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Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in developed countries. Several promising steps toward individualized therapy have been taken recently due to increased knowledge of molecular biology. Multidisciplinary conferences for treatment planning and the centralization to tertiary surgical centers improve quality of surgery and survival. The primary treatment of EOC is radical surgery followed by adjuvant chemotherapy with carboplatin and paclitaxel. Bevacizumab added to the chemotherapy and used as maintenance treatment is standard in the primary treatment of patients with residual tumor or inoperable patients. The PARP inhibitor olaparib is recommended as maintenance treatment of women with platinum sensitive relapsed BRCA mutated high-grade serous EOC who have responded to platinum-based chemotherapy. BRCA testing should be offered to women with EOC. In platinum-resistant recurrence addition of bevacizumab to chemotherapy should be considered., Ovarialcancer har högst mortalitet bland gynekologiska cancersjukdomar. I Sverige insjuknar årligen ca 700 patienter. Överlevnaden är bland de högsta i Europa, men på en låg nivå, 46 procent.Nästan 90 procent av kvinnor-na har symtom även i tidigt stadium.Symtom som ska väcka misstanke om ovarialcancer är ihållande utspänd buk, tidig mättnadskänsla, bäcken- eller buksmärta, ökande urinträngningar och postmenopausal blödning.Kvinnors benägenhet att söka sjukvård och sjukvårdens organisation bidrar till canceröverlevnad.Ovarialcancer sammanfattarflera sjukdomar med skilda tumörkarakteristika och prognos. Individualiserad behandling och preventiva åtgärder utifrån denna nyvunna kunskap kan komma att inverka positivt på överlevnaden.

Background: We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. Methods: We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. Results: Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. Conclusion: Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients.

OBJECTIVE: Metabolic pathway alterations in cancer are thought to be dependent upon tumor type-specific oncogenic activation and local nutrient and oxygen supply during disease progression. In serous ovarian cancer, the typical peritoneal spread of disease is caused by shedding of tumor cells into the abdominal cavity, often along with ascites formation. Not much is known about the metabolic features of these detached serous tumor cells. In this study, we investigate the messenger RNA (mRNA) expression of GAPDH (glycolytic glyceraldehyde 3-phosphate dehydrogenase) and PKM2 (pyruvate kinase isoform M2), ATP5B (mitochondrial β-F1-ATPase), and heat shock protein 60 in matched serous solid tumor and corresponding ascites. MATERIALS/METHODS: Fresh samples from solid tumor and corresponding ascites were prospectively collected from 40 patients undergoing primary surgery for suspected advanced ovarian cancer. Of these, 25 met the study eligibility criteria, that is, stage IIC to IV disease of the serous (24) or endometrioid (1) subtype with solid and ascites specimens containing 50% or more tumor cells and with good quality and quantity mRNA yield. All but 2 patients (92%) had type II disease. GAPDH, PKM2, ATP5B, and HSP60 mRNA expressions were assessed by real-time polymerase chain reaction. For each marker, the mRNA expression in solid tumor was pairwise compared with the corresponding expression in ascites using the Wilcoxon matched pairs signed rank sum test. RESULTS: In contrast to our hypothesis, the mRNA expression of analyzed metabolic markers and HSP60 did not significantly differ between matched solid tumor and malignant ascites. CONCLUSIONS: Our results indicate that further expression changes in genes related to glycolysis or oxidative phosphorylation are not a prerequisite for serous cancer cell survival after detachment.

Small cell carcinomas of the ovary are uncommon and account for less than 1% of ovarian cancers. They were first recognized in 1979, and a number of reports appeared during the next 2 decades. They are highly aggressive tumors and usually carry a poor prognosis, although this may reflect that most are diagnosed at advanced stage; however, those diagnosed as stage 1A have only 30% to 40% of long-term survivors. More reports followed extending our experience in the diagnosis and management of these rare cancers. The classification is described below and shown in Table 1, but a revision is expected to be published from the World Health Organization in 2014.

Small cell carcinoma of the cervix (SCCC) is a rare histological entity of uterine cervical cancer. Compared with other common histological types, squamous cell carcinoma or adenocarcinoma, the outcome of SCCC is poor because of the high incidence of nodal or distant metastasis even with early stage. In this review, current consensus of epidemiology, pathology, and initial treatment for SCCC will be discussed.

