A prospective assessment of musculoskeletal toxicity and loss of grip strength in breast cancer patients receiving adjuvant aromatase inhibitors and tamoxifen, and relation with BMI.

Aromatase inhibitor (AI) therapy for estrogen receptor-positive breast cancer is known to induce or enhance musculoskeletal problems. We have previously reported that loss of grip strength is more pronounced in AI-users with extremes in BMI. We here report results from a larger prospective study. Postmenopausal early breast cancer patients scheduled to start AI or tamoxifen therapy were recruited. A functional assessment grip strength test was performed at baseline, 3, 6, and 12 months of therapy. BMI was assessed, and a rheumatologic questionnaire was completed at each visit. 188 patients on an AI and 104 patients on tamoxifen were enrolled. 74 % of AI-users reported new/worsened musculoskeletal complaints compared with 37 % in the tamoxifen group. This was translated in a larger grip strength decrease in patients experiencing AI-induced pain opposed to patients without new/worsened complaints (p = 0.0002). 15 % of AI-users discontinued therapy due to musculoskeletal symptoms, who were characterized by a larger grip strength reduction versus adherent patients (p = 0.0107). Young age (p = 0.0135), taxane-based chemotherapy (p = 0.0223), and baseline VAS score >4 (p = 0.0155) were predictors for AI-related musculoskeletal pain. In addition, a quadratic trend of BMI with grip strength change (p = 0.0090) and probability of discontinuation was observed (p = 0.0424). Musculoskeletal events were a substantial problem in AI-treated patients and an important reason for treatment discontinuation. The decrease in grip strength was larger in AI- than in tamoxifen-users, with a more pronounced change in symptomatic patients. The inverse relationship between BMI extremes and grip strength change was confirmed in this large group of AI-patients.

Prospective study to assess fluid accumulation and tenosynovial changes in the aromatase inhibitor-induced musculoskeletal syndrome: 2-year follow-up data.

BACKGROUND: Aromatase inhibitors (AIs) frequently lead to the AI-induced musculoskeletal syndrome (AIMSS). Looking into its pathophysiology, 6 months of AI therapy thickens the tendon sheath with intra-articular fluid (IAF) retention and loss of grip strength. We here report 24-month follow-up data. PATIENTS AND METHODS: A prospective cohort study of 33 postmenopausal breast cancer patients received adjuvant endocrine therapy; 27 received an AI and 6 received tamoxifen. At baseline, 6 and 24 months patients had a rheumatologic examination, including a grip strength test, and magnetic resonance imaging of both hands and wrists. The primary end point was tenosynovial changes; secondary end points were changes in morning stiffness, grip strength and IAF. RESULTS: Twenty-three AI and 5 tamoxifen patients completed all investigations. Between month 6 and 24, IAF further increased in AI users (P = 0.04) but not in tamoxifen users, and grip strength further decreased in both groups. The worsened tenosynovial changes were strongly correlated with a decrease in grip strength. At 24 months, morning stiffness continued to be present in over a third of AI users. CONCLUSION: AIMSS represents a substantial problem in breast cancer patients. It is associated with tenosynovial changes, IAF retention, joint stiffness and loss of grip strength that do not improve with prolonged use.

Folate receptor alpha (FRA) expression remains unchanged in epithelial ovarian and endometrial cancer after chemotherapy.

