Peter S. Craighead

A phase I/II evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer

PURPOSE This is a Phase I/II dose escalation study to determine the tolerable dose of tirapazamine (TPZ), and the toxicity of a regimen using TPZ with cisplatin, and radiotherapy in women with locally advanced cervical cancer. METHODS AND MATERIALS Eligible women for this study were those with a diagnosis of locally advanced cervix cancer, who were less than 75 years of age, having provided informed consent, and who had undergone the necessary prestudy investigations. External-beam radiotherapy (RT) was given to a minimum dose of 4500 cGy in 25 fractions (Day 1-35), and brachytherapy then delivered to bring the total dose at point A to 8500 cGy. The first dose level of the study used TPZ 190 mg/m(2) and cisplatin 75 mg/m(2) on Days 1, 15, and 29 of RT. TPZ 160 mg/m(2) alone was used on Days 8, 10, 12 and 22, 24, 26 of RT. A conventional dose-escalation step method was then used to determine the maximum tolerated dose (MTD) of TPZ. RESULTS Four patients were treated at Level 1, 6 at Level 2, and 5 at Level 3. Only 1 patient experienced a dose-limiting toxicity (DLT) at Level 2, but 2 of the 5 patients at Level 3 incurred DLTs. Level 2 was declared the MDT (TPZ 290 mg/m(2) on Days 1, 15, 29 and 220 mg/m(2) on Days 8, 10, 12 and 22, 24, 26). At 6 months, 13 of 15 patients had complete pelvic control of disease. CONCLUSION Level 2 of this regime was identified as the MDT. The use of TPZ with concurrent cisplatin and pelvic radiotherapy has acceptable toxicity and should be considered for further Phase 2 testing in view of the promising responses noted.

PIK3CA mutational status and overall survival in patients with cervical cancer treated with radical chemoradiotherapy

OBJECTIVE Mutational activation of PIK3CA is associated with poor prognosis in patients with solid tumors, and may predict favorable response to PI3K/AKT/mTOR pathway inhibitors. However, PIK3CA mutational status has not previously been evaluated in patients with cervical carcinoma treated with radical chemoradiotherapy (CRT). The aims of this study were (1) to evaluate the frequency of PIK3CA mutations in patients with cervical cancer treated with radical CRT and (2) to examine the effect of tumor PIK3CA mutational status in pre-treatment biopsies on overall survival (OS) and progression-free survival (PFS). METHODS Patients with cervical cancer, treated at a single institution with radical CRT, from 1999 to 2008, were eligible for this retrospective study. Pre-treatment tumor biopsies (n=157) were retrieved. Genomic DNA was extracted from tumor blocks, and exons 9 and 20 of the PIK3CA gene were sequenced for mutations. RESULTS Eighty-two tumors were sequenced for both exon 9 and exon 20. 19/82 (23%) tumors were PIK3CA mutation positive; of these 84% were squamous cell carcinomas. 79% of mutations were in exon 9. PIK3CA mutation status was strongly associated with overall survival (OS) in FIGO stage IB/II patients, unadjusted HR 6.0 (95% CI 2.1-17.5), p=0.0002, but not stage III/IVA patients, unadjusted HR 1.0 (95% CI 0.32-3.1), p=0.98. CONCLUSIONS In cervical cancer patients treated with CRT, tumor PIK3CA mutation status was associated with overall survival in FIGO stage IB/II cervix cancers. Further evaluation with a larger dataset will be required to validate these findings to inform potential clinical trials designs involving PI3K/AKT/mTOR pathway inhibitors.

Image-guided brachytherapy for cervical cancer: a Canadian Brachytherapy Group survey.

