Preclinical studies with the photon radiosurgery system (PRS).

PURPOSE: Determine the radiobiological effectiveness (RBE) for low-energy X-rays (average energy of 23 KeV) produced by the Photon Radiosurgery System (PRS). METHODS AND MATERIALS: RBE values were assessed by comparison with survival data obtained for cells irradiated with either low-energy X-rays from a GE Maxitron 100 machine or high-energy photons from a clinically used Varian 6 MV LINAC. The output of the GE and PRS sources was determined using Baldwin-Farmer and Markus thin window ionization chambers calibrated with 50 kVp X-rays and cross-checked against figures supplied by Photoelectron Corporation. The dose-rate for the PRS was 1.2 Gy/min at a distance of 35 mm with a field flatness of +/-2%. RESULTS: The RBE for the PRS low-energy X-ray source (at 1-mm depth) was greater than either the GE or Varian machines and varied with cell survival. For Chinese hamster ovary (CHO) cells, the PRS was 1.25 and 3.3 times more effective than 90 kVp X-rays and 6 MeV photons at 0.5% cell survival, respectively; by comparison, the PRS was 1.2 and 1.9 times more effective at 0.05% cell survival, respectively. Similar RBE values of 1.4 and 1.2 were obtained for human U373 and T98 glioblastoma cells grown in vitro irradiated with the PRS or GE sources, respectively. Other studies showed that the RBE for the PRS low-energy X-ray source increased with depth. The RBEs for the PRS source at 1-mm and 4-mm depth were 1.2 and 2.5 (0.5% survival) and 1. 2 and 1.9 (0.05% survival). CONCLUSIONS: The biological and physical properties of the PRS low-energy X-rays offer, under the right conditions, a significant advantage for patient treatment over conventional external beam, stereotactic, or brachytherapy treatment.

Radiation therapy in pancreatic cancer: current practice and future trends.

Treatment options for pancreatic cancer remain limited due to the large proportion of patients presenting with advanced disease at the time of diagnosis. Surgery offers the best chance for cure. Localized chemoradiation modestly improves median survival in both localized and locally advanced disease. Interstitial brachytherapy and intraoperative radiotherapy improve local control without providing significant impact on overall survival. Technological advances now allow us to deliver three dimensional conformal external beam irradiation with improved efficacy and decreased morbidity. Novel treatment approaches, such as intraoperative photoelectron radiation (Photon Radiosurgery System; PeC Photoelectron Corporation) and the development of more effective radiosensitizers, are presently under investigation.

Contemporary brachytherapy approaches in non-small-cell lung cancer.

Brachytherapy has the ability to deliver a higher tumor dose compared to external beam irradiation, while sparing normal tissue outside the tumor; it is the most effective means of delivering conformal radiation and can be tailored to clinical circumstances, either at open surgery or in an ambulatory setting, which is currently the preferred method. Intraoperative lung and/or endobronchial brachytherapy in the management of non-small-cell lung cancer offers a good curative potential in patients with accessible localized tumors, well defined and small to moderate in size, that have not metastasized to the lymph nodes and are technically or medically inoperable. Effective palliation can be frequently obtained by endobronchial brachytherapy on an outpatient procedure basis. Brachytherapy administered simultaneously with chemotherapy is better tolerated than a course of external beam irradiation and chemotherapy.

Brachytherapy in cancer of the prostate: an historical perspective.

Carcinoma of the prostate in the United States has increased dramatically in the last few years due to improved detection methods including prostatic specific antigen testing and transrectal ultrasound. More than half of all prostate cancers are discovered while still localized. Radical prostatectomy and definitive radiation are reserved for patients in good health, who have localized disease. Brachytherapy, with its inherent ability to deliver a high dose to an organ-confined tumor, while minimally irradiating the surrounding tissues, has successfully competed with external beam for the treatment of early prostatic tumors. Their respective role is constantly under scrutiny and re-evaluation to improve the accuracy of delivery of radiation. The present review focuses on the role of brachytherapy for treatment of early cancer of the prostate over the span of this century and its future in the next millennium.

Role of brachytherapy in adult soft tissue sarcomas.

The use of brachytherapy in the management of adult soft tissue sarcomas of the extremities has been applied in combination with conservative surgery in an attempt to avoid amputation. Retrospective studies and a single prospective trial currently underway suggest that this combination is highly effective in improving local control for high-grade tumors, independent of size, location in the extremity, and depth. However, no effect has been shown in preventing distant metastases, or in prolonging survival in high-grade tumors. Likewise, no effect has been documented on low-grade tumors. Whether adjuvant chemotherapy can improve overall and disease-free survival remains debatable. New innovative brachytherapy approaches are being investigated to eliminate radiation exposure associated with the use of low-dose-rate Iridium-192 (Ir-192), and to further improve the treatment results in all tumor grades.