OBJECTIVE: Based on its expression profile, folate receptor alpha (FRA) is an attractive candidate for targeted diagnostics and therapeutics. However, applicability of these agents in residual or recurrent disease could be influenced by chemotherapy. We evaluated whether chemotherapy modified FRA expression in non-mucinous epithelial ovarian (EOC) and endometrial carcinoma (EC). METHODS: FRA staining was evaluated by immunohistochemistry, using MAb 26B3, in 81 patients (41 EOCs and 40 ECs) and 17 control tissues (5 benign ovarian cysts, 5 normal ovarian, and 7 normal endometrial tissues). Chemotherapy effect was evaluated in 42 patients (30 paired samples at primary and interval debulking surgery and 12 from primary and recurrent disease). FRA expression was assessed using a semi-quantitative staining algorithm, the M-score (range 0-50). RESULTS: Median difference in M-score between tumor and control samples was 27.5 for EOC (95% CI 10.0 to 45.0) and 6.7 for EC (95% CI -6.7 to 21.7). Paired samples from both primary and interval debulking surgery did not differ in FRA expression in EOC (median difference of M-score between paired samples of 0.0 [95% CI -2.6 to 2.6]). Recurrent EOC tumors reflected FRA status at diagnosis (median difference of M-score between paired samples of 3.3 [95% CI -7.0 to 13.6]). CONCLUSIONS: This study shows no significant difference in FRA expression after chemotherapy, strengthening the rationale for FRA targeted diagnostics and therapeutics in FRA expressing tumors, whether newly diagnosed or at recurrence.

PET/CT in the staging of patients with a pelvic mass suspicious for ovarian cancer.

OBJECTIVE: To prospectively assess the value of PET/CT for staging, diagnosis and operability of ovarian cancer, with special attention to the peritoneal spread. METHODS: From June 2009 to March 2011, 69 patients with suspicion of having an ovarian cancer underwent an (18)F-FDG PET/CT. To identify the diagnostic value of PET/CT, the results were compared with the findings at diagnostic laparoscopy and/or debulking surgery. RESULTS: There were 56 patients with malignant tumors and 13 with benign tumors. We observed a sensitivity and specificity of 93% and 77%, respectively for malignant tumors with PET/CT. CT alone had a sensitivity and specificity of 96% and 38%, respectively. The overall FIGO classification evaluation for PET/CT and CT were the same. For the evaluation of metastases, the sensitivity of PET/CT was worse, while the specificity was better than CT. Retroperitoneal lymph node metastases were diagnosed better with PET/CT, while there was no difference for peritoneal spread and for the intestines. PET/CT detected another unknown primary tumor in 3 (4.3%) cases. CONCLUSION: PET/CT is better than CT in detecting retroperitoneal lymph node metastases, but not for peritoneal metastases.

Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families.

BACKGROUND: Recent data show that mutations in RAD51D have an aetiological role in ovarian carcinoma, yet mutations do not appear to be associated with an increased risk for breast cancer. We studied ovarian and breast cancer families having at least one woman affected by ovarian carcinoma, to assess the importance of RAD51D mutations in such families. METHODS: The coding region of the RAD51D gene was analysed in 175 BRCA1/2-negative families with family histories of both ovarian and breast cancer ascertained from two Canadian and two Belgian institutions. RESULTS: We identified one previously reported deleterious mutation, p.Arg186(*) (c.556C>T), and two novel variants; missense substitution p.Cys119Arg and an intronic variant c.83-26A>G. p.Arg186(*) segregated with the disease in the family and two ovarian carcinomas available for analysis showed loss of the wild-type allele, but the novel variants are likely neutral. CONCLUSION: RAD51D should be included in genetic screening of ovarian cancer families that do not have BRCA1/BRCA2 mutations. We show that mutations are more likely to be found in families with two or more ovarian cancers, or in probands with first-degree relatives with ovarian cancer, and we feel testing should be preferentially offered to affected women from such families.

Applying the 2011 St Gallen panel of prognostic markers on a large single hospital cohort of consecutively treated primary operable breast cancers.

BACKGROUND: Many easily measurable and readily available factors are now established as being prognostic in primary operable breast cancer. We here applied the 2011 St Gallen surrogate definition for breast cancer subclassification using tumor grade instead of Ki67. PATIENTS AND METHODS: Four thousand three hundred and eighteen consecutive patients who had surgery for primary operable breast cancer (1 January 2000 and 31 December 2009) in UZ Leuven excluding primary metastastic male breast cancers and those receiving neoadjuvant therapy. Five different surrogate phenotypes were created using the combined expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 together with tumor grade. Disease-free interval (DFI), distant metastastis-free interval (DMFI), locoregional relapse-free interval (LRRFI), breast cancer-specific survival (BCSS) and overall survival (OS) were calculated. RESULTS: Surrogate phenotypes present with significant differences in DFI, DMFI, LRRFI, BCSS and OS. 'Luminal A' tumors presented with the best outcome parameters but the effect weakened at longer follow-up. CONCLUSIONS: The four surrogate markers, agreed upon by the 2011 St Gallen consensus, defined five prognostic surrogate phenotypes in a large series of consecutively treated breast cancer patients. Their prognostic value changed with longer follow-up. The added value of gene expression profile over classical pathological assessment remains to be defined.

