Anthracycline-induced cardiotoxicity in patients with early-stage breast cancer: the Canadian Cancer Trials Group (CCTG) MA.21 experience.

PURPOSE: Anthracyclines are frequently used in adjuvant treatment for early-stage breast cancer (ESBC). The purpose of this study was to evaluate cardiotoxic effects in the first five years after treatment with different anthracycline-based regimens. METHODS: CCTG MA.21 (NCT000142) was a phase III trial in ESBC that compared cyclophosphamide (75 mg/m2) orally for 14 days, epirubicin (60 mg/m2) and fluorouracil, IV days one and eight (CEF) for six cycles; dose-dense epirubicin (120 mg/m2) and cyclophosphamide, IV every 2 weeks for six cycles with concurrent G-CSF then paclitaxel every 2 weeks for four cycles (ddEC/T); doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks for four cycles then four cycles q3 weekly paclitaxel (175 mg/m2) (AC/T). ENDPOINTS: LVEF decline; LV function changes (heart failure), or Grade 3-4 cardiac ischemia/infarction. A competing risk analysis was performed with endpoints of cardiotoxicity or recurrence in first 5 years after completion of chemotherapy. RESULTS: 2104 women were randomized. Compliance with cardiac LVEF assessments was 70% at 5 years in all arms. The 5-year cumulative risks of any cardiac event for CEF, ddECT, and AC/T were 22.3% (95%CI 18.9 to 25.7), 14.2% (95%CI 11.0 to 17.3), and 8.1% (95%CI 5.8 to 10.4), respectively, p < 0.0001. At 5 years, women in the ddEC/T and AC/T group had significantly lower risk of cardiotoxicity than those given CEF (HR 0.599 and 0.371, respectively). Most events were asymptomatic drop in LVEF. CONCLUSIONS: Asymptomatic changes in LVEF accounted for most of the cardiotoxicity. The majority of cardiac events occurred in year one although occurrence of cardiotoxicity over time highlights the need for improved risk stratification to guide cardiac surveillance strategies.

A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: final analysis of Canadian Cancer Trials Group IND.213.

BACKGROUND: Pelareorep, a serotype 3 reovirus, has demonstrated preclinical and early clinical activity in breast cancer and synergistic cytotoxic activity with microtubule targeting agents. This multicentre, randomized, phase II trial was undertaken to evaluate the efficacy and safety of adding pelareorep to paclitaxel for patients with metastatic breast cancer (mBC). METHODS: Following a safety run-in of 7 patients, 74 women with previously treated mBC were randomized either to paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 4 weeks plus pelareorep 3 × 1010 TCID50 intravenously on days 1, 2, 8, 9, 15, and 16 every 4 weeks (Arm A) or to paclitaxel alone (Arm B). Primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate, overall survival (OS), circulating tumour cell counts, safety, and exploratory correlative analyses. All comparisons used a two-sided test at an alpha level of 20%. Survival analyses were adjusted for prior paclitaxel. RESULTS: Final analysis was performed after a median follow-up of 29.5 months. Pelareorep was well tolerated. Patients in Arm A had more favourable baseline prognostic variables. Median adjusted PFS (Arm A vs B) was 3.78 mo vs 3.38 mo (HR 1.04, 80% CI 0.76-1.43, P = 0.87). There was no difference in response rate between arms (P = 0.87). Median OS (Arm A vs B) was 17.4 mo vs 10.4 mo (HR 0.65, 80% CI 0.46-0.91, P = 0.1). CONCLUSIONS: This first, phase II, randomized study of pelareorep and paclitaxel in previously treated mBC did not show a difference in PFS (the primary endpoint) or RR. However, there was a significantly longer OS for the combination. Further exploration of this regimen in mBC may be of interest.

Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

BACKGROUND: This systematic review addresses the question "What is the optimal targeted therapy for female patients with early-stage human epidermal growth factor receptor 2 (her2)-positive breast cancer?" METHODS: The medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major guideline organizations were also searched. RESULTS: Sixty publications relevant to the targeted therapy portion of the systematic review were identified. In four major trials (hera, National Surgical Adjuvant Breast and Bowel Project B-31, North Central Cancer Treatment Group N9831, and Breast Cancer International Research Group 006), adjuvant trastuzumab for 1 year was superior in disease-free survival (dfs) and overall survival (os) to no trastuzumab; trastuzumab showed no benefit in one trial (pacs 04). A shorter duration of trastuzumab (less than 1 year compared with 1 year) was evaluated, with mixed results for dfs: one trial showed superiority (finher), one trial could not demonstrate noninferiority (phare), another trial showed equivalent results (E 2198), and one trial is still ongoing (persephone). Longer trastuzumab duration (hera: 2 years vs. 1 year) showed no improvement in dfs or os and a higher rate of cardiac events. Newer her2-targeted agents (lapatinib, pertuzumab, T-DM1, neratinib) have been or are still being evaluated in both adjuvant and neoadjuvant trials, either by direct comparison with trastuzumab alone or combined with trastuzumab. In the neoadjuvant setting (neoaltto, GeparQuinto, Neosphere), trastuzumab alone or in combination with another anti-her2 agent (lapatinib, pertuzumab) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response. In the adjuvant setting, lapatinib alone or in combination with trastuzumab, compared with trastuzumab alone (altto) or with placebo (teach), was not superior in dfs. The results of the completed aphinity trial, evaluating the role of dual her2 blockade with trastuzumab and pertuzumab, are highly anticipated. Ongoing trials are evaluating trastuzumab as a single agent without adjuvant chemotherapy (respect) and in patients with low her2 expression (National Surgical Adjuvant Breast and Bowel Project B-47). CONCLUSIONS: Taking into consideration disease characteristics and patient preference, 1 year of trastuzumab should be offered to all patients with her2-positive breast cancer who are receiving adjuvant chemotherapy. Cardiac function should be regularly assessed in this patient population.

Optimal systemic therapy for early breast cancer in women: a clinical practice guideline.

The Breast Cancer Disease Site Group of Cancer Care Ontario identified the need for new guidelines for the adjuvant systemic therapy of early-stage breast cancer. The specific question to be addressed was "What is the optimal adjuvant systemic therapy for female patients with early-stage operable breast cancer, when patient and disease factors are considered?" A systematic review was prepared based on literature searches conducted using the medline and embase databases for the period January 2008 to March 5, 2012, and updated to May 12, 2014. Guidelines were located from that search, from the Standards and Guidelines Evidence directory of cancer guidelines, and from the Web sites of major guideline organizations. The literature located was subdivided into the broad categories of chemotherapy, hormonal therapy, and therapy targeted to her2 (human epidermal growth factor receptor 2). Although several of the systemic therapies discussed in this guideline can be considered in the neoadjuvant setting, the review focused on trials with rates of disease-free and overall survival as endpoints and thus excluded several trials that used pathologic complete response as a primary endpoint. Based on the systematic review, the working group drafted recommendations on the use of chemotherapy, hormonal therapy, and targeted therapy; based on their professional experience, they also drafted recommendations on patient and disease characteristics and recurrence risk. The literature review and draft recommendations were circulated to a consensus panel of medical oncologists who had expertise in breast cancer and who represented the regions of Ontario. Items without initial consensus were discussed at an in-person consensus meeting held in Toronto, November 23, 2012. The final recommendations are those for which consensus was reached before or at the meeting. Some of the key evidence was revised after the updated literature search. Evidence reviews for systemic chemotherapy, endocrine therapy, and targeted therapy for her2-positive disease are reported in separate articles in this supplement. The full three-part 1-21 evidence-based series, including complete details of the development and consensus processes, can be found on the Cancer Care Ontario Web site at https://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/breast-ebs.

