Giridhar R. Gorla

Two fractions of high-dose-rate brachytherapy in the management of cervix cancer: clinical experience with and without chemotherapy

PURPOSE In recent years, high-dose-rate brachytherapy has become popular in the management of carcinoma of the uterine cervix, because it eliminates many of the problems associated with low-dose-rate brachytherapy. However, the optimum time-dose-fractionation remains controversial. Two fractions of high-dose-rate brachytherapy are convenient for patients, but most radiation oncologists in the United States do not use them, because of fear that they could lead to excessive rectal or bladder toxicity. Here we present our experience, which suggests that a two-fraction regimen is indeed safe and effective. METHODS We treated 49 patients with Stages I-III biopsy-proven carcinoma of the uterine cervix by external beam radiation therapy (EBRT), plus two fractions of high-dose-rate brachytherapy. The histology was squamous cell carcinoma in 43 patients (88%) and nonsquamous in 6 (12%). The median size of the primary tumor was 6 cm (range: 3-10 cm). Each patient received EBRT to the pelvis to a median dose of 45 Gy (range: 41.4-50.4 Gy), followed by a parametrial boost when indicated. Thirty patients (61%) also received irradiation to the para-aortic lymph nodes to a dose of 45 Gy. After EBRT, each patient underwent two applications of high-dose-rate brachytherapy, 1 week apart. The dose delivered to point A was 9 Gy per application for 49 applications (50%) and 9.4 Gy for 43 applications (44%), and it varied from 7 to 11 Gy for the rest (6%). The total dose to the rectum from both high-dose-rate brachytherapy applications ranged from 4.7 to 11.7 Gy (median: 7.1 Gy), and the total dose to the bladder from 3.8 to 15.5 Gy (median: 10.5 Gy). Twenty-five of the 49 patients (51%) received concomitant chemotherapy (cisplatin 20 mg/m(2)/day for 5 days) during the first and fourth weeks of EBRT and once after the second high-dose-rate brachytherapy application. Chemotherapy was not assigned in a randomized fashion. The use of chemotherapy increased during the time period spanned by this study as increasing evidence supporting the use of chemotherapy began to appear. RESULTS The observed survival rates after 2, 3, and 5 years were 83%, 78%, and 78%, respectively. The surviving patients have been followed up for a median of 3 years (range: 2-6 years). Eight of the 49 patients suffered local failures. Among patients treated without chemotherapy, the 3-year local control rate was 77%; it was 88% among those receiving chemotherapy. There have been no regional failures. Four patients developed distant metastases. At 3 years, 91% of the patients in each group were free of distant metastases. Ten of the 49 patients (20%) suffered Grade 3 acute toxicity; 11 (22%) had Grade 4. Among the 24 patients treated without chemotherapy, only 1 (4%) suffered Grade 3 toxicity. Among the 25 patients receiving chemotherapy, in contrast, 8 (32%) suffered Grade 3 and 12 (48%) Grade 4 acute toxicity. Only 2 patients suffered late toxicity: One suffered Grade 2 and the other Grade 3 late toxicity. The actuarial risk of Grade 2 or worse late toxicity was 5%, with or without chemotherapy. CONCLUSIONS Our experience suggests that two fractions of high-dose-rate brachytherapy are safe and effective in the management of cervix cancer, even in conjunction with concomitant cisplatin. The fears that the use of two fractions would lead to excessive rectal or bladder toxicity proved unfounded. Guidelines for ensuring a low complication rate are discussed.