Brachytherapy and pancreatic cancer.

Advances in diagnostic and therapeutic technology have not appreciably changed the outlook of patients with pancreatic cancer. While those patients presenting with localized resectable disease have the best prognosis, local control and intra-abdominal metastases remain significant obstacles to survival. Localized chemoradiation has modestly improved median survival in localized and locally advanced disease. Patients presenting with locally advanced disease at diagnosis benefit from surgical palliation which includes biliary and gastric bypass. Intraoperative interstitial brachytherapy has been effective when utilized at laparotomy to improve local control in locally advanced disease. Advances in laparoscopic techniques have provided the ability to more accurately stage patients prior to laparotomy and perform palliative procedures without the need for laparotomy. The utilization of high-dose-rate brachytherapy has proven effective in palliating obstructive symptoms with minimal morbidity on an outpatient basis. Recent efforts have focused on preoperative chemoradiation to improve resectability in selected patients and prophylactic hepatic irradiation to reduce metastases for patients with locally advanced disease.

Lung brachytherapy. An overview and current indications.

Although lung cancer remains a difficult and fatal illness for most patients, recent developments provide hope that control and cure are realistic goals. Conventional brachytherapy judiciously used in selected patients may improve local control or relieve severe symptoms. Systemic brachytherapy with radiolabeled antibodies also may prove to be a potentially useful approach. Combined modality therapy will be the most important area of investigation during the next several years.

Consensus guidelines for high dose rate remote brachytherapy in cervical, endometrial, and endobronchial tumors. Clinical Research Committee, American Endocurietherapy Society.

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.

Wound repair after fractionated external beam radiation therapy and concomitant hyperthermia in an experimental rat model.

BACKGROUND: Fractionated radiation therapy (RT) with adjuvant hyperthermia (HT) is being used in the treatment of cancer with noted clinical success. However, little information regarding wound repair in tissues receiving this combination therapy is available for comparison of surgical risk. Consequently, this study was undertaken to assess the effects of this combined therapy on wound healing by quantitatively evaluating wound repair using tensile strength measurements. METHODS: Four treatment cohorts were designated: sham control, RT alone (600 cGy/d for 4 days), HT alone (water bath at 41.8 degrees C, subcutaneous temperature of 41.0 +/- 0.5 degrees C for 60 minutes on days 1 and 4), and combined RT and HT. At 1 week after treatment, surgical incisions of the dorsal flank were made. Tensile strength measurements of wounds were obtained at 14 and 21 days after incision. RESULTS: No significant differences were observed in the combined treatment arm (RT and HT) compared with the reduced wound breaking strength of RT alone. Statistically significant differences in tensile strength were seen when the control group or HT alone was compared with RT and HT or RT alone. CONCLUSIONS: Concomitant exposure to fractionated RT and specific HT conditions demonstrated no disproportionate alteration in wound tensile strength compared with radiation exposure alone in this animal model.

Permanent interstitial implantation using palladium-103: the New York Medical College preliminary experience.

Palladium-103 is a low energy photon emitter available for permanent interstitial implantation. Pd-103 has energy and safety characteristics similar to Iodine-125, but its initial peripheral dose rate is approximately three times greater. This may provide improved control of rapidly proliferating tumors. At the Westchester Campus of New York Medical College, 15 patients with residual or recurrent unresectable lesions were implanted with Pd-103. There were five males and 10 females with an age range of 41 to 93 years (median 58). Implanted sites included the chest wall, nasopharynx, vagina, and zygomatic region. Peripheral doses ranged from 55 to 203 Gy (median 107 Gy). A complete response was achieved in eight patients and a partial response in seven patients, for an overall response rate of 100%. We noted improved control with smaller volumes and peripheral doses at or above 115 Gy. No unusual skin or mucosal reactions were recorded. Possible advantages of Pd-103 as a substitute for I-125 include improved control of rapidly proliferating tumors and a more rapid clinical response of lesions. Disadvantages include current higher cost and an impracticality in maintaining a running inventory because of the short half-life of the isotope. Our experience suggests that Pd-103 is an attractive alternative to I-125.

Brachytherapy and function-saving resection of soft tissue sarcoma arising in the limb.

