Activated B Cells and Plasma Cells Are Resistant to Radiation Therapy.

PURPOSE: B cells play a key role in outcomes of cancer patients and responses to checkpoint blockade immunotherapies. However, the effect of radiation therapy on B cell populations is poorly understood. Here we characterize the effects of radiation on the development, survival, and phenotype of physiological B-cell subsets. METHODS AND MATERIALS: Naïve and immunized tumor bearing and nontumor bearing mice were treated with large-field or focal stereotactic radiation and distinct B-cell subsets of varying developmental stages were analyzed by flow cytometry and real-time reverse transcription polymerase chain reaction. RESULTS: We first report that focal stereotactic radiation is highly superior to large-field radiation at inducing tumor infiltration of B cells, CD8+ T cells, and macrophages. We observed that radiation affects B cell development in the bone marrow, increasing frequencies of early pro-B cells and late pro-B cells while inducing upregulation of programmed cell death protein 1. We then demonstrate that class switched B cells and plasma cells are highly resistant to radiation therapy compared with naïve B cells and upregulate activation markers programmed cell death 1 ligand 2 and major histocompatibility complex class II) after radiation. Mechanistically, radiation upregulates Xbp1 and Bcl6 in plasma cells, conferring radioresistance. Furthermore, using an immunization approach, we demonstrate that radiation enhances activation-induced cytidine deaminase mediated class switching and somatic hypermutation in primed B cells. CONCLUSIONS: These data demonstrate that stereotactic radiation is superior to large-field radiation at inducing infiltration of immune cells into tumors and that plasma cells and class switched B cells are highly resistant to radiation therapy. These results represent the most comprehensive analysis of the effects of radiation on B cells to date and identify novel mechanisms by which radiation modulates immune cells within the tumor microenvironment.

Bone Marrow-sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2).

PURPOSE: To test the hypothesis that intensity modulated radiation therapy (IMRT) reduces acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally advanced cervical cancer. METHODS AND MATERIALS: We enrolled patients with stage IB-IVA cervical carcinoma in a single-arm phase II trial involving 8 centers internationally. All patients received weekly cisplatin concurrently with once-daily IMRT, followed by intracavitary brachytherapy, as indicated. The primary endpoint was the occurrence of either acute grade ≥3 neutropenia or clinically significant GI toxicity within 30 days of completing chemoradiation therapy. A preplanned subgroup analysis tested the hypothesis that positron emission tomography-based image-guided IMRT (IG-IMRT) would lower the risk of acute neutropenia. We also longitudinally assessed patients' changes in quality of life. RESULTS: From October 2011 to April 2015, 83 patients met the eligibility criteria and initiated protocol therapy. The median follow-up was 26.0 months. The incidence of any primary event was 26.5% (95% confidence interval [CI] 18.2%-36.9%), significantly lower than the 40% incidence hypothesized a priori from historical data (P=.012). The incidence of grade ≥3 neutropenia and clinically significant GI toxicity was 19.3% (95% CI 12.2%-29.0%) and 12.0% (95% CI 6.7%-20.8%), respectively. Compared with patients treated without IG-IMRT (n=48), those treated with IG-IMRT (n=35) had a significantly lower incidence of grade ≥3 neutropenia (8.6% vs 27.1%; 2-sided χ2P=.035) and nonsignificantly lower incidence of grade ≥3 leukopenia (25.7% vs 41.7%; P=.13) and any grade ≥3 hematologic toxicity (31.4% vs 43.8%; P=.25). CONCLUSIONS: IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia.

Target localization and toxicity in dose-escalated prostate radiotherapy with image-guided approach using daily planar kilovoltage imaging.

