Sunday, February 20, 2011
Platinum-based adjuvant chemotherapy on moderate - and high-risk stage I and II epithelian ovarian cancer patients. Long-term single institution exper
Background Although the optimal management of women with FIGO stages I and II epithelial ovarian cancer (EOC) is still controversial, platinum-based adjuvant chemotherapy (CT) is the mainstay of treatment. Suboptimal survival results have led to major efforts to identify prognostic factors, improve surgical staging and develop adjuvant therapies to improve patients' outcomes.
Patients and methods We evaluate in a retrospective study clinical efficacy and the toxicity profile of a platinum-based adjuvant CT in FIGO stages I and II EOC treated at our institution from March 1984 to December 2006. Grade I FIGO stages IA-IB were excluded from the analysis. In the first period (1984-1997), patients received a platinum-based regimen without taxanes. In the second period from 1997 onwards, patients were treated with carboplatin and paclitaxel. Four to six cycles of adjuvant CT were administered. Potential predictive factors of efficacy and the role of paclitaxel addition were also analysed.
Results One hundred and fifty-eight patients (60 treated with paclitaxel) met inclusion criteria and were evaluable. Median age at diagnosis was 53.7 years (range 19-81) and most patients had an Eastern Cooperative Oncology Group performance status score (ECOG) of 0-1 (91.8%); 82.9% patients had pathological stage I and 17.1% pathological stage II. With a median follow up of 8.34 years (range 4.4-11.6), 103 patients (74.1%) were free of disease and 110 of them were alive (79.1%). Median relapse-free survival (RFS) and median overall survival (OS) had not been reached at the time of the analysis. No survival difference was found between paclitaxel and carboplatin combination or non-paclitaxel-containing regimens. Statistically significant prognostic factors for better RFS in the multivariate analysis were: ECOG 0 (p=0.023; HR 0.32; 95% CI 0.17-0.57); FIGO I stage (p<0.001; HR 0.30; 95% CI 0.15-0.58); I-II histological grade (p=0.005; HR 0.38; 95% CI 0.19-0.75); mucinous histology (p=0.013; HR 0.28; 95% CI 0.13-0.53); non-surgical adherences (p<0.002, HR 0.32; 95% CI 0.15-0.54); paracolic gutters inspection (p=0.033; HR 0.50; 95% CI 0.26-0.95) and liver surface biopsies (p=0.048; HR 0.64; 95% CI 0.41-0.98).Toxicity was generally mild and non-haematologic events were the most commonly found (62.9% of the total). The most frequent haematologic toxicities were neutropenia (41.7% in all grades, 9.5% grade 3-4) and anaemia (29.1% in all grades, 3.2% grade 3-4).
Conclusions The long-term outcome of this series is comparable to the published evidence and reflects the limited activity of platinum-based CT in the adjuvant setting. The potential survival advantage of the addition of paclitaxel to carboplatin cannot be definitively answered due to the small number of patients, the limited follow-up and the retrospective nature of the study. More effective and specific treatments are clearly required, in particular for those patients with stage II and undifferentiated tumours. Quality of surgery entails prognostic value.
Patients and methods We evaluate in a retrospective study clinical efficacy and the toxicity profile of a platinum-based adjuvant CT in FIGO stages I and II EOC treated at our institution from March 1984 to December 2006. Grade I FIGO stages IA-IB were excluded from the analysis. In the first period (1984-1997), patients received a platinum-based regimen without taxanes. In the second period from 1997 onwards, patients were treated with carboplatin and paclitaxel. Four to six cycles of adjuvant CT were administered. Potential predictive factors of efficacy and the role of paclitaxel addition were also analysed.
Results One hundred and fifty-eight patients (60 treated with paclitaxel) met inclusion criteria and were evaluable. Median age at diagnosis was 53.7 years (range 19-81) and most patients had an Eastern Cooperative Oncology Group performance status score (ECOG) of 0-1 (91.8%); 82.9% patients had pathological stage I and 17.1% pathological stage II. With a median follow up of 8.34 years (range 4.4-11.6), 103 patients (74.1%) were free of disease and 110 of them were alive (79.1%). Median relapse-free survival (RFS) and median overall survival (OS) had not been reached at the time of the analysis. No survival difference was found between paclitaxel and carboplatin combination or non-paclitaxel-containing regimens. Statistically significant prognostic factors for better RFS in the multivariate analysis were: ECOG 0 (p=0.023; HR 0.32; 95% CI 0.17-0.57); FIGO I stage (p<0.001; HR 0.30; 95% CI 0.15-0.58); I-II histological grade (p=0.005; HR 0.38; 95% CI 0.19-0.75); mucinous histology (p=0.013; HR 0.28; 95% CI 0.13-0.53); non-surgical adherences (p<0.002, HR 0.32; 95% CI 0.15-0.54); paracolic gutters inspection (p=0.033; HR 0.50; 95% CI 0.26-0.95) and liver surface biopsies (p=0.048; HR 0.64; 95% CI 0.41-0.98).Toxicity was generally mild and non-haematologic events were the most commonly found (62.9% of the total). The most frequent haematologic toxicities were neutropenia (41.7% in all grades, 9.5% grade 3-4) and anaemia (29.1% in all grades, 3.2% grade 3-4).
Conclusions The long-term outcome of this series is comparable to the published evidence and reflects the limited activity of platinum-based CT in the adjuvant setting. The potential survival advantage of the addition of paclitaxel to carboplatin cannot be definitively answered due to the small number of patients, the limited follow-up and the retrospective nature of the study. More effective and specific treatments are clearly required, in particular for those patients with stage II and undifferentiated tumours. Quality of surgery entails prognostic value.
Lynch Syndrome and MYH-Associated Polyposis: Review and Testing Strategy. Goodenberger M, Lindor NM.
Abstract
Individuals with Lynch syndrome have an increased risk for colorectal cancer, endometrial cancer, and other associated cancers such as gastric cancer, ovarian cancer, urothelial cancers, hepatobiliary tract cancer, brain cancer, cancer of the small intestine, pancreatic cancer, and particular skin cancers.
Lynch syndrome caused by defects in DNA mismatch repair genes, and diagnostic testing for Lynch syndrome begins with microsatellite instability and immunohistochemical analysis on the tumor specimen followed by germline genetic testing and possibly further studies on the tumor. MYH-associated polyposis syndrome is a recently characterized, autosomal recessive, polyposis syndrome caused by biallelic mutations in the MYH gene. Individuals carrying 2 copies of the mutation have a significantly increased risk of polyposis, colorectal cancer, upper gastrointestinal polyps and additional features commonly seen in familial adenomatous polyposis syndrome. Genetic testing for MYH mutation is complicated by the phenotypic overlap of MYH-associated polyposis with other colorectal cancer syndromes. This study serves to clarify the best testing approach.
Lynch syndrome caused by defects in DNA mismatch repair genes, and diagnostic testing for Lynch syndrome begins with microsatellite instability and immunohistochemical analysis on the tumor specimen followed by germline genetic testing and possibly further studies on the tumor. MYH-associated polyposis syndrome is a recently characterized, autosomal recessive, polyposis syndrome caused by biallelic mutations in the MYH gene. Individuals carrying 2 copies of the mutation have a significantly increased risk of polyposis, colorectal cancer, upper gastrointestinal polyps and additional features commonly seen in familial adenomatous polyposis syndrome. Genetic testing for MYH mutation is complicated by the phenotypic overlap of MYH-associated polyposis with other colorectal cancer syndromes. This study serves to clarify the best testing approach.
Surgical management of bowel obstruction in gynaecological malignancies.
Abstract
PURPOSE OF REVIEW: Bowel obstruction in gynaecological malignancies continues to present clinical challenges and a multidisciplinary approach to discuss management is crucial. Surgery, usually with palliative intent, is associated with significant morbidity and mortality. There is an absence of level 1 evidence and national guidelines, and only limited quality-of-life data.RECENT FINDINGS: Acute bowel obstruction in gynaecological cancer patients is rare and surgery is associated with a higher morbidity and mortality rate. Less commonly, emergency bowel obstruction cases will have had radiotherapy or recent chemotherapy, which also increases surgical morbidity and mortality. However, most often, bowel obstruction in irradiated gynaecological cancer patients is not due to cancer. Ovarian cancer is the most common malignancy. Caution is needed in those EOC patients with ascites, short treatment-free interval, acute abdomen and chemoresistance. Comorbidities are frequent. The decision for surgery should be made on an individual basis. Palliative care input is important early in patient management as for most patients the surgical goal is palliation and not cure. There is still a paucity of published data on quality-of-life assessments.
SUMMARY: There is a need to identify those patients who may benefit from palliative surgical intervention and those who will not. Ideally, agreed national guidelines should be produced and regularly reviewed.
Undetectable antimüllerian hormone levels and recovery of chemotherapy-induced ovarian failure in women with breast cancer on an oral aromatase inhibitors
Abstract
OBJECTIVE: Knowledge of the menopause status of a woman with breast cancer is important for good clinical practice. Long-lasting amenorrhea is frequent in this population, often for reasons other than definitive menopause. Antiestrogens like tamoxifen or oral aromatase inhibitors (AIs) may reactivate the ovary causing vaginal bleeding, menstruation, pregnancy, and unopposed endometrial stimulation. In contrast to tamoxifen, AIs are not active against breast cancer in the presence of functional ovaries. Antimüllerian hormone (AMH) is a potential marker of residual ovarian function that can predict not only the onset of menopause but also chemotherapy-induced amenorrhea (CIA) and fertility. We assess the value of AMH in women who recovered from CIA on an AI.
Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer.
PURPOSE: Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival.
METHODS: The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients' toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis.
RESULTS: Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival.
CONCLUSION: CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.
Sugars in diet and risk of cancer in the NIH-AARP diet and health study
Abstract
Prospective epidemiologic data on the effects of different types of dietary sugars on cancer incidence have been limited. In this report, we investigated the association of total sugars, sucrose, fructose, added sugars, added sucrose and added fructose in the diet with risk of 24 malignancies.
Participants (n = 435,674) aged 50-71 years from the NIH-AARP Diet and Health Study were followed for 7.2 years. The intake of individual sugars was assessed using a 124-item food frequency questionnaire (FFQ)......... We identified 29,099 cancer cases in men and 13,355 cases in women. In gender-combined analyses, added sugars were positively associated with risk of esophageal adenocarcinoma ; added fructose was associated with risk of small intestine cancer ; and all investigated sugars were associated with increased risk of pleural cancer. In women, all investigated sugars were inversely associated with ovarian cancer. We found no association between dietary sugars and risk of colorectal or any other major cancer.
Measurement error in FFQ-reported dietary sugars may have limited our ability to obtain more conclusive findings. Statistically significant associations observed for the rare cancers are of interest and warrant further investigation.
Participants (n = 435,674) aged 50-71 years from the NIH-AARP Diet and Health Study were followed for 7.2 years. The intake of individual sugars was assessed using a 124-item food frequency questionnaire (FFQ)......... We identified 29,099 cancer cases in men and 13,355 cases in women. In gender-combined analyses, added sugars were positively associated with risk of esophageal adenocarcinoma ; added fructose was associated with risk of small intestine cancer ; and all investigated sugars were associated with increased risk of pleural cancer. In women, all investigated sugars were inversely associated with ovarian cancer. We found no association between dietary sugars and risk of colorectal or any other major cancer.
Measurement error in FFQ-reported dietary sugars may have limited our ability to obtain more conclusive findings. Statistically significant associations observed for the rare cancers are of interest and warrant further investigation.
Long-term clinical and immunological effects of p53-SLP® vaccine in ovarian cancer patients
Abstract
Vaccine-induced p53-specific immune responses were previously reported to be associated with improved response to secondary chemotherapy in small cell lung cancer patients. We investigated longterm clinical and immunological effects of the p53-SLP® vaccine in recurrent ovarian cancer patients. Twenty patients were immunized with the p53-SLP® vaccine between July 2006 and August 2007.Follow-up information on patients was obtained. Clinical responses to secondary chemotherapy after p53-SLP® immunizations was determined by computerized tomography and/or tumour marker levels (CA125). Disease-specific survival was compared with a matched historical control group. Immune responses were analysed by flow cytometry, proliferation assay, IFN-γ ELISPOT and/or cytokine bead array. Lymphocytes cultered from skin biopsy were analysed by flow cytometry and proliferation assay.
Of twenty patients treated with the p53-SLP® vaccine, seventeen were subsequently treated with chemotherapy. Eight of these volunteered another blood sample. No differences in clinical response rates to secondary chemotherapy or disease-specific survival were observed between immunized patients and historical controls (p=0.925, resp. p=0.601). P53-specific proliferative responses were observed in 5/8 patients and IFN-γ production in 2/7 patients. Lymphocytes cultured from a prior injection site showing inflammation during chemotherapy did not recognise p53-SLP®. Thus treatment with the p53- SLP® vaccine does not affect responses to secondary chemotherapy or survival, although p53-specific T-cells do survive chemotherapy.
Phase II Clinical Study of the Combination Chemotherapy Regimen of Irinotecan Plus Oral Etoposide for the Treatment of Recurrent Ovarian Cancer
OBJECTIVE: To evaluate the efficacy and safety of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of patients with recurrent ovarian cancer after previous treatment with platinum and taxane agents.
PATIENTS AND METHODS: A total of 42 patients with recurrent ovarian cancer who had an evaluable lesion and provided informed consent for participation in the present study were analyzed. Irinotecan was administered intravenously at a dose of 60 mg/m on days 1 and 15. Etoposide was administered orally at a daily dose of 50 mg/body weight from days 1 to 21. A 28-day period comprised one cycle. The tumor response, adverse events, progression-free survival, and overall survival were examined. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors and the serum CA125 levels (Gynecologic Cancer Intergroup criteria). Adverse events were assessed according to the NCI-CTCAE (version 3.0).
RESULTS: Partial response was observed in 21 patients, stable disease in 14 patients, and progressive disease in 7 patients. The response rate was 50.0%, and the clinical benefit (partial response + stable disease) rate was 83.3%. Hematological toxicities of at least grade 3 severity included leukopenia in 21 patients (50.0%), neutropenia in 22 patients (52.4%), thrombocytopenia in 1 patient (2.4%), anemia in 9 patients (21.4%), and febrile neutropenia in 3 patients (7.1%). Nonhematological toxicities of at least grade 3 severity included queasy feeling in 5 patients (11.9%), vomiting in 3 patients (7.1%), and diarrhea in 2 patients (4.8%). Acute myeloid leukemia occurred in one patient (2.4%).
CONCLUSIONS: It is suggested that combination chemotherapy with irinotecan plus oral etoposide offers significant clinical benefit to patients with recurrent ovarian cancer previously treated with platinum and taxane agents.
Diagnostic performance of urgent referrals for suspected gynaecological malignancies.
PURPOSE: The objective of this study was to investigate the outcome of the urgent referrals with suspected gynaecological malignancy.
CONCLUSION: The overall predictive value of two-week wait referrals for suspected gynaecological malignancies is low. Refinement of the current referral guidelines is required with particular emphasis in the premenopausal women where the diagnostic performance of the urgent referrals is significantly poorer.
Gynecological Cancers. [Methods Mol Biol. 2011]
Abstract
The clinical problems raised in patients presenting with all forms of gynecological malignancy are currently addressed using conventional cross-sectional imaging, usually MRI. In general, F-18 FDG PET-CT has not been shown to have a clinical role in any of these cancers at presentation, although studies are under way to use this form of metabolic imaging to predict prognosis and the response to treatment. Although F-18 FDG PET-CT is superior to conventional imaging techniques, it is only moderately sensitive in demonstrating lymph node metastasis preoperatively, and is inadequate for local staging of patients with endometrial cancer. In ovarian cancer, F-18 FDG PET-CT provides an accurate assessment of the extent of disease, particularly in areas difficult to assess for metastases by CT and MRI such as the abdomen and pelvis, mediastinum, and supraclavicular region. F-18 FDG PET-CT is a sensitive method of detecting pelvic and para-aortic lymph nodal disease in cervical cancer, and appears to be superior to MRI and CT despite the limitations in identifying small foci of disease. In the main, as elsewhere in patients with cancer, the value of PET-CT is in identifying and defining the extent of recurrent disease, in distinguishing between posttreatment fibrosis and recurrence, and possibly in monitoring response to therapy.
Non-Curable Tumours of the Female Genital Tract: Therapeutic Options in Bowel Stenosis and Bleeding
BACKGROUND: ...... Ovarian cancer is in particular associated with peritoneal carcinomatosis or local tumour progression entailing different intestinal complications.
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