A randomized placebo-controlled study of tamoxifen after adjuvant chemotherapy in premenopausal women with early breast cancer (National Cancer Institute of Canada--Clinical Trials Group Trial, MA.12).

BACKGROUND: In the early 1990s, the role of adjuvant tamoxifen in premenopausal women with early breast cancer (EBC) was not established. Similarly, optimum timing relative to adjuvant chemotherapy and efficacy of tamoxifen in hormone receptor-negative tumors were unclear. PATIENTS AND METHODS: Premenopausal women with EBC, any hormone receptor status, after surgery received standard adjuvant chemotherapy [doxorubicin (adriamycin)/cyclophosphamide, cyclophosphamide/methotrexate/5-fluorouracil, or cyclophosphamide/epirubicin/5-fluorouracil] followed by randomization to tamoxifen or placebo for 5 years. Outcomes were overall survival (OS), disease-free survival (DFS), toxicity, and compliance with therapy. RESULTS: Median follow-up for 672 women was 9.7 years. Multivariate analysis showed improved DFS [78.2% versus 71.3% at 5 years; hazard ratio (HR) 0.77; P = 0.056] and a trend for improved OS (86.6% versus 82.1% at 5 years; HR 0.78; P = 0.12). There was no evidence of greater benefit for the receptor-positive subgroup. Compliance with treatment was suboptimal in both arms, with 103 (31%) women on tamoxifen and 70 (21%) on placebo-stopping therapy early because of toxicity, refusal, or other choices. CONCLUSIONS: Adjuvant tamoxifen, given after chemotherapy to premenopausal women with EBC, improved 5-year DFS. Poor compliance may have reduced treatment efficacy.

The malignant wound assessment tool: a validation study using a Delphi approach.

Malignant wounds, caused by the direct invasion of cancer into the skin, occur in cancer patients with primary skin tumours and as cutaneous metastasis in approximately 10% of patients with metastatic internal malignancies. Malignant wounds have a profound impact on patients, family members and health care providers. The assessment of the patient with malignant wounds can be complex and there is no widely accepted, consistent approach. Valid, descriptive survey research methods were used to develop the Malignant Wound Assessment Tool (MWAT). The authors developed two versions of the MWAT: a brief clinical version (MWAT-C) and a more detailed research version (MWAT-R). Domains include clinical wound features, physical effects and emotional and social impacts of the wound. The two tools underwent content and construct validity testing using a Delphi process. An international panel of professionals with clinical or research expertise related to malignant wounds was formed. Panelists participated in two rounds of review for each tool. Development and face validity testing of the MWAT-C and MWAT-R tools through the Delphi process have resulted in tools ready for clinical application and will support clinical and research activities to improve care for patients with this devastating condition.

A dose escalation trial of adjuvant cyclophosphamide and epirubicin in combination with 5-fluorouracil using G-CSF support for premenopausal women with breast cancer involving four or more positive nodes.

BACKGROUND: Dose-dense and dose-intensive regimens have improved the outcome of breast cancer in high-risk women with operable disease. PATIENTS AND METHODS: Sixty-three premenopausal women with Stage 2, 3 breast cancer and > or =4 positive axillary nodes were treated in three successive cohorts with 70 mg/m(2) of epirubicin, 500 mg/m(2) of 5-fluorouracil and G-CSF every 14 days for 12 cycles. Cyclophosphamide (C) was given at 700 mg/m(2), 900 mg/m(2), and 1100 mg/m(2) doses. Patients were evaluated for dose-limiting toxicities (DLTs) in the first four cycles, the primary endpoint of the trial. RESULTS: No DLTs were seen at C 700 mg/m(2); at C 900 mg/m(2) two of 16 patients experienced febrile neutropenia and poor performance status; at C 1100 mg/m(2), 1 of 31 patients experienced poor performance status. Over 6 months, febrile neutropenia, grade 4 thrombocytopenia, grade 3 anemia and severe fatigue were observed. Clinical congestive heart failure occurred in three patients over 4 years. CONCLUSION: A dose-intense and dose-dense regimen of cyclophosphamide, epirubicin and 5-fluorouracil was delivered with G-CSF without apparent increase in acute toxicity. Cyclophosphamide could be increased to more than twice the standard dose at the cost of more anemia and fatigue.