Dose escalation with intensity-modulated radiation therapy (IMRT) for carcinoma of the prostate has augmented the need for accurate prostate localization prior to dose delivery. Daily planar kilovoltage (kV) imaging is a low-dose image-guidance technique that is prevalent among radiation oncologists. However, clinical outcomes evaluating the benefit of daily kV imaging are lacking. The purpose of this study was to report our clinical experience, including prostate motion and gastrointestinal (GI) and genitourinary (GU) toxicities, using this modality. A retrospective analysis of 100 patients treated consecutively between December 2005 and March 2008 with definitive external beam IMRT for T1c-T4 disease were included in this analysis. Prescription doses ranged from 74-78 Gy (median, 76) in 2 Gy fractions and were delivered following daily prostate localization using on-board kV imaging (OBI) to localize gold seed fiducial markers within the prostate. Acute and late toxicities were graded as per the NCI CTCAEv3.0. The median follow-up was 22 months. The magnitude and direction of prostate displacement and daily shifts in three axes are reported. Of note, 9.1% and 12.9% of prostate displacements were ≥ 5 mm in the anterior-posterior and superior-inferior directions, respectively. Acute grade 2 GI and GU events occurred in 11% and 39% of patients, respectively, however no grade 3 or higher acute GI or GU events were observed. Regarding late toxicity, 2% and 17% of patients developed grade 2 toxicities, and similarly no grade 3 or higher events had occurred by last follow-up. Thus, kV imaging detected a substantial amount of inter-fractional displacement and may help reduce toxicity profiles, especially high grade events, by improving the accuracy of dose delivery.

An exploratory analysis of HER-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group study.

OBJECTIVES: To investigate the frequency and potential prognostic or predictive value of HER-2 amplification or overexpression in advanced and recurrent endometrial cancers. METHODS: Immunohistochemical staining (IHC; DAKO Herceptest) and fluorescence in situ hybridization (FISH; Vysis Inc. PathVysion DNA Probe Kit) were performed on specimens collected on a randomized Gynecologic Oncology Group (GOG) protocol testing the addition of paclitaxel to doxorubicin/cisplatin. RESULTS: HER-2 overexpression (either 2+ (moderate) or 3+ (strong) immunostaining) and HER-2 gene amplification (a ratio of HER-2 copies to chromosome 17 (CEP17) copies > or = 2) were detected in 44% (104 of 234; 58 were 2+ and 46 were 3+) and 12% (21 of 182) of specimens, respectively. There was a significant increased frequency of overexpression in serous tumors vs. all others (23 of 38, 61% vs. 81 of 196, 41%, respectively, P=0.03). HER-2 amplification also appeared to be more common in serous tumors, but results were not significant (6 of 28, 21% vs. 15 of 141, 11%, P=0.12). There was a significant association between grade and HER-2 amplification among nonserous tumors, with grades 1, 2, and 3 cancers demonstrating 3%, 2%, and 21% amplification, respectively (P=0.003). Neither overexpression nor amplification predicted overall survival (OS) after adjusting for treatment and performance status. CONCLUSIONS: HER-2 amplification was more common in high grade tumors with a trend to being more common in serous tumors. There was no clear evidence for a survival difference or a difference in benefit from the addition of paclitaxel for women with HER-2 amplified or overexpressed tumors; however, power to detect clinically meaningful differences was low.

Paclitaxel, carboplatin, and concomitant radiotherapy for resected patients with high risk head and neck cancer.

Many resected patients with locally advanced head and neck cancer are found on pathological assessment to have high-risk features for recurrence. We thus performed a feasibility trial of post-operative radiotherapy with paclitaxel and carboplatin in high-risk carcinoma of the head and neck. All patients were planned for 6 cycles of weekly paclitaxel (40 mg/m2) and carboplatin (AUC=1) and concomitant radiotherapy, 60 Gy in 6 weeks. The most common side effect was grade 3 and 4 mucositis in 5/6 patients and g-tube placement in 4/6 patients. Five out of 6 patients remain alive without evidence of disease at a mean time of 19 months since completion of therapy. Our pilot study treated 6 postoperative patients. Since 4 of 6 enrolled patients were unable to complete the treatment as prescribed, we conclude that this regimen is not feasible. With an 83% grade 3 or 4 mucositis rate and 67% of patients enrolled requiring feeding tube placement, this regimen is not tolerable.

A longitudinal neuropsychological study of partial brain radiation in adults with brain tumors.