PURPOSE To survey the current use and future plans for image-guided brachytherapy (BT) for cervical cancer by radiation oncologists in Canada. METHODS AND MATERIALS Canadian radiation oncologists treating gynecologic malignancies were identified in January 2009. A 29-item questionnaire (English and French) querying the current practice in the use of imaging in BT planning, and plans for transition to three-dimensional (3D) image guidance for BT for cervical cancer (curative intent, intact cervix), was electronically circulated. Questionnaire responses were tabulated and analyzed by respondent and by center. RESULTS Response rate was 62% (36 of 58 radiation oncologists), representing 71% (22 of 31) of Canadian radiation oncology centers with a gynecologic BT facility. Most of the centers were using high-dose-rate BT (68%), followed by low-dose-rate BT (23%) and pulsed dose-rate BT (10%). Main imaging used for treatment planning by center was plain X-ray (50%), computerized tomography (CT) (45%), and magnetic resonance imaging (MRI) (5%). For respondents using CT or MRI for planning, point A was the most common dose prescription point (50%), followed by gross tumor volume/clinical target volume as per Groupe Européen de Curiethérapie and the European Society for Therapeutic Radiology and Oncology guidelines (44%). For centers using plain X-rays for planning, 73% planned to transition to a 3D image-based approach, with the majority to adopt CT imaging. Eighty percent of respondents agreed that 3D image-guided BT should become standard of care for treatment of cervical cancer in Canada, and additionally support the development of national guidelines. CONCLUSIONS Most of the Canadian radiation oncologists surveyed and Canadian cancer centers are either using 3D imaging and planning or transitioning to a 3D image-based approach within the next year. Point A remained a commonly documented prescription point. Access to MRI was very low. These results may lead to national treatment guidelines.

Low ERCC1 mRNA and protein expression are associated with worse survival in cervical cancer patients treated with radiation alone

PURPOSE To evaluate the association of excision repair cross-complementation group 1 (ERCC1) expression, using both mRNA and protein expression analysis, with clinical outcome in cervical cancer patients treated with radical radiation therapy (RT). EXPERIMENTAL DESIGN Patients (n=186) with locally advanced cervical cancer, treated with radical RT alone from a single institution were evaluated. Pre-treatment FFPE biopsy specimens were retrieved from 112 patients. ERCC1 mRNA level was determined by real-time PCR, and ERCC1 protein expression (FL297, 8F1) was measured using quantitative immunohistochemistry (AQUA®). The association of ERCC1 status with local response, 10-year disease-free (DFS) and overall survival (OS) was analyzed. RESULTS ERCC1 protein expression levels using both FL297 and 8F1 antibodies were determined for 112 patients; mRNA analysis was additionally performed in 32 patients. Clinical and outcome factors were comparable between the training and validation sets. Low ERCC1 mRNA expression status was associated with worse OS (17.9% vs 50.1%, p=0.046). ERCC1 protein expression using the FL297 antibody, but not the 8F1 antibody, was significantly associated with both OS (p=0.002) and DFS (p=0.010). After adjusting for pre-treatment hemoglobin in a multivariate analysis, ERCC1 FL297 expression status remained statistically significant for OS [HR 1.9 (1.1-3.3), p=0.031]. CONCLUSIONS Pre-treatment tumoral ERCC1 mRNA and protein expression, using the FL297 antibody, are predictive factors for survival in cervical cancer patients treated with RT, with ERCC1 FL297 expression independently associated with survival. These results identify a subset of patients who may derive the greatest benefit from the addition of cisplatin chemotherapy.

Brachytherapy for carcinoma of the cervix: A Canadian survey of practice patterns in a changing era