Criteria of tumor response used in clinical trials of chemotherapy.

We have studied 61 published reports of trials of cancer chemotherapy to evaluate the criteria for tumor response that were used and the adequacy of their description in the publication. Our sample comprised recent articles published in three major journals that addressed the influence of chemotherapy on patients with recurrent or metastatic colorectal cancer, non-small cell lung cancer, and head and neck cancer. Incomplete information was sought through a questionnaire mailed to the senior author of each paper, and 48 of them responded. We conclude that: no article contained all of the information required to define precisely criteria for tumor responses; criteria for tumor response are variable; and differences in response criteria contribute to the wide variation in reported rates of tumor response. Meaningful intercomparison of clinical trials will require the establishment of uniform criteria for assessing and reporting the response of tumors to chemotherapy.

Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

PURPOSE: This pilot phase II study investigated the efficacy and toxicity of docetaxel with doxorubicin and cyclophosphamide (TAC) as first-line chemotherapy for anthracycline-naive patients with metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients received a total of 359 courses consisting of docetaxel 75 mg/m2 given intravenously (IV) over 1 hour, preceded by IV doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for a maximum of eight 3-week cycles. RESULTS: After an independent panel review, the overall objective response rate was 77% (complete response, 6%). Overall objective response rates in patients with visceral, bone, and liver involvement were 82%, 82%, and 80%, respectively. Median duration of response was 52 weeks, and median time to progression was 42 weeks. With a median follow-up of 32 months, the median survival had not yet been reached, whereas the 2-year survival was 57%. The main toxicities were hematologic (neutropenia grade 3/4 in 100% of patients and 95% of cycles; febrile neutropenia in 34% of patients and 9% of cycles). Documented grade 3 infection was seen in one patient (2%) in one cycle, and no toxic death was reported. Severe acute or chronic nonhematologic adverse events were infrequent, and docetaxel-specific toxicities (such as fluid retention and nail changes) were mild, with only one patient being discontinued for fluid retention. Congestive heart failure was seen in two patients (4%). CONCLUSION: TAC is an active and manageable regimen that has been chosen as the basis of five randomized phase III trials, including two pivotal studies comparing TAC to fluorouracil plus doxorubicin and cyclophosphamide in the metastatic and adjuvant treatment of breast cancer.

Elevated plasma osteopontin in metastatic breast cancer associated with increased tumor burden and decreased survival.

Osteopontin (OPN) is a secreted, integrin-binding phosphoprotein that has been implicated in both normal and pathological processes; qualitative increases in OPN blood levels have been reported in a small number of patients with metastatic tumors of various kinds. We measured plasma OPN levels in 70 women with known metastatic breast carcinoma, 44 patient controls who were on follow-up after completion of adjuvant treatment for early breast cancer, and 35 normal volunteers. The median plasma OPN of patients with metastatic disease was 142 microgram/liter (range, 38-1312 microgram/liter) and was significantly different (P < 0.0001, Mann Whitney U test) from both control groups (medians, 60 and 47 microgram/liter; ranges, 15-117 and 22-122 microgram/liter). Furthermore, we found that increasing plasma OPN is associated with shorter survival (P < 0.001) when patients were grouped in terciles for plasma OPN. This was also demonstrated when using a Cox proportional hazards model. Median plasma OPN levels were significantly increased for three or more sites of involvement (median, 232 microgram/liter; n = 13) versus 1 or 2 metastatic sites (medians, 129 and 130 microgram/liter; n = 29 and 28, respectively). Plasma OPN levels were correlated with other biochemical markers related to the extent of disease, such as serum alkaline phosphatase, aspartate succinate aminotransaminase, and albumin (r = 0.81, 0.62, and -0.56, respectively; all P < 0.001). This study demonstrates a statistically significant elevation in plasma OPN in the majority ( approximately 70%) of a large series of patients with metastatic breast cancer when compared (95th percentile) to healthy women or patients who had completed adjuvant treatment for early-stage breast cancer. Furthermore, this is the first study to demonstrate that higher OPN levels in patients with metastatic breast cancer may be associated with an increased number of involved sites and decreased survival.