OBJECTIVE: To investigate longitudinal cognitive functioning in patients with brain tumor treated with modern highly conformal fractionated partial brain radiation therapy (RT). METHODS: Seventeen (of 22 initial consecutive patients) adults with primarily low-grade brain neoplasms who underwent either biopsy or tumor resection were tested at pre-RT baseline and at 3, 6, 12, and 24 months after baseline. Participants were classified as RT-treated nonprogressors (n = 12) or progressors (n = 3) based on serial follow-up structural imaging. Two patients received surgery only and served as controls to help minimize surgical, practice, test form, or other potential non-RT effects. Serial neuropsychological assessments were conducted using alternate forms of the Selective Reminding Test, 10/36 Spatial Recall Test, and Symbol Digit Modality Test (oral, written) as well as the Shipley Scale (baseline only), Wechsler Adult Intelligence Scale-Revised Digit Span, Trail Making Test, and the Symptom Checklist-90-Revised Global Severity Index scale. RESULTS: There was evidence of subtle attention and memory improvement in RT-treated nonprogressors throughout the 2-year period, with no evidence of cognitive decline. In contrast, patients with disease progression evidenced more substantial decline in memory and attention. CONCLUSIONS: Partial brain fractionated RT was not associated with adverse neuropsychological effects through the first 2 years following therapy.

Outcome and management of pathological stage I endometrial carcinoma patients with involvement of the lower uterine segment.

OBJECTIVE: The objective was to evaluate the clinicopathologic characteristics and outcome of pathologic stage I endometrial carcinoma patients with lower uterine segment (LUS) involvement. METHODS: We retrospectively reviewed the characteristics and outcomes of pathologic stage I endometrial carcinoma patients treated with primary surgery at our institution between 1988 and 1998. The significance of LUS involvement was examined with univariate and multivariate analyses. Median patient follow-up was 37.3 months. RESULTS: Of the 98 cases reviewed, 41 (42%) had LUS involvement. No differences were seen in the clinicopathologic features, extent of surgical staging, or adjuvant therapies between patients with and without LUS involvement. Univariate analysis revealed that grade, lymphovascular invasion (LVI), myometrial invasion (MI), and histology were correlated with recurrence. While the 5-year actuarial disease-free survival was worse in women with LUS involvement (80.3 vs 94.0%) compared to those without, this difference did not reach statistical significance (P = 0.14). Moreover, after controlling for pathologic features in a multivariate model, LUS involvement was not correlated with patient outcome (P = 0.98; hazard rate 0.97; 95% confidence interval 0.24, 4.0). LUS was also not correlated with pelvic recurrence. Of 25 low-risk patients (superficial MI and grade 1-2 disease) with LUS involvement, none recurred in the pelvis following surgery alone. In contrast, pelvic recurrence was common (5/12 or 41.6%) in high-risk patients (deep MI and/or grade 3 tumors) following surgery alone regardless of LUS involvement. CONCLUSION: LUS involvement is common in pathologic stage I endometrial carcinoma but is not correlated with a worse outcome. Moreover, in the absence of adverse pathologic features, LUS involvement is not associated with an increased risk of pelvic recurrence and should not be used as an indication for adjuvant radiation therapy.

Phase I trial of concomitant vinorelbine, paclitaxel, and pelvic irradiation in cervical carcinoma and other advanced pelvic malignancies.

OBJECTIVE: The aim of this study was to determine the feasibility and toxicity of concomitant vinorelbine, paclitaxel, and pelvic radiation therapy (RT) in patients with advanced cervical cancer and other pelvic malignancies. METHODS: Eligible patients included those with large or locally advanced cervical cancer. In addition, patients with other advanced gynecologic malignancies were eligible. In part I, vinorelbine was administered as a single agent during pelvic RT at a starting dose of 10 mg/m(2)/week with subsequent cohorts being escalated in 5 mg/m(2)/week increments. In part II, paclitaxel was added to vinorelbine (20 mg/m(2)/week) and pelvic RT at a starting dose of 20 mg/m(2)/week. RESULTS: Thirty-three women with pelvic malignancies (22 cervix, 6 vagina, 3 endometrium, 2 vulva) were enrolled. Twenty-seven received vinorelbine and 6 received both paclitaxel and vinorelbine in combination with pelvic RT. Escalating vinorelbine doses to 25 mg/m(2)/week were well tolerated, with the primary toxicity being hematologic. RT was delayed in only 1 patient due to acute hematologic toxicity. In contrast, the combination of paclitaxel, vinorelbine, and pelvic RT was not well tolerated. Five of 6 patients (83%) experienced grade > or = 2 leukopenia, with 2 patients missing > 1 cycle of chemotherapy. Moreover, RT was delayed for 1 week in 2 of 6 patients (33%). CONCLUSIONS: Concomitant pelvic RT and vinorelbine with doses to 25 mg/m(2)/week is well tolerated. The addition of paclitaxel to this combination is associated with significant hematologic toxicity and is thus not a feasible approach.

