Missed therapeutic and prevention opportunities in women with BRCA-mutated epithelial ovarian cancer and their families due to low referral rates for genetic counseling and BRCA testing: A review of the literature.

Answer questions and earn CME/CNE Fifteen percent of women with epithelial ovarian cancer have inherited mutations in the BRCA breast cancer susceptibility genes. Knowledge of her BRCA status has value both for the woman and for her family. A therapeutic benefit exists for the woman with cancer, because a new family of oral drugs, the poly ADP-ribose polymerase (PARP) inhibitors, has recently been approved, and these drugs have the greatest efficacy in women who carry the mutation. For her family, there is the potential to prevent ovarian cancer in those carrying the mutation by using risk-reducing surgery. Such surgery significantly reduces the chance of developing this, for the most part, incurable cancer. Despite these potential benefits, referral rates for genetic counseling and subsequent BRCA testing are low, ranging from 10% to 30%, indicating that these therapeutic and prevention opportunities are being missed. The authors have reviewed the relevant available literature. Topics discussed are BRCA and its relation to ovarian cancer, the rates of referral for genetic counseling/BRCA testing, reasons for these low rates, potential strategies to improve on those rates, lack of effectiveness of current screening strategies, the pros and cons of risk-reducing surgery, other prevention options, and the role and value of PARP inhibitors. CA Cancer J Clin 2017;67:493-506. © 2017 American Cancer Society.

Single or two drug combination therapy as initial treatment for low risk, gestational trophoblastic neoplasia. A Canadian analysis.

INTRODUCTION: Low risk gestational trophoblastic neoplasia, WHO prognostic score of 0 to 6, is highly curable. There is no consensus on the optimal chemotherapy. Common regimens are q2wk actinomycin-D (ACT-D), weekly intramuscular methotrexate (MTX) or multi-day MTX. Combination MTX/ACT-D is rarely used. METHODS: A four centre, retrospective cohort study was carried out comparing commonly used regimens: weekly MTX, q2weekly ACT-D and q2 weekly MTX and ACT-D. RESULTS: 412 patients - 196 MTX/ACT-D, 107 MTX, 109 ACT-D - were treated between October 1994 and January 2019. Initial regimen failure (secondary to resistance or toxicity) occurred in 37% (MTX), 21% (ACT-D) and 5% (MTX/ACT-D). Relapse after completion of primary therapy (initial plus switch to another therapy if needed) was rare (0-5%). All eventually were cured. Mean number of cycles required to achieve remission were 10.1 (MTX), 7 (ACT-D) and 5.6 (MTX/ACT-D) with corresponding mean treatment durations of 3.12, 2.9 and 2.26 months. Dosage reductions occurred in 3% (MTX), 0% (ACT-D) and 29% (MTX/ACT-D). Higher failure rates occurred with WHO prognostic scores of 5 to 6 and HCG levels ≥10,000. SUMMARY: Initial regimen failure ie the need to switch to an alternative treatment was more common with MTX. ACT-D and MTX/ACT-D were similar within prognostic score 0-4 or HCG < 10,000. ACT-D then appears the better initial choice with its superior convenience. Above these levels primary failure rates are less with MTX/ACT-D, making it a better choice.

Survival Benefit of Adjuvant Radiotherapy: An Analysis of Low-Stage Invasive Ovarian Mucinous Carcinomas.

OBJECTIVE: Our aim was to evaluate the population-based outcomes of stages I and II invasive ovarian mucinous carcinomas (MCs) treated with adjuvant platinum-based chemotherapy and abdominopelvic radiotherapy (XRT). METHODS: International Federation of Gynecology and Obstetrics stage I/II MC cases referred to the British Columbia Cancer Agency between 1984 and 2014 were reviewed. Chemotherapy (minimum of 3 cycles) and XRT were the institutional policy for stages IA/B (grade 2/3) and IC/II (any grade). Physician patterns of practice determined XRT use in eligible patients, allowing for the comparison of outcomes based on receipt of XRT treatment on disease-free survival (DFS) and overall survival (OS). RESULTS: We identified 129 patients. Univariate analyses on substages IA, IC no rupture, IC with intraoperative rupture, and IC with preoperative rupture demonstrated 10-year DFS rates of 67%, 67%, 67%, and 27% (P = 0.004), respectively, and OS rates of 72%, 72%, 67%, and 38% (P = 0.01), respectively. For all patients, adjuvant XRT demonstrated improved 10-year DFS (78% vs 36%, P = 0.05) and OS (83% vs 36%, P = 0.02). Subgroup analysis did not detect a benefit of adjuvant therapy for stage IA grade 1/2. Multivariate analysis confirmed the benefit of XRT on DFS (hazard ratio, 0.14; 95% confidence interval, 0.02-0.98; P = 0.047) and a trend to improved OS (hazard ratio, 0.12; 95% confidence interval, 0.009-1.64; P = 0.11), whereas decision tree analysis demonstrated a reduced rate of relapse (33% vs 77%) and death (20% vs 46%) with the use of XRT, exclusive of patients with preoperative rupture. CONCLUSIONS: This population-based retrospective study is the first to demonstrate that the use of adjuvant abdominopelvic XRT after chemotherapy can improve survival in patients diagnosed as having stage I/II MC. Patients with stage IA grade 1 and grade 2 MC can have adjuvant therapy omitted.