BACKGROUND AND PURPOSE This survey aimed to document practices of Canadian radiation oncologists performing gynecologic brachytherapy for carcinoma of the cervix and to determine what the effect of the phasing-out of LDR after-loading systems from the commercial market is having on practice. MATERIALS AND METHODS A 26-item questionnaire was developed to survey various aspects of brachytherapy practice to include: number of patients treated, prescription points/volume, dose and fractionation, timing, critical structure delineation, expected changes due to the phasing-out of support for low dose rate systems, and support for the development of national guidelines. A link to a web-based survey collection instrument was emailed to each radiation oncologist in Canada practicing gynecologic brachytherapy. RESULTS A 67% response rate was achieved in this web-based survey. Radiation oncologists currently using HDR brachytherapy are most commonly delivering 5 fractions of 6 Gy in addition to an EBRT dose of 45 Gy in 25 fractions. The median total dose equivalents to Point A was 82.9 Gy for both early and advanced disease. In response to the announcement by a major vendor that they would be phasing-out service for a popular LDR after-loader, 49% of Canadian radiation oncologists who practice brachytherapy for cervix cancer are changing to an HDR technique with a further 9% changing to a PDR technique. Eighty-six percent of respondents would support the development of national guidelines for cervix brachytherapy in Canada. CONCLUSIONS Variation in practice exists in Canada in brachytherapy for cervix cancer. Many centers are in the process of phasing-out LDR techniques in response to the withdrawal of commercial support for these systems. Support for the development of Canadian national guidelines is high.

The Significance of Tumoral ERCC1 Status in Patients With Locally Advanced Cervical Cancer Treated With Chemoradiation Therapy: A Multicenter Clinicopathologic Analysis

PURPOSE ERCC1 (excision repair cross-complementation group 1) expression has been shown to be a molecular marker of cisplatin resistance in many tumor sites, but has not been well studied in cervical cancer patients. The purpose of this study was to measure tumoral ERCC1 in patients with locally advanced cervical cancer treated with chemoradiation therapy (CRT) in a large multicenter cohort, and to correlate expression with clinical outcome parameters. METHODS AND MATERIALS A total of 264 patients with locally advanced cervical cancer, treated with curative-intent radical CRT from 3 major Canadian cancer centers were evaluated. Pretreatment formalin-fixed, paraffin-embedded tumor specimens were retrieved, and tissue microarrays were constructed. Tumoral ERCC1 (FL297 antibody) was measured using AQUA (R) technology. Statistical analysis was performed to determine the significance of clinical factors and ERCC1 status with progression-free survival (PFS) and overall survival (OS) at 5 years. RESULTS The majority of patients had International Federation of Gynecology and Obstetrics (FIGO) stage II disease (n=119, 45%); median tumor size was 5 cm. OS was associated with tumor size (HR 1.16, P=.018), pretreatment hemoglobin status (HR 2.33, P=.00027), and FIGO stage. In addition, tumoral ERCC1 status (nuclear to cytoplasmic ratio) was associated with PFS (HR 2.33 [1.05-5.18], P=.038) and OS (HR 3.13 [1.27-7.71], P=.013). ERCC1 status was not significant on multivariate analysis when the model was adjusted for the clinical factors: for PFS (HR 1.49 [0.61-3.6], P=.38); for OS (HR 2.42 [0.94-6.24] P=.067). CONCLUSIONS In this large multicenter cohort of locally advanced cervical cancer patients treated with radical CRT, stage, tumor size, and pretreatment hemoglobin status were significantly associated with PFS and OS. ERCC1 status appears to have prognostic impact on univariate analysis in these patients, but was not independently associated with outcome on multivariate analysis.

Are recommendations from carcinoma of the cervix patterns of care studies (PCS) in the united states of America (USA) applicable to centers in developing countries

PURPOSE To compare patient demographics, treatment resources, practice patterns, and outcome results for squamous cell carcinoma of the uterine cervix (SCC) between the 1978 and 1983 Patterns of Care studies (PCS) in the United States of America (USA) and a nonacademic center within a developing country. METHOD AND MATERIALS Patient details (race, age, stage, and number per year), treatment used, and treatment outcome were retrieved from the charts of the 1160 cases registered at this center with SCC of the cervix between 1976 and 1985. Demographic variables and Kaplan-Meier survival estimates were calculated and compared with results from published PCS reviews. RESULTS There is a significant difference in the racial group presentation of cervix cancer at this center compared with the PCS reviews (p < 0.005), and median ages are significantly lower at this center (t = p < 0.001). The proportion of patients with Stage III or more was significantly higher at this center than the PCS centers (24 vs. 47%, p < 0.001). There were also vast differences in facility resources. Fewer cases at this center underwent intracavitary insertions than at PCS centers. Mean Point A doses were significantly reduced for this center compared with the PCS reviews. Kaplan-Meier estimates were similar for Stage I and II in PCS centers and this center, but were inferior for this center in Stage III patients (p < 0.05 for OS and p < 0.01 for LC). Late morbidity rates were similar for both PCS centers and this center. CONCLUSION PCS recommendations may be applicable to nonacademic centers within developing countries, if the latter use staging techniques that are consistent with the PCS staging guidelines.

