S Cosio

Surveillance procedures for patients treated for epithelial ovarian cancer: a review of the literature.

Epithelial ovarian cancer is the leading cause of death from gynecological cancer in the Western countries. Approximately 20%–30% of patients with early-stage disease and 50%–75% of those with advanced disease who obtain a complete response following first-line chemotherapy will ultimately develop recurrent disease, which more frequently involves the pelvis and abdomen. Few formal guidelines exist regarding the surveillance of these patients, and there is no agreement in the literature about the type and timing of examinations to perform. Moreover, the objective of follow-up is unclear as recurrent epithelial ovarian cancer continues to be a therapeutic dilemma and quite all the relapsed patients will eventually die of their disease. The follow-up of asymptomatic patients generally include complete clinical history, serum cancer antigen (CA)125 assay, physical examination, and often ultrasound examination, whereas additional radiologic imaging techniques are usually performed when symptoms or signs appear. 18Fluoro-2-deoxy-glucose (18FDG)–positron emission tomography (PET) has a sensitivity of 90% and a specificity of 85% approximately for the detection of recurrent disease, and this examination appears to be particularly useful for the diagnosis of recurrence when CA125 levels are rising and conventional imaging is inconclusive or negative. Recently, technologic advances have led to novel combined 18FDG-PET/computed tomography (CT) devices, which perform contemporaneous acquisition of both 18FDG-PET and CT images. The role of 18FDG-PET/CT for the detection of recurrent ovarian cancer is very promising, and this technique may be especially useful for the selection of patients with late recurrent disease who may benefit from secondary cytoreductive surgery.

Smoking habit, immune suppression, oral contraceptive use, and hormone replacement therapy use and cervical carcinogenesis: a review of the literature

High-risk human papillomaviruses (HPVs) are involved in the etiopathogenesis of cervical intraepithelial neoplasia (CIN) and cervical cancer. After taking HPV into account, smoking habit appears to be the most significant environmental risk factor, and the risk of this malignancy increases significantly with intensity and duration of smoking. Women with human immunodeficiency virus (HIV) infection experience a higher incidence of CIN and invasive cervical cancer. Among HIV+ women, the highly active antiretroviral therapy increases the regression rate of CIN, but the majority of these lesions do not regress to normal. As far as oral contraceptives (OCs), a systematic review of 28 studies found that, compared with never pill users, the relative risk (RR) of cervical cancer increased with increasing duration of OC use. The results were similar for squamous cell carcinoma and adenocarcinoma, and the RRs decreased after pill discontinuation. However, by weighing risks and benefits, the World Health Organization does not recommend any change in OC practice. There is no correlation between hormone replacement therapy and cervical cancer. Experimental data have shown that estradiol and progesterone can modulate the host immune response to HPV16. Prophylactic vaccination in conjunction with cervical screening is the best prevention strategy for cervical cancer.

Serum and tissue biomarkers as predictive and prognostic variables in epithelial ovarian cancer

Tumour stage, residual disease after initial surgery, histological type and tumour grade are the most important clinical-pathological factors related to the clinical outcome of patients with epithelial ovarian cancer. In the last years, several investigations have assessed different biological variables in sera and in tissue samples from patients with this malignancy in order to detect biomarkers able to reflect either the response to chemotherapy or survival. The present paper reviewed the literature data about the predictive or prognostic relevance of serum CA 125, soluble cytokeratin fragments, serum human kallikreins, serum cytokines, serum vascular endothelial growth factor and plasma d-dimer as well as of tissue expression of cell cycle- and apoptosis-regulatory proteins, human telomerase reverse transcriptase, membrane tyrosine kinase receptors and matrix metalloproteinases. A next future microarray technology will hopefully offer interesting perspectives of translational research for the identification of novel predictive and prognostic biomarkers for epithelial ovarian cancer.

Surveillance of patients after initial treatment of ovarian cancer.