Early-stage endometrioid ovarian carcinoma: population-based outcomes in British Columbia.

OBJECTIVE: Specific outcomes for early-stage ovarian endometrioid carcinoma (OEC) have not been well characterized. In addition, the benefit of any type of postsurgical therapy remains unclear. Our aims were to delineate (1) potential prognostic factors and (2) the impact of adjuvant treatment on survival in such patients. METHODS: Women with FIGO stages I and II OEC referred to one of the centers of the British Columbia Cancer Agency from 1984 to 2008 were included in a retrospectively abstracted computerized database. Irradiation (abdominal-pelvic) in addition to chemotherapy (3 cycles of platinum combination) was to be given for stage IA/B, grade 2/3; stage IC, any grade; and stage II, any grade, except from 1989 to 1994 when irradiation was dropped from the paradigm for all patients. Univariate analysis and a multivariate analysis, using a decision tree analysis, were carried out of disease-free survival (DFS). RESULTS: One hundred seventy-two patients were identified. Twelve percent were grade 3; 55%, 85%, and 89% of stages IA/B, IC, and II received postoperative adjuvant treatment. Five-year DFS was 95%, 84%, and 74% for stages IA/B and IC based upon rupture alone, IC other (cytologic positivity and/or surface involvement), and II, respectively. No benefit in DFS was accrued in stage IA/B from adjuvant treatment. Decision tree analysis defined 2 poor prognostic groups: those 55 years or older with stage IC based upon positive washings or surface involvement and any patient with stage II disease; in these, an apparent DFS benefit from irradiation was seen (relative risk (RR), 1.77; 95% confidence interval (CI), 0.74-4.24). CONCLUSION: Omission of adjuvant treatment can be considered in most early-stage OECs.

Preoperative radiotherapy for inoperable stage II endometrial cancer: insights into improving treatment and outcomes.

OBJECTIVE: To review recurrence patterns and survival outcomes of women receiving preoperative radiotherapy for clinical stage II endometrial cancer in British Columbia. METHODS: We performed a retrospective population-based cohort study of all patients with clinical stage II endometrial cancer who were referred to the British Columbia Cancer Agency from 2000 to 2008, deemed ineligible for primary surgery, and therefore offered preoperative radiotherapy followed by surgery. Patient demographics, uterine risk factors, timing and details of treatments, and timing and sites of recurrence were obtained from patient records. Primary outcome measures were the sites and rates of recurrence and recurrence-free survival. RESULTS: We identified 29 patients with a mean age of 61 years (range 41 to 83) and median follow-up of 3.1 years (range 0.3 to 5.3). Three-year overall survival was 79%, and median recurrence-free survival was 2.5 years. Eight patients had recurrence of disease (27.6%), with a median time to recurrence of 1.3 years, (range 0.4 to 2.7). Six of these eight women had two or more high-risk uterine factors (deep myometrial invasion, grade 3 tumour), ovarian involvement, or adverse histological type (carcinosarcoma), compared with only one of 21 patients without recurrence. Seven of eight women had recurrence outside the radiated volume of tissue. Median survival after recurrence was 1.0 years (range 0.4 to 2.2). CONCLUSIONS: Women with clinical stage II endometrial cancer had a significant risk of recurrence when treated with preoperative radiotherapy followed by surgery. They were more likely to have distant recurrences, implying the need for an alternate treatment paradigm.

