Timothy P. Mate

High dose-rate afterloading 192iridium prostate brachytherapy: feasibility report

Background: Results from localized prostate cancer series using seed implants have been most encouraging. However, with current techniques, inadequate dosimetry sometimes occurs. Remote afterloading high dose rate 192Iridium brachytherapy (HDR-Ir192) theoretically remedies some potential inadequacies of seed implantation by performing the dosimetry after the needles are in place. This study was undertaken to determine the feasibility of incorporating multifractionated HDR-Ir192 in the brachytherapy management of prostate carcinoma. Methods: From October 1989 to August 1995, 104 patients were treated with a combination of multifractionated HDR-Ir192 and external beam. Patients ranged in age from 48–78 years, with a mean of 68.6 years. By TNM clinical stage, there were 1 T1b, 31 T1c, 28 T2a, 24 T2b, 9 T2c, 8 T3a, and 3 T3c lesions. For the group, the mean initial pretreatment PSA was 12.9 ng/ml (median 8.1), with 90% of the patients having had a pretreatment PSA greater than a normal value of 4.0 ng/ml. Patients with prostate volumes up to 105 cc were implanted. Treatment was initiated with perineal needle placement using ultrasound guidance. A postoperative CT scan was obtained to provide the basis for treatment planning. Four HDR-Ir192 treatments were given over a 40-h period, with a minimal peripheral dose (MPD) ranging from 3.00 to 4.00 Gy per fraction over the course of this study. Two weeks later, external beam radiation was added using 28 fractions of 1.80 Gy daily, to a dose of 50.40 Gy. Results: Follow-up ranged from 10 to 89 months, with a mean of 46 months and median of 45 months. At various follow-up points, the patient numbers at risk were: 1 year, 101; 3 years, 69; 5 years, 28. The technique proved to be uniformly applicable to a wide range of prostate volumes and was very well tolerated by patients. Nearly all significant late in-field treatment complications were genitourinary in nature. Of the patients, 6.7% developed urethral strictures that were readily manageable. Changes in technique implemented in 1993 appear to have significantly lessened the incidence of this complication. Two patients developed significant uropathy within the first treatment year, but both resolved; 1 of these 2 patients had a prior TURP. Other bladder or rectal complications have been minimal. Using PSA progression as a marker of tumor response, approximately 84% of patients whose initial PSA was less than 20 ng/ml were free of progression at 5 years by actuarial analysis. Conclusions: We found the use of transperineal ultrasonography, postimplant CT-based dosimetry, coupled with adjustable dose delivery inherent to remote afterloading technology, to give unparalleled control in performing this complex brachytherapy task. Thus, it may be advantageous in certain clinical situations where the resultant MPD is needed to reliably cover the target volume, such as in patients with carcinomas at base locales, when the possibility of moderate to extensive intraprostatic tumor exists, and in patients with large glands. Early PSA data suggest that it may be effective as a definitive treatment with rates of adverse late tissue effects that are acceptable using current technique and doses described herein. Longer follow-up is needed to ascertain its position among the various treatment regimens for prostate carcinoma.

A clinical and histopathologic analysis of the results of conservation surgery and radiation therapy in stage I and II breast carcinoma

One hundred eighty women with clinical Stage I or II operable breast carcinoma were treated by radiotherapy following local tumor excision at Yale‐New Haven Hospital through 1980. With a median follow‐up time of 6.9 years, the actuarial 5‐year overall and disease‐free survival rates were 82% and 78%, respectively. The 5‐year actuarial breast‐recurrence‐free survival rate was 92%. Several clinical‐histopathologic features and treatment parameters were assessed for their significance as predictors of local breast failure or distant relapse. Cox lifetable regression analysis showed that patients with clinical Stage II carcinomas had significantly worse overall and relapse‐free survival rates, but clinical stage alone had no effect on the rate of breast recurrence. Furthermore, a decrease in overall and disease‐free survival was evident when necrosis was present in the tumor or when patients had an infiltrating lobular carcinoma. Breast recurrence‐free survival was also influenced adversely by the presence of these two tumor features, especially when either tumor necrosis or infiltrating lobular carcinoma was found in conjunction with clinical Stage II lesions. Other histologic features such as grade, vascular invasion, perineural invasion, or the presence of an intraductal component of carcinoma did not affect outcome, nor did the treatment techniques employed appear to have a differential effect.