Adjuvant chemotherapy for early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

BACKGROUND: The Program in Evidence-Based Care (pebc) of Cancer Care Ontario recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question "What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?" The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and human epidermal growth factor receptor 2 (her2)-directed therapy. METHODS: For the systematic review, the medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were "breast cancer" and "systemic therapy" (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. RESULTS: Several hundred documents that met the inclusion criteria were retrieved. The Early Breast Cancer Trialists' Collaborative Group meta-analyses encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. Chemotherapy was reviewed mainly in three classes: anti-metabolite-based regimens (for example, cyclophosphamide-methotrexate-5-fluorouracil), anthracyclines, and taxane-based regimens. In general, single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population. Anthracycline-taxane-based polychemotherapy regimens are, overall, considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes. Regimens with varying anthracycline and taxane doses and schedules are options; in general, paclitaxel given every 3 weeks is inferior. Evidence does not support the use of bevacizumab in the adjuvant setting; other systemic therapy agents such as metformin and vaccines remain investigatory. Adjuvant bisphosphonates for menopausal women will be discussed in later work. CONCLUSIONS: The results of this systematic review constitute a comprehensive compilation of the high-level evidence that is the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. Use of cytotoxic chemotherapy is presented here; the results addressing endocrine therapy and her2-targeted treatment, and the final clinical practice recommendations, are published separately in this supplement.

Adjuvant endocrine therapy for early breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

BACKGROUND: Cancer Care Ontario's Program in Evidence-Based Care (pebc) recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question "What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?" The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and her2 (human epidermal growth factor receptor 2)-targeted therapy. METHODS: For the systematic review, the literature in the medline and embase databases was searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were "breast cancer" and "systemic therapy" (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. RESULTS: Several hundred documents that met the inclusion criteria were retrieved. Meta-analyses from the Early Breast Cancer Trialists' Collaborative Group encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. SUMMARY: The results of the systematic review constitute a comprehensive compilation of high-level evidence, which was the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. The review of the evidence for systemic endocrine therapy (adjuvant tamoxifen, aromatase inhibitors, and ovarian ablation and suppression) is presented here; the evidence for chemotherapy and her2-targeted treatment-and the final clinical practice recommendations-are presented separately in this supplement.

Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer.

UNLABELLED: The pi3k/Akt/mtor (phosphatidylinositol 3 kinase/ Akt/mammalian target of rapamycin) signalling pathway is an established driver of oncogenic activity in human malignancies. Therapeutic targeting of this pathway holds significant promise as a treatment strategy. Everolimus, an mtor inhibitor, is the first of this class of agents approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Everolimus has been associated with significant improvements in progression-free survival; however, it is also associated with increased toxicity related to its specific mechanism of action. METHODS: A comprehensive review of the literature conducted using a focused medline search was combined with a search of current trials at http://ClinicalTrials.gov/. Summary tables of the toxicities of the various classes of pi3k/Akt/mtor inhibitors were created. A broad group of Canadian health care professionals was assembled to review the data and to produce expert opinion and summary recommendations for possible best practices in managing the adverse events associated with these pathway inhibitors. RESULTS: Differing toxicities are associated with the various classes of pi3k/Akt/mtor pathway inhibitors. The most common unique adverse events observed in everolimus clinical trials in breast cancer include stomatitis (all grades: approximately 60%), noninfectious pneumonitis (15%), rash (40%), hyperglycemia (15%), and immunosuppression (40%). To minimize grades 3 and 4 toxicities and to attempt to attain optimal outcomes, effective management of those adverse events is critical. Management should be interdisciplinary and should use approaches that include education, early recognition, active intervention, and potentially prophylactic strategies. DISCUSSION: Everolimus likely represents the first of many complex oral targeted therapies for the treatment of breast cancer. Using this agent as a template, it is essential to establish best practices involving and integrating multiple disciplines for the management of future pi3k/Akt/mtor signalling pathway inhibitors.

Preference weights for chemotherapy side effects from the perspective of women with breast cancer.