Objectif : Passer en revue les profils de récurrence et les issues en matière de survie, en ce qui concerne les femmes qui reçoivent une radiothérapie préopératoire en raison de la présence d'un cancer de l'endomètre de stade clinique II en Colombie-Britannique. Méthodes : Nous avons mené une étude de cohorte rétrospective en population générale qui portait sur toutes les patientes présentant un cancer de l'endomètre de stade clinique II qui ont été orientées vers la British Columbia Cancer Agency entre 2000 et 2008, qui étaient estimées comme étant inadmissibles à la chirurgie primaire et qui, donc, se sont vu offrir une radiothérapie préopératoire suivie d'une chirurgie. Les caractéristiques démographiques des patientes, les facteurs de risque utérins, la chronologie et les détails des traitements, et la chronologie et les sites des récurrences ont été tirés des dossiers des patientes. La survie sans récurrence et les sites et les taux de récurrence constituaient les critères d'évaluation primaires. Résultats : Nous avons identifié 29 patientes dont l'âge moyen était de 61 ans (plage de 41 à 83) et dont le suivi médian était de 3,1 ans (plage de 0,3 à 5,3). Le taux global de survie à trois ans était de 79 % et la survie médiane sans récurrence était de 2,5 ans. Huit patientes ont connu une récurrence de la maladie (27,6 %), le délai médian avant l'apparition de la récurrence étant de 1,3 an (plage de 0,4 à 2,7). Six de ces huit femmes présentaient deux facteurs de risque utérins élevés ou plus (envahissement myométrial profond, tumeur de grade 3), un envahissement ovarien ou un type histologique indésirable (carcinosarcome), par comparaison avec seulement une des 21 patientes n'ayant pas connu de récurrence. Sept des huit femmes ont connu une récurrence au-delà du volume de tissu irradié. La survie médiane à la suite de la récurrence était de 1,0 an (plage de 0,4 à 2,2). Conclusions : Les femmes présentant un cancer de l'endomètre de stade clinique II étaient exposées à un risque significatif de récurrence lorsqu'elles ont été traitées au moyen d'une radiothérapie préopératoire suivie d'une chirurgie. Elles étaient plus susceptibles de présenter des récurrences distantes, ce qui sous-entend la nécessité de formuler un autre paradigme de traitement.

The role of the fallopian tube in ovarian cancer.

High-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer. Research over the past decade has strongly suggested that "ovarian" HGSC arises in the epithelium of the distal fallopian tube, with serous tubal intraepithelial carcinomas (STICs) being detected in 5-10% of BRCA1/2 mutation carriers undergoing risk-reducing surgery and up to 60% of unselected women with pelvic HGSC. The natural history, clinical significance, and prevalence of STICs in the general population (ie, women without cancer and not at an increased genetic risk) are incompletely understood, but anecdotal evidence suggests that these lesions have the ability to shed cells with metastatic potential into the peritoneal cavity very early on. Removal of the fallopian tube (salpingectomy) in both the average and high-risk populations could therefore prevent HGSC, by eliminating the site of initiation and interrupting spread of potentially cancerous cells to the ovarian/peritoneal surfaces. Salpingectomy may also reduce the incidence of the 2 next most common subtypes, endometrioid and clear cell carcinoma, by blocking the passageway linking the lower genital tract to the peritoneal cavity that enables ascension of endometrium and factors that induce local inflammation. The implementation of salpingectomy therefore promises to significantly impact ovarian cancer incidence and outcomes.

Which is the better surgical strategy for newly diagnosed epithelial ovarian cancer: primary or interval debulking?

PURPOSE OF REVIEW: Surgical debulking is a mainstay of therapy for epithelial ovarian cancer. The traditional timing of this surgery has been prior to chemotherapy, but this view has been challenged over the last decade. This review will focus on the recently completed phase III studies of surgical timing and discuss exceptions to the superior paradigm of neoadjuvant chemotherapy followed by interval debulking. RECENT FINDINGS: The two completed studies have shown that neoadjuvant chemotherapy followed by interval debulking is the superior strategy for stage IIIc and IV ovarian cancer compared to primary surgery followed by chemotherapy. Survival outcomes were the same, but the morbidity for the patient and cost to the system and patient were less with interval debulking. Exceptions to this sequence are potentially stage I or II patients and those stage III patients who can be optimally debulked so as to receive intraperitoneal chemotherapy. SUMMARY: Chemotherapy followed by interval debulking will result in fewer and simpler operations and lesser morbidity for the patients resulting in cost savings for the healthcare system and less inconvenience and toxicity for the patient with equivalent survival outcomes. As such it is the superior strategy.

Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines.

Doxorubicin plays an integral role in the treatment of patients with diffuse large B-cell lymphoma (DLBCL) but can be associated with significant toxicity. Treatment guidelines of British Columbia (BC) Cancer recommend the substitution of etoposide for doxorubicin in standard-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (R-CEOP) for patients who have a contraindication to anthracyclines; however, it is unknown if this compromises treatment outcome. We identified all patients with newly diagnosed DLBCL who were treated in BC with curative intent with R-CEOP (n = 70) within the study period. Outcome in this population was compared with a 2:1 case-matched control group (n = 140) treated with R-CHOP and matched for age, clinical stage, and International Prognostic Index score. The 10-year time to progression and disease-specific survival were not significantly different for patients treated with R-CEOP compared with patients in the R-CHOP control group (53% vs 62% [P = .089] and 58% vs 67% [P = .251], respectively). The 10-year overall survival was lower in the R-CEOP group (30% vs 49%, P = .002), reflecting the impact of underlying comorbidities and frailty of this population. R-CEOP represents a useful treatment alternative for patients with DLBCL and an absolute contraindication to the use of anthracyclines, with curative potential.

Reuse of carboplatin and paclitaxel in patients with relapsed endometrial cancer--the British Columbia Cancer Agency experience.

OBJECTIVE: To evaluate the efficacy of reusing carboplatin and taxol in women with relapsed endometrial cancer. METHODS: Retrospective analysis of our database of newly diagnosed high-risk patients with endometrial cancer treated with carboplatin-paclitaxel at diagnosis, with subsequent relapse for the period of 1995-2007. RESULTS: 111 patients of 200 relapsed. They had either endometroid or papillary serous histologies. Strategies utilized upon first relapse were: no treatment (n=33), surgery (n=4), hormones (n=8), irradiation (n=14) and chemotherapy (n=52). Carboplatin and paclitaxel was reused in 31 (60% of 52 retreated with chemotherapy or 29% of the total cohort of 111). There was no statistically significant difference in stage at diagnosis or grade at diagnosis between those retreated with chemotherapy or not or with carboplatin-paclitaxel versus another regimen. The patients retreated were a selected subgroup as only those with initial response or treated adjuvantly were offered carboplatin-paclitaxel. CR or PR were achieved in 8 (42%) patients with endometroid type cancer. In the papillary serous group 6 (50%) had CR or PR. Median PFS from first relapse was 8 months for endometroid and 9 months for papillary serous histology. OS was 15 months and 26 months respectively from first relapse. CONCLUSION: Carboplatin-taxol regimen is an efficacious treatment. Due to the patient selection these outcomes reported are likely to be an overstatement of what could be achieved in practice.

Carboplatin plus paclitaxel for advanced or recurrent uterine malignant mixed mullerian tumors. The British Columbia Cancer Agency experience.

OBJECTIVES: Uterine MMMTs are aggressive malignancies that are rarely cured by purely local therapies. Effective chemotherapy is needed. The phase III proven, ifosfamide-based combinations are inconvenient and costly. Carboplatin and paclitaxel (CT) are easy to deliver and is effective against endometrial carcinoma and should be against MMMT (as they are now regarded as epithelial in nature). METHODS: A review of all women with uterine MMMT treated with CT. Paclitaxel 175 mg/m2 over 3 h preceded carboplatin (AUC 5-6) every 4 weeks for 3-6 cycles+/-subsequent pelvic irradiation. RESULTS: Twenty-eight newly diagnosed women (20 evaluable) and 12 recurrent (11 evaluable) were treated. Response rates were 60% (12 of 20, CR 5, PR 7) and 55% (6 of 11, CR 2, PR 4) with median PFS of 16 and 12 months. Dose reduction occurred in 5%, treatment delay in 10%. CONCLUSIONS: Carboplatin-paclitaxel is effective against uterine MMMT, with similar efficacy to ifosfamide combinations. It is more convenient, less costly and easy to deliver.

