Geraldine M. Jacobson

Postoperative radiation therapy for pathologic stage C prostate cancer

From 1971 to 1981, 26 patients with pathologic Stage C prostate cancer were referred to this department for postoperative radiation therapy. During the same period 24 patients, undergoing radical prostatectomy at this institution, were found to have pathologic Stage C disease but did not receive adjuvant irradiation. Both groups of patients are compared at 5 years post surgery for disease-free survival, local control, and distant failure in an attempt to determine whether there is a demonstrable benefit of adjuvant irradiation in this setting. All irradiated patients started therapy 1 to 4 months post surgery. All were treated with megavoltage irradiation. The majority were treated to the pelvis by a 4-field technique to an absorbed dose of 46-50 Gy followed by a prostate boost via multiple fields to a total dose of 54-70 Gy. Three patients received 50-52 Gy to the pelvis only and 5 patients received 56-65 Gy to localized prostate fields only. Moderate complications in the irradiated group were 23% with no severe complications observed. This rate may be reduced with treatment of local prostate fields only. There was no significant difference in 5-year survival, 5-year disease-free survival, or distant metastases in patients treated with surgery only or surgery plus radiation. However, local recurrence at 5 years was significantly different (p = 0.046), 16.6% in the surgery only group and 0 in the irradiated group. This difference was more pronounced in the subset of patients with seminal vesicle invasion: 30% local recurrence in the surgery only group versus 0 in the irradiated group. These data suggest that the addition of postoperative irradiation in pathologic Stage C prostate cancer yields an improvement in local control, and that for the subset of patients at significant risk of local relapse, those with seminal vesicle invasion, adjuvant prostate bed irradiation should be recommended.

Preservation of immune function in cervical cancer patients during chemoradiation using a novel integrative approach

Patients receiving chemoradiation for cervical cancer are at risk for distress, chemoradiation-related side-effects, and immunosuppression. This prospective randomized clinical trial examined effects of a complementary therapy, Healing Touch (HT), versus relaxation training (RT) and usual care (UC) for (1) supporting cellular immunity, (2) improving mood and quality of life (QOL), and (3) reducing treatment-associated toxicities and treatment delay in cervical cancer patients receiving chemoradiation. Sixty women with stages IB1 to IVA cervical cancer were randomly assigned to receive UC or 4 ×/weekly individual sessions of either HT or RT immediately following radiation during their 6-week chemoradiation treatment. Patients completed psychosocial assessments and blood sampling before chemoradiation at baseline, weeks 4 and 6. Multilevel regression analyses using orthogonal contrasts tested for differences between treatment conditions over time. HT patients had a minimal decrease in natural killer cell cytotoxicity (NKCC) over the course of treatment whereas NKCC of RT and UC patients declined sharply during chemoradiation (group by time interaction: p = 0.018). HT patients showed greater decreases in two different indicators of depressed mood (CES-D depressed mood subscale and POMS depression scale) compared to RT and UC (group by time interactions: p<0.05). No between group differences were observed in QOL, treatment delay, or clinically-rated toxicities. HT may benefit cervical cancer patients by moderating effects of chemoradiation on depressed mood and cellular immunity. Effects of HT on toxicities, treatment delay, QOL, and fatigue were not observed. Long-term clinical implications of findings are not known.

Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress

Cancer cells (relative to normal cells) demonstrate alterations in oxidative metabolism characterized by increased steady-state levels of reactive oxygen species (i.e., hydrogen peroxide, H(2)O(2)) that may be compensated for by increased glucose metabolism, but the therapeutic significance of these observations is unknown. In this study, inhibitors of glucose (i.e., 2-deoxy-d-glucose, 2DG) and hydroperoxide (i.e., l-buthionine-S,R-sulfoximine, BSO) metabolism were utilized in combination with a chemotherapeutic agent, paclitaxel (PTX), thought to induce oxidative stress, to treat breast cancer cells. 2DG + PTX was more toxic than either agent alone in T47D and MDA-MB231 human breast cancer cells, but not in normal human fibroblasts or normal human mammary epithelial cells. Increases in parameters indicative of oxidative stress, including steady-state levels of H(2)O(2), total glutathione, and glutathione disulfide, accompanied the enhanced toxicity of 2DG + PTX in cancer cells. Antioxidants, including N-acetylcysteine and polyethylene glycol-conjugated catalase and superoxide dismutase, inhibited the toxicity of 2DG + PTX and suppressed parameters indicative of oxidative stress in cancer cells, whereas inhibition of glutathione synthesis using BSO further sensitized breast cancer cells to 2DG + PTX. These results show that combining inhibitors of glucose (2DG) and hydroperoxide (BSO) metabolism with PTX selectively (relative to normal cells) enhances breast cancer cell killing via H(2)O(2)-induced metabolic oxidative stress, and suggest that this biochemical rationale may be effectively utilized to treat breast cancers.