Perceptions among women with breast cancer about the relative importance of different potential chemotherapy side effects is not well understood. A survey was performed by women receiving chemotherapy for breast cancer. Grade I/II (mild to moderate) and III/IV (moderate to severe) descriptions of nine common chemotherapy side effects were assigned preference weights using the standard gamble technique. For each hypothetical side effect, patients could choose to stay in the respective side effect state or take a gamble between full health (probability p) or being dead (1 - p). For each side effect, p was varied until the patient was indifferent between these options. The survey also included questions about the importance of survival, slowing cancer growth, and quality of life. This analysis included 69 patients; mean age 54 years (range 35-84), representing all cancer stages. Standard gamble preferences were lowest (i.e., least preferred) for grade III/IV nausea/vomiting (0.621), indicating that patients would, on average, risk a 38 % chance of being dead to avoid having grade III/IV nausea/vomiting for the rest of their lives. The next least preferred side effects were grade III/IV diarrhea (0.677) and grade III/IV sensory neuropathy (0.694). Survival appeared more important than slowing cancer growth and maintaining quality of life across cancer stages. Nevertheless, patients with advanced disease placed less importance on survival (p = 0.09) and higher importance on quality of life (p = 0.05). These standard gamble utilities provide unique insights into chemotherapy toxicities from the patient perspective. Differences in the relative importance of overall survival and quality of life with treatment existed between patients with different stages of disease. These studies should be expanded as the data may also be used to calculate quality-adjusted life expectancy in cost-effectiveness evaluations of breast cancer chemotherapies.

NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies.

PURPOSE: AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. PATIENTS AND METHODS: Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D). RESULTS: 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months). CONCLUSION: In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.

Use and delivery of granulocyte colony-stimulating factor in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy-single-centre experience.

BACKGROUND: Use of granulocyte colony-stimulating factor (g-csf) as primary prophylaxis against chemotherapy-induced neutropenia has significant cost implications. We examined use of g-csf for early-stage breast cancer patients at our centre. The study also examined the pattern of nurse-led patient teaching with respect to drug self-administration. METHODS: Patients who received g-csf between November 2009 and October 2010 were identified from pharmacy records. After consent had been obtained, electronic charts were examined to extract data on chemotherapy and use of g-csf. Patients were contacted by telephone to obtain information on the utilization of home-care nursing visits for g-csf administration. RESULTS: The study analyzed 36 patients. Median age was 58 years (range: 31-78 years). Of the 36 patients, 30 (83%) had received adjuvant treatment, and 6 (17%), neoadjuvant treatment. Most patients (71%) received 10 days (range: 7-10 days) of filgrastim. Of the 36 patients, 29 (81%) received g-csf as primary prophylaxis. In 90% of those patients, primary prophylaxis commenced with the taxane component of treatment. Of the 36 patients, 7 (19%) received g-csf after neutropenia, including 2 who had febrile neutropenia. In 96% of the patients, injections were received at home with the help of a nurse; those patients were subsequently taught self-injection techniques. The median number of nursing visits was 2 (range: 1-3 visits). Most patients were satisfied with the home care and g-csf teaching they received. CONCLUSIONS: Most of the g-csf used in breast cancer treatment during the study period was given for primary prophylaxis. A major reason for the decision to use g-csf appears to have been physician-perceived risk of febrile neutropenia. Delivery of g-csf by home-care nurses was well received by patients.

Real-world experience with adjuvant fec-d chemotherapy in four Ontario regional cancer centres.

BACKGROUND: The efficacy of adjuvant chemotherapy with fec-d (5-fluorouracil-epirubicin-cyclophosphamide followed by docetaxel) is superior to that with fec-100 alone in women with early-stage breast cancer. As the use of fec-d increased in clinical practice, health care providers anecdotally noted higher-than-expected toxicity rates and frequent early treatment discontinuations because of toxicity. In the present study, we compared the rates of serious adverse events in patients who received adjuvant fec-d chemotherapy in routine clinical practice with the rates reported in the pacs-01 trial. METHODS: We retrospectively reviewed all patients prescribed adjuvant fec-d for early-stage breast cancer at 4 regional cancer centres in Ontario. Information was collected from electronic and paper charts by a physician investigator from each centre. Data were analyzed using chi-square tests, independent samples t-tests, one-way analysis of variance, and univariate regression. RESULTS: The 671 electronic and paper patient records reviewed showed a median patient age of 52.2 years, 229 patients (34.1%) with N0 disease, 508 patients (75.7%) with estrogen or progesterone receptor-positive disease (or both), and 113 patients (26%) with her2/neu-overexpressing breast cancer. Febrile neutropenia occurred in 152 patients (22.7%), most frequently at cycle 4, coincident with the initiation of docetaxel [78/152 (51.3%)]. Primary prophylaxis with hematopoietic growth factor support was used in 235 patients (35%), and the rate of febrile neutropenia was significantly lower in those who received prophylaxis than in those who did not [15/235 (6.4%) vs. 137/436 (31.4%); p < 0.001; risk ratio: 0.20]. CONCLUSIONS: In routine clinical practice, treatment with fec-d is associated with a higher-than-expected rate of febrile neutropenia, in light of which, primary prophylaxis with growth factor should be considered, per international guidelines. Adoption based on clinical trial reports of new therapies into mainstream practice must be done carefully and with scrutiny.