Outcome of endometrial carcinoma patients with involvement of the uterine serosa.

OBJECTIVE: The goal of this work was to evaluate the outcome of endometrial carcinoma patients undergoing primary surgery who have serosal involvement (SI). METHODS: Between 1980 and 1998, 562 women underwent primary surgery for endometrial cancer at the University of Chicago. Thirty-nine were noted to have SI. FIGO stages were IIIA (19), IIIB (1), IIIC (7), and IV (12). Of the 19 IIIA patients, 15 had solitary SI. Twenty-six patients received pelvic radiation therapy (RT) with or without vaginal brachytherapy (VB). One patient received whole-abdomen radiation therapy, and 13, adjuvant chemotherapy. Solitary SI patients received pelvic RT with or without VB as their sole adjuvant therapy. Disease-free survivals (DFSs) were estimated using the method of Kaplan and Meier and prognostic factors were analyzed by the log-rank test. RESULTS: With a median follow-up of 30.3 months, the 5-year actuarial DFS of the entire group was 28.9%. Factors correlated with disease recurrence included tumor stage (P = 0.003) and lymph node involvement (P = 0.04). In addition, patients with solitary SI had a better 5-year DFS (41.5% vs 20%, P = 0.04) than patients with SI plus other extrauterine sites. Relapse occurred in 23 women overall and in 7 of 15 solitary SI patients. The most common site of disease recurrence was distant both in the entire group and in the solitary SI patients. While abdominal recurrences were common in the entire group, they were infrequent in solitary SI patients. CONCLUSION: Endometrial carcinoma patients with SI have a high rate of relapse and a poor outcome. Even when patients have extrauterine disease limited to SI, the outcome is relatively unfavorable. Nonetheless, our results demonstrate the need to distinguish patients with solitary SI and those with SI plus other extrauterine disease sites.

Initial clinical experience with intensity-modulated whole-pelvis radiation therapy in women with gynecologic malignancies.

OBJECTIVE: Our goal in this article to describe our initial experience with intensity-modulated whole-pelvis radiation therapy (IM-WPRT) in gynecologic malignancies. METHODS: Between February and August 2000, 15 women with cervical (9) or endometrial (6) cancer received IM-WPRT. All patients received a treatment planning computed tomography (CT) scan. On each scan, the target volume (upper vagina, parametrial tissues, presacral region, uterus, and regional lymph nodes) and normal tissues (small bowel, bladder, and rectum) were identified. Using commercially available software, an IM-WPRT plan was generated for each patient. The goal was to provide coverage of the target with the prescription dose (45 Gy) while minimizing the volume of small bowel, bladder, and rectum irradiated. Acute gastrointestinal (GI) and genitourinary (GU) toxic effects in these women were compared with those seen in 25 patients treated with conventional WPRT. RESULTS: IM-WPRT plans provided excellent coverage of the target structures in all patients and were highly conformal, providing considerable sparing of the bladder, rectum, and small bowel. Treatment was well tolerated, with grade 0-1 GI and GU toxicity in 46 and 93% of patients, respectively. IM-WPRT patients had a lower rate of grade 2 GI toxicity (53.4% vs 96%, P = 0.001) than those treated with conventional WPRT. Moreover, the percentage of women requiring no or only infrequent antidiarrheal medications was lower in the IM-WPRT group (73.3% vs 20%, P = 0.001). While grade 2 GU toxicity was also lower in the IM-WPRT patients (6.7% vs 16%), this difference did not reach statistical significance (P = 0.38). CONCLUSION: IM-WPRT provides excellent coverage of the target structures while sparing critical neighboring structures in gynecology patients. Treatment is well tolerated with less acute GI toxicity than conventional WPRT. More patients and longer follow-up are needed to evaluate the full merits of this approach.