The surveillance of ovarian cancer patients after initial treatment is a challenging question in clinical practice. Serum CA 125 assay, physical examination, and imaging examinations have been employed with different time schedules for the follow-up of asymptomatic patients. Rising serum CA 125 levels may precede the clinical detection of relapse in 56-94% of cases with a median lead time of 3-5 months. An ongoing randomised phase III European trial is comparing the benefits of early administration of chemotherapy based on serum CA 125 assay alone versus delaying treatment until clinical or radiological detection of recurrent disease. Physical examination, with or without ultrasound, is very useful for the surveillance of these patients, since approximately 25-50% of relapses involve the pelvis. Additional radiological imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), are usually performed in asymptomatic patients with rising CA 125 levels as well as in patients with suspicious symptoms or signs. Integrated positron emission tomography (PET) and CT scanners (PET/CT) can identify recurrent disease in tissues that appear normal at CT imaging as well as metastatic lesions intimately associated with the bowel wall that are difficult to detect with CT or MRI, so that in most series PET/CT has a higher diagnostic reliability than that of conventional imaging techniques. Moreover, PET/CT can disclose unusual supra-diaphragmatic spreading of the disease and may be very helpful for treatment planning, especially for the selection of patients suitable for secondary surgical cytoreduction. A prospective, randomised trial of therapeutic interventions based on stratification by PET/CT disease status could elucidate the real impact of this diagnostic procedure in the management of patients with recurrent ovarian cancer.

Relationship Between Time Interval From Primary Surgery to the Start of Taxane- Plus Platinum-Based Chemotherapy and Clinical Outcome of Patients With Advanced Epithelial Ovarian Cancer: Results of a Multicenter Retrospective Italian Study

PURPOSE To assess whether the interval from primary surgery to the start of taxane- plus platinum-based chemotherapy has any impact on the clinical outcome of advanced ovarian cancer patients. PATIENTS AND METHODS The study was conducted on 313 patients who underwent surgery followed by taxane- plus platinum-based chemotherapy. The median follow-up of survivors was 30.7 months (range, 6 to 109 months). RESULTS The 25%, 50%, and 75% quantiles of intervals from surgery to the start of chemotherapy were 11, 21, and 31 days, respectively. After the sixth cycle, 102 patients achieved a pathologic complete response at second-look surgery and 98 obtained a clinical complete response but were not submitted to second-look surgery. Taking into consideration the best assessed response, a complete (either clinical or pathologic) response was found in 200 patients. Residual disease (< or = 1 v > 1 cm; P < .0001) and ascites (absent v present; P = .003) were independent predictive factors for achieving a complete response, whereas residual disease (P = .001) and stage (IIc to III v IV; P = .04) were independent prognostic variables for survival. Conversely, statistical analyses failed to detect significant differences in complete response rates and survival among patients with an interval from surgery to chemotherapy shorter than 11 days, 12 to 21 days, 22 to 31 days, and longer than 31 days. CONCLUSION The interval from surgery to the start of taxane- plus platinum-based chemotherapy seems to have neither a predictive value for response to treatment nor a prognostic relevance for survival of advanced ovarian cancer patients.

Are surveillance procedures of clinical benefit for patients treated for ovarian cancer? A retrospective italian multicentric study