Reactions of tumors and normal tissues in mice to irradiation in the presence and absence of a perfluorochemical emulsion

The effect of pre-treatment with the perfluorochemical emulsion, Fluosol-DA, on the radiation response of normal tissues and EMT6 mammary tumors in BALB/c mice was examined. Pre-treating tumor-bearing mice with .015 ml/g of Fluosol and 30 min of carbogen (95% O2/5% CO2) increased the number of tumor cells killed by irradiation with doses of 2.5-20 Gy; the change in the radiation dose-response curve was consistent with a reduction in the hypoxic fraction. Fluosol did not alter the response of tumors in air-breathing or N2-asphyxiated mice and carbogen alone did not alter the radiation response of this tumor significantly. Carbogen treatments 5-60 min in duration produced similar enhancements of tumor radiosensitivity in Fluosol-treated animals. Pre-treatment with Fluosol plus carbogen also increased the number of tumor cells killed by a fractionated regimen of four 2.5 Gy fractions given over 2 days. Pre-treatment with Fluosol-DA plus carbogen, therefore, increased the antineoplastic effects of radiotherapy in both single-dose and multi-fraction radiation regimens. In contrast, Fluosol did not increase the effect of radiation on the partially committed (CFU-GM) or pluripotent (CFU-S) stem cells of the bone marrow or on the CFU-GM of the spleen. The radiation response of the skin was only slightly enhanced by pre-treatment with Fluosol plus carbogen. These data show that treatment of mice with perfluorochemical emulsions plus carbogen can produce therapeutic gain by improving the radiation response of solid tumors, without producing an equivalent increase in the radiation response of potentially dose-limiting normal tissues. These findings encourage further evaluations of these agents as adjuncts to clinical radiotherapy.

Iodine-125 implants for carcinoma of the prostate

One hundred-thirteen patients underwent Iodine-125 prostate implant and lymphadenectomy at Yale-New Haven Hospital from 1974 through 1980. The distribution by clinical stage was: 7 Stage A2, 86 Stage B, and 20 Stage C patients. Ninety-four patients had a negative lymphadenectomy (N-) and 19 patients (17%) had metastatic disease in the pelvic lymph nodes (N+). The actuarial 5-year survival for all 113 patients was 87% (+/- 6%: 95% confidence limits). Sixty-five percent of our 113 patients are disease free (NED) from 2 to 9 years following implant. Sixty-seven (N-) patients with clinical Stage B disease, whose tumors were either well differentiated or moderately well differentiated, have an actuarial 5-year NED survival of 84% (+/- 8%). Twenty (N-) patients with either clinical Stage C disease or poorly differentiated tumors have an actuarial 5-year NED survival of only 31% (+/- 20%). For the 19 (N+) patients, the actuarial 5-year NED survival is 38% (+/- 22%). Local tumor control was 85% for all Stage B patients and 75% for all Stage C patients. Only 10 patients (9%) have developed long-term gastrointestinal or genitourinary complications following their implant. Iodine-125 implant appears to be a reasonable alternate form of therapy in highly selected groups of patients with carcinoma of the prostate.

Suppressor cells induced by total lymphoid irradiation affect proliferation and lymphokine production of murine T helper cell clones

A key response to antigen is the activation of helper T cells to release lymphokines which stimulate and effect the immune reaction. This T cell population can secrete many different factors with diverse, often multifunctional roles, such as amplifying T or B cell antigen responses or being effectors of cell mediated delayed type hypersensitivity. Among these lymphokines are gamma-interferon (gamma-IFN), interleukin-2 (IL-2), or T cell growth factor, and lymphotoxin (LT) which has cytotoxic activity against a variety of cells. Immune suppression in mice following total lymphoid irradiation (TLI) has been correlated with the presence in lympho-reticular tissues of an antigen non-specific, null suppressor cell. This study examined what effects radiation induced suppressor cells had upon the in vitro activation and lymphokine responses of the ovalbumin (OVA) specific T helper cell clone, 153E6, following antigen presentation. Splenocytes from TLI treated mice obtained early in the post-irradiation period exerted a pan-inhibitory effect upon OVA induced 153E6 proliferation and its concomitant release of gamma-IFN, LT, and IL-2. As the interval from irradiation increased, splenocytes from TLI treated mice showed persistent suppression of 153E6 proliferation and gamma-IFN release, but had rapidly diminishing effects on the T cells capacity to produce LT and IL-2. These findings suggest that suppressor cells induced by TLI have a marked inhibitory effect in vivo upon T helper cell proliferative responses to antigen and the production of various T helper cell lymphokines necessary to mediate the immune response. Such processes could contribute to the immunosuppressive effects of extensive nodal irradiation.