LIVER IRRADIATION: A POTENTIAL PREPARATIVE REGIMEN FOR HEPATOCYTE TRANSPLANTATION

Advances in the understanding of hepatocyte engraftment and repopulation of the host liver have already led to the use of hepatocyte transplantation (HT) with some success in the treatment of inherited and acquired liver diseases. Wider application of HT is severely limited by the unavailability of large number of transplantable hepatocytes and difficulties associated with transplanting an adequate number of cells for achieving therapeutically satisfactory levels of metabolic correction. Therefore, there is a need for preparative regimens that provide a growth advantage to the transplanted (healthy) hepatocytes over the hosts own (diseased) hepatocytes so that the former can repopulate the host liver. We have recently shown that when the liver of recipient rats was subjected to radiotherapy and partial hepatectomy before HT, the transplanted hepatocytes engrafted in and massively repopulated the liver, and also ameliorated the adverse clinical and histopathological changes associated with hepatic irradiation. This protocol was then used as a preparative regimen for transplanting normal hepatocytes into jaundice mutant rats (Gunn strain), which lack hepatic bilirubin-uridinediphosphoglucuronate glucuronosyltransferase and is a model of Crigler-Najjar syndrome Type I. The results showed long-term correction of the metabolic abnormality, suggesting that the transplanted hepatocytes repopulated an irradiated liver and were metabolically functional. This strategy could be useful in the treatment of various genetic, metabolic, or malignant diseases of the liver.

Biliary copper excretion capacity in intact animals: Correlation between ATP7B function, hepatic mass, and biliary copper excretion

Copper toxicosis can occur in the absence of biliary copper excretion. To demonstrate whether biliary copper excretion capacity is correlated with hepatic mass and ATP7B function, we undertook studies in intact animals. Copper‐histidine was injected intrasplenically after baseline bile collection, followed by measurement of copper excretion in Long‐Evans Cinnamon (LEC) rats lacking atp7b function and in normal, syngeneic Long‐Evans Agouti (LEA) rats. The basal biliary copper excretion was very low in LEC rats compared with LEA rats, 8 ± 4 and 37 ± 18 ng copper/min, respectively; p < 0.05. After addition of copper, copper excretion increased significantly (by two‐ to five‐fold) in LEA rats during the 30 minute study period, whereas LEC rats showed only a slight and transient increase in copper excretion. After one‐third and two‐thirds partial hepatectomy immediately before copper loading, copper excretion decreased progressively. The studies indicate that biliary copper excretion depends on hepatocyte mass and ATP7B gene function. Analysis of copper excretion with our nonradioactive method will facilitate testing of novel therapies and pathophysiological mechanisms in copper toxicity.

Point vs. volumetric bladder and rectal doses in combined intracavitary-interstitial high-dose-rate brachytherapy: Correlation and comparison with published Vienna applicator data

PURPOSE We correlated rectal and bladder point and volumetric dose data in patients treated for advanced cervix cancers with combined intracavitary-interstitial high-dose-rate (HDR) brachytherapy (BT). The results are compared with published Vienna applicator data. METHODS AND MATERIALS We retrospectively analyzed 30 individual combined intracavitary plus interstitial implants from 10 patients treated with external beam radiation therapy (EBRT) followed by HDR BT for locally advanced cervix carcinoma. EBRT consisted of 45 Gy to the pelvis followed by 9-14.4 Gy boost to involved parametria. BT consisted of a total dose of 21 Gy delivered in 7 Gy fraction. For each implant, CT-image-based simulation and image-guided BT treatment planning was performed. Bladder and rectal doses were evaluated and analyzed using both International commission on Radiation Units and Measurements (ICRU) reference points and dose-volume histograms. The cumulative doses to the rectum and bladder were calculated by combining contributions from external beam therapy and BT. To facilitate comparison with published literature, the total doses were normalized to equivalent dose in 2-Gy fractions (EQD2) using the equation EQD2total = EQD2EBRT + EQD2BT. RESULTS For the patient population considered, the mean ICRU bladder dose was 75 (+/-4) Gy3 compared to bladder D0.1 cc and D2 cc doses of 84 (+/-4) and 78 (+/-3) Gy3, respectively. The mean ICRU rectal dose was 73 (+/-4) Gy3 compared to rectal D0.1 cc and D2 cc doses of 79 (+/-5) and 74 (+/-4) Gy3, respectively. For rectum, the mean dose ratios (D0.1 cc/D(ICRU)) and (D2 cc/D(ICRU)) were 1.08 and 1.01, respectively, compared to Vienna applicator study mean dose ratios of 1.08 and 0.93, respectively. ICRU rectal dose correlated with volumetric rectal doses and best with volumetric D2 cc dose (rS = 0.91, p = 0.0003); however, ICRU bladder dose did not correlate with volumetric bladder dose. CONCLUSIONS Our study findings reveal a strong correlation between ICRU rectal reference dose and volumetric rectal D2 cc dose in combined intracavitary-interstitial HDR brachytherapy. This surrogate rectal-dose relationship is valuable in establishing rectal tolerance dose levels in transitioning from traditional two-dimensional to image-based three-dimensional dose planning.