Endocrine therapy for male breast cancer: rates of toxicity and adherence.

PURPOSE: Most male breast cancer tumours are hormone receptor-positive; the patients therefore receive endocrine therapy. There is, however, a paucity of published data on toxicities experienced by male breast cancer patients who are prescribed endocrine therapy. In the present study, we examined rates of adherence to and toxicity from endocrine treatments in male breast cancer patients treated at a single institution. PATIENTS AND METHODS: We conducted a retrospective study of male patients diagnosed with breast cancer at The Ottawa Hospital Cancer Centre during 1981-2003. Data collected included patient age, hormone receptor status, therapy adherence, self-reported toxicities, and type and duration of endocrine therapies. RESULTS: The review located 59 cases of early-stage and metastatic male breast cancer. Median patient age was 68.0 years. Tamoxifen was given to 38 patients (64.4%), anastrozole to 8 (13.6%), and letrozole to 5 (8.5%). Of patients who received endocrine therapy, 10 (25%) received adjuvant systemic chemotherapy. Toxicity was reported by 19 patients taking tamoxifen (50%), with hot flashes being the most common complaint (18.4%). Decreased libido, weight gain, and malaise were reported by 5 patients (13.2%). Rash and erectile dysfunction were reported by 3 patients (7.9%). Increased liver enzymes, pulmonary embolism, superficial thrombophlebitis, myalgia, depression, visual blurring, and loose stools were each reported in 1 patient (2.6%). Tamoxifen therapy was discontinued secondary to toxicity in 9 patients (23.7%). Of the patients treated with anastrozole, 3 (37.5%) reported toxicity, with 1 report each of decreased libido, leg swelling, and depression (12.5%). Toxicity was reported in 2 patients taking letrozole (40%), with both reporting peripheral edema, and 1 reporting hot flashes. No patient discontinued anastrozole or letrozole because of toxicity. CONCLUSIONS: Few studies specifically report data on adherence to and toxicities from endocrine therapies in male breast cancer patients. The rate of discontinuation at our institution because of toxicity (23.7%) is similar to that reported in the female breast cancer population. Future prospective studies should explore strategies to improve adherence to endocrine therapy in this population.

Phase II study of troxacitabine (BCH-4556) in patients with advanced non-small-cell lung cancer.

Troxacitabine. a promising new L-nucleoside, inhibits DNA polymerase and leads to complete DNA chain termination. The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) conducted a phase II study to assess the efficacy and toxicity of troxacitabine in untreated patients with advanced non-small-cell lung cancer (NSCLC). Previously untreated patients were eligible if they had inoperable stage IIIB or IV NSCLC, ECOG PS < or = 2, adequate hematology and biochemistry, and at least one bidimensionally measurable lesion. Patients with prior malignancy or brain metastases were excluded. Troxacitabine (10 mg/m(2)) was administered intravenously over 30 minutes every 3 weeks. Between June 1999 and May 2000, 17 eligible patients received treatment. Patient characteristics included: median age 64 years; female 41%; stage IV (94%); PS 0 (12%), 1 (59%), and 2 (29 %), 3 or more disease sites (59%). In 17 patients, there were 8 stable disease, 9 disease progression, and no objective responses. Median duration of stable disease was 3.6 months (range = 2.0-7.1). A total of 56 cycles were administered (median = 3), and 88% of patients received 90% or more of the planned dose intensity. The majority (82%) of patients experienced skin rash. Hematologic and biochemical toxicities, grade 3/4 (%) were: granulocytopenia (41), anemia (12), thrombocytopenia (6), and hyperglycemia (6). Troxacitabine appears to have little activity in NSCLC in the dose and schedule tested.