The treatment of soft tissue sarcoma of the limb by function-saving resection and brachytherapy (BRT) was systematically studied from 1975 to 1990 at the Memorial Sloan-Kettering Cancer Center, using iridium-192 temporary tumor-bed implants. Initial experiences showed an 88% local control rate in 33 patients who had locally advanced sarcomas, many of which would have required treatment by amputation. The technique also controlled 70% of tumors that abutted or invaded a major neurovascular bundle that was dissected out and preserved. A prospective randomized study (BRT vs no BRT) confirmed the highly significant efficacy of BRT in preventing local recurrence. This salutary effect is mainly seen in high-grade tumors. Major complications of wound healing occurred in the earlier years of this experience. Adoption of improved techniques of surgical wound repair, standardization of radiation dose planning, and in particular, postponing the loading of radiation sources until after the fifth postoperative day has reduced the rate of serious wound complications, to a level not significantly different from that seen after surgical resection alone. These results rival those currently achieved in centers experienced in external beam therapy of soft tissue sarcomas, and offer the advantage of completion of treatment in one relatively short hospital stay.

The effect of local control on metastatic dissemination in carcinoma of the prostate: long-term results in patients treated with 125I 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.

New intraoperative brachytherapy techniques for positive or close surgical margins.

Tumors attached or adjacent to critical structures can often not be completely resected or resected with adequate surgical margins. Sites involving major blood vessels, the paravertebral spaces, or critical abdominal structures often present technical difficulties for standard brachytherapy procedures using I-125 or Ir-192 implants. These techniques allow for a high-dose delivery to the tumor bed with minimal normal tissue toxicity. A relatively simple and accurate method is described using I-125 seeds in Vicryl suture threaded through Gelfoam. These permanent implant procedures with radioactive I-125 seeds effectively treat small residual tumors or suspicious margins where standard brachytherapy techniques may be unsatisfactory and technically difficult to perform.

Wound complications of adjuvant radiation therapy in patients with soft-tissue sarcomas.

Adjuvant radiation therapy by the brachytherapy technique has been suggested by us to diminish local recurrence following resection of extremity and superficial truncal soft-tissue sarcoma. However, loading of the catheters with radioactive sources on the first through the fifth postoperative days results in a 48% significant wound-complication rate. Our previous animal experiments would suggest that delay of application of radiation to one week after wounding is accompanied by significant improvement in wound-breaking strength, new H3 hydroxyproline accumulation, and improved force-tension curves. As part of our ongoing prospective randomized trial of the effects of brachytherapy on local control, one change was made: the catheters were loaded five or more days after operation. Wound complications were then reviewed in 50 patients following this single change in brachytherapy delivery. Of the 21 patients receiving brachytherapy, 14% had significant wound complications; 10% of the 29 patients who did not receive radiation had wound complications of similar severity. This decrease in wound complications represents a major improvement over our prior experience and suggests that the timing of radioactive source loading in the postoperative period is a major factor in radiation-induced wound-healing delay.

Treatment planning for permanent and temporary percutaneous implants with custom made templates.

Nine patients who were presented at MSKCC with primary or recurrent pelvic or head and neck tumors and for whom surgery or further external radiation were excluded, were treated with percutaneous permanent or temporary implants, with individual pre-treatment planning and custom made templates. The tumor dose distributions achieved were as good as for implants performed at the time of surgical exploration. No serious complications have been encountered.

The current state of intraoperative interstitial brachytherapy in lung cancer.

Low dose-rate intraoperative brachytherapy allows for a more precise tumor localization of the delivered radiation and its easier adaptation to the tumor shape than it is possible with external radiation. As a result a higher dose is usually delivered to the tumor volume and the damage to the normal lung is less. In an attempt to determine the value of lung brachytherapy we provide in this article a complete review of the evolution of brachytherapy in lung cancer at Memorial Sloan-Kettering Cancer Center, an experience which exceeds 1,000 patients. The use of encapsulated sources of I-125, greatly reduced radiation outside the treatment volume and simplified medical and nursing staff radiation protection. Lung brachytherapy in combination with surgery and postoperative external radiation, improved local tumor control in advanced tumors (from 63% to 76%) with no increase in late pulmonary morbidity, but only a modest survival advantage. The results of brachytherapy in patients with early lung cancer who had limited pulmonary reserve, suggest that intraoperative brachytherapy is an effective alternative treatment option. The limited experience with interstitial brachytherapy under fluoroscopic and CT guidance is encouraging, but needs more investigation.

The combined neurosurgical-thoracic management of superior sulcus tumors.

Thirty patients with superior sulcus carcinoma were prospectively evaluated over an 18-month period. All patients underwent complete neuroradiological evaluation by computed tomography (CT) and myelography. Prior to operation, brachial plexopathy was noted in 20 patients (67%), and invasion of the spine in eight (27%). Using a team approach, gross total resection of tumor was achieved in 17 of 26 patients (65%) undergoing thoracotomy. There was no operative mortality. The use of a team approach allows extended surgical resection, especially when the spine is involved. In patients presenting with brachial plexopathy or cord compression, de novo surgery before radiation may provide better long-term palliation and pain relief.