Lowell L. Anderson

The effect of local control on metastatic dissemination in carcinoma of the prostate: Long-term results in patients treated with 1251 implantation

The study evaluates the effect of the locally recurring tumor on the incidence of metastatic disease in early stage carcinoma of the prostate. The probability of distant metastases was studied in 679 patients with Stage B-C/N0 carcinoma of the prostate treated at MSKCC between 1970 and 1985 (median follow-up of 97 months). Patients were staged with pelvic lymph node dissection and treated with retropubic 125I implantation. The actuarial distant metastases free survival (DMFS) for patients at risk at 15 years after initial therapy was 37%. Cox proportional hazard regression analysis of covariates affecting the metastatic outcome showed that local failure, used in the model as a time dependent variable, was the most significant covariate, although stage, grade, and implant volume were also found to be independent variables. The relative risk of metastatic spread subsequent to local failure was 4-fold increased compared to the risk without evidence of local relapse. The 15-year actuarial DMFS in 351 patients with local control was 77% compared to 24% in 328 patients who developed local relapses (p less than 0.00001). The relation of distant spread to the local outcome was observed regardless of stage, grade, or implant dose. Even stage B1/N0-Grade I patient with local control showed a 15-year actuarial DMFS of 82%, compared to 22% in patients with local relapse; p less than 0.00001). The median local relapse-free survival (LRFS) in the 268 patients with local recurrences who did not receive hormonal therapy before distant metastases were detected was 51 months, compared to a median of 71 months for DMFS in the same patients (p less than 0.001), consistent with the possibility that distant dissemination may develop secondary to local failure. Furthermore, distant metastases in patients with local control, apparently already existing as micrometastases before treatment, were detected earlier (median DMFS of 37 months) than in patients with local relapse (median DMFS of 54 months; p = 0.009). These data suggest that the existence and re-growth of local residual disease in localized prostatic carcinoma promotes an enhanced spread of metastatic disease, and that early and complete eradication of the primary tumor is required if a long term cure is to be achieved, although the clinical expression of secondary metastases may not become apparent for 6.5 years or more in one-half of the patients.

Code of practice for brachytherapy physics: Report of the AAPM Radiation Therapy Committee Task Group No. 56

Recommendations of the American Association of Physicists in Medicine (AAPM) for the practice of brachytherapy physics are presented. These guidelines were prepared by a task group of the AAPM Radiation Therapy Committee and have been reviewed and approved by the AAPM Science Council.

Permanent prostate seed implant brachytherapy: report of the American Association of Physicists in Medicine Task Group No. 64.

There is now considerable evidence to suggest that technical innovations, 3D image-based planning, template guidance, computerized dosimetry analysis and improved quality assurance practice have converged in synergy in modern prostate brachytherapy, which promise to lead to increased tumor control and decreased toxicity. A substantial part of the medical physicists contribution to this multi-disciplinary modality has a direct impact on the factors that may singly or jointly determine the treatment outcome. It is therefore of paramount importance for the medical physics community to establish a uniform standard of practice for prostate brachytherapy physics, so that the therapeutic potential of the modality can be maximally and consistently realized in the wider healthcare community. A recent survey in the U.S. for prostate brachytherapy revealed alarming variance in the pattern of practice in physics and dosimetry, particularly in regard to dose calculation, seed assay and time/method of postimplant imaging. Because of the large number of start-up programs at this time, it is essential that the roles and responsibilities of the medical physicist be clearly defined, consistent with the pivotal nature of the clinical physics component in assuring the ultimate success of prostate brachytherapy. It was against this background that the Radiation Therapy Committee of the American Association of Physicists in Medicine formed Task Group No. 64, which was charged (1) to review the current techniques in prostate seed implant brachytherapy, (2) to summarize the present knowledge in treatment planning, dose specification and reporting, (3) to recommend practical guidelines for the clinical medical physicist, and (4) to identify issues for future investigation.

High-dose-rate intraoperative radiation therapy (HDR-IORT) for retroperitoneal sarcomas ☆

