Basil S. Hilaris

Intraoperative radiotherapy for breast cancer

Postoperative radiotherapy, which forms part of breast-conserving therapy, may not need to encompass the whole breast. Apart from the consumption of huge resources and patients time, postoperative radiotherapy deters many women from receiving the benefits of breast-conserving surgery, forcing them to choose a mastectomy instead. If radiotherapy could be given in the operating theatre immediately after surgery, many of these disadvantages could be overcome. One striking fact about local recurrence after breast-conserving surgery is that most occurs in the area of breast immediately next to the primary tumour; this is despite the finding that two-thirds of mastectomy samples have microscopic tumours distributed throughout the breast, even when radiotherapy is omitted. Thus, only the area adjacent to the tumour may need treatment with radiotherapy. On the basis of this premise, clinical scientists have used new technology to administer radiotherapy to the area at greatest risk of local recurrence, with the aim of completing the whole local treatment in one sitting. In this review, we have elaborated on the rationale and different methods of delivery of intraoperative radiotherapy. If this approach is validated by the results of current randomised trials, it could save time, money, and breasts.

Long-Term Results of Targeted Intraoperative Radiotherapy (Targit) Boost During Breast-Conserving Surgery

PURPOSEnWe have previously shown that delivering targeted radiotherapy to the tumour bed intraoperatively is feasible and desirable. In this study, we report on the feasibility, safety, and long-term efficacy of TARGeted Intraoperative radioTherapy (Targit), using the Intrabeam system.nnnMETHODS AND MATERIALSnA total of 300 cancers in 299 unselected patients underwent breast-conserving surgery and Targit as a boost to the tumor bed. After lumpectomy, a single dose of 20 Gy was delivered intraoperatively. Postoperative external beam whole-breast radiotherapy excluded the usual boost. We also performed a novel individualized case control (ICC) analysis that computed the expected recurrences for the cohort by estimating the risk of recurrence for each patient using their characteristics and follow-up period.nnnRESULTSnThe treatment was well tolerated. The median follow up was 60.5 months (range, 10-122 months). Eight patients have had ipsilateral recurrence: 5-year Kaplan Meier estimate for ipsilateral recurrence is 1.73% (SE 0.77), which compares well with that seen in the boosted patients in the European Organization for Research and Treatment of Cancer study (4.3%) and the UK STAndardisation of breast RadioTherapy study (2.8%). In a novel ICC analysis of 242 of the patients, we estimated that there should be 11.4 recurrences; in this group, only 6 recurrences were observed.nnnCONCLUSIONSnLumpectomy and Targit boost combined with external beam radiotherapy results in a low local recurrence rate in a standard risk patient population. Accurate localization and the immediacy of the treatment that has a favorable effect on tumour microenvironment may contribute to this effect. These long-term data establish the long-term safety and efficacy of the Targit technique and generate the hypothesis that Targit boost might be superior to an external beam boost in its efficacy and justifies a randomized trial.

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

PURPOSEnA 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.nnnMETHODS AND MATERIALSnThe Clinical Research Committee (CRC) of the American Endocurietherapy Society (AES) met to formulate consensus guidelines for HDRAB in cervical, endometrial, and endobronchial tumors.nnnCONCLUSIONnEach 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.

Preclinical studies with the photon radiosurgery system (PRS).

PURPOSEnDetermine the radiobiological effectiveness (RBE) for low-energy X-rays (average energy of 23 KeV) produced by the Photon Radiosurgery System (PRS).nnnMETHODS AND MATERIALSnRBE 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%.nnnRESULTSnThe 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).nnnCONCLUSIONSnThe 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.

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. J. Surg. Oncol. 1998;69:258–264.

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.

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.

Targeted Intraoperative Radiotherapy (Targit) Boost after Breast Conserving Surgery Results in a Remarkably Low Recurrence Rate in a Standard Risk Population: 5 Year Results.

Background: In 1998 we started a phase II study of TARGeted Intraoperative radioTherapy (Targit) using the IntrabeamTM system. We present the updated results of this first group of breast cancer patients treated with breast conserving surgery where Targit was used as a boost to the tumour bed.Patients and Method: We treated 300 cancers in 299 patients undergoing breast-conserving surgery with no other selection criteria. 32% of the patients were younger than 51 years, 57% of cancers were between 1 to 2cm, (21% > 2cm), 29% had a grade 3 tumour and 29% were node positive. After lumpectomy, a single dose of 20Gy was delivered intraoperatively using 50 kV X-rays –calculated at the surface of the tumour bed1. In all except 9 patients Targit was delivered at the time of the lumpectomy. Postoperative external beam radiotherapy excluded the usual boost. We analyzed recurrences according to their position within the ipsilateral breast.Results: The treatment was well tolerated. The median follow up is 60.5 months (range 10-120 months). 8 patients have had ipsilateral recurrence: 5- year Kaplan Meier estimate for ipsilateral recurrence 1.74% (SE 0.77). 5 of these 8 patients had recurrence in the tumor bed: 5-year Kaplan Meier recurrence rate is 1.04% (SE 0.59). Additionally, 7 patients developed a contralateral breast cancer. Our results appear superior to those seen in the boosted patients in the EORTC study (4.3%) and the START-B study (2.8%) despite a higher node positivity in our series (29%), compared with 21% in the EORTC and 24% in the START-B trial and a larger proportion of younger women (<50 were 32% in Targit, 37% in EORTC and 21% in START-B).Conclusion: Lumpectomy and Targit boost combined with external beam radiotherapy results in an exceptionally low tumor bed recurrence rate in an unselected patient population. This could be attributed to both accurate localisation and timeliness of the treatment that could have a favorable effect on tumour micro-environment2. When used as a boost Targit is likely to be superior to conventional external boost. These data establish the long-term safety and efficacy of the Targit technique, which is being used in the soon to be completed randomised TARGIT trial of partial breast irradiation vs conventional external beam whole breast radiotherapy.1. Vaidya JS, Baum M, Tobias JS, Morgan S, DSouza D. The novel technique of delivering targeted intraoperative radiotherapy (Targit) for early breast cancer. Eur J Surg Oncol 2002;28(4):447-54.2. Belletti B, Vaidya JS, DAndrea S, Entschladen F, Roncadin M, Lovat F, et al. Targeted Intraoperative radiotherapy (TARGIT) impairs surgical wound-stimulated breast cancer cell proliferation and invasion Clin.Cancer Res. 2008;14(5):1325-32.

5 ORAL A very low recurrence rate is achieved by a targeted intraoperative radiotherapy (TARGIT) boost after breast conserving surgery for cancer

Results: The margin status was clear (>1mm), close (<1mm) and positive in 149/203 (73.3%), 23/203 (11.33%) and 31/203 (15.2%) of the patients. All 54 patients with positive or close margins underwent re-excision or mastectomy and residual tumour was found in 23/54 patients which represent 11.3%(23/203) of the total study (BCT) group. Risk of residual tumour was significant with positive or close margin (P<0.001), large tumour size (P<0.001) and High grade DCIS (P<0.019). Local (Ipsilateral) breast cancer recurrence occurred in 3/203 of patients with a median follow up of 24 months. 2/3 of these patients had High grade DCIS. Conclusion: Our unit policy is supported by the study that BCT with acceptable early local recurrence rate (1% per annum) is achievable with at least 1mm pathological tumour free margin.