Second primary malignancies following the treatment of early stage ovarian cancer: update of a study by the National Cancer Institute of Canada--Clinical Trials Group (NCIC-CTG).

BACKGROUND: Ovarian cancer is the leading cause of death from gynecological malignancies and the fourth most frequent fatal malignancy in women. Despite improved surgical techniques as many as 20% of women with early stage disease will eventually relapse and die from their disease. The post-operative management of these women remains controversial. Here we present the long term follow-up data of our previously published study, as well as the incidence of second primary malignancies in these women. PATIENTS AND METHODS: Two hundred fifty-seven eligible patients with stage I, IIA 'high risk' ovarian carcinoma and IIB, IIIO (disease confined to pelvis) were randomized to either whole abdominal radiotherapy 2.250 rads in ten fractions (107 patients), melphalan 8 mg/m2/d x 4 weeks x 18 courses (106 patients) or intraperitoneal chromic phosphate 10-20 mCi (44 patients). All patients were initially treated with pelvic radiotherapy. RESULTS: Overall survival estimates at 10 years were: 45% in the whole abdominal radiotherapy arm; 49% in the melphalan arm and 50% in the intraperitoneal chromic phosphate arm (P = 0.30). Relapse-free survival estimates at 10 years were: 50% in the whole abdominal radiotherapy arm, 62% in the melphalan arm and 51% in the chromic phosphate arm (P = 0.147). Long term follow-up has not demonstrated a significant difference between treatment arms. Second primary malignancies developed in 29 women (11%) after 2,229 person years of follow-up. This compares to 18.7 second primary malignancies which would have been expected in this group of age-matched controls and was statistically significant (P = 0.018). There was no significant difference in the total number of second primary malignancies between treatment arms. Melphalan appeared to be associated with an increased risk of developing leukemia/myelodysplastic syndrome compared to the whole abdominal radiotherapy arm (P = 0.06). CONCLUSIONS: Long-term follow-up has not demonstrated a significant difference in overall or disease free survival between treatment arms. An excess of second primary malignancies (35%) was observed suggesting that lifelong surveillance is required in this population. Further research with newer treatment programs are needed to improve the cure rates in this population.

Phase I trial design: are new methodologies being put into practice?

BACKGROUND: The primary goal of phase I studies is to efficiently and accurately determine the recommended dose of a new agent for further investigation. Issues of concern ranging from the ethics of these trials to selection of starting dose and rapidity of dose escalation, have led to suggested modifications of the traditional phase I design. We wanted to assess the frequency with which these new approaches are being applied to recent phase I trials and, if possible, their impact. METHODS: Reports of phase I trials of single agent cytotoxics published between 1993 and 1995 were identified by computer search and review of cancer journals. Data on starting dose, toxicology, dose escalation method, definition of dose limiting toxicity (DLT), actual maximum tolerated dose (MTD) and recommended phase II dose were abstracted. RESULTS: Reports of 46 phase I trials were identified: 27 were the first clinical studies of 17 new cytotoxic agents (group A) and 19 were repeat studies of 14 agents (group B). Starting doses in group A were based on preclinical animal toxicology (usually mouse or dog) and for group B on previous clinical experience. Dog toxicology appropriately influenced starting dose in 3 of 6 trials. The majority of group A (19/27) studies employed modified Fibonacci dose escalation; group B studies commonly escalated doses by fixed increments. The definition of DLT was highly variable across studies. MTD was usually defined as the dose level at which > 2/6 patients experienced DLT but several studies required 3-4/6 patients. In 30 trials, the recommended phase II dose was one dose level below the MTD; but in 10 trials the terms MTD and recommended phase II dose were considered synonymous. CONCLUSION: Despite proposed new methodologies (particularly dose escalation) for phase I trials, very few are being employed in practice. A concerted effort should be made to prospectively evaluate these to determine which provides the best combination of safety and efficacy. In addition, the lack of standardization in the definition of limiting toxicity is surprising. Those involved in drug development should strive for agreement on the acceptable degree of toxicity for phase II dose selection.