Gordon O. Downey

Pretreatment surgical staging in cervical carcinoma: Therapeutic efficacy of pelvic lymph node resection

Pretreatment surgical staging in cervical carcinoma has been studied extensively to define a group for extended field radiation or adjuvant chemotherapy. A theoretical, but as yet unproved, benefit from this surgery is the resection of large, presumably radioresistant, pelvic nodal metastases before radiation therapy. One hundred fifty-six patients were divided by pelvic nodal status after surgical staging with excision of pelvic lymph nodes: group A, negative (n = 81); group B, microscopic metastases only (n = 18); group C, macroscopic nodal metastases resected (n = 48); and group D, unresectable nodal metastases (n = 9). The 5-year recurrence-free survival in group C (51%) approached that of group B (57%) and was significantly better than that of group D (0%). The groups are compared by International Federation of Gynecology and Obstetrics stage, grade, histology, and incidence of paraaortic metastases. Patterns of recurrence imply improved pelvic control in patients undergoing resection of pelvic nodal metastases. Surgical removal of pelvic nodal metastases before radiation therapy is recommended.

The role of surgical debulking in cancer of the uterine cervix

From 1978 to 1985, 159 women with advanced cervical cancer received definitive radiation therapy following extraperitoneal surgical staging including pelvic lymph node dissection and periaortic lymph node sampling. Relapse-free survival was a strong function of peritoneal and nodal metastases but was independent of clinical stage. The 5-year relapse-free rate fell from 86% in women without pelvic node metastases to 0% in those with unresectable pelvic node metastases. Women with microscopically positive pelvic node metastases had virtually the same (56%) relapse-free rate as those with grossly positive but completely resected metastases (57%). The overall pelvic failure rate was 16.4% and was significantly higher in women with unresectable pelvic node metastases. Periaortic and peritoneal metastases substantially increased the probability of recurrence. Although histologic grade was prognostically significant, histopathologic category was not. Severe enteric morbidity occurred in 3.6% of patients treated solely to the pelvis and in 7.9% of patients treated to the pelvis and periaortics. Therapeutic implications of debulking pelvic node metastases are discussed.

Temsirolimus with or without Megestrol Acetate and Tamoxifen for Endometrial Cancer: a Gynecologic Oncology Group Study

OBJECTIVES To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma. BACKGROUND Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy. METHODS We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma. RESULTS There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded. CONCLUSIONS Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.

Symptomatic central venous thrombosis and long-term right atrial catheters

The use of long-term right atrial access catheters is increasing due to their value as aids in the administration of chemotherapy and hyperalimentation. A rare complication of catheter use is subclavian vein thrombosis. Suspicion of subclavian venous thrombosis based on clinical findings should be confirmed by venography. Therapy should be individualized, but may include antibiotics, catheter removal, thrombolytics, and anticoagulants. Resolution of symptoms is the usual outcome, but this may be influenced by other compounding factors.

A quality process study of lymph node evaluation in endometrial cancer.

Our objective was to analyze the reported lymph node counts between surgeons, histology prosectors, and pathologists using a cohort of patients enrolled on a national protocol that standardized surgical intent.This is a retrospective review of patients with uterine cancer who underwent a standardized formal staging procedure as dictated by a National Cancer Institute sponsored protocol. Patients were staged using the International Federation of Gynecology and Obstetrics 1988 guidelines. All patients required a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. Lymphadenectomy specimens were separated by the following regions: external iliac, obturator, common iliac, and periaortic. Lymph node counts were analyzed by region, surgeon, histology prosector, and pathologist.There were 78 patients enrolled in the protocol during the study period. Of them, 72 (92%) patients met the inclusion criteria. A total of 2397 lymph nodes were counted, with an average total number of 33 (SD=9) lymph nodes dissected per patient. Surgeons A, B, and C had an average lymph node count of 32, 33, and 35, respectively, with no significant difference in mean node count (P=0.66). Prosectors 1 to 4 dissected an average of 34, 33, 28, and 35 lymph nodes, respectively (P=0.091). There were 2 pathologists with ≥ 10 cases. Their mean lymph node counts were 35 and 30, respectively, with no significant difference in mean node count (P=0.079).This systematic review did not identify a discrepancy in nodal count among surgeons, prosectors, or pathologists at our institution. The methods used may be helpful in structuring interdepartmental reviews for completeness of nodal dissections in cases where surgical intent has been standardized.

