Phase II evaluation of capecitabine in refractory nonsquamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

We conducted a multi-institutional study to assess the activity and toxicity of capecitabine in patients with persistent or recurrent nonsquamous cancer of the cervix. Eligible patients were required to possess adequate renal, hepatic and bone marrow function and a Gynecologic Oncology Group performance status of 0-2. Histologic confirmation of the original primary cancer was mandated. Patients must have received one prior systemic chemotherapeutic regimen for cervical cancer that did not include the chemotherapy that may have been administered in conjunction with prior radiation therapy. The initial dose schedule was 2500 mg/m2 orally daily in two divided doses for 14 consecutive days, followed by a 7-day rest, such that each cycle was 21 days. Responses were assessed using response evaluation criteria in solid tumors. Twenty-one patients were entered into the trial. One patient was declared ineligible for wrong cell type; thus, 20 were evaluable for toxicity. A median of 2.5 cycles was administered (range 1-11). There was one septic death. Grade 4 neutropenia, renal, neurologic, and pulmonary toxicity was seen in 5%, 5%, 5%, and 10% patients, respectively. There were no responses. Nine patients (45%) each had stable disease and nine showed progression. The remaining two cases (10%) did not have subsequent disease assessment and response could not be assessed. Oral capecitabine at the dose and schedule tested has insignificant activity in nonsquamous cervical cancer patients previously treated with chemotherapy.

Cervical cancer: successes and failures.

The decline in deaths from cervical cancer in the US, as well as the improved survival of women with advanced disease have resulted, according to Dr. Rubin, from widespread application of routine screening with the Pap test, the emergence of gynecologic oncology as a distinct medical subspecialty, and the completion of important clinical trials.

Survival of BRCA1 negative ovarian cancer patients based on family history.

OBJECTIVE: To compare survival of ovarian cancer patients with and without a family history of breast or ovarian cancer who are known to be without mutations in BRCA1. METHODS: Patients with ovarian cancer were tested for germline mutations in BRCA1 by polymerase chain reaction amplification of DNA for single-strand conformation polymorphism and direct sequencing analysis to examine the 22 coding exons of BRCA1 in fresh and archived tumor specimens. Demographic and survival data were collected for statistical analysis. Survival data were calculated by the method of Kaplan and Meier and compared by the log-rank test. RESULTS: Of the 110 patients tested at our institution, 100 were noted to be negative for BRCA1 mutations. After exclusion of nonepithelial histologies, benign tumors, primary peritoneal carcinoma, and incomplete staging, 87 patients remained for analysis, of which 37 demonstrated a family history of breast or ovarian cancer. The two groups showed similar age at diagnosis, stage, grade, residual disease, and type of chemotherapy. Median actuarial survival was 75 months for those patients with a family history versus 70 months for those without (P = 0.73). Evaluation of patients with two or more relatives with breast or ovarian cancer also revealed no differences in survival. CONCLUSIONS: Family history of breast or ovarian cancer does not affect survival of patients with ovarian cancer in the absence of mutations in BRCA1. Previously described differences in survival among patients with BRCA1 mutations may be more related to genetic factors than to biases introduced by the presence of family history.

Gene therapy for ovarian cancer.

Advances in molecular virology and biotechnology have led to the engineering of vectors that can efficiently transfer genes to target cells. Gene therapy strategies were developed along two lines: Cytotoxic approaches involve the transfer of genes that encode enzymes, which convert inactive prodrugs into cytotoxic drugs. Corrective gene therapy approaches aim to repair specific molecular alterations in signal transduction mechanisms that control the cell cycle or induce apoptosis. Clinical evidence suggests that gene therapies are best suited for patients with minimal residual disease. Multimodality approaches with conventional strategies and novel therapeutic tools in various combinations will most likely prove advantageous, compared to single-modality treatments. However, clinical trials will need to test these hypotheses.

Cytoreductive surgery for ovarian cancer.

Cytoreductive surgery is a crucial component of the management of cancer of the ovary. Surgical cytoreduction of ovarian cancer volume has been associated with an increase in survival in all settings in which it has been studied. This association seems strongest, and the benefits of aggressive surgery are generally greatest, in patients with chemosensitive disease. Effective surgical management of ovarian cancer, therefore, requires competence in surgical anatomy and cytoreductive techniques and a thorough understanding of the patient's disease status and therapeutic goals.

Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer.

Immunosuppression may contribute to the progression of cancer. In this study we assessed the structural and functional status of T cells from tumor specimens obtained from patients with early stage non-small cell lung cancer and late-stage ovarian cancer. Although some groups have described structural alterations in the TCR in patients with other malignancies, we did not observe decreased expression of the CD3zeta subunit in the tumor-associated T cells. However, increased percentages of CD4(+)CD25(+) T cells were observed in the non-small cell lung cancer tumor-infiltrating lymphocytes and ovarian cancer tumor-associated lymphocytes. Furthermore, these CD4(+)CD25(+) T cells were found to secrete transforming growth factor-beta, consistent with the phenotype of regulatory T cells. Despite a generalized expression of lymphocyte activation markers in the tumor-associated T-cell populations, the CD8(+) T cells expressed low levels of CD25. To determine whether expression of CD25 could be restored on the CD8 cells, tumor-associated T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. After stimulation, nearly all of the CD8 T cells expressed CD25. Furthermore, despite the low levels of interleukin 2, IFN-gamma, and tumor necrosis factor-alpha secretion by the tumor-associated and peripheral blood T cells at baseline, stimulation with anti-CD3 and anti-CD28 monoclonal antibodies significantly increased the fraction of cells producing these cytokines. Thus, tumor-associated T cells from patients with early and late-stage epithelial tumors contain increased proportions of CD4(+)CD25(+) T cells that secrete the immunosuppressive cytokine transforming growth factor-beta. Furthermore, our results are consistent with previous reports showing impaired expression of CD25 on CD8(+) T cells in cancer patients. Finally, increased lymphocyte costimulation provided by triggering the CD28 receptor is able to increase CD25 expression and cytokine secretion in tumor-associated T cells. These observations provide evidence for the contribution of regulatory T cells to immune dysfunction in cancer patients.

Phase II trial of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors.

BACKGROUND: Photodynamic therapy (PDT) combines photosensitizer drug, oxygen, and laser light to kill tumor cells on surfaces. This is the initial report of our phase II trial, designed to evaluate the effectiveness of surgical debulking and PDT in carcinomatosis and sarcomatosis. METHODS: Fifty-six patients were enrolled between April 1997 and January 2000. Patients were given Photofrin (2.5 mg/kg) intravenously 2 days before tumor-debulking surgery. Laser light was delivered to all peritoneal surfaces. Patients were followed with CT scans and laparoscopy to evaluate responses to treatment. RESULTS: Forty-two patients were adequately debulked at surgery; these comprise the treatment group. There were 14 GI malignancies, 12 ovarian cancers and 15 sarcomas. Actuarial median survival was 21 months. Median time to recurrence was 3 months (range, 1-21 months). The most common serious toxicities were anemia (38%), liver function test (LFT) abnormalities (26%), and gastrointestinal toxicities (19%), and one patient died. CONCLUSIONS: Photofrin PDT for carcinomatosis has been successfully administered to 42 patients, with acceptable toxicity. The median survival of 21 months exceeds our expectations; however, the relative contribution of surgical resection versus PDT is unknown. Deficiencies in photosensitizer delivery, tissue oxygenation, or laser light distribution leading to recurrences may be addressed through the future use of new photosensitizers.

Second-look laparotomy for epithelial ovarian cancer: a reappraisal.

Although second-look laparotomy (SSL) has been used in the management of ovarian cancer for over three decades, its current clinical use is limited. On average, over 50% of patients with a clinical complete response are noted to have disease at the time of SLL, emphasizing our lack of accurate noninvasive methods for determining pathologic response. Although findings at SLL have some prognostic significance, there is no definitive evidence that those patients undergoing SLL have improved survival, and even 50% of patients with negative findings at SLL have recurrences. The lack of survival advantage for patients enduring SLL highlights the need to identify consistently effective salvage and consolidation regimens. Few published studies provide definitive evidence regarding efficacy of treatment. Prospective, randomized, controlled trials are needed to evaluate the various therapies available. In general, the performance of SLL should be confined to those patients enrolled in clinical trials.

Management of intestinal obstruction in the patient with ovarian cancer.