Significant pelvic recurrence in high-risk pathologic stage I--IV endometrial carcinoma patients after adjuvant chemotherapy alone: implications for adjuvant radiation therapy.

OBJECTIVE: To evaluate the risk of pelvic recurrence (PVR) in high-risk pathologic Stage I--IV endometrial carcinoma patients after adjuvant chemotherapy alone. METHODS: Between 1992 and 1998, 43 high-risk endometrial cancer patients received adjuvant chemotherapy. All patients underwent primary surgery consisting of total abdominal hysterectomy and bilateral salpingo-oophorectomy. No patients received preoperative radiation therapy (RT). Regional lymph nodes and peritoneal cytology were sampled in 62.8% and 83.7% of cases, respectively. Most patients had Stage III--IV disease (83.7%) or unfavorable histology tumors (74.4%). None had evidence of extra-abdominal disease. All patients received 4-6 cycles of chemotherapy as the sole adjuvant therapy, consisting primarily of cisplatin and doxorubicin. Recurrent disease sites were divided into pelvic (vaginal, nonvaginal) and extrapelvic (para-aortic, upper abdomen, liver, and extra-abdominal). Median follow-up was 27 months (range, 2--96 months). RESULTS: Twenty-nine women (67.4%) relapsed. Seventeen (39.5%) recurred in the pelvis and 23 (55.5%) in extrapelvic sites. The 3-year actuarial PVR rate was 46.5%. The most significant factors correlated with PVR were cervical involvement (CI) (p = 0.01) and adnexal (p = 0.05) involvement. Of the 17 women who developed a PVR, 8 relapsed in the vagina, 3 in the nonvaginal pelvis, and 6 in both. The 3-year vaginal and nonvaginal PVR rates were 37.8% and 26%, respectively. The most significant factor correlated with vaginal PVR was CI (p = 0.0007). Deep myometrial invasion (p = 0.02) and lymph nodal involvement (p = 0.03) were both correlated with nonvaginal PVR. Nine of the 29 relapsed patients (31%) developed PVR as their only (6) or first site (3) of recurrence. Factors associated with a higher rate of PVR (as the first or only site) were CI and Stage I--II disease. CONCLUSIONS: PVR is common in high-risk pathologic Stage I-IV endometrial cancer patients after adjuvant chemotherapy alone. These results support the continued use of locoregional RT in patients undergoing adjuvant chemotherapy. Further studies are needed to test the addition of chemotherapy to locoregional RT.

Surgery and postoperative radiation therapy in FIGO Stage IIIC endometrial carcinoma.

OBJECTIVE: To determine the outcome, pattern(s) of failure, and optimal treatment volume in Stage IIIC endometrial carcinoma patients treated with surgery and postoperative radiation therapy (RT). METHODS: Between 1983 and 1998, 30 Stage IIIC endometrial carcinoma patients were treated with primary surgery and postoperative RT at the University of Chicago. All underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, sampling of pelvic lymph nodes (PLN), and peritoneal cytology. All were noted to have PLN involvement. Para-aortic lymph nodes (PALN) were sampled in 26 cases, and were positive in 14 cases (54%). Twenty women received whole-pelvic RT (WPRT) and 10 (WPRT), plus paraortic RT (extended-field RT, EFRT). One EFRT patient also underwent concomitant whole-abdominal RT (WART). Adjuvant vaginal brachytherapy (VB) was delivered in 10, chemotherapy in 5, and hormonal therapy in 7 patients. RESULTS: At a median follow-up of 32 months, the actuarial 5-year disease-free and cause-specific survivals of the entire group were 33.9% and 55.8%, respectively. Overall, 16 women (53%) relapsed. Sites of failure included the pelvis (23%), abdomen (13%), PALN (13%), and distant (40%). Of the 7 pelvic failures, 4 were vaginal (3 vaginal only). Patients treated with VB had a trend to a lower vaginal recurrence rate (0/10 vs. 4/20, p = 0.12) than those not receiving VB. All 4 PALN failures were in women treated with WPRT (2 negative, 1 unsampled, and 1 positive PALN). None of the 10 EFRT patients (2 negative, 8 positive PALN) recurred in the PALN. No patient developed an isolated abdominal recurrence. Two patients developed significant RT sequelae: chronic diarrhea in 1 patient treated with WPRT and VB, and small bowel obstruction in 1 patient treated with EFRT. CONCLUSION: FIGO Stage IIIC disease comprises a small percentage of endometrial carcinoma patients but carries a poor prognosis. Our failure pattern suggests that the optimal adjuvant RT volume is EFRT, even in women with negative PALN sampling. VB should also be administered to improve local control. The low rate of abdominal recurrence does not support the routine use of WART in these women. Given the predominance of failure in distant sites, attention should be focused on the development of systemic chemotherapy protocols.

Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies.

PURPOSE: To evaluate the ability of intensity-modulated radiation therapy (IMRT) to reduce the volume of small bowel irradiated in women with gynecologic malignancies receiving whole pelvic radiotherapy (WPRT). METHODS AND MATERIALS: Ten women with cervical (5) or endometrial (5) cancer undergoing WPRT were selected for this analysis. A planning CT scan of each patient was obtained following administration of oral, i.v., and rectal contrast. The clinical target volume (CTV) was defined as the proximal vagina, parametrial tissues, uterus (if present), and regional lymph nodes. The CTV was expanded uniformly by 1 cm in all directions to produce a planning target volume (PTV). The bladder, rectum, and small bowel were also delineated in each patient. Two plans were created: a standard "4-field box" with apertures shaped to the PTV in each beam's eye view and an IM-WPRT plan designed to conform to the PTV while minimizing the volume of normal tissues irradiated. Both plans were normalized to deliver 45 Gy to the PTV. Isodose distributions and dose-volume histograms (DVH) were compared. RESULTS: The IM-WPRT plan reduced the volume of small bowel irradiated in all 10 patients at doses above 30 Gy. At the prescription dose, the average volume of small bowel irradiated was reduced by a factor of two (17.4 vs. 33.8%, p = 0.0005). In addition, the average volume of rectum and bladder irradiated at the prescription dose was reduced by 23% in both cases (p = 0.0002 and p = 0.0005, respectively). The average PTV doses delivered by the conventional and IM-WPRT plans were 47.8 Gy and 47.4 Gy, respectively. Corresponding maximum doses were 50.0 Gy and 54.8 Gy, respectively. However, on average, only 3.2% of the PTV received greater than 50.0 Gy in the IM-WPRT plans. CONCLUSION: Our results suggest that IM-WPRT is an effective means of reducing the volume of small bowel irradiated in women with gynecologic malignancies receiving WPRT. This approach potentially offers a method for reducing small bowel complications in patients with gynecologic malignancies.

Characteristics and outcome of endometrial carcinoma patients age 45 years and younger.

Recent reports have suggested that the pathologic features of young patients with endometrial cancer are less favorable than previously thought. We retrospectively reviewed the characteristics and outcome of young patients with endometrial cancer at our institution. A total of 457 surgically staged patients were divided in 2 groups: Group A (age < or =45 years, n = 41) and B (age >45, n = 416). Groups A and B had a similar distribution of tumor stage, grade, histology, lymphovascular invasion, synchronous ovarian primaries, and positive cytology. Although group A tumors had less myometrial invasion (MI) (p = 0.004) and were lower grade (p = 0.06), a trend to more frequent nodal involvement was seen in group A women (p = 0.09). Adverse pathologic features, in particular deep MI, were more common in group A patients older than age 40. Group A patients had a disease-free (p = 0.56) and cause-specific (p = (0.26) survival that was similar to that of group B patients. Young patients with endometrial cancer have a distribution of most pathologic features and equivalent outcome similar to that of older women. However, adverse features are not equally distributed in young women. A discordance may also exist between MI, grade, and nodal involvement.

Synchronous ovarian and endometrial malignancies.