Fatal reactivation of hepatitis B post-chemotherapy for lymphoma in a hepatitis B surface antigen-negative, hepatitis B core antibody-positive patient: potential implications for future prophylaxis recommendations.

In the absence of prophylaxis, the reactivation of hepatitis B in oncology patients who are hepatitis B carriers is a well-known and often fatal complication of chemotherapy. The current recommendations in Canada and the USA are that patients who are positive for hepatitis B surface antigen (HBsAg) receive antiviral prophylaxis prior to chemotherapy. We report a 67-year-old man with B-cell lymphoma who developed hepatitis B reactivation following chemotherapy with cyclophosphamide, adriamycin, vincristine, prednisone and rituximab. Pre-chemotherapy, the patient was negative for HBsAg, positive for hepatitis B core antibody (anti-HBc) and weakly positive for hepatitis B surface antibody. Despite treatment with lamivudine, the patient died of fulminant hepatic failure. Our experience indicates that patients who are negative for HBsAg but positive for anti-HBc are still at risk for reactivation of latent hepatitis B during and after chemotherapy and may be considered for prophylaxis.

Low-stage ovarian clear cell carcinoma: population-based outcomes in British Columbia, Canada, with evidence for a survival benefit as a result of irradiation.

PURPOSE: To evaluate the population-based outcomes of stage I and II ovarian clear cell carcinoma (OCCC) in a North American population treated with carboplatin/paclitaxel and abdominopelvic irradiation. PATIENTS AND METHODS: Retrospective analysis was performed of 241 patients referred in the carboplatin/paclitaxel era. Irradiation was to be used with a few defined exceptions. However, because of differing beliefs as to its effectiveness, its use was consistently avoided by specific oncologists, allowing the opportunity to study its possible effect on disease-free survival (DFS) in these concurrent cohorts. RESULTS: Five- and 10-year DFS rates were 84% and 70% for stage IA/B; 67% and 57% for stage IC; and 49% and 44% for stage II, respectively. Five- and 10-year DFS rates for those with stage IC disease based purely on rupture were similar to rates for patients with stage IA/B, at 92% and 71%, respectively. The remaining patients with stage IC had 48% 5- and 10-year DFS. Multivariate analysis using a decision tree identified positive cytology as the most important factor (72% relapse rate if positive and 27% if negative or unknown). If, in addition, the capsule surface was involved, then the relapse rate was 93%. Irradiation had no discernible survival benefit for patients with stage IA and IC (rupture alone), whereas for the remainder of patients with stage IC and stage II, it improved DFS by 20% at 5 years (relative risk, 0.5); the benefit was most evident in the cytologically negative/unknown group. CONCLUSION: DFS is similar in this North American population with early OCCC to the DFS reported in Asia. A potential benefit from irradiation was evident in a subset.

International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era.

PURPOSE: The International Prognostic Score (IPS) is the most widely used risk stratification index for Hodgkin's lymphoma (HL). It is based on patients treated before 1992 and predicts 5-year freedom from progression (FFP) and overall survival (OS) ranging from 42% to 84% and 56% to 89%, respectively. The IPS has not been validated in a recently treated population in which outcomes have improved compared with historic results. PATIENTS AND METHODS: By using the British Columbia Cancer Agency Lymphoid Cancer Database, we identified all patients age ≥ 16 years newly diagnosed with advanced-stage HL (stage III to IV, or stage I to II with "B" symptoms or bulky disease ≥ 10 cm) from 1980 to 2010, treated with curative intent with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or an ABVD-equivalent regimen with complete clinical information. RESULTS: In all, 740 patients were identified. Five-year FFP and OS were 78% and 90%, respectively. The IPS was prognostic for both FFP (P < .001) and OS (P < .001), with 5-year FFP ranging from 62% to 88% and 5-year OS ranging from 67% to 98%. Analysis limited to patients age 16 to 65 years (n = 686) demonstrated a narrower range of outcomes, with 5-year FFP ranging from 70% to 88% and 5-year OS ranging from 73% to 98%. CONCLUSION: The IPS remains prognostic for advanced-stage HL, but the range of outcomes has narrowed considerably. This improvement in outcome with ABVD should be acknowledged before consideration of alternate initial therapies and when comparing results from current trials with those of historic controls.

Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group.

PURPOSE: Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting. PATIENTS AND METHODS: Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles. RESULTS: In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome. CONCLUSION: mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.

Population-based analysis of incidence and outcome of transformed non-Hodgkin's lymphoma.