AN INTERNET-READY DATABASE FOR PROSPECTIVE RANDOMIZED CLINICAL TRIALS OF HIGH-DOSE-RATE BRACHYTHERAPY FOR ADENOCARCINOMA OF THE PROSTATE

PURPOSE To demonstrate a new interactive Internet-ready database for prospective clinical trials in high-dose-rate (HDR) brachytherapy for prostate cancer. METHODS AND MATERIALS An Internet-ready database was created that allows common data acquisition and statistical analysis. Patient anonymity and confidentiality are preserved. These data forms include all common elements found from a survey of the databases. The forms allow the user to view patient data in a view-only or edit mode. Eight linked forms document patient data before and after receiving HDR therapy. The pretreatment forms are divided into four categories: staging, comorbid diseases, external beam radiotherapy data, and signs and symptoms. The posttreatment forms separate data by HDR implant information, HDR medications, posttreatment signs and symptoms, and follow-up data. The forms were tested for clinical usefulness. CONCLUSION This Internet-based database enables the user to record and later analyze all relevant medical data and may become a reliable instrument for the follow-up of patients and evaluation of treatment results.

High Dose-Rate Afterloading 192Iridium Prostate Brachytherapy: Feasibility Report

BACKGROUND RESULTS from localized prostate cancer series using seed implants have been most encouraging. However, with current techniques, inadequate dosimetry sometimes occurs. Remote afterloading high dose rate 192Iridium brachytherapy (HDR-Ir192) theoretically remedies some potential inadequacies of seed implantation by performing the dosimetry after the needles are in place. This study was undertaken to determine the feasibility of incorporating multifractionated HDR-Ir192 in the brachytherapy management of prostate carcinoma. METHODS From October 1989 to August 1995, 104 patients were treated with a combination of multifractionated HDR-Ir192 and external beam. Patients ranged in age from 48-78 years, with a mean of 68.6 years. By TNM clinical stage, there were 1 T1b, 31 T1c, 28 T2a, 24 T2b, 9 T2c, 8 T3a, and 3 T3c lesions. For the group, the mean initial pretreatment PSA was 12.9 ng/ml (median 8.1), with 90% of the patients having had a pretreatment PSA greater than a normal value of 4.0 ng/ml. Patients with prostate volumes up to 105 cc were implanted. Treatment was initiated with perineal needle placement using ultrasound guidance. A postoperative CT scan was obtained to provide the basis for treatment planning. Four HDR-Ir192 treatments were given over a 40-h period, with a minimal peripheral dose (MPD) ranging from 3.00 to 4.00 Gy per fraction over the course of this study. Two weeks later, external beam radiation was added using 28 fractions of 1.80 Gy daily, to a dose of 50.40 Gy. RESULTS Follow-up ranged from 10 to 89 months, with a mean of 46 months and median of 45 months. At various follow-up points, the patient numbers at risk were: 1 year, 101; 3 years, 69; 5 years, 28. The technique proved to be uniformly applicable to a wide range of prostate volumes and was very well tolerated by patients. Nearly all significant late in-field treatment complications were genitourinary in nature. Of the patients, 6.7% developed urethral strictures that were readily manageable. Changes in technique implemented in 1993 appear to have significantly lessened the incidence of this complication. Two patients developed significant uropathy within the first treatment year, but both resolved; 1 of these 2 patients had a prior TURP. Other bladder or rectal complications have been minimal. Using PSA progression as a marker of tumor response, approximately 84% of patients whose initial PSA was less than 20 ng/ml were free of progression at 5 years by actuarial analysis. CONCLUSIONS We found the use of transperineal ultrasonography, postimplant CT-based dosimetry, coupled with adjustable dose delivery inherent to remote afterloading technology, to give unparalleled control in performing this complex brachytherapy task. Thus, it may be advantageous in certain clinical situations where the resultant MPD is needed to reliably cover the target volume, such as in patients with carcinomas at base locales, when the possibility of moderate to extensive intraprostatic tumor exists, and in patients with large glands. Early PSA data suggest that it may be effective as a definitive treatment with rates of adverse late tissue effects that are acceptable using current technique and doses described herein. Longer follow-up is needed to ascertain its position among the various treatment regimens for prostate carcinoma.