A phase II study of high-dose hydroxyurea and dacarbazine (DTIC) in the treatment of metastatic malignant melanoma.

Dacarbazine (DTIC) exerts its major biochemical effect through the formation of methylated DNA adducts. Hydroxyurea (HU) is a ribonucleotide reductase inhibitor which blocks DNA excision-repair by the depletion of intracellular ribonucleotides. Combination of HU and DTIC was used to enhance the activity of DTIC by inhibiting DNA repair. 16 patients with metastatic malignant melanoma were treated with the combination. All patients had measurable disease and none had received prior systemic therapy. Hydroxyurea was given as a continuous intravenous (i.v.) infusion of 1 g/h (total 36 g) and DTIC 1 g/m2 i.v. over 1 h, 23 h from the start of hydroxyurea infusion. 4 patients achieved partial remission with an objective remission rate of 25% [95% confidence interval (CI) 7-52%]. Median duration of response was 3.5 months. 3 of the responding patients had predominant visceral metastases. Disease was stabilised in 5 patients with a median time to progression of 16 months. The predominant toxicity to this treatment was gastrointestinal, with 3 patients developing grade 3 nausea/vomiting. Only 1 patient developed grade 3 leucopenia complicated by septicaemia. It is concluded that the combination of hydroxyurea and DTIC is a well-tolerated regimen with activity against visceral metastases from malignant melanoma but the duration of response to this treatment is short.

Taxane-based three-drug combination in metastatic and adjuvant treatment of breast cancer.

Considering the recommended dose of the docetaxel/doxorubicin combination (75 mg/m2 and 50 mg/m2, respectively), we decided to proceed with a pilot program in untreated metastatic breast cancer aimed at defining a multidrug regimen that could be later randomly compared with a standard doxorubicin-containing polychemotherapy regimen with equidoses of doxorubicin such as the FAC protocol (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2) in first-line metastatic and adjuvant treatment of breast cancer patients. We proceeded with a pilot phase II study of the TAC combination, which consists of docetaxel 75 mg/m2 as a 1-hour infusion preceded by doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2, both given as an intravenous bolus. Three hundred seventy courses were delivered in 54 anthracycline-naive patients, among whom 62% had visceral metastases. Median relative dose intensity was above 98% for all drugs. Grade 4 neutropenia was the main toxicity (70% of cycles) and the incidence of febrile neutropenia and infection was acceptable (6% and 0.8% of cycles, respectively). Acute and chronic extrahematologic toxicities were mild, mostly grade 2, and the docetaxel-specific toxicities (fluid retention, nail changes, etc) were not major clinical problems; no patient was discontinued due to fluid retention. The major response rate was 73% overall and 79% in measurable disease. Time to progression and survival are still under evaluation. The TAC combination is an active and well-tolerated regimen that is the basis of two currently open, pivotal, randomized phase III trials comparing TAC with FAC in the metastatic and adjuvant treatment of breast cancer.

Review of docetaxel and doxorubicin-based combinations in the management of breast cancer: from metastatic to adjuvant setting.