Fibromatosis of the female pelvis.

Fibromatosis is a benign, infiltrating, nonmetastasizing neoplasm which is rarely completely resected. Therefore, the incidence of recurrence is high. Fibromatosis is more common in females and is frequently diagnosed during pregnancy. Inasmuch as fibromatosis of the female pelvis appears to be a discrete entity, management poses significant problems for the gynecologist. Radiation therapy, frequently used following incomplete resection or for recurrence, is undesirable due to the loss of ovarian function and fertility. Hormonal manipulation and combination chemotherapy are alternatives which have been effective in some reports. Three patients with pelvic fibromatosis, referred within 1 year, are reported. The various aspects of this neoplasm and the diagnostic procedures are discussed. Treatment modalities whose effects are reversible are recommended for recurrent fibromatosis. Radiation therapy can be reserved for patients in the older age groups or for those with progressive disease not responding to other therapy.

Tumor mutational analysis of GOG248, a phase II study of temsirolimus or temsirolimus and alternating megestrol acetate and tamoxifen for advanced endometrial cancer (EC): An NRG Oncology/Gynecologic Oncology Group study

OBJECTIVE Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development. METHODS Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next-generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored. RESULTS Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01-0.78) and RR (response difference 0.83; 95% CI 0.03-0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20-0.97) but not RR (response difference 0.00, 95% CI -0.34-0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR. CONCLUSIONS Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus.

resection of the Pubic Bone as an Adjunct to Management of Primary, Recurrent, and Metastatic Pelvic Malignancies

&NA; Patients with locally advanced vulvovaginal carcinomas with pubic bone encroachment or fixation pose a treatment dilemma. The purpose of this study was to evaluate the outcome in 12 patients who have undergone pubic bone resection at the University of Minnesota as part of treatment of locally extensive primary, recurrent, or metastatic vulvovaginal carcinomas. Six patients with primary vulvar carcinomas and six patients with recurrent or metastatic vulvovaginal carcinomas underwent bone resection as part of their surgical therapy. Survival in the primary treatment group was 50%, with no local recurrences. Survival in the recurrent/metastatic disease group was 83%, with a follow‐up time of 9 months to 15 years. One vulvar and one groin recurrence have occurred in the recurrent/metastatic group. Pubic bone resection added little to surgical morbidity and gave good functional results. Pubic bone resection, in combination with radical extirpative procedures, is an option for treatment of patients with locally extensive vulvovaginal carcinomas, particularly those with previous radiation therapy. (Obstet Gynecol 73:1022, 1989)

Concomitant whole-abdominal radiation and intraperitoneal chemotherapy in advanced ovarian carcinoma. A pilot study.

Because the use of cisplatin‐based chemotherapy for ovarian carcinoma has not significantly improved 5‐year survival rates compared with either whole‐abdominal radiation (WAR) or single‐agent chemotherapy, a pilot study was begun to assess the feasibility of concomitant radiation and chemotherapy. Eleven previously untreated patients with Stages III and IV ovarian carcinoma were treated concomitantly with 2000 cGy of WAR and intraperitoneal (IP) cisplatin followed by additional IP cisplatin after debulking surgery. Toxicity was moderate to severe. Sixty‐four percent of patients had Grades 3 to 4 hematologic toxicity, and 36% required hospitalization for sepsis during WAR/IP cisplatin. Hematologic toxicity was less pronounced during IP cisplatin alone. All patients experienced moderate gastrointestinal toxicity. The average percentage of total body weight lost was 13.5%. Fifty‐five percent of all patients demonstrated a complete clinical response to therapy, and patients with minimal postoperative residual disease fared better. One patient with persistent disease had acute nonlymphocytic leukemia (ANLL) 24 months after initial diagnosis. No patients with residual disease greater than 20 mm survived, while 50% of patients with less than 20 mm are clinically free of disease. Toxicity appears to be additive with the combination of WAR and IP cisplatin. Therapeutic efficacy was comparable with standard chemotherapy regimens, but no therapeutic or survival advantages were demonstrated with the use of this treatment protocol.