Synchronous ovarian primaries are infrequently found in patients with endometrial cancer. Although numerous investigators have examined the characteristics of these women, most include patients with tumors of similar histology, which may simply represent ovarian metastases. To overcome this problem, we present here patients found to have tumors of dissimilar histology. Of 499 patients with endometrial cancer undergoing primary surgery between 1980 and 1997, 18 (3.6%) were found to have endometrial and ovarian primaries of dissimilar histology. The median age was 64.2 years. Most had stage I, grades I and II, minimally invasive endometrial adenocarcinomas and stage IA mucinous or serous ovarian cystadenocarcinomas. Most ovarian tumors were either borderline or grades I and II. The 5-year actuarial disease-free (DFS) and cause-specific survivals of the entire group were 81.2% and 89.5%, respectively. Those with both stage I ovarian and endometrial primaries had a trend to a better DFS (100 versus 68.6%, p = 0.07) than did women with higher stage disease. Our data demonstrate that synchronous ovarian primaries of dissimilar histology are infrequently found in women undergoing surgery for endometrial cancer. These women seek treatment at a relatively advanced age, and have early-stage, low grade disease in both sites. Their outcome is favorable, particularly those with stage I disease in both sites.

Do conventional pathologic features lose their prognostic significance following postoperative radiation therapy in pathologic stage I-II endometrial adenocarcinoma?

Recent data have suggested that conventional pathologic features (myometrial invasion (MI), grade, stage) lose their prognostic significance following postoperative radiation therapy (RT) in Stage I-II endometrial carcinoma. Our goal was to test this finding in a large cohort of women treated at our institution. Between 1980 and 1997, 188 Stage I (140) and II (48) endometrial adenocarcinoma patients received postoperative RT. RT consisted of pelvic RT (112), vaginal brachytherapy (36), or both (40). Clinicopathologic factors were evaluated as prognostic factors on both univariate and multivariate analyses. Factors correlated with recurrence on univariate analysis included MI (P = 0.05), grade (P = 0.07), lymphovascular invasion (LVI) (P = 0.001) and stage (P = 0.03). Multivariate analysis confirmed the significance of grade (P = 0.02), LVI (P = 0.001), and stage (P = 0.02). Conventional pathologic features do not lose their prognostic significance in pathologic Stage I-II endometrial adenocarcinoma patients following postoperative RT. These factors should continue to be used to identify women at risk for recurrence despite adjuvant RT. New prognostic markers are needed to better identify high-risk patients. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 224-230 (2000).

Age as a prognostic factor for recurrence in patients with endometrial carcinoma.

PURPOSE: The aim of this study was to evaluate age as a prognostic factor for recurrence in endometrial cancer patients treated with primary surgery. METHODS: Between 1983 and 1998, 455 endometrial cancer patients underwent primary surgery at our institution. Patients were divided into three age groups based on age at diagnosis: Group A (age <60, n = 156), B (age 60-69, n = 147), and C (age >/=70, n = 152). Clinicopathologic, treatment factors, and outcome were compared among the three groups. Prognostic factors were evaluated by univariate and multivariate analysis. RESULTS: The three age groups had a similar distribution of most pathologic features including stage, histology, cervical involvement, positive cytology, adnexal involvement, nodal metastases, serosal involvement, and lymphovascular invasion (LVI). Older women had a higher rate, however, of deep (>1/2) myometrial invasion (P < 0.0001) and grade 3 tumors (P < 0.0001). The extent of surgical staging and use of adjuvant radiation therapy were similar. Five-year disease-free survivals (DFS) of Groups A, B, and C were 74.3, 70.2, and 60.3%, respectively (P = 0.08). A significant difference in DFS was seen when Groups A and B were combined and compared with Group C (72.0 vs 60.3%, P = 0.03). Multivariate analysis confirmed the significance of race, stage, grade, and LVI. Age was not found to be associated with recurrence (HR 1.1, 95% C.I. 0.91-1.5, P = 0.21). CONCLUSION: Our results reveal that, in a large cohort of comparably staged and treated endometrial carcinoma patients, age is not a prognostic factor for recurrence.

Low grade gliomas treated with adjuvant radiation therapy in the modern imaging era.

The purpose of this study is to evaluate tumor control and failure patterns in patients with low grade gliomas treated with surgery and conventional adjuvant radiation therapy. Twenty-eight patients with low grade gliomas (7 grade I, 21 grade II) were retrospectively evaluated. Extent of resection was gross total (3), subtotal (17), and biopsy alone (8). All grade I tumors underwent subtotal resection. Median radiation therapy dose was 54 Gy delivered to localized fields. Tumor control and patterns of failure were determined from follow-up computed tomography and/or magnetic resonance scans. Median follow-up was 86 months (range, 2.4-177 months). Thirteen patients (46%) (four grade I, nine grade II) developed tumor progression. The 5-year actuarial progression-free survival rates for grade I and grade II patients were 86% and 51%, respectively. Corresponding 5-year actuarial survival rates were 100% and 70%. All recurrences were within the treated volume. Our results reveal that conventional adjuvant radiation therapy is associated with high rates of local tumor progression in both grade II and incompletely resected grade I low grade gliomas. Alternative strategies need to be explored in these patients in an effort to improve tumor control and outcome.

One versus two intracavitary brachytherapy applications in early-stage cervical cancer patients undergoing definitive radiation therapy.

PURPOSE: The purpose of this study was to compare the outcomes of early stage cervical cancer patients undergoing definitive radiation therapy (RT) with one versus two low-dose-rate intracavitary brachytherapy (ICB) applications. METHODS AND MATERIALS: Between 1983 and 1993, 140 stage IB-IIA patients underwent whole-pelvis RT (WPRT) and ICB. Prior to 1988, 56 patients (40%) received two ICB applications. After 1988, our policy was modified and subsequently 84 (60%) patients underwent one application. Patient, tumor, and treatment characteristics, outcome, and complications of the two groups were compared. RESULTS: The groups were balanced in terms of race, hemoglobin level, histology, grade, treatment duration, chemotherapy, and follow-up. The single-application group, however, had more stage IB disease, had small (< or =4 cm) tumors, and received higher WPRT and lower point A doses. Overall, the two groups had similar 5-year local control (P = 0.83) and disease-free (P = 0.23) and cause-specific (P = 0.29) survival rates. Moreover, no differences were seen when analyzed by tumor size or stage. On multivariate analysis, the number of applications was not correlated with recurrence (P = 0.59, hazard rate = 1.1, 95% confidence interval = 0.6-2.2). Chronic complications were similar in the two groups. CONCLUSION: Our nonselected comparison of one versus two ICB applications in early-stage cervical cancer patients reveals comparable outcomes and complication rates for the two approaches. These results support the use of a single application in early-stage patients undergoing definitive RT.

Acute problems during low-dose-rate intracavitary brachytherapy for cervical carcinoma.

OBJECTIVE: To estimate the incidence and severity of problems arising during the hospitalization of cervical carcinoma patients undergoing low-dose-rate intracavitary brachytherapy (ICB). METHODS: One hundred seventy ICB implants in 128 cervical carcinoma patients undergoing curative radiation therapy were reviewed. All events during the hospitalization requiring physician evaluation and/or intervention were scored as a "problem" and divided into 10 categories (fever/infection, pain, gastrointestinal, renal, pulmonary, cardiac, dermatologic, gynecologic, endocrinologic, psychiatric). Problems were scored as mild (no significant morbidity, therapy not discontinued), moderate (therapy discontinued but no significant morbidity), or severe (significant morbidity or mortality). Patient and treatment factors were correlated with acute problems. RESULTS: Forty-two implants (24.7%) were associated with acute problems (95% minor, 5% moderate, 0% severe). The most common types were fever/infection (14.1%) and gastrointestinal problems (5. 9%). Other problem types occurred in <3% of implants. No patient or treatment factor including age, comorbid disease, weight, implant duration, or anesthesia type was significantly correlated with acute problems. Patients who developed acute problems had a survival (P = 0.21) and risk of late sequelae (P = 0.74) similar to those of patients without acute problems. CONCLUSION: Problems occur during the hospitalization in approximately one-quarter of cervical carcinoma patients undergoing low-dose-rate ICB. However, most are minor and do not result in morbidity, require discontinuation of therapy, or adversely impact on outcome.