Considering the efficacy of docetaxel (Taxotere, Rhône-Poulenc Rorer, Antony, France) and doxorubicin in advanced breast cancer and their potential noncross-resistance, two pilot studies of docetaxel/doxorubicin (TA)-based combinations were conducted, one being a phase I dose-finding study of TA and the second a phase II study of docetaxel/doxorubicin/cyclophosphamide (TAC). The only significant toxicity, seen in both trials, was neutropenia and its consequences such as febrile neutropenia without significant documented infections. Extrahematologic and particularly docetaxel-specific side effects (fluid retention) were mild. Particularly noteworthy was the absence of significant cardiac toxicity; overall, there was only one case of congestive heart failure (1%). In terms of efficacy, response rates in excess of 70% and 80% were noted in both studies, even for patients with visceral metastases. Several phase III randomized trials using TA or TAC are presently being performed in first-line metastatic breast cancer and most importantly in the adjuvant setting to assess whether TA-based combinations will change the natural history of breast cancer.

Docetaxel (Taxotere) in combination with anthracyclines in the treatment of breast cancer.

Considering the single-agent activity of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and doxorubicin in breast cancer and their potential non-cross-resistance, several docetaxel/anthracycline-based combination chemotherapies were developed in phase I and II programs for metastatic breast cancer patients. The rationale for these combinations was also reinforced by the fact that docetaxel showed significant activity in phase III trials in patients previously exposed or having failed anthracycline chemotherapy. In a pivotal randomized phase III study of doxorubicin plus docetaxel versus doxorubicin plus cyclophosphamide as first-line chemotherapy for 429 patients with metastatic breast cancer, doxorubicin/docetaxel emerged as the more effective regimen. Despite a lower-dose intensity of doxorubicin, patients receiving doxorubicin/docetaxel experienced a higher response rate as well as a significantly longer time to progression and time to treatment failure. This difference was seen even in patients with poor-prognosis disease. Febrile neutropenia was more common in doxorubicin/docetaxel-treated patients. However, there were no septic deaths among 213 patients receiving doxorubicin/ docetaxel. Extrahematologic toxicity appeared mild for both regimens and the combination docetaxel/doxorubicin did not increase the cardiac toxicity expected for an anthracycline-containing regimen. Docetaxel plus doxorubicin is the first regimen, involving a newly developed agent, proven superior to a standard anthracycline-containing combination in metastatic breast cancer and its potential is now being investigated in the adjuvant setting.

The academic global virtual concept in clinical cancer research and its application to breast cancer: The Breast Cancer International Research Group.

In contrast to previous decades, the 1990s have witnessed an increase of new agents with significant activity in breast cancer, including chemotherapy, hormone therapy, and, more recently, biologic modifiers. All information appears to confirm that such a trend will persist and even accelerate in the coming decades. Unless clear strategies of development for new drugs are strictly followed, it will become difficult to adequately assess the many new agents with potentially important activity against breast cancer, and patient access may become a limiting key factor. The academic, global virtual concept is calling for the definition of a new relationship between the pharmaceutical industry and clinical researchers. The main aspect is related to the creation of partnerships with an academically controlled global strategy of development for promising new agents, in which the quality and independence of processes (adjuvant setting, for example) are critical. The means are based on the globalization of patient access (worldwide network) and the virtuality of the approach (modern means of communication as well as access to subgroups of patients). The Breast Cancer International Research Group is the first academic global virtual cooperative group in breast cancer and is making contributions in the development of new drugs, such as taxanes, new antiestrogens, and new cytokines.

Docetaxel and anthracycline polychemotherapy in the treatment of breast cancer.

Given the single-agent activity of docetaxel and doxorubicin in metastatic breast cancer and their potential non-cross-resistance, several phase I/II pilot studies of either docetaxel/doxorubicin (TA) or TA plus cyclophosphamide (TAC) were conducted. The results of these studies show that the main toxicity is related to neutropenia and its consequences, although documented infections are rarely reported. Other toxicities are mild, while docetaxel-specific toxicities (fluid retention, nail changes, etc) are seldom seen. No significant cardiotoxicity, even when patients are exposed to a cumulative doxorubicin dose greater than 360 mg/m2, has been observed. In terms of efficacy, response rates in the range of 70% to 80% were noted in all studies, even for patients with visceral metastases. Preliminary data suggest that the combination of docetaxel with epirubicin is also feasible, with manageable toxicities and significant activity. Several phase III randomized trials using TA or TAC are presently being performed in first-line metastatic breast cancer and, most importantly, in the adjuvant setting to assess whether TA-based combinations will change the natural history of breast cancer.