PURPOSE Retroperitoneal sarcomas represent a formidable challenge to the treating oncologist due to their location, large size, and poor prognosis. The purpose of this study was to determine if the addition of high-dose-rate intraoperative radiation therapy (HDR-IORT) to surgery and external beam radiotherapy (EBRT) would improve the outcome in these patients. METHODS AND MATERIALS Thirty-two patients with retroperitoneal soft tissue sarcoma were prospectively treated according to a protocol that included maximal tumor resection, HDR-IORT, and postoperative EBRT when feasible. Twelve patients presented with primary and 20 with locally recurrent disease. The tumors were high-grade in 20 patients and low-grade in 12 patients. Complete gross resection was achieved in 30 patients. HDR-IORT was given to a dose of 12-15 Gy. Additional EBRT was given to 78% of patients to a dose of 45-50.4 Gy. The two patients with gross residual disease received an additional I-125 permanent implant to a median peripheral dose of 140-160 Gy. The median follow-up was 33 months (range 1-77 mo). RESULTS The 5-year actuarial local control rate for the whole group was 62%. For patients with primary disease, the local control rate was 74% compared to 54% in patients with recurrent disease (p = 0.4). The overall 5-year distant metastasis-free survival rate was 82%. In patients with high-grade tumors the rate was 70% vs. 100% in those with low-grade tumors. This difference was statistically significant, p = 0.05. The 5-year disease-free and overall survival rates were 55% and 45%, respectively. The most common type of post-treatment complication was gastrointestinal obstruction (18%) followed by fistula formation (9%), peripheral neuropathy (6%), hydronephrosis (3%), and wound complication (3%). CONCLUSIONS We are encouraged by the favorable local control rate and the acceptable morbidity with this new technique applied to a challenging patient population.

High dose rate intraoperative radiation therapy (HDR-IORT) as part of the management strategy for locally advanced primary and recurrent rectal cancer

PURPOSE Primary unresectable and locally advanced recurrent rectal cancer presents a significant clinical challenge. Local failure rates are high in both situations. Under such circumstances, there is a significant need to safely deliver tumoricidal doses of radiation in an attempt to improve local control. For this reason, we have incorporated a new approach utilizing high dose rate intraoperative radiation therapy (HDR-IORT). METHODS AND MATERIALS Between 11/92-12/96, a total of 112 patients were explored, of which 68 patients were treated with HDR-IORT, and 66 are evaluable. The majority of the 44 patients were excluded for unresectable disease or for distant metastases which eluded preoperative imaging. There were 22 patients with primary unresectable disease, and 46 patients who presented with recurrent disease. The histology was adenocarcinoma in 64 patients, and squamous cell carcinoma in four patients. In general, the patients with primary unresectable disease received preoperative chemotherapy with 5-fluorouracil (5-FU) and leucovorin, and external beam irradiation to 4500-5040 cGy, followed by surgical resection and HDR-IORT (1000-2000 cGy). In general, the patients with recurrent disease were treated with surgical resection and HDR-IORT (1000-2000 cGy) alone. All surgical procedures were done in a dedicated operating room in the brachytherapy suite, so that HDR-IORT could be delivered using the Harrison-Anderson-Mick (HAM) applicator. The median follow-up is 17.5 months (1-48 mo). RESULTS In primary cases, the actuarial 2-year local control is 81%. For patients with negative margins, the local control was 92% vs. 38% for those with positive margins (p = 0.002). The 2-year actuarial disease-free survival was 69%; 77% for patients with negative margins vs. 38% for patients with positive margins (p = 0.03). For patients with recurrent disease, the 2-year actuarial local control rate was 63%. For patients with negative margins, it was 82%, while it was 19% for those with positive margins (p = 0.02). The disease-free survival was 47% (71% for negative margins and 0% for positive margins) (p = 0.04). Prospective data gathering indicated that significant complications occurred in approximately 38% of patients and were multifactorial in nature, and manageable to complete recovery. CONCLUSION HDR-IORT using our technique is versatile, safe, and effective. The local control rates for primary disease compare quite well with other published series, especially for patients with negative margins. For patients with recurrent disease, locoregional control and survival are especially encouraging in patients with negative resection margins. Further follow-up is needed to see whether these encouraging data will continue.

A CT-based evaluation method for permanent implants: application to prostate

A computerized tomography-based 3-dimensional evaluation scheme, using semi-automatic seed localization from transverse computerized tomography-images, has been developed for permanent implants. The treatment isodose contour is generated at each scan plane and overlaid on the corresponding target contour for coverage visualization. Volume and surface dose histograms are generated for the target and neighboring normal structures. Dose inhomogeneity within the target is also estimated from the full-width at half maximum of the differential volume dose histogram. The matched peripheral dose is calculated from the ellipsoidal volume approximation for the target. The present evaluation method has been applied here to 10 actual permanent I-125 prostatic implantations. Coverages by 150 Gy and 100 Gy levels are found to range from 78-96% and 91-99% of the target volume, respectively. The average matched peripheral dose is found to be about two times the average peripheral dose (the dose encompassing 99% target) and about three times the average minimum peripheral dose (the dose encompassing 100% target). The dose inhomogeneities within the target volume, in these 10 cases, range from 220-420 Gy.

