radiotherapy may improve results. Chemotherapy may prove to be useful when more active agents are identified.

The dose—time relationship in the radiotherapy of carcinoma of the cervix uteri: An application of the CRE formalism

A correlation could be obtained between the likelihood of control of central and nodal disease and the corresponding local CRE levels attained in a group of 79 cases of carcinoma of the cervix uteri treated according to a multistage protocol involving a combination of external telecobalt irradiation and intracavitary radium application. A nodal CRE level of 1700 reu and a central CRE value of 2900 reu seemed to be optimal for control of modal metastases and central disease respectively. These CRE levels seemed to be well tolerated even if salvage surgery had to be performed.

Pharmacokinetics of etanidazole (SR-2508) in bladder and cervical cancer: Evidence of diffusion from urine

Following an IV infusion of 2.0 g/m2 of Etanidazole, the mean tumor concentration 40 min after injection was 126 micrograms/g in bladder cancer and 65 micrograms/g in cervical cancer. The tumor/plasma concentration ratio was 1.88 in bladder and 0.85 in cervical cancer. This high tumor concentration in bladder cancer could be accounted for by diffusion from a highly concentrated urine. This renders bladder cancer a suitable clinical model for testing this sensitizer.