Stellate ganglion block for the management of hot flashes and sleep disturbances in breast cancer survivors: an uncontrolled experimental study with 24 weeks of follow-up.

BACKGROUND: We studied the stellate ganglion block (SGB) recently suggested for the treatment of severe vasomotor symptoms and sleep disturbances in breast cancer survivors. Following an initial pilot study, which focused on the acceptability and safety of SGB for this important problem, we evaluated its short- and long-term efficacy. MATERIALS AND METHODS: Postmenopausal breast cancer survivors with severe vasomotor symptoms resistant to standard nonhormonal pharmacological intervention were eligible. Diaries were used to measure daily hot flash scores (frequency and intensity) and sleep quality (Pittsburgh Sleep Quality Index) during scheduled visits at baseline, 1, 4, 12 and 24 weeks following the SGB. Efficacy data were analyzed using longitudinal regression models. RESULTS: Thirty-four patients participated and none refused the SGB procedure. Most patients received more than one SGB. The pilot study found SGB to be safe. In the main study, hot flash scores were reduced from baseline by 64% [95% confidence interval (CI) -74% to -49%] and 47% (95% CI -62% to -27%) at weeks 1 and 24, respectively. The odds ratio of better sleep quality relative to baseline was 3.4 at week 1 (95% CI 1.6-7.2) and 4.3 at week 24 (95% CI 1.9-9.8). CONCLUSION: In the short term, SGB appears to be an effective treatment with acceptable morbidity for some breast cancer survivors with therapy-resistant vasomotor symptoms and/or sleep disturbances. Although sleep quality was maintained out to 24 weeks the efficacy of SGB for hot flashes was reduced over time. A randomized controlled trial is needed to confirm these findings.

Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing.

Despite extensive analysis of the BRCA1 and BRCA2 genes, germline mutations are detected in <20% of families with a presumed genetic predisposition for breast and ovarian cancer. Recent literature reported RAD51C as a new breast cancer susceptibility gene. In this study, we report the analysis of 410 patients from 351 unrelated pedigrees. All were referred for genetic testing and we selected families with at least one reported case of ovarian cancer in which BRCA1&2 mutations were previously ruled out. We analyzed the coding exons, intron-exons boundaries, and UTRs of RAD51C. Our mutation analysis did not reveal any unequivocal deleterious mutation. In total 12 unique sequence variations were identified of which two were novel. Our study and others suggest a low prevalence of RAD51C mutations with an exception for some founder populations. This observation is in favor of the rare allele hypothesis in the debate over the nature of the genetic contribution to individual susceptibility to breast and ovarian cancer and further genome-wide studies in high risk families are warranted.

HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm.

BACKGROUND: Recently, a Risk of Ovarian Malignancy Algorithm (ROMA) utilising human epididymis secretory protein 4 (HE4) and CA125 successfully classified patients as presenting a high or low risk for epithelial ovarian cancer (EOC). We validated this algorithm in an independent prospective study. METHODS: Women with a pelvic mass, who were scheduled to have surgery, were enrolled in a prospective study. Preoperative serum levels of HE4 and CA125 were measured in 389 patients. The performance of each of the markers, as well as that of ROMA, was analysed. RESULTS: When all malignant tumours were included, ROMA (receiver operator characteristic (ROC)-area under curve (AUC)=0.898) and HE4 (ROC-AUC)=0.857) did not perform significantly better than CA125 alone (ROC-AUC=0.877). Using a cutoff for ROMA of 12.5% for pre-menopausal patients, the test had a sensitivity of 67.5% and a specificity of 87.9%. With a cutoff of 14.4% for post-menopausal patients, the test had a sensitivity of 90.8% and a specificity of 66.3%. For EOC vs benign disease, the ROC-AUC of ROMA increased to 0.913 and for invasive EOC vs benign disease to 0.957. CONCLUSION: This independent validation study demonstrated similar performance indices to those recently published. However, in this study, HE4 and ROMA did not increase the detection of malignant disease compared with CA125 alone. Although the initial reports were promising, measurement of HE4 serum levels does not contribute to the diagnosis of ovarian cancer.