BACKGROUND: Quality of life (QoL) in endometrial cancer (EC) is understudied. Incorporation of QoL questionnaires and patient-reported outcomes in clinical trials has been inconsistent, and the tools and interpretation of these measures are unfamiliar to most practitioners. In 2012, the Gynecologic Cancer InterGroup Symptom Benefit Working Group convened for a brainstorming collaborative session to address deficiencies and work toward improving the quality and quantity of QoL research in women with EC. METHODS: Through literature review and international expert contributions, we compiled a comprehensive appraisal of current generic and disease site-specific QoL assessment tools, strengths and weaknesses of these measures, assessment of sexual health, statistical considerations, and an exploration of the unique array of histopathologic and clinical factors that may influence QoL outcomes in women with EC. RESULTS: This collaborative composition is the first publication specific to EC that addresses methodology in QoL research and the components necessary to achieve high quality QoL data in clinical trials. Future recommendations regarding (1) the incorporation of patient-reported outcomes in all clinical trials in EC, (2) definition of an a priori hypothesis, (3) utilization of validated tools and consideration of new tools corresponding to new therapies or specific symptoms, (4) publication within the same time frame as clinical outcome data, and (5) attempt to correct for disease site-specific potential confounders are presented. CONCLUSIONS: Improved understanding of methodology in QoL research and an increased undertaking of EC-specific QoL research in clinical trials are imperative if we are to improve outcomes in women with EC.

Squamous cell carcinoma of the ovary is a rare complication of mature cystic teratoma. The epidemiology, pathology, diagnosis, and management of this rare tumor are reviewed. Clinical characteristics, preoperative imaging, and tumor markers may help to predict malignancy preoperatively. Complete cytoreduction should be the aim of surgery. The prognosis for stage 1A disease is good, but for women with advanced or recurrent disease, it is very poor and has not improved in recent years. At present, there are insufficient data to provide clear guidance on the optimal management strategy for advanced disease, and there is a need to gain an understanding of the biology and to develop novel effective therapies. This will require coordinated international collaboration.

Vulvovaginal melanomas are rare tumors that account for a small fraction of all vulvovaginal cancers. Biologically, they seem to be similar to mucosal and acral melanomas of other sites. There are limited data specific to vulvovaginal melanomas, especially regarding systemic therapies. Most treatment decisions are based on extrapolation from data regarding cutaneous melanomas of other sites. It is reasonable to follow already established guidelines from other professional groups and societies. Outcomes tend to be worse compared with cutaneous melanomas likely because of the later presentation and physical biological characteristics of these tumors.

BACKGROUND: There is increasing recognition that quality of life (QoL) and patient-reported outcomes (PROs) are of fundamental importance and particularly relevant given the relatively high likelihood of long-term survival in most women with endometrial cancer (EC). However, there has been relatively little research focused on this topic. Our objective was to analyze our current knowledge and identify research questions to be included in the design of next clinical trials. METHODS: Analyze and critically assess reported clinical trials in EC that have included QoL and PROs as primary or secondary end points. RESULTS: Surgery has a significant impact on physical and functional domains of QoL particularly in the first 6 months after diagnosis. Minimally invasive surgery is associated with less acute morbidity than open procedures and this persists over time. Lymphadenectomy is associated with increased incidence of lymphedema, important late effect. Adjuvant external irradiation may cause gastrointestinal and genitourinary symptoms that impact on physical functioning and which can persist over time. In contrast, vaginal brachytherapy has less toxicity and fewer late effects than external irradiation. The impact of treatment on sexuality has been poorly evaluated in EC survivors. There are few published data on QoL and PROs in patients treated with chemotherapy and the long-term impact has not been addressed. There is no evidence that palliative chemotherapy reduces symptoms and improves QoL. There are very few longitudinal studies on survivorship that is an important concern in EC survivors. CONCLUSIONS: Although there have been some studies addressing QoL and PROs in EC, we have identified deficiencies and gaps in our knowledge. Careful consideration of QoL and PROs end points and how to include them in clinical trials will result in a better appreciation of how treatments can impact on patients QoL and lead to conduct interventions to reduce late effects.

PURPOSE: The aim of this study was to investigate what bowel organ and delivered dose levels are most relevant for the development of 'emptying of all stools into clothing without forewarning' so that the related dose-responses could be derived as an aid in avoiding this distressing symptom in the future. MATERIAL AND METHODS: Of the 77 gynecological cancer survivors treated with radiotherapy (RT) for gynecological cancer, 13 developed the symptom. The survivors were treated between 1991 and 2003. The anal-sphincter region, the rectum, the sigmoid and the small intestines were all delineated and the dose-volume histograms were exported for each patient. The dose-volume parameters were estimated fitting the data to the Relative Seriality (RS), the Lyman and the generalized Equivalent Uniform Dose (gEUD) model. RESULTS: The dose-response parameters for all three models and four organs at risk (OARs) were estimated. The data from the sigmoid fits the studied models best: D50 was 58.8 and 59.5 Gy (RS, Lyman), γ50 was 1.60 and 1.57 (RS, Lyman), s was 0.32, n was 0.13 and a was 7.7 (RS, Lyman, gEUD). The estimated volume parameters indicate that the investigated OARs behave serially for this endpoint. Our results for the three models studied indicate that they have the same predictive power (similar LL values) for the symptom as a function of the dose for all investigated OARs. CONCLUSIONS: In our study, the anal-sphincter region and sigmoid fit our data best, but all OARs were found to have steep dose-responses for 'emptying of all stools into clothing without forewarning' and thus, the outcome can be predicted with an NTCP model. In addition, the dose to the four studied OARs may be considered when minimizing the risk of the symptom.

