Thomas W. Burke

Lymphatic Mapping and Sentinel Node Identification in Patients With Cervix Cancer Undergoing Radical Hysterectomy and Pelvic Lymphadenectomy

PURPOSE The purpose of this study was to determine the feasibility of sentinel node identification in patients with invasive cervix cancer undergoing radical hysterectomy and pelvic lymphadenectomy using preoperative and intraoperative lymphatic mapping. PATIENTS AND METHODS Thirty-nine patients at two institutions were enrolled onto this institutional review board-approved study. All underwent preoperative lymphoscintigraphy and intraoperative lymphatic mapping with blue dye and a handheld gamma probe. Radical hysterectomy was aborted in four patients because metastatic disease was discovered on frozen section analysis of the sentinel node. RESULTS Preoperative lymphoscintigraphy revealed at least one sentinel node in 33 patients (85%), including 21 (55%) with bilateral sentinel nodes. All 39 patients had at least one sentinel node identified intraoperatively. Eighty percent of sentinel nodes were in three pelvic locations: iliac, obturator, and parametrial (in descending order of frequency). The remaining sentinel nodes were in the common iliac and para-aortic nodal basins. A total of 132 nodes were identified clinically as sentinel nodes; 65 (49%) were both blue and hot, 35 (27%) were blue only, and 32 (24%) were hot only. Eight patients (21%) had metastatic disease. In five of these patients, sentinel nodes were the only positive lymph nodes. One patient had false-negative sentinel nodes. She had four microscopically positive parametrial nodes that were resected in continuity with the uterus. The sensitivity of the sentinel node was 87.5% and the negative predictive value was 97%. CONCLUSION Preoperative lymphoscintigraphy and intraoperative lymphatic mapping were highly successful at identifying sentinel nodes in patients undergoing radical hysterectomy.

Gynecologic cancer as a sentinel cancer for women with hereditary nonpolyposis colorectal cancer syndrome

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40–60% lifetime risk for colon cancer, a 40–60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number of women with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their “sentinel cancer.” METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the “sentinel cancer,” preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome. LEVEL OF EVIDENCE: II-3

Risk factors for young premenopausal women with endometrial cancer

OBJECTIVE: Endometrial cancer is the most common gynecologic malignancy in the United States. The mean age at diagnosis is 61 years; however, 5–30% of women are aged younger than 50 years at the time of diagnosis. The objective of this study was to conduct a clinical and pathologic review of endometrial cancers diagnosed in premenopausal women aged younger than 50 years, to better identify the risk factors for this subgroup of women. METHODS: We conducted a retrospective cohort study of patients with histologically confirmed endometrial cancer treated at the University of Texas, M. D. Anderson Cancer Center from 1989 to 2003. Clinical characteristics including age, body mass index (BMI), parity, diabetes, and personal or family history of cancer were obtained from the medical record. Pathologic information was obtained from pathology reports. RESULTS: Twelve percent (188/1531) of all patients with endometrial adenocarcinoma were aged younger than 50 years. The mean age at diagnosis was 41 years (range 21–49 years). Mean BMI was 34 kg/m2 (range 18–68); 58% of patients had a BMI of 30 or greater. Fifty-five percent were nulliparous and 39% reported irregular menstrual cycles. The incidence of both diabetes and hypertension was 23%. Thirty-six patients (19%) had synchronous ovarian cancers. CONCLUSION: We found that the majority of patients diagnosed with endometrial cancer at a young age were obese and nulliparous. In addition, we found a high incidence of synchronous primary ovarian cancers in this cohort of young, premenopausal women. LEVEL OF EVIDENCE: III

A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma

Dysregulation of phosphatase and tensin homolog (PTEN) and the gene that encodes the p110α catalytic subunit of phosphatidylinositol‐3‐kinase (PI3K), PIK3CA, are the most common mutations in endometrial carcinoma (EC). Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT, which leads to up‐regulation of mammalian target of rapamycin (mTOR). Everolimus is an oral rapamycin analog that acts by selectively inhibiting mTOR.

Malignant mixed Müllerian tumors of the uterus: Analysis of patterns of failure, prognostic factors, and treatment outcome