Aromatase inhibitor-induced loss of grip strength is body mass index dependent: hypothesis-generating findings for its pathogenesis.

BACKGROUND: Our preliminary results showed that tenosynovial changes and decrease in grip strength are associated with the aromatase inhibitor-induced musculoskeletal syndrome (AIMSS). Here, we report the final results and assess the relationship between grip strength and body mass index (BMI). PATIENTS AND METHODS: We conducted a prospective study including postmenopausal early breast cancer patients receiving either an aromatase inhibitor (AI) or tamoxifen. Primary end point was change from baseline in tenosynovial abnormalities. Secondary end points were changes from baseline in morning stiffness, intra-articular fluid and grip strength and its association with BMI. RESULTS: After 6 months of therapy, 74% [95% confidence interval (CI) 51% to 89%] of AI-treated patients had worsened tenosynovial abnormalities, 56% (95% CI 34% to 75%) had increased intra-articular fluid, and 22% (95% CI 9% to 45%) had increased morning stiffness. Grip strength decreased 8% for the left hand (95% CI 2% to 21%) and 11% for the right (95% CI 4% to 17%). Regression analysis suggested that grip strength decreased more for subjects with high or with low BMI. CONCLUSIONS: AIMSS is characterized by tenosynovial changes, intra-articular fluid and morning stiffness. We hypothesize that the quadratic association between BMI and loss of grip strength reflects AI-induced changes on the endocrine control of the growth hormone insulin-like growth factor-I pathway.

Lobular and non-lobular breast cancers differ regarding axillary lymph node metastasis: a cross-sectional study on 4,292 consecutive patients.

Invasive lobular carcinoma (ILC) accounts for 8-14% of all breast cancers and carries distinct prognostic and biologic implications. The goal of our study was to investigate the impact of lobular histology on axillary lymph node (ALN) involvement. This is a cross-sectional study of 4,292 consecutive patients surgically treated for breast carcinoma at the University Hospitals Leuven. Logistic regression analysis was used to relate ILC to lymph node involvement while controlling for the following clinicopathologic features: tumor size, multifocal disease, tumor grade, lobular subtype and the combined steroid, and Her-2 status. Odds ratios (ORs) and 95% confidence intervals (CIS) were computed. A subgroup analysis was performed for patients that underwent a sentinel lymph node (SLN) procedure. The observed incidence of ILC was 13%. ILCs were larger, were more often grade II, multifocal, steroid receptor positive and Her-2 negative, and tended to be present in older patients. Incidence of ALN involvement was 42.0% for ILCs versus 38.3% for other tumors (OR 1.17, 95% CI 0.97-1.40). For the SLN subgroup, ILCs were less often ALN positive than non-ILCs (20.5% versus 28.3%, OR 0.66, 95% CI: 0.41-1.00). In the multivariable analysis, the lobular subtype was identified as less likely to have ALN involvement (adjusted OR 0.66, 95% CI 0.53-0.82). The analysis for the SLN subgroup showed comparable results (adjusted OR 0.49, 95% CI 0.30-0.78). This study has demonstrated that the lobular subtype is an independent predictor of lymph node involvement with ILC having a lower incidence of involved lymph nodes. The mildly higher incidence of ALN metastasis in lobular cancers in univariable analysis is not due to the lobular subtype, but due to confounding factors that interact with lymph node involvement.

Diaphragmatic surgery during primary debulking in 89 patients with stage IIIB-IV epithelial ovarian cancer.

OBJECTIVES: The aim of this study was to describe the role of diaphragmatic surgery in achieving optimal debulking in patients with advanced ovarian cancer and the assessment of the relative post-operative complications. METHODS: Retrospective review was performed of medical records of 89 patients with epithelial ovarian cancer who underwent diaphragmatic surgery during their primary debulking surgery between September 1993 and December 2007. Four different approaches were performed: coagulation (group 1), stripping (group 2), combination stripping with coagulation (group 3) and diaphragm full thickness resection (group 4). Cytoreductive outcome, morbidity, overall survival (OS) and disease-free survival (DFS) were analysed. RESULTS: Eight (8.9%) patients had FIGO stage IIIB, 64 (72%) stage IIIC and 17 (19.1%) stage IV disease. In 20 patients (22%) the diaphragmatic disease was coagulated, in 31 patients (35%) was only stripped, in 31 patients (35%) a combination of these techniques was applied and in 7 (8%) the disease was resected with the adjacent infiltrated part of the diaphragm muscle and the pleura above it. Debulking to no residual tumor was achieved in 90%, 86%, 86% and 100% for groups 1, 2, 3 and 4 respectively. Median DFS was 15, 15, 17 and overall survival OS for groups 1, 2, and 3 was 40, 42, and 50 months respectively and was not yet reached for group 4. Minor and major complications were comparable among the groups. Pleural effusion was the most frequent associated complication and chest tube placement (17%) or thoracocentesis (12%) was necessary for the relief of respiratory distress. The perioperative mortality rate was 0%. The majority of cases were treated in the last five years of our 15-year experience. CONCLUSIONS: Diaphragmatic surgery increases the rates of optimal primary debulking surgery and improves survival with an acceptable and manageable morbidity rate. In patients with thick (>0.3 cm) or large (>4 cm) lesions stripping the diaphragm or full thickness resection of the diaphragmatic muscle is preferred.

Neoadjuvant chemotherapy followed by interval debulking surgery in patients with serous endometrial cancer with transperitoneal spread (stage IV): a new preferred treatment?

BACKGROUND: To investigate the value of neoadjuvant chemotherapy (NACT), followed by interval debulking surgery (IDS), in endometrial cancer with transperitoneal spread (stage IV). METHODS: Patients with endometrial cancer with transperitoneal spread, as determined by laparoscopy (+/-pleural effusion), were treated with NACT. Efficacy was determined according to the Response Evaluation Criteria in Solid Tumors, residual tumour at IDS and histopathological assessment of tumour regression. RESULTS: A total of 30 patients (median age: 65 years; range:44-81 years) received 3-4 cycles of NACT (83% paclitaxel/carboplatin). Histopathological subtypes were as follows: serous (90%), clear cell (3%) and endometrioid (6%) carcinoma. Response according to RECIST was as follows: 2 (7%) complete remission, 20 (67%) partial remission, 6 (20%) stable disease and 2 (7%) progressive disease (PD). Patients with PD were not operated upon. A total of 24 patients (80%) had optimal cytoreduction (R

Prevalent breast cancer patients with a homozygous mutant status for CYP2D6*4: response and biomarkers in tamoxifen users.

Retrospective studies suggest that single nucleotide polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene predict reduced tamoxifen metabolism, better tolerance and worse treatment outcome. We hypothesized that women with this genotype lack tamoxifen-induced endometrial and biochemical changes in follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG). We identified 56 breast cancer patients attending the follow-up clinic with a homozygous mutant (HM) status for the CYP2D6*4 null variant. Here, we report a detailed assessment of tamoxifen activity in 19 CYP2D6 HM women, while they were using tamoxifen either for metastatic (n = 5) or for early disease (n = 14). We assessed response to tamoxifen in metastatic disease. Endometrial appearances and serum levels of FSH and SHBG were assessed from retrospective and prospective testing. Our findings do suggest that the presence of two CYP2D6*4 alleles does not exclude a durable response of tamoxifen in metastatic breast cancer. The transvaginal ultrasonographic appearance of the endometrium in CYP2D6*4/*4 patients on tamoxifen is similar as seen in the normal population of tamoxifen users. The endometrium is increased in thickness with subepithelial cysts and endometrial polyps. Serum levels of FSH and SHBG in CYP2D6*4 HM tamoxifen users were in the range of what would be expected during tamoxifen treatment in the general population. Our findings do show CYP2D6*4/*4 carriers to have activity of tamoxifen on breast cancer, endometrium and serum levels of FSH and SHBG. They support clinical trials prospectively testing the effect of CYP2D6 genetic variability in response to tamoxifen before denying this drug to breast cancer patients only based on their CYP2D6*4 status.

Limited clinical benefit from trastuzumab in recurrent endometrial cancer: two case reports.

BACKGROUND: It is hypothesized that the HER-2/neu receptor could be used for targeted therapy in recurrent endometrial cancer. CASES: A patient with type II endometrial cancer (serous), showing strong HER-2/neu overexpression and gene amplification in both primary and recurrent tumor, received single-agent trastuzumab (3x weekly, 8 mg/kg loading, 6 mg/kg maintenance dose). Because of progression after 4 cycles, weekly paclitaxel-trastuzumab (80 mg/m(2) paclitaxel; trastuzumab 4 mg/kg loading, 2 mg/kg maintenance dose) was initiated. However, progressive disease was also noted after 11 weeks of combined treatment. A second patient, with recurrent type II endometrial cancer (grade III endometrioid), had HER-2/neu gene amplification in the primary tumor. However, biopsy from a lung metastasis 3 years later appeared to be HER-2/neu-negative. CONCLUSION: Based on lack of response and changes in tumor biology, trastuzumab was of little clinical value in 2 cases of recurrent type II endometrial cancer. This report underscores the importance of reassessment of a recurrent tumor before initiating targeted treatment.

Timing of debulking surgery in advanced ovarian cancer.

It is clear that primary debulking remains the standard of care within the treatment of advanced ovarian cancer (FIGO stage III and IV). This debulking surgery should be performed by a gynecological oncologist without any residual tumor load, or so-called "optimal debulking." Over the last decades, interest in the use of neoadjuvant chemotherapy together with an interval debulking has increased. Neoadjuvant therapy can be used for patients who are primarily suboptimally debulked due to an extensive tumor load. In this situation, based on the randomized European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on the GOG 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecological oncologist. Neoadjuvant chemotherapy can also be used as an alternative to primary debulking. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of future randomized trials to know whether neoadjuvant chemotherapy followed by interval debulking surgery is a good alternative to primary debulking surgery in stage IIIc and IV patients. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery.

Role of diaphragmatic surgery in 69 patients with ovarian carcinoma.

Diaphragmatic stripping or coagulation is a technique aiming to optimally cytoreduce ovarian cancer. We investigated the complications, the overall survival, and the relapse rate following this procedure. Records of 69 patients with diaphragmatic involvement who underwent debulking surgery between September 1993 and December 2001 were reviewed. A total of 69 patients underwent diaphragmatic surgery as part of cytoreductive surgery for epithelial ovarian cancer. In 17 cases, the diaphragmatic tumors were stripped from the muscle, in 22 cases coagulated, and in 30 cases stripped and coagulated. Postoperative complications were pleural effusion (41 cases, 3 needed a chest drain, 7 needed a pleural puncture, 1 needed both) and pneumothorax (4 cases, 1 needed a chest drain). In one case of bilateral pleural effusion, the patient developed pneumonia. In one case of pleural effusion on the right side, the patient needed a pleural puncture and developed a partial atelectasis of the middle lobe of the right lung. The median overall survival was 66 months in the stripping group compared with 49 months in the coagulation group. In 56 cases (81%), the patient developed a relapse, and the first site of relapse was the diaphragm in 11 cases (20%). We conclude that diaphragmatic resection is an important part of optimal debulking surgery with an acceptable morbidity.