Intestinal obstruction in the patient with ovarian cancer is a difficult situation for both patient and physician. In women presenting with ovarian cancer, obstruction is almost never complete. These women should undergo aggressive bowel surgery only if it is part of an optimal surgical cytoreduction. Women known to have ovarian cancer who develop intestinal obstruction have a poor prognosis: Few will live more than a year from the time of obstruction. Some, however, have an excellent performance status, and would be relatively unimpaired were it not for their obstruction. These women, who usually have a discrete obstruction and still display some response to chemotherapy, may benefit from surgical correction of the obstruction. Women who are not candidates for surgery can be effectively palliated pharmacologically so that they are comfortable with the obstruction, often without intestinal drainage. Algorithms are available to assist in the management of ovarian cancer patients with obstruction, but ultimately the treatment decision rests with the patient. The oncologist must use his or her knowledge and clinical judgment to help the patient develop an appropriate, individualized plan.

Oncolytic herpes simplex virus-1 lacking ICP34.5 induces p53-independent death and is efficacious against chemotherapy-resistant ovarian cancer.

Replication-restricted herpes simplex virus-1 (HSV-1) strains lacking ICP34.5 are emerging as powerful anticancer agents against several solid tumors including epithelial ovarian cancer (EOC). Although chemotherapy-resistant tumors would be likely candidates for treatment with HSV-1 mutants lacking ICP34.5, the efficacy of these mutants on such tumors is unknown. In the present study, we investigated whether chemotherapy resistance affects the response of ovarian cancer cells to HSV-R3616, an ICP34.5-deficient, replication-restricted HSV-1. Primary EOC cultures obtained from patients who varied in their responses to platinum/paclitaxel induction chemotherapy displayed similar sensitivity to HSV-R3616. Similarly, chemotherapy-sensitive ovarian cancer cells A2780 and PA-1, possessing wild-type p53, and their respective chemotherapy-resistant clones A2780/200CP, lacking p53 function, and PA-1/E6, permanently expressing the HPV E6 gene, were equally sensitive to HSV oncolysis. Because wild-type HSV can kill cells by apoptosis and nonapoptotic mechanisms, we investigated the involvement of apoptosis and the role of the p53 tumor suppressor gene in oncolysis induced by HSV-R3616. Infection of ovarian cancer cell lines by HSV-R3616 was followed by cell death via apoptosis or nonapoptotic mechanisms as noted by morphology, cell cycle analysis, and in situ TUNEL assay. p53 protein levels remained unchanged, and Bax protein levels decreased in cells possessing intact p53 and that mainly underwent HSV-induced apoptosis. Loss of p53 function did not affect the frequency or rate of apoptosis or the sensitivity of EOC cells to the oncolytic effect of HSV-R3616. These results suggest that recombinant HSV-1 lacking ICP34.5 is capable of killing ovarian cancer cells that lack p53 function, resist apoptosis, and/or are chemotherapy resistant. These data support the hypothesis that HSV-based oncolytic therapy may be efficacious in chemotherapy-resistant tumors, including tumors that are deficient in p53.

Multi-attenuated herpes simplex virus-1 mutant G207 exerts cytotoxicity against epithelial ovarian cancer but not normal mesothelium and is suitable for intraperitoneal oncolytic therapy.

Recombinant strains of herpes simplex virus-1 (HSV-1) harboring mutations in the infected cell product (ICP)34.5 region lose their neurovirulence and replicate more efficiently in dividing tumor cells than stationary cells, becoming replication-selective oncolytic agents. Additional mutation of the ICP6 gene, which encodes ribonucleotide reductase, further impairs the ability of HSV-1 mutants to replicate in normal cells, enhancing tumor selectivity. The present study investigated the effect of HSV-G207, a recombinant HSV-1 lacking ICP34.5 and ICP6, against epithelial ovarian cancer (EOC) in vitro and in vivo in a mouse xenograft model. To assess the selectivity of multimutated HSV-G207 against malignant cells, HSV-G207 and wild-type HSV-F were comparatively tested against normal human peritoneal mesothelial cells and EOC cells in vitro. HSV-G207 infected both EOC cells and mesothelial cells; however, unlike EOC cells, mesothelial cells provided a poor substrate for replication of HSV-G207. In contrast to wild-type HSV-F, HSV-G207 exerted a potent oncolytic effect on EOC cells but spared normal mesothelial cells in vitro. Primary EOC cells were more sensitive to the virus than established EOC cell lines. A single intraperitoneal injection of HSV-G207 resulted in a significant reduction in tumor volume and tumor spread in vivo. HSV-G207 was shown to penetrate deeply within tumor nodules and caused no apparent intraperitoneal toxicity. Oncolytic therapy with multimutated replication-restricted HSV may offer a novel approach in the treatment of EOC.

Prolonged remission of recurrent, metastatic placental site trophoblastic tumor after chemotherapy.

BACKGROUND: Placental site trophoblastic tumor (PSTT) is a form of gestational trophoblastic neoplasm that is frequently resistant to chemotherapy. In most cases disease is confined to the uterus and can be cured by curettage or simple hysterectomy. Patients with metastases, however, frequently have progression of disease and die despite aggressive multiagent chemotherapy. CASE: A 31-year-old woman was found on review of uterine curettings to have a PSTT. Imaging studies revealed multiple lung lesions, a liver lesion, and an enlarged irregular uterus. Hysterectomy and staging surgery revealed a large tumor in the endometrial cavity and multiple metastases. She was treated with etoposide-methotrexate-dactinomycin and cyclophosphamide-vincristine and had a complete clinical remission. Six months later, however, she had a recurrence. She was then treated with six cycles of etoposide-methotrexate-dactinomycin and etoposide-cisplatin. Three years after completion of the second regimen she is without evidence of disease. CONCLUSION: Treatment with multiagent chemotherapy can produce long-term remission, even in patients with recurrent, metastatic PSTT. Addition of platinum may be helpful in patients who have recurred or progressed after treatment with non-platinum-containing regimens.

Early ovarian cancer.

Epithelial ovarian cancer may appear to be confined to the ovaries or pelvis in approximately one-third of patients at exploration, but up to 30% of them will be upstaged following surgical staging. Substage and histotype are the most important prognostic factors that determine the need for adjuvant treatment. Patients with stage Ia or Ib and well-differentiated (other than clear cell) tumors do not require adjuvant treatment. Patients with stage Ia or Ib grade 3 or clear cell histology, as well as any stage Ic and II disease, are at high risk for recurrence. Platinum-based chemotherapy is the mainstay of treatment. Four to six courses are probably adequate, although grade 3 tumors may require further treatment. Preservation of the uterus and the uninvolved contralateral ovary is a viable option in young women with unilateral early disease.

Surgical management of ovarian cancer.

Ovarian cancer affects over 25,000 women each year in the United States. The performance of appropriate surgery for ovarian cancer is critical in directing further therapies and improving survival. Systematic surgical staging must be performed in patients who appear to have early stage ovarian cancer because a significant proportion of these women have occult metastases. A marked improvement in survival has been demonstrated in patients with bulky disease if all masses larger than 2 cm can be surgically removed. Despite the dramatic effect of surgery on the subsequent course of the disease, recent studies show that only a minority of women with ovarian cancer receive appropriate initial surgery. We review the evidence and rationale for systematic surgical treatment of ovarian cancer.

Complete hydatidiform mole. A disease with a changing profile.

OBJECTIVE: To retrospectively evaluate the clinical presentation of complete molar pregnancies in an academic primary obstetrics and gynecology practice over the past decade. STUDY DESIGN: All cases of abnormal pregnancy presenting to our institution during the first half of gestation were identified through a computerized database. Clinical presentation and course of complete moles were analyzed. RESULTS: Twenty-four complete molar pregnancies were identified among 2,431 abnormal early gestations (1%). The patients' mean age was 24.5 years, and the mean gestational age was 9.5 weeks of amenorrhea (range, 8-25). Seventy-five percent of the patients presented with vaginal bleeding and 54% with excessive uterine size. None had hyperemesis gravidarum, preeclampsia, clinical hyperthyroidism or ovarian enlargement. All patients had abnormally elevated serum beta-hCG. Transvaginal ultrasound was diagnostic in more than half the patients, while it was suggestive of the diagnosis in the remainder. One patient experienced postevacuation trophoblastic embolization and developed persistent gestational trophoblastic disease. CONCLUSION: Due to the routine use of transvaginal ultrasound and serum beta-hCG in the workup of early gestational abnormalities, complete molar pregnancy rarely presents today with the traditional signs and symptoms. Despite their absence, the potential for persistent trophoblastic disease still exists, and careful follow-up is warranted.