Electron arc therapy: chest wall irradiation of breast cancer patients

From 1980 to October 1985 we treated 45 breast cancer patients with electron arc therapy. This technique was used in situations where optimal treatment with fixed photon or electron beams was technically difficult: long scars, recurrent tumor extending across midline or to the posterior thorax, or marked variation in depth of target tissue. Forty-four patients were treated following mastectomy: 35 electively because of high risk of local failure, and 9 following local recurrence. One patient with advanced local regional disease was treated primarily. The target volume boundaries on the chest wall were defined by a foam lined cerrobend cast which rested on the patient during treatment, functioning as a tertiary collimator. A variable width secondary collimator was used to account for changes in the radius of the thorax from superior to inferior border. All patients had computerized tomography performed to determine Internal Mammary Chain depth and chest wall thickness. Electron energies were selected based on these thicknesses and often variable energies over different segments of the arc were used. The chest wall and regional node areas were irradiated to 45 Gy-50 Gy in 5-6 weeks by this technique. The supraclavicular and upper axillary nodes were treated by a direct anterior photon field abutted to the superior edge of the electron arc field. Follow-up is from 10-73 months with a median of 50 months. No major complications were observed. Acute and late effects and local control are comparable to standard chest wall irradiation. The disadvantages of this technique are that the preparation of the tertiary field defining cast and CT treatment planning are labor intensive and expensive. The advantage is that for specific clinical situations large areas of chest wall with marked topographical variation can be optimally, homogeneously irradiated while sparing normal uninvolved tissues.

Randomized Trial of Pentoxifylline and Vitamin E vs Standard Follow-up After Breast Irradiation to Prevent Breast Fibrosis, Evaluated by Tissue Compliance Meter

PURPOSE To conduct a randomized clinical trial to determine whether the combination of pentoxifylline (PTX) and vitamin E given for 6 months after breast/chest wall irradiation effectively prevents radiation-induced fibrosis (RIF). METHODS AND MATERIALS Fifty-three breast cancer patients with localized disease were enrolled and randomized to treatment with oral PTX 400 mg 3 times daily and oral vitamin E 400 IU daily for 6 months after radiation (n=26), or standard follow up (n=27). Tissue compliance meter (TCM) measurements were obtained at 18 months to compare tissue compliance in the irradiated and untreated breast/chest wall in treated subjects and controls. Measurements were obtained at 2 mirror image sites on each breast/chest wall, and the average difference in tissue compliance was scored. Differences in TCM measurements were compared using a t test. Subjects were followed a minimum of 2 years for local recurrence, disease-free survival, and overall survival. RESULTS The mean difference in TCM measurements in the 2 groups was 0.88 mm, median of 1.00 mm (treated) and 2.10 mm, median of 2.4 mm (untreated). The difference between the 2 groups was significant (P=.0478). Overall survival (100% treated, 90.6% controls at 5 years) and disease-free survival (96.2% treated, 86.8% controls at 5 years) were not significantly different in the 2 groups. CONCLUSIONS This study of postirradiation breast cancer patients treated with PTX/vitamin E or standard follow-up indicated a significant difference in radiation-induced fibrosis as measured by TCM. There was no observed impact on local control or survival within the first 2 years of follow-up. The treatment was safe and well tolerated. Pentoxifylline/vitamin E may be clinically useful in preventing fibrosis after radiation in high-risk patients.