The aim of this retrospective investigation was to assess the pattern of failures of 412 patients with recurrent ovarian cancer followed up with different surveillance protocols. Time to recurrence was less than 6 months in 98 women (23.8%), 6 to 12 months in 102 women (24.7%), and more than 12 months in 212 women (51.5%). Symptoms at relapse were referred by 81 women (19.7%). Among the 331 asymptomatic patients, the surveillance procedure that raised the suspect of recurrent disease was clinical examination in 49 (14.8%), imaging technique in 90 (27.2%), serum CA 125 in 77 (23.3%), and both serum CA 125 and imaging technique in 115 (34.7%). At univariate analysis, survival from initial diagnosis was related to stage (P = 0.004), residual disease after initial surgery (P < 0.0001), time to recurrence (P < 0.0001), site of relapse (P = 0.04), and treatment at recurrence (P < 0.0001), and survival after recurrence was related to stage (P = 0.01), residual disease (P < 0.0001), time to recurrence (P < 0.0001), and treatment at recurrence (P < 0.0001). Conversely, symptoms at recurrence had no prognostic relevance. Cox proportional hazards model showed that residual disease and time to recurrence were the only independent prognostic variables for both survival from initial diagnosis (P < 0.0001) and survival after recurrence (P < 0.0001). In conclusion, there was no survival difference between asymptomatic and symptomatic patients at the time of relapse, and therefore, the diagnostic anticipation allowed by a scheduled follow-up protocol did not seem to improve the clinical outcome of patients who ultimately developed recurrent disease.

Ovarian function and childbearing issues in breast cancer survivors

The increasing number of breast cancer survivors makes the issues of ovarian dysfunction and childbearing ability more and more relevant for the quality of life of these patients. The incidence of ovarian dysfunction is related to patient age, the specific agents used and the total dose administered, especially the dose of alkylating agents such as cyclophosphamide. Amenorrhea rates following combination chemotherapy consisting of cyclophosphamide + methotrexate + 5-flurouracil (CMF regimen) range from 21 to 71% in women aged 40 years and younger, and from 40 to 100% in older ones. In most series anthracycline-based adjuvant chemotherapy regimens appear to have a lower incidence of amenorrhea, which is probably due to the lower cumulative cyclophosphamide dose administered compared with that given in the CMF regimen. Few data are currently available regarding ovarian function in women treated with taxane-based chemotherapy. In a recent retrospective study on 191 patients, the amenorrhea rate was 64% for women who received doxorubicin + cyclophosphamide (AC regimen) followed by a taxane, compared with 55% (p = 0.05) for those treated with AC alone. Forty percent of women aged 40 years or younger resumed menstruation, whereas the amenorrhea was more likely to be irreversible in older women; however, the addition of a taxane did not change the reversibility rate. Ovarian reserve can be tested with serum assays of follicle-stimulating hormone, inhibin B, estradiol and anti-Müllerian hormone, as well as by ultrasound assessment of antral follicle count. A review of literature data failed to show that a subsequent pregnancy increases the risk of recurrence and death in breast cancer survivors, and some series have even detected longer survival for patients who get pregnant after breast cancer treatment. This apparent survival benefit, probably due to a selection bias called the ‘healthy mother effect’, suggests that breast cancer survivors who subsequently conceive are a self-selecting group of women with better prognosis. The little available information appears to show no increase in the incidence of prematurity, stillbirth or congenital malformations in their babies. In conclusion, future pregnancy is a viable option for a woman treated for early-stage breast cancer and does not appear to be detrimental to either the mother or her offspring.

Molecular target therapies in endometrial cancer: from the basic research to the clinic.

Molecular targeted therapies represent an interesting field of pharmacological research in endometrial cancer. The loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, with consequent activation of the PI3K (phosphatidylinositol-3-kinase)–AKT (serine/threonine-specific protein kinase)–mTOR (mammalian target of rapamycin) signaling pathway, occurs in 32–83% of endometrioid-type endometrial carcinomas, thus suggesting a role for mTOR inhibition in this malignancy. Some analogues of rapamycin (CCI-799, RAD-001, AP-23573) have been developed and tested in different tumors including endometrioid-type endometrial carcinoma. For example, AP-23573 achieved a clinical benefit response in 33% of 27 heavily pretreated patients, and CCI-799 obtained a 26% partial response rate and a 63% stable disease rate in 19 patients. Overexpression of ErbB-2 (epidermal growth factor type II receptor) has been detected in 18–80% of uterine papillary serous carcinomas (UPSCs), thus providing a biological rationale for the use of trastuzumab in these aggressive tumors. UPSC often overexpresses claudin-3 and claudin-4, which represent the epithelial receptors for Clostridium perfringens enterotoxin (CPE). CPE-mediated therapy might be a novel treatment modality for UPSC resistant to chemotherapy. A better understanding of the signaling transduction pathways that are dysregulated in endometrioid-type endometrial carcinoma and UPSC will allow the development of novel molecular targeted therapies.

Human telomerase reverse transcriptase mRNA expression assessed by real-time reverse transcription polymerase chain reaction predicts chemosensitivity in patients with ovarian carcinoma

PURPOSE To evaluate in vivo whether the expression of the human telomerase reverse transcriptase (hTERT) gene, the catalytic subunit of the telomerase complex, is predictive of response to chemotherapy in ovarian cancer patients. PATIENTS AND METHODS Fifty-nine advanced-stage ovarian cancer patients who were treated with platinum-based chemotherapy were studied. hTERT levels were evaluated by real-time reverse transcriptase polymerase chain reaction (RT-PCR) on tumor specimens obtained before the treatment. Variables were analyzed by the chi(2) and Fishers exact tests. Logistic regression analysis was also performed to account for the effects of all the covariates investigated (residual disease, stage, histotype, and grade). RESULTS Twenty-eight (47%) of the 59 tumors showed low hTERT levels, whereas 31 (53%) tumors displayed high hTERT levels. Seventy-five percent of complete responders showed high levels of hTERT expression, whereas 66% of partial responders or nonresponders exhibited low hTERT levels (P =.002). Only residual disease and hTERT expression were independent predictors of response (odds ratios, 13.455 and 7.586, respectively). The combination of these two parameters provides powerful predictive information: 18 of the 20 patients with residual disease more than 2 cm and low hTERT levels were partial responders or nonresponders, whereas 11 of the 12 patients with residual disease less than 2 cm and high hTERT levels showed a complete response (chi(2) = 21,416; P <.00001). CONCLUSION Our data indicate that hTERT expression, measured by real-time RT-PCR, is a possible independent marker of response to platinum-based therapy in advanced stage ovarian cancer patients. Prospective validation of this marker will be required to further define its predictive value.

Is there a role for postoperative treatment in patients with stage Ib2–IIb cervical cancer treated with neo-adjuvant chemotherapy and radical surgery? An Italian multicenter retrospective study

PURPOSE Neoadjuvant chemotherapy [NACT] followed by radical hysterectomy is an alternative therapeutic option to concurrent chemotherapy-radiotherapy for locally advanced cervical cancer. However there are very few data about the effectiveness of any post-operative treatment in this clinical setting. The purpose of this study was to correlate the patterns of recurrence and the clinical outcomes of cervical cancer patients who received NACT, with postoperative adjuvant treatment. PATIENTS AND METHODS This retrospective multicenter study included 333 patients with FIGO stage Ib2-IIb cervical cancer who underwent platinum-based NACT followed by radical surgery. Pathological responses were retrospectively assessed as complete; optimal partial; and suboptimal response. Overall optimal response rate was the sum of complete and optimal partial response rates. RESULTS On the whole series, recurrence-free survival was significantly longer in patients who achieved an overall optimal response than in those who did not (p<0.0001), and in patients who received adjuvant chemotherapy compared to those who did not (p=0.0001). On multivariate analysis, consolidation therapy (p=0.0012) was the only independent prognostic variable for recurrence-free survival; whereas FIGO stage (p=0.0169) and consolidation therapy (p=0.0016) were independent prognostic variables for overall survival. CONCLUSION Optimal responders after chemo-surgical treatment for FIGO stage Ib2-IIb cervical cancer do not need any further treatment. Additional cycles of chemotherapy could be of benefit for patients with suboptimal response and intra-cervical residual disease. Both adjuvant chemotherapy and adjuvant radiation treatments do not seem to improve the clinical outcome of patients with extra-cervical residual disease compared to no further treatment.