The effect of 3-aminobenzamide in the radiation response of three human cervix carcinoma xenografts.

By means of growth delay measurements, the in vivo radiation response of three recently established human cervix carcinoma xenograft lines has been determined at both high (70 cGy/min) and low dose rate (5 cGy/min). In addition, we have investigated the role of the polyADP-ribosylation inhibitor, 3-aminobenzamide, (3-AB, administered at 450 mg/kg) in modifying the xenograft response to continuous low dose rate irradiation (5 cGy/min). For all three lines, less growth delay was observed for 9 Gy administered at 5 cGy/min compared to 70 cGy/min; in terms of the times for tumours to reach twice their original weight (T2 values), low dose rate effect sparing ratios of 2.1 for HX 155, 1.5 for HX 156 and 2.4 for HX 160 were observed. 3-AB exerted no significant effect on the growth of unirradiated tumours. When 3-AB was given during irradiation at 5 cGy/min to 9 Gy, an enhancement in growth delay was observed for each line. However, the degree of radioenhancement by 3-AB varied among the lines; significant enhancement (p less than 0.01) at all time points tested was observed for HX 156, while for the other two lines, the degree of enhancement was not significant. Enhancement effect ratios (in terms of T2 values) were 1.37 for HX 155, 1.55 for HX 156 and 1.02 for HX 160. Similar differential radiosensitizing effects with 3-AB have been observed previously in vitro. More potent poly(ADP-ribosylation) inhibitors are probably required along with additional normal tissue studies before such an approach may be proposed at the clinical level.

A comparison of the in vivo and in vitro radiation response of three human cervix carcinomas.

The radiation response of three carcinoma of the cervix tumours has been compared in vivo in xenografts using growth delay and in vitro by means of a monolayer-based clonogenic assay. Tumours have been irradiated with 60Co gamma-rays at both high (70-100 cGy/min) and continuous low dose rates (3-5 cGy/min) in order to determine the relative in vivo and in vitro sparing effects associated with lowering radiation dose rate. In vitro, two of the lines (HX155c and HX156c) showed significant low dose rate sparing when compared to the HX160c line (which showed little sparing) (p = 0.012). Despite greater scatter for the in vivo data, there was a general tendency for the in vivo results to follow that predicted from the in vitro experiments. In vivo, HX156 exhibited significant sparing (p = 0.011) whereas HX160 again exhibited no significant sparing (p = 0.15). Although the HX155 line did show some sparing in vivo this did not reach significance (p = 0.111). All three lines showed less actual specific growth delay in vivo than that predicted from in vitro data. These in vitro/in vivo findings lead to the conclusion that rapid predictive testing of radiosensitivity (ideally utilising low dose rate irradiation) would be beneficial in determining the choice of radiotherapy regimens for the treatment of this disease.

Quantification of osteopontin in human plasma with an ELISA: basal levels in pre- and postmenopausal women.

OBJECTIVES: To develop an immunoassay for osteopontin (OPN), a secreted phosphoglycoprotein that is implicated in a number of human diseases, and establish basal plasma OPN levels in healthy women. DESIGN AND METHODS: An antigen-capture ELISA was developed to quantity OPN in plasma using a combination of mouse monoclonal and rabbit polyclonal antibodies. Basal OPN levels were determined in blood plasma of 21 pre- and 14 postmenopausal women obtained at 7-day intervals over a 4-week period. RESULTS: A group of 35 healthy women had a median OPN level of 31 micrograms/L (range = 14-64 micrograms/L). Comparison between pre- and postmenopausal women showed that their 4-week average OPN levels did not differ significantly (p > 0.16, Mann-Whitney test), and that levels in each premenopausal individual remained constant during the menstrual cycle, unaffected by cyclical levels of leuteinizing hormone and progesterone. CONCLUSION: Systematic quantification of plasma OPN can now be done by ELISA, which was used to establish basal plasma OPN levels in a group of healthy women. Levels in pre- and postmenopausal women appeared relatively stable over a 4-week period.