The dosimetric impact of heterogeneity corrections in high-dose-rate 192Ir brachytherapy for cervical cancer: Investigation of both conventional Point-A and volume-optimized plans

PURPOSE To evaluate the dosimetric impact of heterogeneity corrections on both conventional and volume-optimized high-dose-rate (HDR) ¹⁹²Ir brachytherapy tandem-and-ovoid treatment plans. METHODS AND MATERIALS Both conventional and volume-optimized treatment plans were retrospectively created using eight unique CT data sets. In the volume-optimized plans, the clinical target volume (CTV) and organs-at-risk (rectum, bladder, and sigmoid) were contoured on the CT data sets by a single physician. For each plan, dose calculations representing homogeneous water medium were performed using the Task Group (TG-43) formalism and dose calculations with heterogeneity corrections were performed using a commercially available treatment planning system. RESULTS For the conventional plans, the change in dose between TG-43 and heterogeneity-corrected calculations was assessed for the following points: Point-A (left and right) and International Commission on Radiation Units and Measurements (ICRU) 38 defined rectum and bladder points. It was found that the dose to the ICRU bladder decreased the most (-2.2±0.9%), whereas ICRU rectum (-1.7±0.8%), Point-A right (-1.1±0.4%), and Point-A left (-1.0±0.3%) also showed decreases with heterogeneity-corrected calculations. For the volume-optimized plans, the change in dose between TG-43 and heterogeneity-corrected calculations was assessed for the following dose-volume histogram parameters: D(90) of the CTV and D(2cc) of the rectum, bladder, and sigmoid. It was found that D(90) of the CTV decreased by -1.9±0.7% and D(2cc) decreased by -2.6±1.4%, -1.0±0.4%, and -2.0±0.6% for the rectum, bladder and sigmoid, respectively, with heterogeneity-corrected calculations. CONCLUSIONS Heterogeneity corrections on high-dose rate plans were found to have only a small dosimetric impact over TG-43-based dose calculations for both conventional Point-A and volume-optimized plans.

Breast irradiation following silicone gel implants

Little information is found in the literature regarding breast irradiation in patients with reconstructed or augmented breasts. From November 1970 to October 1984, we treated ten patients with silicone gel prostheses with external radiation for recurrent disease, or as primary therapy. All patients were treated with megavoltage equipment. Technique and doses varied with the clinical situation, but generally, patients received 5000 rad in five weeks to the breast or mound with opposed tangential fields. The majority of patients had excellent cosmetic results with minimal late skin changes and no fibrosis or contracture. We conclude that, with proper surgical and radiotherapeutic techniques, good cosmetic results can be obtained in these patients, without compromising their therapy.

Thromboembolic events in patients with cervical carcinoma: Incidence and effect on survival☆

OBJECTIVES The purpose of this study was to determine whether thromboembolic events (TE) in cervical cancer patients are associated with survival by comparing the survival of patients with and without thromboembolic events over a seven year period. METHODS Utilizing a retrospective chart review we identified patients with any diagnosis of a TE, associated risk factors for TE development and overall survival. We also collected clinico-pathological data including stage, histology, height, weight, smoking history, radiation and chemotherapy treatment data and the temporal relationship of the development of TE to the time of cancer diagnosis. Data sources included the University of Iowa Hospitals and Clinics (UIHC) Tumor Registry and the UIHC Gynecologic Oncology Tumor Data Base as well as a search of UIHC medical record data bases using ICD-9 codes to initially identify all patients diagnosed with cervical carcinoma. RESULTS In this study, the incidence of TE in cervical cancer patients was 11.7%. There was a clear and significant difference in survival between patients with and without TE. We identified an association between TE and stage, chemotherapy, brachytherapy, and radiation therapy. CONCLUSIONS The major findings of our study are a significant incidence of thromboembolism in patients with cervical cancer, and a significant decrease in survival in patients who experience thromboembolism at presentation or during treatment. Deaths in these patients were overwhelmingly related to progressive cancer rather than the TE itself, suggesting that this adverse prognostic event may be related to aggressive tumor biology.