Use of carrier cells to deliver a replication-selective herpes simplex virus-1 mutant for the intraperitoneal therapy of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) remains localized within the peritoneal cavity in a large number of patients, lending itself to i.p. approaches of therapy. In the present study, we investigated the effect of replication-selective herpes simplex virus-1 (HSV-1) used as an oncolytic agent against EOC and the use of human teratocarcinoma PA-1 as carrier cells for i.p. therapy. HSV-1716, a replication-competent attenuated strain lacking ICP34.5, caused a direct dose-dependent oncolytic effect on EOC cells in vitro. A single i.p. administration of 5 x 10(6) plaque-forming units resulted in a significant reduction of tumor volume and tumor spread and an increase in survival in a mouse xenograft model. PA-1 cells supported HSV replication in vitro and bound preferentially to human ovarian carcinoma surfaces compared with mesothelial surfaces in vitro and in vivo. In comparison with the administration of HSV-1716 alone, irradiated PA-1 cells, infected at two multiplicities of infection with HSV-1716 and injected i.p. at 5 x 10(6) cells/animal, led to a significant tumor reduction in the two models tested and the significant prolongation of mean survival in one model. Histological evaluation revealed extensive necrosis in tumor areas infected by HSV-1716. Immunohistochemistry against HSV-1 revealed areas of viral infection within tumor nodules, which persisted for several weeks after treatment. Administration of HSV-infected PA-1 carrier cells resulted in larger areas of tumor infected by the virus. Our results indicate that replication-competent attenuated HSV-1 exerts a potent oncolytic effect on EOC, which may be further enhanced by the utilization of a delivery system with carrier cells, based on amplification of the viral load and possibly on preferential binding of carrier cells to tumor surfaces.

Endometrial carcinoma associated with pregnancy: A report of three cases and review of the literature.

Endometrial carcinoma associated with pregnancy is uncommon. In case 1, a 40-year-old gravida 2, para 2, was diagnosed with focal well-differentiated papillary adenocarcinoma 4 months postpartum. In case 2, a 35-year-old gravida 1, para 0, was diagnosed with a well-differentiated papillary adenocarcinoma of the endometrium after a D&C for an incomplete abortion at 7 weeks gestation. In case 3, a 32-year-old gravida 2, para 1, was diagnosed with a moderately differentiated adenocarcinoma with squamous metaplasia 4 months postpartum. All are without evidence of disease more than 2 years after therapy. A literature review shows 24 previous cases of pregnancy associated with endometrial cancer. These cases demonstrate the importance of endometrial sampling for abnormal postpartum bleeding despite the protective effects of pregnancy.

Occult bilateral involvement in stage I epithelial ovarian cancer.

OBJECTIVE: The aim of this study was to determine the incidence of occult bilateral involvement in Stage I epithelial ovarian cancer. METHODS: We retrospectively reviewed the records of all patients (n = 135) with Stage I epithelial ovarian cancer treated at the University of Pennsylvania Cancer Center between 1985 and 1996. A study group of patients (n = 118) who underwent a bilateral salpingo-oophorectomy as part of their staging laparotomy was identified. Operative notes, pathology reports, and discharge summaries were reviewed to document stage, grade, histology, intraoperative impression, gross pathological description, and microscopic diagnosis. Clinically occult bilateral involvement was defined as pathologically documented ovarian involvement by tumor in an ovary that appeared normal to the surgeon during staging laparotomy. RESULTS: The study group consisted of mostly Stage IA (79/118, 67%), followed by Stage IC (35/118, 30%) and Stage IB (4/118, 3%), tumors. In 9/118 (7.6%) of these cases, bilateral disease was documented in the pathology report. In 3/118 (2.5%) of these cases, the bilateral involvement by tumor was clinically occult at the time of surgery. In only 1/118 (0.85%) of these cases did a clinically abnormal appearing ovary not contain tumor. CONCLUSION: Occult involvement by early ovarian cancer is uncommon at the time of staging laparotomy. In appropriately counseled patients strongly desiring to preserve fertility, a unilateral salpingo-oophorectomy may be considered as part of a staging procedure for apparent Stage IA epithelial ovarian cancer if the contralateral ovary appears normal to the surgeon. Consideration should be given to a wedge biopsy with intraoperative frozen section to help exclude occult disease in the normal appearing ovary.