Neither toxicity nor dose intensity of carboplatin is affected by glomerular filtration rate versus body surface area dose calculation in gynecologic malignancy.

Twelve patients were given 31 courses of carboplatin using a glomerular filtration rate (GFR)-based area under the curve (AUC) dose schedule, and nine patients were given 35 cycles at a body surface area (BSA) dose of 350 mg m-2 every 3 weeks. The GFR was determined using technetium-99m-DTPA. The dose given was calculated according to AUC, 5 for previously treated and 7 for previously untreated patients x GFR + 25. Patients treated using the GFR had a 22% lower projected dose intensity (DI) and a 15% lower received DI compared with controls. The percentage difference between the received and projected DI was not different between the two groups of patients. In 11 of 12 patients treated according to the GFR, if the BSA calculation dose had been used it would have resulted in a higher dose of carboplatin. Twenty per cent (six of 30 courses) of GFR-based doses were delayed compared to 29% (10 of 35) of the BSA-calculated control groups. We conclude that giving a dose according to a BSA of 350 mg m-2 leads to a higher DI and total dose and does not substantially effect toxicity. It is also cost effective as it eliminates the need for unnecessary radiometric GFR determination.

Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer?

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol, Bristol-Myers Squibb and docetaxel, Taxotere, Rhône-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.

HTLV-1 associated T-cell lymphoma in a patient with a 10-year history of non-epidermotropic T-cell skin infiltrates.

We report a patient who had non-epidermotropic T-cell infiltrates of the skin for 10 years prior to the development of a HTLV-1 associated disseminated T-cell lymphoma. The presentation and initial course of the lymphoma were unusual and we believe this is the first report of such an association. We therefore feel that patients of Caribbean origin with non-Hodgkin's lymphoma should be tested for HTLV-1 so that appropriate chemotherapy can be instituted at the outset in this poor prognosis group.

Osteopontin and p53 expression are associated with tumor progression in a case of synchronous, bilateral, invasive mammary carcinomas.

OBJECTIVE: To examine the association between expression of osteopontin (OPN), p53, other molecular markers (Ki-67, c-erb B2, and estrogen receptor protein) and tumor progression in a case of synchronous, bilateral, invasive mammary carcinomas of the same histology. DESIGN: Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections. Plasma OPN level was determined by a quantitative antigen capture assay. SETTING: The patient was seen, treated, and followed up for a period of 5 years at the London Regional Cancer Centre, Ontario, Canada. PATIENT: A 60-year-old woman presented with bilateral infiltrating mammary carcinomas of the same histologic type and grade. Bilateral mastectomy and axillary node dissection showed involvement of 3 of 12 right axillary and 0 of 11 left axillary lymph nodes. She later developed a right chest wall recurrence, followed by widespread metastatic disease to the skull, liver, and left femur. RESULTS: The primary tumor of the right breast was OPN- and p53-positive, whereas the tumor of the left breast was negative for both markers. The development of right axillary lymph node metastases, chest wall recurrence, and distant metastases was associated in all instances with an immunohistochemical profile of high level expression of OPN and p53. Plasma assay for OPN at the time of last admission showed a markedly elevated OPN level. CONCLUSIONS: Increased p53 expression was found to be associated with increased tumor aggressiveness. The association of increased OPN expression with increased malignancy in breast cancer is a novel finding and raises the possibility of a role for OPN in tumor progression, as well as the potential for this marker in predicting clinical aggressiveness.

Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective.

Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer.Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention.