Endometrial Carcinomas With Subclonal Loss of Mismatch Repair Proteins: A Clinicopathologic and Genomic Study.

Subclonal loss of mismatch repair (MMR) proteins has been described in a small subset of endometrial carcinomas (ECs), but the genomic basis for this phenomenon has received limited attention. Herein, we retrospectively evaluated all ECs with MMR immunohistochemistry (n=285) for subclonal loss, and in those (n=6), performed a detailed clinicopathologic and genomic comparison of the MMR-deficient and MMR-proficient components. Three tumors were FIGO stage IA, and one each stage IB, II, and IIIC2. Patterns of subclonal loss were as follows: (1) 3 FIGO grade 1 endometrioid carcinomas with subclonal MLH1/PMS2, MLH1 promoter hypermethylation, and no MMR gene mutations; (2) POLE -mutated FIGO grade 3 endometrioid carcinoma with subclonal PMS2, and PMS2 and MSH6 mutations limited to the MMR-deficient component; (3) dedifferentiated carcinoma with subclonal MSH2/MSH6, as well as complete loss of MLH1/PMS2, MLH1 promoter hypermethylation, and PMS2 and MSH6 mutations in both components; (4) dedifferentiated carcinoma with subclonal MSH6, and somatic and germline MSH6 mutations in both components, but with a higher allele frequency in MMR-deficient foci. Recurrences occurred in 2 patients, one consisted of the MMR-proficient component from a FIGO 1 endometrioid carcinoma, while the other was from the MSH6 -mutated dedifferentiated endometrioid carcinoma. At the last follow-up (median: 44 mo), 4 patients were alive and disease-free and 2 were alive with disease. In summary, subclonal MMR loss reflects subclonal and often complex genomic and epigenetic alterations, which may have therapeutic implications and therefore must be reported when present. In addition, subclonal loss can occur in both POLE -mutated and Lynch syndrome-associated ECs.

Reversible posterior leukoencephalopathy syndrome following intravenous paclitaxel and intraperitoneal cisplatin chemotherapy for fallopian tube cancer.

BACKGROUND: Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical and radiologic syndrome of heterogeneous etiology. Although it has been described in association with intravenous cytotoxic chemotherapy including cisplatin and molecularly targeted therapies such as bevacizumab and sorafenib, it has not been described in the setting of intraperitoneal chemotherapy. CASE: A 64-year-old woman with stage IIIC fallopian tube cancer developed acute mental status changes and radiologic findings consistent with RPLS in conjunction with hypertension after one cycle of intravenous paclitaxel, followed by intraperitoneal (IP) cisplatin. Symptoms resolved over the course of 4 days with no obvious residual effects. CONCLUSION: The use of an intravenous paclitaxel and intraperitoneal cisplatin regimen can be associated with RPLS. Hypertension should be controlled in patients prior to receiving this chemotherapy regimen due to potential toxicity.

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.

Intent-to-treat analysis of stage Ib and IIa cervical cancer in the United States: radiotherapy or surgery 1988-1995.

OBJECTIVE: To estimate the patterns of care and outcome of women with early cervical cancer in the United States based on surgical or radiation intent-to-treat principles. METHODS: The Surveillance, Epidemiology, and End Results 1995 public-use file was the data source. Subjects between the ages of 15 and 80 years at diagnosis who were treated for stage Ib or IIa cervical cancer were identified. The 1039 women who comprised the study group were stratified according to age at diagnosis (40 years or less, older than 40 years), primary treatment intent (surgery, radiotherapy), tumor size (4 cm or less, over 4 cm), registry site, and ethnicity. Survival analyses included 784 women who had at least 2 years of follow-up. RESULTS: There were 276 cancers (26.5%) over 4 cm, and 586 (56%) women were older than 40 years at diagnosis. There were 741 (71%) subjects in the surgical intent-to-treat group, and the remainder (298) were in the radiation intent-to-treat group. Kaplan-Meier analysis indicated a 5-year survival advantage for women with tumors 4 cm or less who were in the surgical intent-to-treat group compared with the radiation intent-to-treat group (86% and 71%, P <.001). Treatment group was not prognostic for cervical cancers over 4 cm (surgical intent-to-treat compared with radiation intent-to-treat; 72% and 68% survival, respectively). Multivariable analysis confirmed a survival advantage for women with surgical intent-to-treat and tumors of 4 cm or less. CONCLUSION: In the United States there is a survival advantage for surgical intent-to-treat compared with radiation intent-to-treat for women with tumors 4 cm or less, independent of ethnicity, adjuvant therapy, or age.