BACKGROUND: A deregulated energy metabolism is a hallmark of malignant disease that offers possible future targets for treatment. We investigated the prognostic value of the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and pyruvate kinase type M2 (PKM2), mitochondrial β-F1-ATPase (ATP5B) and the bioenergetic cellular (BEC) index in advanced ovarian cancer. METHODS: Fresh tumor samples were prospectively collected from 123 patients undergoing primary surgery for suspected advanced ovarian cancer. Of these, 57 met the eligibility criteria; stage IIC-IV, serous or endometrioid subtype, specimens containing ≥ 50% tumor cells and patients receiving platinum-based chemotherapy. An adequate amount of mRNA could be extracted in all but one case, with a resultant study population of 56 patients. Eighty-six percent of cases had serous tumors, and 93% were grade 2-3. GAPDH, PKM2 and ATP5B mRNA- and protein expression was assessed by real-time PCR and immunohistochemistry. We estimated the association with platinum-free interval (PFI) and overall survival (OS) by Cox proportional hazards models. Median follow-up was 60 months. RESULTS: High GAPDH mRNA levels (HR 2.1, 95% CI 1.0-4.5) and low BEC-index (HR 0.47, 95% CI 0.23-0.95) were both independently associated with shorter PFI. Median PFI for patients with high GAPDH mRNA was 5.0 months compared to 10.1 months for low expression cases (p = 0.031). Similarly, median PFI for patients with low BEC-index based on mRNA was 5.3 months compared to 9.8 months for high BEC-index cases (p = 0.028). CONCLUSIONS: High GAPDH or low BEC-index mRNA expression indicate early disease progression in advanced serous ovarian cancer.

OBJECTIVE: Heat shock protein 60 (HSP60) plays an essential role in malignant cell survival. We evaluated the prognostic and treatment predictive value of HSP60 in advanced ovarian cancer. METHODS: Fresh tumor samples were prospectively collected from 123 patients undergoing primary surgery for suspected advanced ovarian cancer. Of these, 57 fulfilled the eligibility criteria, that is, International Federation of Gynecology and Obstetrics stage IIC-IV, serous/endometrioid tumors, platinum-based chemotherapy, and specimens with 50% tumor cells or greater. Heat shock protein 60 mRNA and protein expression was determined by real-time polymerase chain reaction and immunohistochemistry. We estimated the association between HSP60 and overall survival (OS) and platinum-free interval (PFI) by Cox proportional hazards models and its relationship with treatment response by Fisher's exact test. Median follow-up was 60 months. RESULTS: High HSP60 mRNA expression was associated with shorter OS (hazard ratio [HR], 3.4; 95% confidence interval [CI], 1.3-8.5) and PFI (HR, 3.3; 95% CI, 1.5-7.2). Likewise, high HSP60 protein expression was associated with shorter OS (HR, 3.2; 95% CI, 1.5-7.1) and PFI (HR, 2.6; 95% CI, 1.3-5.3). Median survival for patients with high HSP60 protein expression was 31 months compared with 55 months for low expression cases (P = 0.016). The impact on OS and PFI was even stronger in the subgroup of grade 3 serous tumors. All patients with low HSP60 levels responded to first-line chemotherapy. CONCLUSION: Heat shock protein 60 may identify groups of advanced serous ovarian cancer with different prognosis and treatment response.

Background Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. less thanbrgreater than less thanbrgreater thanMethods A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. less thanbrgreater than less thanbrgreater thanResults The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0x10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4x10(-5) and rs1159057, p=6.8x10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4x10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1x10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0x10(-7)). less thanbrgreater than less thanbrgreater thanConclusions This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy., Funding Agencies|Spanish Ministry of Science and Innovation|SAF2006-01139SAF2009-08307|Spanish Ministry of Economy and Competiveness|SAF2012-35779|Swedish Cancer Society||Swedish Research Council||Fondkistan||Stiftelsen Sigurd och Elsa Goljes Minne and Markus Borgstroms stiftelse||Cancer Research Funds of Radiumhemmet||FIS fellowship|FI08/00375

Purpose: Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated through beta-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in beta-tubulin genes. Experimental Design: We measured variation in gene expression of three beta-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel-induced cytotoxicity in lymphoblastoid cell lines was compared with beta-tubulin expression as measured by Affymetrix exon array. Results: We found a 63-fold variation in beta-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at -101, -112, and -157 in TUBB2A promoter correlated with increased mRNA levels. The -101 and -112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42-0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity. Conclusions: This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a beta-tubulin gene., QC 20120928