Predictive value of linear-quadratic model in the treatment of cervical cancer using high-dose-rate brachytherapy

PURPOSE To determine whether a dose-response relationship exists between the biologic effective dose (BED) at Point A and the bladder and rectum and the clinical outcomes in our experience with external beam radiotherapy (EBRT) and high-dose-rate brachytherapy in the treatment of cervical carcinoma. METHODS AND MATERIALS This was a retrospective study. A total of 49 patients with cervical cancer were treated with a combination of EBRT (median 45 Gy, range 41.4-50.4) and high-dose-rate brachytherapy (median 18 Gy; range 18-19, in two fractions). Twenty-three patients received concomitant cisplatin-based chemotherapy. The cumulative BEDs were calculated at Point A (BED10) and at bladder and rectal reference points (BED3) using the linear-quadratic equation. The BED10 values, after incorporating a time factor (BED10tf) in the formula, were also calculated. RESULTS In patients treated with RT alone, the local failure rate was 10% (1 of 10) and 19% (3 of 16) in patients receiving a BED10 >89 Gy10 or <89 Gy10 to Point A, respectively (p = 0.2). The corresponding local failure rates were 20% (3 of 15) and 0% (0 of 8) in patients treated with concomitant chemotherapy (p = 0.3). In patients treated with RT alone, the local failure rate was 7.7% (1 of 13) and 23% (3 of 13) in patients with a BED10tf >64 Gy10 or <64 Gy10 (p = 0.1), respectively. The median BED3 values at the rectal and bladder point was 95.5 Gy3 and 103.6 Gy3, respectively. Only 1 case of Grade 2 late rectal toxicity (2%) and no late bladder toxicity occurred. CONCLUSION In patients treated with RT alone, a BED10 >89 Gy and a BED10tf >64 Gy indicated a trend toward a better local control rate. This difference was not observed in patients receiving chemotherapy. A BED3 <100 Gy3 was associated with negligible late toxicity. Although the BED10 in our study was about 10-15 Gy10 less than that in the published data, the 4-year local control rate of 80% and 83% and disease-free survival rate of 75% and 70% with and without chemotherapy, respectively, compare well with the rates in other studies in the literature.

Dendritic Cells Pulsed with Irradiated Prostate Tumor Cells Express CC Receptor-7 and Its Ligands and Initiate a Tumor Specific Immune Response

AIM: Dendritic cells (DCs) are potent antigen-presenting cells that play a pivotal role in regulating immune response in cancer. This study is to address whether irradiated prostate cancer cells have the capability to induce DCs to respond against a tumor. METHODS: A highly tumorigenic mouse prostate tumor cell line RM-1 was subjected to γ-irradiation and tested for induction of apoptosis by exploiting DNA analysis and Hoechst staining. Various in vitro experiments were carried out to ascertain whether the irradiated tumor cells could activate DCs, and whether the DCs pulsed with irradiated tumor cells could stimulate splenocytes obtained from naive C57BL/6J animals. RESULTS: Irradiation (10 and 60 Gy) caused apoptosis in RM-1 cells and DCs were able to preferentially take up irradiated RM-1 cells. The irradiated RM-1 cells were immunostimulatory even at comparatively low stimulator/responder ratios as determined by co-culture experiments. By contrast, non-irradiated tumor cells were unable to stimulate comparable response. Moreover, the DCs pulsed with irradiated RM-1 cells could express high amounts of CCR-7 and its ligands, CCL-19 and CCL-21. The splenocytes when stimulated with these activated DCs showed significant cytotoxic activity against fresh RM-1 cells, and they also secreted high levels of interferon-γ and interleukin-12. CONCLUSION: This is the first demonstration that irradiated prostate tumor cells can activate DCs and these DCs express CCR-7 and its ligands, CCL-19 and CCL-21. The activated DCs are further capable of stimulating splenocytes of naive animals. These results have potential implications in designing effective DC-based immunotherapeutic strategy for prostate cancer treatment.