Determining the need and utilization of radiotherapy in cancers of the breast, cervix, lung, prostate and rectum: A population level study

PURPOSE Determining the appropriate rate of radiotherapy (RT) utilization is important for health care planning and resource allocation. The difference between the observed and the appropriate RT rate is influenced by the choice of a criterion based benchmarking (CBB) or evidence-based estimates (EBEST) measure. Our primary objective was to determine the utilization of radiotherapy for cancers of the breast (B), cervix (C), lung (L), prostate (P) and rectum (R) in Alberta (AB) Canada and to compare the observed RT rates to estimates of need derived from the criterion based benchmarking (CBB) and evidence-based estimates (EBEST). MATERIALS AND METHODS All incident cases of B,C,L,P and R cancers diagnosed in AB during 2004-8 (prior to the decentralization of provincial RT capacity) were identified from the Alberta Cancer Registry. Patients receiving RT within one year (RT-1y) of diagnosis were identified and the proportion receiving RT-1y was then calculated. Factors associated with RT utilization were analysed by region. Estimates of the need for RT were derived from CBB and EBEST methods in the literature. RESULTS A total of n=68,164 cancer cases were identified from the ACR. RT-1y rates (95% C.I.) were B: 51.5% (50.1-52.9), C: 48.9% (43.8-54.0), L: 37.1% (35.4-38.8), P: 26.9% (25.1-28.7) and R: 39.3% (36.5-42.1). Observed rates of RT in AB were lower than estimates derived using the CBB and EBEST estimates. Shortfalls varied across cancer sites according to whether a CBB or EBEST estimate was used ranging from a low of -0.3% in cancer of the cervix to a high of 30.3% in rectal cancer. CONCLUSIONS RT shortfalls exist in the utilization of RT in AB, Canada despite centralized cancer care and a publically funded health care system. Decisions to address shortfalls need to be mindful of how model selection can impact on findings.

IMPROVEMENT IN TANGENTIAL BREAST PLANNING EFFICIENCY USING A KNOWLEDGE-BASED EXPERT SYSTEM

A knowledge-based expert system was developed for the purpose of improving radiotherapy planning efficiency for a standardized, tangential breast technique. Treatment parameters pertaining to 150 previously planned patients were used for correlating the midplane breast contour of a new patient with an appropriate set of tangential beam weights and wedge angles; other treatment parameters including, planning target volume and isocenter, were specified by a radiation oncologist. Treatment plans generated by the expert system approach and a traditional, dosimetric approach were compared and rated prospectively in 45 patients. In addition, planning time was measured for both approaches. A performance rating of 97% was achieved for the expert system, in which an artificial neural network was used to correlate breast contours to treatment parameters, and approximately 30 minutes per patient was saved in treatment planning time. This high performance rating validated various assumptions concerning the expert system: namely, that the resultant dose distribution was not influenced by tangential field width (within the range of 7 to 12 cm), nominal beam energy (6 MV), or wedge type (physical vs. enhanced dynamic). Hence, the knowledge base may be directly transferable to other cancer centers using the same breast technique, and suggests that a global resource of radiotherapy treatment plans as well as planning strategies, categorized by treatment site, stage, and technique, may be viable.

Quality indicators for ductal carcinoma in situ (DCIS) of the breast: Development using a multidisciplinary delphi process and its use in monitoring population-based treatment

Evaluation of the management of DCIS poses challenges, as standard breast cancer outcome measures such as mortality do not apply. We have developed quality indicators (QIs) to measure the quality of DCIS treatment in Alberta, Canada.