PDGFR-alpha as a potential therapeutic target in uterine sarcomas.

OBJECTIVE: Uterine sarcomas are a heterogeneous group of tumors with a propensity for metastasis and resistance to conventional therapy. Recent success in the treatment of other solid tumors with the targeted tyrosine kinase inhibitor imatinib mesylate offers new avenues for investigation. The primary target of imatinib is c-kit, but the drug also inhibits PDGFR-alpha and PDGFR-beta. Given the lack of identified molecular targets in endometrial stromal sarcomas, leiomyosarcomas, and carcinosarcomas, the purpose of this study was to determine the protein expression of c-kit, PDGFR-alpha, and PDGFR-beta in these tumors as a preliminary step to determining their susceptibility to directed therapy. A secondary goal was to identify specific gene mutations that might be associated with activation of these proteins in uterine sarcomas. METHODS: Archived tissue from 42 cases of uterine sarcomas was stained for c-kit, PDGFR-alpha, and PDGFR-beta using immunohistochemistry. Laser-capture microdissected samples of uterine carcinosarcomas, or homogeneous areas of leiomyosarcomas or endometrial stromal sarcomas, were subjected to genetic analysis of PDGFR-alpha exons 12 and 18. RESULTS: The majority (38/42, 90%) of uterine sarcomas lacked c-kit expression and 90% (38/42) demonstrated negative or weak staining for PDGFR-beta. In contrast, 70% (30/42) of cases had strong staining for PDGFR-alpha in the tumor but not in normal myometrium or endometrium. Sequencing results revealed no mutations in exons 12 or 18 of PDGFR-alpha. CONCLUSION: c-kit and PDGFR-beta are unlikely to represent primary treatment targets in uterine sarcomas. The strong expression of PDGFR-alpha in uterine sarcoma specimens suggests a role for this receptor in tumor development, although its potential as a therapeutic target requires further investigation.

Conservative management of chylous ascites after removal of a symptomatic growing retroperitoneal teratoma.

BACKGROUND: Chylous ascites as a postoperative complication of gynecologic surgery is uncommon. Cases usually occur from trauma to the lymphatic system during retroperitoneal dissection. Initial management includes paracentesis with institution of a low-fat, medium-chain triglyceride diet and total parenteral nutrition (TPN). Surgical intervention may be required. CASE: A 19-year-old female patient with a history of an immature teratoma treated with chemotherapy presented with a retroperitoneal mass. Removal of the mass revealed mature teratoma and resulted in chylous ascites formation. Multiple paracenteses were performed in conjunction with dietary modification and TPN. Three months after the patient's surgery, the ascites spontaneously resolved. CONCLUSION: Although surgical intervention is recommended after failure of conservative management, this case demonstrates that damage to the cisterna chyli may spontaneously resolve.

Cancer of the endometrium and corpus uteri.

Uterine cancer is often diagnosed at an early stage and is therefore considered one of the most curable gynecologic malignancies. Despite this, a substantial number of women who present at more advanced stage or with unfavorable histologies suffer significant morbidity and death from this disease. Research continues along several fronts in an attempt to improve the prognosis for this group of women. Basic scientific research has continued to evaluate mechanisms of carcinogenesis in the hope that better targets for treatment and prevention of disease will be found. Epidemiologic studies have attempted to further define risk factors as well as elucidate risk in those patients receiving combination estrogen and progestin hormone replacement therapy. Clinical studies have further defined prognostic factors, and examined new surgical staging techniques and the need for adjuvant therapy after primary surgery. However, treatment options for advanced and recurrent disease remain limited.

Ovarian carcinoma cell cultures are resistant to TGF-beta1-mediated growth inhibition despite expression of functional receptors.

OBJECTIVE: The purpose of this study was to determine the response of ovarian carcinoma cells to TGF-beta1 and to examine components of the TGF-beta signaling pathway. METHODS: Twenty-three primary ovarian cancer cell (CSOC) cultures established from solid ovarian carcinomas were treated with TGF-beta1 and assayed for growth response by MTT assay. Expression of TGF-beta receptor I (TbetaR-I) and receptor II (TbetaR-II), essential for effective signaling, was determined by Western analysis of CSOC cultures. TGF-beta1 ligand-induced phosphorylation of TbetaR-I was determined by immunoprecipitation of TbetaR-I followed by a protein kinase assay to assess TbetaR-I phosphorylation, an essential first step in TGF-beta signal transduction. Gelatin zymography performed on 5 CSOC cultures incubated with TGF-beta1 was used to determine TGF-beta's effect on matrix metalloproteinase production. Normal ovarian surface epithelial cells were used for comparison. RESULTS: Eighteen of twenty-three (78%) CSOC cultures demonstrated no significant growth inhibition in response to TGF-beta1 treatment. All cell cultures expressed TbetaR-I and TbetaR-II and exhibited TbetaR-I phosphorylation following TGF-beta1 treatment. CSOC cultures produced significantly higher levels of matrix metalloproteinase-2 (MMP-2) than normal ovarian surface epithelial cells; however, the level of MMP-2 expression was not regulated by TGF-beta1. CONCLUSION: These results indicate that TGF-beta1 resistance and higher levels of MMP-2 production may be inherent properties of the ovarian cancer phenotype. The initial steps in the TGF-beta signaling pathway, receptor expression, ligand binding, and TbetaR-I phosphorylation, appear to be functional in primary ovarian cancer cell cultures. Therefore, the mechanism of growth resistance is downstream of TbetaR-I phosphorylation.

Altered expression of transforming growth factor-beta ligands and receptors in primary and recurrent ovarian carcinoma.

BACKGROUND: Resistance to the potent growth inhibitory effects of transforming growth factor-beta (TGF-beta) is a characteristic of many malignancies. TGF-beta insensitivity has been attributed to alterations in the number and function of the TGF-beta receptors as well as disturbances of downstream signal transduction. Paradoxically, increased levels of TGF-beta ligand have been demonstrated in several types of malignant tumors. TGF-beta also may play a role in ovarian carcinogenesis; however, the nature of this interaction has yet to be defined completely. METHODS: To explore the potential role of TGF-beta-mediated autocrine and paracrine influences in epithelial ovarian carcinoma, mRNA expression levels of the three TGF-beta ligand isoforms (TGF-beta1, TGF-beta2, and TGF-beta3) and the three TGF-beta receptors (TbetaR-I, T/betaR-II, and TbetaR-III) were examined by Northern blot analysis in both primary and recurrent ovarian carcinoma specimens. Immunohistochemical analysis was performed to localize expression of TbetaR-I and TbetaR-II, whereas the presence of genetic alterations in TbetaR-1 was examined through Southern blot analysis. RESULTS: Compared with normal ovarian tissue, both primary and recurrent ovarian carcinomas demonstrated significant overexpression of the TGF-beta1 and TGF-beta3 mRNA transcripts. TGF-beta2 expression was detectable in 75% of primary and only 53% of recurrent tumor specimens. Alterations also were detected in TbetaR mRNA expression. Expression levels of TbetaR-III were significantly reduced in both primary and recurrent ovarian carcinomas. Furthermore, detectable levels of TbetaR-I and TbetaR-III mRNA transcripts were present in only 47% and 50% of recurrent ovarian tumors, respectively. Immunohistochemical staining demonstrated that TbetaR-I and TbetaR-II expression localized to tumor cells; however, receptor staining in stromal tissue also was detected. Southern blot analysis of TbetaR-I did not reveal any major genetic changes to account for the absence of TbetaR-I expression. CONCLUSIONS: Alterations in expression of TGF-beta ligands and receptors consistently were greater in recurrent ovarian carcinomas compared with primary tumors, and may reflect a phenotype that promotes tumor recurrence or chemoresistance. Together, these data suggest that enhanced expression of TGF-betaI and TGF-beta3, as well as the loss of expression of TbetaR-I and TbetaR-III, contribute to ovarian carcinogenesis and/or tumor progression.

Complete response of a stage IV uterine papillary serous carcinoma to neoadjuvant chemotherapy with Taxol and carboplatin.

Uterine papillary serous carcinoma (UPSC) is an aggressive histologic subtype of endometrial cancer. Currently, no effective chemotherapy regimens exist. We report a case of complete response of a stage IV UPSC to neoadjuvant chemotherapy with Taxol and carboplatin.

An alpha-fetoprotein-producing hepatoid adenocarcinoma of the endometrium.

BACKGROUND: Hepatoid adenocarcinomas are tumors that arise outside the liver but resemble hepatic tissue and produce alpha-fetoprotein. These neoplasms have been described in many locations, including the lung, gastrointestinal tract, and urogenital tract, and have been associated with a poor prognosis. Two previously reported cases of hepatoid adenocarcinoma of the endometrium described aggressive tumors that were unresponsive to multiple forms of therapy. CASE: We report a case of an alpha-fetoprotein-producing hepatoid adenocarcinoma of the endometrium that was successfully treated with surgery and adjuvant chemotherapy. CONCLUSION: Eight years after therapy, the patient is alive with no evidence of disease, suggesting that cytoxan, adriamycin, and cis-platinum are active agents in this unusual entity.

Pathologic variables and adjuvant therapy as predictors of recurrence and survival for patients with surgically evaluated carcinosarcoma of the uterus.

BACKGROUND: The purpose of this study was to determine clinicopathologic variables associated with extrauterine disease, recurrence, and survival in patients with carcinosarcoma (CS) of the uterus. METHODS: Patients believed to have disease confined to the uterine corpus who underwent primary surgical assessment were identified and data retrospectively reviewed. RESULTS: Occult metastases were found in 38 (61%) of 62 patients. At last follow-up, 31 (50%) had had recurrence, with an extrapelvic component in 43%, and 53% had died. Depth of myometrial invasion and lymph-vascular space invasion (LVSI) were associated with extrauterine disease. Five-year survival for patients with disease confined to the corpus (74%) was significantly greater than for those with more advanced disease (24%, P = 0.0013). Factors associated with recurrence and survival included depth of myometrial invasion, LVSI, adnexal and serosal involvement, positive cytology, and lymph node metastases. Of 24 patients with uterine disease only, 11 received no adjuvant therapy, yet 8 (73%) were free of disease at last follow-up. Neither adjuvant radiotherapy nor chemotherapy was identified as an independent prognostic variable for recurrence or survival. CONCLUSIONS: More than half of patients with CS clinically confined to the uterine corpus harbor occult metastases in a pattern similar to that found with endometrial carcinoma. Survival is significantly diminished for this group. Although the benefit of adjuvant therapy cannot be demonstrated by this study, a number of early stage patients survive without adjuvant therapy. This argues for extending the International Federation of Gynecology and Obstetrics endometrial carcinoma surgical staging system to include CS, and also for conducting prospective trials to examine the benefits of adjuvant therapy for patients with early stage disease.

Young age as a prognostic factor in cervical cancer: results of a population-based study.

OBJECTIVE: Our goal was to use population-based data to determine the difference in 5-year survival in women diagnosed with cervical cancer between those aged 18-34 years and those aged 40-60 years. STUDY DESIGN: The SEER (Surveillance, Epidemiology, and End Results) public-use database, 1973-1994, was used for this investigation. Only subjects with cervical carcinoma diagnosed between 1988 and 1990 were included. Subjects were stratified on age at diagnosis (<35 years or 40-60 years), clinical stage, histologic type, race-ethnicity, and grade. RESULTS: Two thousand cases of invasive cervical cancer were identified. The younger subgroup of patients was diagnosed with earlier-stage disease more frequently than the older group (P =.0001). When adjustments were made for non-cervical cancer causes of death, there was no difference in 5-year survival between the 2 cohorts. African American women had a poorer 5-year survival (P =.02) CONCLUSION: There was no overall difference in survival between the 2 cohorts when appropriate adjustments were made for cause of death and for stage, histologic type, and grade of disease.

Molecular similarities between primary peritoneal and primary ovarian carcinomas.

The objective of this paper was to characterize expression patterns of biologic markers to distinguish papillary serous peritoneal carcinoma (PPC) from papillary serous ovarian carcinoma (POC). Immunohistochemical analysis of HER-2/neu, p53, bcl-2, and nm23-H1 expression was performed on archival paraffin-embedded tissues. Antigen expression was compared at ovarian and extra-ovarian sites. Thirty-two PPC cases were compared to 18 POC cases. Mean age, stage, grade, and survival outcome were comparable between the two groups. Antigen expression patterns were not significantly different between PPC and POC for the four markers studied. In all cases, nm23-H1 was expressed. Conversely, bcl-2 was expressed at only a single tissue site in three of 32 (9.4%) PPC cases and in one of 18 (5.6%) POC cases. Eleven of 32 (34.4%) PPC cases overexpressed HER-2/neu, vs. four of 18 (22.2%) POC cases. P53 staining results were positive in 23 of 32 (71.9%) PPC and 13 of 18 (72.2%) POC cases. Intrapatient antigen expression was identical at primary and metastatic tumor sites in 50% of the POC and 48.4% of the PPC cases. We conclude that PPC and POC have a comparable immunohistochemical phenotype for these four molecular markers, which is reflected by their similar clinical courses.

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.

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.