PURPOSE: To assess the incidence and predictive factors for development of transformed lymphoma in a population-based series of patients with follicular lymphoma (FL). PATIENTS AND METHODS: The Lymphoid Cancer Database was used to identify patients with FL diagnosed and treated in the province of British Columbia, Canada. Transformed lymphoma was defined as the development of aggressive non-Hodgkin's lymphoma (NHL) in patients with FL. Factors present at the time of initial diagnosis of indolent NHL and at transformation were analyzed for their impact on risk of transformation and subsequent outcome. RESULTS: Between 1986 and 2001, 600 patients with newly diagnosed FL met the inclusion criteria. With a median follow-up of 109 months (range, 10 to 244), 170 (28%) developed transformation, 107 (63%) based on biopsy confirmation. The annual risk of transformation was 3% continuously through 15 years. A multivariate analysis of clinical factors at diagnosis identified advanced stage as the only predictor of future transformation. The median post-transformation survival was 1.7 years. The 5-year survival was superior for patients with limited extent transformation compared with those with advanced cases (66% v 19%, P < .0001). Patients with transformation based on clinical versus histological criteria had an identical median survival of 1.8 years (P = .2). CONCLUSION: The annual risk of transformation of FL is 3% continuing without plateau beyond 15 years. Advanced stage at diagnosis is predictive of future transformation. Clinically diagnosed transformation has an equal impact on outcome as biopsy proven transformation.

Phase II study of erlotinib in recurrent or metastatic endometrial cancer: NCIC IND-148.

PURPOSE: Epidermal growth factor receptor (EGFR) overexpression is common in endometrial cancers and may have a major role in tumor growth and progression. Erlotinib is an orally active, selective inhibitor of EGFR tyrosine kinase activity. PATIENTS AND METHODS: A multinomial design two-stage phase II study was performed to evaluate single-agent activity of erlotinib in women with advanced endometrial cancer with recurrent or metastatic disease who were chemotherapy naïve and had received up to one line of prior hormonal therapy. Erlotinib was administered at daily dose of 150 mg. Archival tumor tissue was analyzed for EGFR expression by immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridization (FISH). Mutational status of EGFR was determined in responders. RESULTS: Thirty-two of 34 entered patients are assessable for response. Treatment was well tolerated and severe toxicity infrequent, with the only grade 4 toxicity being an elevation of transaminases (AST). There were four confirmed partial responses (PRs; 12.5%; 95% CI, 3.5% to 29%) lasting 2 to 36 months. Fifteen patients had stable disease (SD), with median duration of 3.7 months (range, 2 to 12 months). EGFR expression was analyzed in thirty patients; 19 were positive, nine were negative, and two were not assessable. Of the 19 patients who were EGFR positive, three had PR (16%), seven SD, and eight progressive disease, and one was not assessable. No mutations were identified in responders. FISH showed no correlation of response with gene amplification. CONCLUSION: Erlotinib is well tolerated with an overall objective response rate of 12.5%. Molecular analysis did not identify EGFR mutations in responders or correlation of response with gene amplification.

Identifying patients unlikely to benefit from further chemotherapy: a descriptive study of outcome at each relapse in ovarian cancer.

OBJECTIVE: Not all patients with relapsed ovarian cancer (EOC) benefit from further treatment and thus treatment should be selectively applied. METHODS/PATIENTS: A retrospective review of survival and response outcomes in 120 women with relapsed EOC, all treated at original diagnosis with surgery and platin plus paclitaxel, who had all their initial and subsequent relapse therapy carried out at the BCCA. RESULTS: In those patients selected for re-treatment upon relapse, lack of progression rates were 63%, 50%, 45%, 44%, 29%, and 20% respectively for first through sixth relapse. The corresponding median survivals from that relapse were 14, 10, 6, 7, 8, and 5 months. A predictive model based upon the length of the interval between the two preceding relapses (or diagnosis to 2nd relapse) predicted which patients would survive less than 6 months (patient defined "lack of benefit" to chemotherapy criterion): diagnosis to second relapse <12 months; first to third relapse <6 months; second to fourth <6 months; third to fourth <6 months, and fifth to sixth <6 months. CONCLUSION: In selected patients, multiple episodes of re-treatment are of value. A time-based statistic identifies those who will not benefit, defined as survival less than 6 months.