PURPOSE To determine the survival outcomes, prognostic factors, and patterns of failure in patients with malignant mixed Müllerian tumor (MMMT) of the uterus. METHODS AND MATERIALS Between 1954 and 1998, 300 patients with clinical Stage I-III MMMT of the uterus were treated with curative intent at The University of Texas M. D. Anderson Cancer Center. Their hospital records were reviewed to obtain patient and tumor characteristics; details of surgery, radiotherapy (RT), and chemotherapy; and long-term outcome. Surviving patients were followed for a median of 109 months (range 15-138). Survival rates were calculated using the Kaplan-Meier method, with differences assessed by log-rank tests. RESULTS Of the 300 patients, 113 (38%) were treated with surgery alone, 160 (53%) with surgery plus adjuvant EBRT or ICRT, and 27 (9%) with RT alone. Forty-eight patients received adjuvant chemotherapy. At 5 years, the overall rates of survival and cause-specific survival were 31% and 33%, respectively. Women who were postmenopausal or had a history of prior pelvic RT, pain at presentation, clinical Stage II-III disease, uterine enlargement (>/=12 weeks), or an abnormal Papanicolaou smear finding had a significantly poorer prognosis than the other patients in the series. Of the 273 patients who underwent surgery, those who had positive abdominal washings, uterine length >10 cm, or extrauterine spread of disease to the cervix, adnexa, or peritoneum had a significantly worse prognosis than the other patients. Factors found on multivariate analysis to have an independent adverse influence on cause-specific survival included postmenopausal status (p = 0.0007, relative risk [RR] 3.3), uterine length >10 cm (p = 0.0001, RR 2.2), cervical involvement (p = 0.002, RR 1.8), and peritoneal involvement (p = 0.0001, RR 4.3). At 5 years, the rates of pelvic and distant disease recurrence for the entire group of 300 patients were 38% and 57%, respectively. The most common site of distant recurrence was the peritoneal cavity. Patients treated with pelvic RT had a lower rate of pelvic recurrence than patients treated with surgery alone (28% vs. 48%, p = 0.0002), but the overall survival rates (36% vs. 27%, p = 0.10) and distant metastasis rates (57% vs. 54%, p = 0.96) were not significantly different. However, patients treated with pelvic RT had a longer mean time to any distant relapse (17.3 vs. 7.0 months, p = 0.001) than patients treated with surgery alone. The use of adjuvant chemotherapy did not correlate with the survival rate or rate of distant metastasis. CONCLUSION Adjuvant pelvic RT decreased the risk of pelvic recurrence and may delay the appearance of distant metastases after hysterectomy for MMMT. However, the survival rates remain poor because of a high rate of distant recurrence. As more effective systemic chemotherapy is developed to control microscopic distant disease, the role of RT in controlling locoregional disease in the pelvis and abdomen may become more important. Future research should consider programs that integrate surgery, RT, and chemotherapy to maximize the probability of cure.

Her-2/neu Overexpression and Amplification in Uterine Papillary Serous Carcinoma

PURPOSE Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer characterized by early metastasis, resistance to therapy, and a high mortality rate. Little is known about the biology of these tumors. Smaller studies suggest that Her-2/neu may be involved in the tumorigenesis of this disease. The purpose of this study was to evaluate the protein expression and gene amplification of Her-2/neu in UPSC and to determine its prognostic value. PATIENTS AND METHODS Tumor tissue from 68 patients with UPSC treated at The University of Texas M.D. Anderson Cancer Center from 1989 to 2002 was available. Her-2/neu expression was evaluated by immunohistochemistry (IHC). Overexpression was defined as complete membrane staining in greater than 10% of the cells. In tumors with overexpression of Her-2/neu by IHC, fluorescence in situ hybridization (FISH) was performed to assess gene amplification. Clinical and pathologic information was obtained from medical records. RESULTS Twelve (18%) of 68 tumors demonstrated Her-2/neu overexpression. Of these, only two showed gene amplification. When evaluating all 68 patients, Her-2/neu overexpression was associated with a poorer overall survival (OS; P = .008). In our multivariate Cox proportional hazards models, Her-2/neu IHC overexpression, lymph node status, and stage were each associated with OS (P < or = .05). CONCLUSION Positive IHC overexpression of Her-2/neu was seen in 18% of UPSCs but was rarely correlated with Her-2/neu gene amplification. Overexpression of Her-2/neu was associated with a worse overall prognosis. The use of trastuzumab (Herceptin; Genentech, South San Francisco, CA) in women with UPSC should be further evaluated in a clinical trial setting.

Estrogen replacement therapy following treatment for stage I endometrial carcinoma.

Abstract One hundred forty-four patients with clinical stage I endometrial adenocarcinoma were treated over an 11-year period at Madigan Army Medical Center and Brooke Army Medical Center. Following surgical staging, 44 selected patients were placed on oral estrogen replacement for a median duration of 64 months. In the estrogen user group, there were no recurrent endometrial cancer and no intercurrent death. Of the 99 nonestrogen users, there were 8 recurrences (8%) and 8 intercurrent deaths. Patients placed on estrogen replacement had low-risk factors for recurrence, namely, low tumor grade (grades 1 and 2), less than 12 myometrial invasion, and no metastases to lymph nodes or other organs. Postoperative estrogen replacement appears to be safe in selected low-risk patients.

Neoadjuvant chemotherapy and interval debulking for advanced epithelial ovarian cancer

A retrospective matched-control study was conducted to review our experience with FIGO stage III and IV epithelial ovarian cancer in patients referred after initial laparotomy and biopsy only. The study group comprised 22 patients; planned treatment was two to four cycles of chemotherapy, interval debulking surgery, six more chemotherapy cycles, and second-look laparotomy. Two control groups were matched with the study group according to FIGO stage, histologic type, and grade (2 or 3) and patient age +/- 5 years. The first control group (22 patients) had greater than 2 cm residual disease after initial surgery; their planned treatment was a minimum of six cycles of chemotherapy plus second-look laparotomy. The second control group (18 patients) was referred after initial laparotomy and biopsy only; their disease was immediately reexplored and debulked. Subsequent planned treatment was a minimum of six cycles of chemotherapy plus second-look laparotomy. All patients received cisplatin-based chemotherapy. Optimal cytoreduction to less than or equal to 2 cm was achieved for 77% of the study group vs 39% of the immediate-reexploration group (P = 0.02). Median survival times for the three groups were not different (16 vs 19.3 vs 18 months, respectively) (P = 0.58). Within the study group, patients who were optimally debulked survived significantly longer than those who were not (18.1 vs 7.5 months) (P = 0.02). Morbidity of the interval debulking procedure was acceptable. Study findings suggest that patients with bulky residual disease have a uniformly poor prognosis regardless of the timing of further surgery.

Treatment of poor-prognosis sex cord-stromal tumors of the ovary with the combination of bleomycin, etoposide, and cisplatin

Objective To investigate the clinical activity of the combination of bleomycin, etoposide, and cisplatin for metastatic ovarian sex cord-stromal, cord-stromal tumors of all types and poorly differentiated Sertoli-Leydig cell tumors confined to the ovary. Methods The regimen was administered as follows: bleomycin 10–15 mg/day by continuous intravenous (IV) infusion on days 1–3; etoposide 100 mg/m2 IV per day on days 1–3; cisplatin 100 mg/m2 IV on day. 1. End points for analysis included response, progression-free survival, and survival. Results Nine patients were entered in this trial. The median age was 37 years (range 12–69). Histologic types included adult granulosa cell tumor in five patients, juvenile granulosa cell tumor in one, poorly differentiated Sertoli-Leydig cell tumor in two, and mixed tumor in one. Stage distribution was as follows: stage Ia, two: stage IIc, one; stage IIc, one; recurrent, five. Of the six patients with measurable disease, two (33%) had a complete response (one surgical and one clinical), and three (50%) had a partial response, for an overall response rate of 83%l; one patient had no response. Toxicity was acceptable; two patients had mild bleomycin pulmonary toxicity. Of the three patients with nonmeasurable disease, one relapsed, one developed progressive disease, and one remains in remission. Of the seven patients with metastatic disease, only one (14%) had a durable remission. Median progression-free survival was 14 months. Median survival time was 28 months. At the time of analysis, two patients alive disease-free, three were alive with disease, and four were dead of disease. Conclusion Although the overall response rate to the combination of bleomycin, etoposide, and cisplatin was high, the regimen apparently lacks durable activity in this groups of tumors. More active drugs and modalities should continue to be investigated.

Uterine papillary serous carcinoma (UPSC) treated with cisplatin, doxorubicin, and cyclophosphamide (PAC)

Uterine papillary serous carcinoma (UPSC) is an aggressive malignancy that accounts for a disproportionate number of intraabdominal failures among endometrial carcinoma patients. The histologic appearance and tendency toward intraabdominal spread resemble those of papillary serous adenocarcinoma of the ovary. Because approximately 70% of untreated ovarian carcinoma patients respond to platinum-based chemotherapy, it has been suggested that UPSC patients might respond to similar treatment regimens. Twenty patients with UPSC were treated with cisplatin, doxorubicin (Adriamycin), cyclophosphamide (PAC) chemotherapy between January 1982 and December 1989. They included 9 patients with advanced primary disease, 5 with recurrence, and 6 who received PAC as adjuvant therapy. Patients received a mean of five cycles of PAC. Only 2 of 11 patients with measurable disease greater than 2 cm achieved complete clinical responses of 12 and 31 months duration; there were no partial responses. Actuarial 5-year survival for all patients was 23%. The mean progression-free interval was 9 months. Patients with clinical stages I or II disease had a higher survival rate than those with stage III or IV disease (P = 0.003). Survival did not correlate with depth of myometrial invasion (P = 0.81) or size of residual tumor following initial surgery (P = 0.16). Estrogen or progesterone receptors were detected in 10 of 11 tumors tested. Seven of 9 patients tested had elevated serum levels of CA-125 (greater than 35 U/ml). Correlation between CA-125 value and clinical course was demonstrated in 3 of 5 patients who had serial measurements. Of all patients, 3 are currently alive; 1 has documented disease. Moderate to severe toxicity was seen in 14 patients (70%). There was one possible treatment-related death from cardiomyopathy. UPSC, despite its histologic and clinical similarities to ovarian carcinoma, was relatively resistant to PAC chemotherapy in this mixed group of patients.