BACKGROUND: In ovarian cancer, massive intraperitoneal dissemination is due to exfoliated tumor cells in ascites. Tumor-initiating cells (TICs or cancer stem cells) and cells showing epithelial-mesenchymal-transition (EMT) are particularly implicated. Spontaneous spherical cell aggregates are sometimes observed, but although similar to those formed by TICs in vitro, their significance is unclear. METHODS: Cells freshly isolated from malignant ascites were separated into sphere samples (S-type samples, n=9) and monolayer-forming single-cell suspensions (M-type, n=18). Using western blot, these were then compared for expression of protein markers of EMT, TIC, and of cancer-associated fibroblasts (CAFs). RESULTS: S-type cells differed significantly from M-type by expressing high levels of E-cadherin and no or little vimentin, integrin-β3 or stem cell transcription factor Oct-4A. By contrast, M-type samples were enriched for CD44, Oct-4A and for CAF markers. Independently of M- and S-type, there was a strong correlation between TIC markers Nanog and EpCAM. The CAF marker α-SMA correlated with clinical stage IV. This is the first report on CAF markers in malignant ascites and on SUMOylation of Oct-4A in ovarian cancer. CONCLUSIONS: In addition to demonstrating potentially high levels of TICs in ascites, the results suggest that the S-type population is the less tumorigenic one. Nanog(high)/EpCAM(high) samples represent a TIC subset which may be either M- or S-type, and which is separate from the CD44(high)/Oct-4A(high) subset observed only in M-type samples. This demonstrates a heterogeneity in TIC populations in vivo which has practical implications for TIC isolation based on cell sorting. The biological heterogeneity will need to be addressed in future therapeutical strategies.

PURPOSE: To investigate the relative importance of patient-reported hip and sacral pain after pelvic radiotherapy (RT) for gynecological cancer and its relationship to the absorbed doses in these organs. METHODS AND MATERIALS: We used data from a population-based study that included 650 long-term gynecological cancer survivors treated with pelvic RT in the Gothenburg and Stockholm areas in Sweden with a median follow-up of 6 years (range, 2-15) and 344 population controls. Symptoms were assessed through a study-specific postal questionnaire. We also analyzed the hip and sacral dose-volume histogram data for 358 of the survivors. RESULTS: Of the survivors, one in three reported having or having had hip pain after completing RT. Daily pain when walking was four times as common among the survivors compared to controls. Symptoms increased in frequency with a mean absorbed dose >37.5 Gy. Also, two in five survivors reported pain in the sacrum. Sacral pain also affected their walking ability and tended to increase with a mean absorbed dose >42.5 Gy. CONCLUSIONS: Long-term survivors of gynecological cancer treated with pelvic RT experience hip and sacral pain when walking. The mean absorbed dose was significantly related to hip pain and was borderline significantly related to sacral pain. Keeping the total mean absorbed hip dose below 37.5 Gy during treatment might lower the occurrence of long-lasting pain. In relation to the controls, the survivors had a lower occurrence of pain and pain-related symptoms from the hips and sacrum compared with what has previously been reported for the pubic bone.

BACKGROUND: Many patients treated with radiotherapy to the pelvic region report a change in bowel habits. Loose stools, urgency and fecal incontinence may have a significant impact on daily life and social functioning. MATERIAL AND METHODS: We attempted to follow up 789 women, treated with pelvic radiotherapy for a gynecological cancer during 1991 to 2003 at two departments of gynecological oncology in Sweden. A control group of 478 women from the Swedish Population Registry was also included. As a preparatory study, we made in-depth interviews with 26 women previously treated for gynecological cancer. Based on their narratives, we constructed a study-specific questionnaire including 351 questions and validated it face-to-face. The questionnaire covered questions of physical symptoms originating in the pelvis, demographics, psychological and quality of life factors. In relation to bowel symptoms, 60 questions were asked. RESULTS: Six-hundred and sixteen (78%) gynecological cancer survivors and 344 (72%) control women participated. Two-hundred and twenty-six (37%) cancer survivors reported loose stools at least once a week. Eighty-three percent of the survivors with loose stools every day reported defecation urgency with fecal leakage, compared to 20% of cancer survivors without loose stools. Cancer survivors with loose stools at least once a week were 7.7 times more likely to suffer from defecation urgency with fecal leakage (95% CI 4.4-13.3) compared to those who had loose stools once a month or less. In order to avoid loose stools affected survivors with loose stools often skipped meals (13%), made an active choice of food (47%) and preferentially used prescribed medication (36%). DISCUSSION: There is a relation between loose stools and defecation urgency with fecal leakage among long-term gynecological cancer survivors treated with pelvic radiotherapy. Targeting loose stools can possibly help survivors to decrease frequency of fecal leakage.

The 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup was held in Vancouver, Canada, in June 2010. Representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. Group C, 1 of the 3 discussion groups, examined recurrent ovarian cancer, and we report the consensus reached regarding 4 questions. These included the following: (1) What is the role of cytoreductive surgery for recurrent ovarian cancer? (2) How do we define distinct patient populations in need of specific therapeutic approaches? (3) Should end points for trials with recurrent disease vary from those of first-line trials? (4) Is CA-125 progression alone sufficient for entry/eligibility into clinical trials?

PURPOSE: To analyze the relationship between mean absorbed dose to the pubic bone after pelvic radiotherapy for gynecological cancer and occurrence of pubic bone pain among long-term survivors. METHODS AND MATERIALS: In an unselected, population-based study, we identified 823 long-term gynecological cancer survivors treated with pelvic radiotherapy during 1991-2003. For comparison, we used a non-radiation-treated control population of 478 matched women from the Swedish Population Register. Pain, intensity of pain, and functional impairment due to pain in the pubic bone were assessed with a study-specific postal questionnaire. RESULTS: We analyzed data from 650 survivors (participation rate 79%) with median follow-up of 6.3 years (range, 2.3-15.0 years) along with 344 control women (participation rate, 72 %). Ten percent of the survivors were treated with radiotherapy; ninety percent with surgery plus radiotherapy. Brachytherapy was added in 81%. Complete treatment records were recovered for 538/650 survivors, with dose distribution data including dose-volume histograms over the pubic bone. Pubic bone pain was reported by 73 survivors (11%); 59/517 (11%) had been exposed to mean absorbed external beam doses <52.5 Gy to the pubic bone and 5/12 (42%) to mean absorbed external beam doses ≥ 52.5 Gy. Thirty-three survivors reported pain affecting sleep, a 13-fold increased prevalence compared with control women. Forty-nine survivors reported functional impairment measured as pain walking indoors, a 10-fold increased prevalence. CONCLUSIONS: Mean absorbed external beam dose above 52.5 Gy to the pubic bone increases the occurrence of pain in the pubic bone and may affect daily life of long-term survivors treated with radiotherapy for gynecological cancer.

To survey the centers that can provide subspecialty surgical training and education in gynecological oncology in the Nordic countries, we developed an online questionnaire in co-operation with the Nordic Society of Gynecological Oncology. The link to the survey was mailed to 22 Scandinavian gynecological centers in charge of surgical treatment of cancer patients. Twenty (91%) centers participated. Four centers reported to be accredited European subspecialty training centers, a further six were interested in being accredited, and 11 centers were accredited by the respective National Board. Fourteen (74%) centers were interested in being listed for exchange of fellows. Our data show a large Nordic potential and interest in improving the gynecologic oncology standards and can be used to enhance the awareness of gynecologic oncology training in Scandinavia and to facilitate the exchange of fellows between Nordic countries.

BACKGROUND: We surveyed the occurrence of physical symptoms among long-term gynaecological cancer survivors after pelvic radiation therapy, and compared with population-based control women. METHODS: We identified a cohort of 789 eligible gynaecological cancer survivors treated with pelvic radiation therapy alone or combined with surgery in Stockholm or Gothenburg, Sweden. A control group of 478 women was randomly sampled from the Swedish Population Registry. Data were collected through a study-specific validated postal questionnaire with 351 questions concerning gastrointestinal and urinary tract function, lymph oedema, pelvic bones and sexuality. Clinical characteristics and treatment details were retrieved from medical records. RESULTS: Participation rate was 78% for gynaecological cancer survivors and 72% for control women. Median follow-up time after treatment was 74 months. Cancer survivors reported a higher occurrence of symptoms from all organs studied. The highest age-adjusted relative risk (RR) was found for emptying of all stools into clothing without forewarning (RR 12.7), defaecation urgency (RR 5.7), difficulty feeling the need to empty the bladder (RR 2.8), protracted genital pain (RR 5.0), pubic pain when walking indoors (RR 4.9) and erysipelas on abdomen or legs at least once during the past 6 months (RR 3.6). Survivors treated with radiation therapy alone showed in general higher rates of symptoms. CONCLUSION: Gynaecological cancer survivors previously treated with pelvic radiation report a higher occurrence of symptoms from the urinary and gastrointestinal tract as well as lymph oedema, sexual dysfunction and pelvic pain compared with non-irradiated control women. Health-care providers need to actively ask patients about specific symptoms in order to provide proper diagnostic investigations and management.

INTRODUCTION: Fecal incontinence is a symptom reported by cancer survivors after pelvic radiotherapy and is recognized to be one of the most troubling symptom-induced sources of distress to patients. OBJECTIVE: To investigate how fecal incontinence, patient-reported as emptying of all stools into clothing without forewarning, impact self-assessed quality of life from a social, psychological, sexual, and functional aspect among gynecological cancer survivors treated with pelvic radiotherapy. METHODS: We identified a cohort of 789 eligible women in the Stockholm and Gothenburg areas treated with pelvic radiotherapy alone or as combined treatment of gynecological cancer. From the Swedish Population Registry, we identified 478 control women. Data were collected using a study-specific, validated, postal questionnaire including questions covering symptoms from the pelvic region, demographics, social functioning, psychological, and quality-of-life issues. RESULTS: Participation was 78% for cancer survivors and 72% for control women. The fecal incontinence symptom emptying of all stools into clothing without forewarning was reported by 70 cancer survivors (12%), with lowered quality of life in 74% of the 70 cancer survivors. This symptom kept the survivors from going to parties (relative risk [RR], 11.8; 95% confidence interval [CI], 6.6-21.1), kept the survivors from traveling (RR, 9.3; 95% CI, 5.3-16.5), affected their work ability (RR, 7.9; 95% CI, 3.8-16.4), hindered their sexual life (RR, 9.2; 95% CI, 4.8-17.6), and changed them as persons (RR, 4.9; 95% CI, 2.9-8.1). The prevalence of the symptom emptying of all stools into clothing without forewarning among control women was 3 (1%) of 344. CONCLUSIONS: Among gynecological cancer survivors having undergone pelvic radiotherapy alone or as part of a combined treatment, fecal incontinence is associated with social, psychological, sexual, and functional consequences.

PURPOSE: This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) with carboplatin (CD) compared with standard carboplatin and paclitaxel (CP) in patients with platinum-sensitive relapsed/recurrent ovarian cancer (ROC). PATIENTS AND METHODS: Patients with histologically proven ovarian cancer with recurrence more than 6 months after first- or second-line platinum and taxane-based therapies were randomly assigned by stratified blocks to CD (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m(2)) every 4 weeks or CP (carboplatin AUC 5 plus paclitaxel 175 mg/m(2)) every 3 weeks for at least 6 cycles. Primary end point was progression-free survival (PFS); secondary end points were toxicity, quality of life, and overall survival. RESULTS: Overall 976 patients were recruited. With median follow-up of 22 months, PFS for the CD arm was statistically superior to the CP arm (hazard ratio, 0.821; 95% CI, 0.72 to 0.94; P = .005); median PFS was 11.3 versus 9.4 months, respectively. Although overall survival data are immature for final analysis, we report here a total of 334 deaths. Overall severe nonhematologic toxicity (36.8% v 28.4%; P < .01) leading to early discontinuation (15% v 6%; P < .001) occurred more frequently in the CP arm. More frequent grade 2 or greater alopecia (83.6% v 7%), hypersensitivity reactions (18.8% v 5.6%), and sensory neuropathy (26.9% v 4.9%) were observed in the CP arm; more hand-foot syndrome (grade 2 to 3, 12.0% v 2.2%), nausea (35.2% v 24.2%), and mucositis (grade 2-3, 13.9% v 7%) in the CD arm. CONCLUSION: To our knowledge, this trial is the largest in recurrent ovarian cancer and has demonstrated superiority in PFS and better therapeutic index of CD over standard CP.

PURPOSE: One attempt to improve long-term survival in patients with advanced ovarian cancer was thought to be the addition of more non-cross-resistant drugs to platinum-paclitaxel combination regimens. Gemcitabine was among the candidates for a third drug. PATIENTS AND METHODS: We performed a prospective, randomized, phase III, intergroup trial to compare carboplatin plus paclitaxel (TC; area under the curve [AUC] 5 and 175 mg/m(2), respectively) with the same combination and additional gemcitabine 800 mg/m(2) on days 1 and 8 (TCG) in previously untreated patients with advanced epithelial ovarian cancer. TC was administered intravenously (IV) on day 1 every 21 days for a planned minimum of six courses. Gemcitabine was administered by IV on days 1 and 8 of each cycle in the TCG arm. RESULTS: Between 2002 and 2004, 1,742 patients were randomly assigned; 882 and 860 patients received TC and TCG, respectively. Grades 3 to 4 hematologic toxicity and fatigue occurred more frequently in the TCG arm. Accordingly, quality-of-life analysis during chemotherapy showed a disadvantage in the TCG arm. Although objective response was slightly higher in the TCG arm, this did not translate into improved progression-free survival (PFS) or overall survival (OS). Median PFS was 17.8 months for the TCG arm and 19.3 months for the TC arm (hazard ratio [HR], 1.18; 95% CI, 1.06 to 1.32; P = .0044). Median OS was 49.5 for the TCG arm and 51.5 months for the TC arm (HR, 1.05; 95% CI, 0.91 to 1.20; P = .5106). CONCLUSION: The addition of gemcitabine to carboplatin plus paclitaxel increased treatment burden, reduced PFS time, and did not improve OS in patients with advanced epithelial ovarian cancer. Therefore, we recommend no additional clinical use of TCG in this population.

The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ovarian cancer patients. Thirty-eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy., This is the authors’ version of the following article: Henrik Green, Peter Söderkvist, Per Rosenberg, Rajaa A Mirghani, Per Rymark, Elisabeth Avall Lundqvist and Curt Peterson, Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer, 2009, Basic and clinical pharmacology and toxicology, (104), 2, 130-137. which has been published in final form at: http://dx.doi.org/10.1111/j.1742-7843.2008.00351.x Copyright: Blackwell Publishing http://eu.wiley.com/WileyCDA/Brand/id-35.html

The presence of lymph node metastases is associated with poor prognosis in early stage cervical cancer. As of yet, no molecular markers predicting lymph node metastases have been identified. We examined single genetic markers and a composite marker, comprised of three fluorescence in situ hybridization (FISH) probes targeting the genes LAMP3, PROX1, and PRKAA1, in pretreatment cervical biopsies from 16 lymph node positive cases and 15 lymph node negative controls from women with stage IB and IIA cervical cancer. In addition, we determined clonal patterns by including CCND1 to compare the clonal constitution of primary tumors and associated lymph node metastases. The composite FISH marker allowed for classification of patients into those with and without lymph node metastases with a sensitivity and specificity of 75% and 87%, respectively (P = 0.001). The positive predictive value and negative predictive value were 86% and 76%, respectively. Clonal patterns varied among the tumors. In many cases, changes between the primary tumor and lymph node metastases in the most common clones may indicate that certain clones have a growth advantage for establishing metastases in lymph nodes. We conclude that the composite FISH marker may be useful for determining risk for subsequent development of lymph node metastases in patients with cervical cancer.

New promising therapeutic agents targeting epidermal growth factor receptor (EGFR) have been developed although clinical information concerning EGFR status in oral tongue squamous cell carcinoma (OTSCC) is limited. We investigated EGFR protein expression and gene copy numbers in 78 pretreatment OTSCC paraffin samples. EGFR protein expression was found in all 78 tumours, of which 72% showed an intense staining. Fifty-four percent of the tumours had high (> or =four gene copies) EGFR gene copy numbers. EGFR gene copy number was significantly associated with EGFR protein expression (P=0.002). Pretreatment EGFR staining intensity tended to be associated with non-pathological complete remission after preoperative radiotherapy for Stage II OTSCC. No correlation was found between EGFR status and survival. EGFR FISH results were significantly (P=0.003) higher in more advanced tumours (Stages II, III and IV) than in the tumours in Stage I. Non-smokers exhibited a significantly higher EGFR gene copy number and protein overexpression in Stages I and II OTSCC than smokers (P=0.001, P=0.009). In conclusion, EGFR was found to be overexpressed in all OTSCCs making this cancer type interesting for exploring new therapeutic agents targeting the EGFR receptor.

We have here examined chemopotentiating effects of glycolysis inhibitor 2-deoxy-d-glucose (DG) in two epithelial ovarian carcinoma (EOC) cell lines and 17 freshly isolated ascitic EOC cell samples, and we identify low expression of the beta-F1-ATPase involved in mitochondrial ATP production as a candidate marker for sensitivity to this strategy. Although in the majority of samples, DG per se did not induce apoptosis, cotreatment with DG potentiated apoptosis and total antiproliferative effects of cisplatin and, to a lesser degree, carboplatin. In the cell lines, combination treatment with DG and cisplatin or carboplatin at noninhibitory concentrations prevented posttreatment regrowth in drug-free medium over a total of 5 days. DG per se allowed complete recuperation in drug-free medium. The more platinum-resistant a cell line was, the more sensitive it was to potentiation by DG and showed higher glucose uptake, DG-sensitive lactate production, and lower beta-F1-ATPase levels. In the ascitic samples, DG reduced the median IC(50) for cisplatin by 68% and, in the most sensitive samples, up to 90%, and DG-mediated potentiation correlated with low expression of beta-F1-ATPase. By contrast, cisplatin sensitivity did not correlate with beta-F1-ATPase levels. The findings validate targeting cancer cell glucose metabolism for potentiating platinum chemotherapy in EOC and indicate that reduced beta-F1-ATPase/oxidative phosphorylation distinguishes cells that are amenable to this strategy.

Oral tongue squamous cell carcinoma (OTSCC) is an aggressive cancer associated with poor prognosis. Methods for determining the aggressiveness of OTSCC from analysis of the primary tumour specimen are thus highly desirable. We investigated whether genomic instability and proliferative activity (by means of Ki-67 activity) could be of clinical use for prediction of locoregional recurrence in 76 pretreatment OTSCC paraffin samples (stage I, n=22; stage II, n=33; stage III, n=8; stage IV, n=13). Eleven surgical tumour specimens were also analysed for remnants of proliferative activity after preoperative radiotherapy. Ninety-seven percent of cases (n=72) were characterised as being aneuploid as measured by means of image cytometry. Preoperative radiotherapy (50-68 Gy) resulted in significant reduction of proliferative activity in all patients for which post-treatment biopsies were available (P-value=0.001). Proliferative activity was not associated with response to radiation in stage II patients. However, we report a significant correlation between high proliferation rates and locoregional recurrences in stage I OTSCC patients (P-value=0.028). High-proliferative activity is thus related to an elevated risk of recurrence after surgery alone. We therefore conclude that Ki-67 expression level is a potentially useful clinical marker for predicting recurrence in surgically treated stage I OTSCC.

The primary aim of this study was to investigate if the expression of the DNA damage identifying protein DNA-PKcs known to be involved in DNA repair after treatment with ionising radiation can be used as a predictive marker for radiotherapy (RT) response in cervical cancer. Formalin-fixed primary tumour biopsies from 109 patients with cervical cancer, FIGO-stage IB-IIA, treated with preoperative brachytherapy followed by radical surgery were analysed by immunohistochemistry. In addition, correlation studies between early pathological tumour response to radiation and expression of Ku86, Ku70, Mdm-2, p53 and p21 in primary tumours were also performed. We found that tumour-transformed tissue shows positive immunostaining of DNA-PKcs, Ku86 and Ku70, while non-neoplastic squamous epithelium and tumour-free cervix glands show negative immunoreactivity. Expression of DNA-PKcs positively correlated with both Ku86 and Ku70, and a statistically significant correlation between the Ku subunits was also found. After RT, 85 patients demonstrated pathologic complete remission (pCR), whereas 24 patients had residual tumour in the surgical specimen (non-pCR). The main finding of our study is that there was no correlation between the outcome of RT and the expression of DNA-PK subunits. Positive p53 tumours were significantly more common among non-pCR cases than in patients with pCR (P=0.031). Expression of p21 and Mdm-2 did not correlate with the outcome of RT.

The aim of the study was to acquire knowledge that can be used to refine radical hysterectomy to improve quality-of-life outcome. Data were collected in 1996-1997 by means of an anonymous postal questionnaire in a follow-up study of two cohorts (patients and population controls). We attempted to enroll all 332 patients with stage IB-IIA cervical cancer registered in 1991-1992 at the seven departments of gynecological oncology in Sweden and 489 population controls. Ninety three (37%) of the 256 women with a history of cervical cancer who answered the questionnaire (77%) were treated with surgery alone. Three-hundred fifty population controls answered the questionnaire (72%). Women treated with radical hysterectomy, as compared with controls, had an 8-fold increase in symptoms indicating lymphedema (25% reported distress due to lymphedema), a nearly 9-fold increase in difficult emptying of the bladder, and a 22-fold increase in the need to strain to initiate bladder evacuation. Ninety percent of the patients were not willing to trade off survival for freedom from symptoms. Avoiding to induce long-term lymphedema or bladder-emptying difficulties would probably improve quality of life after radical hysterectomy (to cure cervical cancer). Few women want to compromise survival to avoid long-term symptoms.

Experiencing a sexual abuse creates a life-long traumatic memory. The life-long effect of such abuse on sexuality, well-being, the risk of contracting cervical cancer, or problems after treatment for cervical cancer is not known. A population-based follow-up study in 1996-97 that used an anonymous postal questionnaire for data collection, 256 women with stage IB-IIA cervical cancer registered in 1991-92 in Sweden, and 350 women without cervical cancer frequency matched for age and region of residence, provided information. Among the women with a history of cervical cancer and the control women, 46 (18%) and 50 (15%), respectively, reported a history of sexual abuse. The follow-up was 1-70 years after the sexual abuse. The relative risk (with 95% confidence interval) of decreased well-being was 2.4 (1.1-5.2) among controls and 2.7 (1.1-6.4) among former cervical cancer patients. A history of both sexual abuse and cervical cancer gave a relative risk of 30.0 (7.0-129.0) for superficial dyspareunia. Sexual abuse increased the risk of sexual problems after treatment. The sexually abused cervical cancer patients were generally less willing than other patients to trade off possible maximal survival and forgo parts of the treatment. A history of sexual abuse and cervical cancer are both independent risk factors for sexual dysfunction and decreased well-being, and there may be a large synergy when both factors are combined. Diagnosis and treatment of cervical cancer may be improved by recognition of a sexual abuse history.