The position of neoadjuvant chemotherapy within the treatment of ovarian cancer.

It is clear that primary debulking remains the standard of care within the treatment of advanced ovarian cancer (International Federation of Gynaecology and Obstetrics, FIGO, stage III and IV). Debulking surgery should be performed by a gynaecologic oncologist without any residual tumour load, or so called optimal debulking'. Over the last decades, interest in the use of neoadjuvant chemotherapy together with an interval debulking has increased. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery. Neoadjuvant therapy can be used for patients that are primarily suboptimally debulked due to an extensive tumor load. In this situation, based on the randomized EORTC-GCG trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on the GOG 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecological oncologist. Neoadjuvant chemotherapy can also be used as an alternative to primary debulking. In retrospective analyses neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of future randomized trials to know whether neoadjuvant chemotherapy followed by interval debulking surgery is a good alternative to primary debulking surgery in stage IIIc and IV patients.

An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib.

BACKGROUND: Olaparib is poorly soluble, requiring advanced drug delivery technologies for adequate bioavailability. Sixteen capsules/day are required for the approved 400 mg twice-daily dose; a tablet formulation was developed to reduce pill burden. This clinical trial evaluated the optimal dose and administration schedule of the tablet formulation. PATIENTS AND METHODS: Two stages of sequentially enrolled cohorts: stage 1, pharmacokinetic properties of tablet and capsule formulations were compared in patients with advanced solid tumours; stage 2, tablet dose escalation with expansion cohorts at doses/schedules of interest in patients with solid tumours and BRCAm breast/ovarian cancers. RESULTS: Olaparib 200 mg tablets displayed similar Cmax,ss, but lower AUCss and Cmin,ss than 400 mg capsules. Following multiple dosing, steady-state exposure with tablets ≥300 mg matched or exceeded that of 400 mg capsules. After dose escalation, while 400 mg twice daily was the tablet maximum tolerated dose based on haematological toxicity, 65 % of patients in the randomized expansion phase eventually required dose reduction to 300 mg. Intermittent tablet administration did not significantly improve tolerability. Tumour shrinkage was similar for 300 and 400 mg tablet and 400 mg capsule cohorts. CONCLUSIONS: The recommended monotherapy dose of olaparib tablet for Phase III trials was 300 mg twice daily, simplifying drug administration from 16 capsules to four tablets per day. CLINICAL TRIAL NUMBER: NCT00777582 (ClinicalTrials.gov).

Primary invasive mucinous ovarian carcinoma of the intestinal type: importance of the expansile versus infiltrative type in predicting recurrence and lymph node metastases.

AIMS: Investigate the role of expansile versus infiltrative type of primary invasive intestinal type mucinous epithelial ovarian carcinoma (mEOC) in predicting recurrence and lymph node metastases. METHODS: Retrospective study. Differentiation was defined according to the Shimizu-Silverberg and expansile/infiltrative type according to the Lee-Scully criteria. RESULTS: Out of 104 patients with mucinous ovarian carcinomas, 44 primary invasive mucinous epithelial carcinomas of the intestinal type (mEOC) were identified. Patients with a mEOC of the expansile type are mainly diagnosed in stage I (21 out 23) and have an excellent prognosis (no relapses in 21 Stage I patients). Patients with mEOC tumours of the infiltrative type are less frequently diagnosed in stage I (12 out of 21) and 2 recurrences were noted out of 12 Stage I patients. Lymph node metastases were not observed in patients with apparent Stage I disease of the expansile type, but were present in 3 out 10 patients with infiltrative disease. Degree of differentiation did not predict recurrence or the presence of lymph node metastases. Prognosis was poor in patients with Stage II or higher disease, irrespective of type of infiltration. CONCLUSIONS: Expansile mEOC is mainly diagnosed in stage I and is not associated with lymph node metastases. Infiltrative mEOC has a worse prognosis and is associated with lymph node metastases. Degree of differentiation was unreliable in predicting recurrence or lymph node metastases.