High resolution (3 Tesla) MRI-guided conformal brachytherapy for cervical cancer: consequences of different high-risk CTV sizes

Purpose To evaluate conventional brachytherapy (BT) plans using dose-volume parameters and high resolution (3 Tesla) MRI datasets, and to quantify dosimetric benefits and limitations when MRI-guided, conformal BT (MRIG-CBT) plans are generated. Material and methods Fifty-five clinical high-dose-rate BT plans from 14 cervical cancer patients were retrospectively studied. All conventional plans were created using MRI with titanium tandem-and-ovoid applicator (T&O) for delivery. For each conventional plan, a MRIG-CBT plan was retrospectively generated using hybrid inverse optimization. Three categories of high risk (HR)-CTV were considered based on volume: non-bulky (< 20 cc), low-bulky (> 20 cc and < 40 cc) and bulky (≥ 40 cc). Dose-volume metrics of D90 of HR-CTV and D2cc and D0.1cc of rectum, bladder, and sigmoid colon were analyzed. Results Tumor coverage (HR-CTV D90) of the conventional plans was considerably affected by the HR-CTV size. Sixteen percent of the plans covered HR-CTV D90 with the prescription dose within 5%. At least one OAR had D2cc values over the GEC-ESTRO recommended limits in 52.7% of the conventional plans. MRIG-CBT plans showed improved target coverage for HR-CTV D90 of 98 and 97% of the prescribed dose for non-bulky and low-bulky tumors, respectively. No MRIG-CBT plans surpassed the D2cc limits of any OAR. Only small improvements (D90 of 80%) were found for large targets (> 40 cc) when using T&O applicator approach. Conclusions MRIG-CBT plans displayed considerable improvement for tumor coverage and OAR sparing over conventional treatment. When the HR-CTV volume exceeded 40 cc, its improvements were diminished when using a conventional intracavitary applicator.

Target volume changes through high-dose-rate brachytherapy for cervical cancer when evaluated on high resolution (3.0 Tesla) magnetic resonance imaging

PURPOSE To evaluate tumor volume changes that occurred during courses of high-dose-rate brachytherapy (HDR) using high resolution (3.0 Tesla) magnetic resonance imaging (MRI), along with the regression after external beam radiation therapy (EBRT). METHODS AND MATERIALS Fourteen patients with International Federation of Gynecology and Obstetrics stage IB1-IV cervical cancer were studied retrospectively. All patients underwent EBRT with concurrent chemotherapy followed by HDR brachytherapy. Gross tumor volume (GTV) and high-risk clinical target volume (HR-CTV) were contoured on a 3.0 Tesla MRI on the day of the HDR and on diagnostic MRI (1.5 Tesla) prior to EBRT. Two physicians independently contoured the GTV and HR-CTV on a total of 46 MRI data sets for the HDR plans. The percent volume changes of GTV and HR-CTV were quantified after EBRT and again after each HDR. The conformity indices (CIs) of the 2 contours were assessed. RESULTS GTV and HR-CTV considerably regressed after the first ( --31.7% ± 19.3% and --26.4% ± 6.9%, respectively) and the second (--26.8% ± 14.3% and --23.8% ± 11.0%) fraction of HDR while relatively small regressions were observed after the third (--16.3% ± 14.2% and --10.6% ± 13.4%) and the fourth (--8.0% ± 3.4% and --9.0% ± 8.0%) fractions. The lymph node-positive on positron emission tomography (PET) and stage III or IV group showed, on average, more than 200% larger GTV and HR-CTV before EBRT than those of the other patients. The GTV and HR-CTV for the group were larger on average more than 150% after EBRT and before the first HDR fraction than the other group. Interobserver CI did not vary significantly (0.75 ± 0.11) for HR-CTV, although a smaller CI (0.56 ± 0.21) was found for GTV. CONCLUSIONS Larger tumor regressions were observed after the first and second fractions of HDR than after all subsequent fractions. The PET-identified lymph node-positive patient group and stage III or higher tumors showed larger tumor volumes before and after EBRT than other cases.