The relative biological effectiveness of I-125 and Pd-103

PURPOSE To determine the relative biological effectiveness (RBE) of I-125 and Pd-103 relative to Co-60. METHODS AND MATERIALS A cell line REC:ras, derived from rat embryo cells, was used. Cells in exponential or plateau phase were irradiated at dose rates of about 0.07 Gy/h and 0.14 Gy/h. To circumvent the interface effect, cells were grown and irradiated on membranes made of cellulose acetate, which has an effective Z of 7.5. I-125 and Pd-103 seeds were placed in a custom designed template that yielded a homogeneous dose distribution in the plane of the cell culture. The dose rates of irradiation were measured by calibrated thermoluminescence dosimetry (TLD) chips. RESULTS AND CONCLUSIONS Our measurements yielded an RBE of about 1.4 for I-125 at dose rates of about 0.07 Gy/h, and an RBE of about 1.9 for Pd-103 at dose rates of about 0.07 Gy/h and 0.14 Gy/h. The RBE of I-125 is similar to those measured by other investigators, the RBE for Pd-103 is being reported for the first time.

A "natural" volume-dose histogram for brachytherapy.

The most useful formulation of the volume-dose histogram for brachytherapy is one which suppresses inverse square law effects while preserving proportionality between volume and the area under the curve. These objectives are met by plotting the distribution of volume per unit-3/2 power of dose rate versus the-3/2 power of dose rate; such a distribution is constant for a single point source. Adding sources results in the formation of a peak, which provides a graphical indication of dose rate uniformity. Evaluation of other peak parameters such as width, position, and contained volume, in relation to treatment dose rate, permits a quantitative and clinically relevant volume-dose assessment of interstitial implants.

Treatment of primary unresectable carcinoma of the pancreas with I-125 implantation

Between January 1 1974 and October 31 1987, 98 patients with biopsy proven unresectable adenocarcinoma of the pancreas were treated with I-125 implants during laparotomy. Presenting symptoms were pain (57 patients), jaundice (45 patients), and weight loss (34 patients). All patients underwent laparotomy and surgical staging. Thirty patients had T1NoMo disease, 47 patients had T2-3NoMo disease, and 21 patients had significant regional lymph node involvement (T1-3N1Mo). The surgical procedure performed was biopsy only (16 patients), gastric bypass (36 patients), biliary bypass (49 patients), and partial or total pancreatectomy with incomplete resection (5 patients). The total activity and the number of seeds used were determined from the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram. Stereoshift localization X ray films were taken 3-6 days after operation. The mean activity, minimal peripheral dose (MPD), and volume of the implants were 35 mCi, 13,660 cGy, and 53 cm3, respectively. In addition, 27 patients received postoperative external irradiation and 27 patients received chemotherapy. Postoperative complications were observed in 19 patients. These included post-operative death (1 patient), biliary fistula (4), intraabdominal abscess (4), GI bleeding (3), gastric or small bowel obstruction (6), sepsis (5), and deep vein thrombophlebitis (4). Pain relief was obtained in 37/57 patients (65%) presenting with pain. A multivariate analysis showed that four factors significantly affected survival: T stage, N stage, administration of chemotherapy, and more than 30% reduction in the size of the implant on follow-up films. The median survival for the entire group was 7 months. A subgroup of patients with T1No stage disease who received chemotherapy survived 18.5 months. The indications for I-125 seed implantation in unresectable carcinoma of the pancreas are discussed.

Consensus guidelines for high dose rate remote brachytherapy in cervical, endometrial, and endobronchial tumors*

PURPOSE A large number of medical centers have recently instituted the use of High Dose-Rate Afterloading Brachytherapy (HDRAB). There is wide variation in treatment regimens, techniques, and dosimetry being used and there are no national standard protocols or guidelines for optimal therapy. METHODS AND MATERIALS The Clinical Research Committee (CRC) of the American Endocurietherapy Society (AES) met to formulate consensus guidelines for HDRAB in cervical, endometrial, and endobronchial tumors. CONCLUSION Each center is encouraged to follow a consistent treatment policy in a controlled fashion with complete documentation of treatment parameters and outcome including efficacy and morbidity. Until further clinical data becomes available, the linear quadratic model can be used as a guideline to formulate a new HDR regimen exercising caution when changing from a Low Dose Rate (LDR) to a HDRAB regimen. The treatments should be fractionated as much as practical to minimize long term morbidity. As more clinical data becomes available, the guidelines will mature and be updated by the Clinical Research Committee of the AES.