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Featured researches published by Lee Manchul.


Radiotherapy and Oncology | 1998

Oxygenation predicts radiation response and survival in patients with cervix cancer

Anthony Fyles; Michael Milosevic; R. Wong; Mary-Claire Kavanagh; Melania Pintilie; Alex Sun; William Chapman; W. Levin; Lee Manchul; Thomas J. Keane; Richard P. Hill

BACKGROUND AND PURPOSE Hypoxia appears to be an important factor in predicting tumor relapse following radiation therapy. This study measured oxygenation prior to treatment in patients with cervix cancer using a polarographic oxygen electrode to determine if oxygenation was an important prognostic factor with regard to tumor control and survival. MATERIALS AND METHODS Between May 1994 and June 1997, 74 eligible patients with cervix cancer were entered into an ongoing prospective study of tumor oxygenation prior to primary radiation therapy. All patients were evaluated with an Eppendorf oxygen electrode during examination under anesthesia. Oxygenation data are presented as the hypoxic proportion, defined as the percentage of pO2 readings of <5 mm Hg (abbreviated as HP5). RESULTS The HP5 ranged from 2 to 99% with a median of 52%. With a median follow-up of 1.2 years, the disease-free survival (DFS) rate was 69% for patients with HP5 of < or =50% compared with 34% for those with HP5 of >50% (log-rank P = 0.02). Tumor size above and below the median of 5 cm was also significantly related to DFS (P = 0.0003) and patients with bulky hypoxic tumors had a significantly lower DFS (12% at 2 years) than either bulky oxygenated or non-bulky oxygenated or hypoxic tumors (65%, P = 0.0001). CONCLUSIONS Hypoxia and tumor size are significant adverse prognostic factors in a univariate analysis of disease-free survival in patients with cervix cancer. A high risk group of patients with bulky hypoxic tumors have a significantly higher probability of relapse and death.


Radiotherapy and Oncology | 1995

Prognostic factors in patients with cervix cancer treated by radiation therapy: results of a multiple regression analysis

Anthony Fyles; Melania Pintilie; Peter Kirkbride; Wilfred Levin; Lee Manchul; Gayle A. Rawlings

A retrospective analysis of 965 patients with invasive cervix cancer treated by radiation therapy between 1976 and 1981 was performed in order to evaluate prognostic factors for disease-free survival (DFS) and pelvic control. FIGO stage was the most powerful prognostic factor followed by radiation dose and treatment duration (P values = 0.0001). If the analysis was limited to patients treated with radical doses of 75 Gy or more, dose was no longer significant. Young age at diagnosis, non-squamous histology and transfusion during treatment were also adverse prognostic factors for survival and control. Para-aortic nodal involvement on lymphogram was associated with a reduction in DFS (P = 0.0027), whereas pelvic lymph node involvement alone was not. In patients with Stage I and IIA disease, tumour size was the most powerful prognostic factor for survival (P = 0.0001) and the extent of pelvic sidewall involvement was significant in patients with Stage III tumours (P = 0.007). Histological grade appeared to be a predictive factor but was only recorded in 712 patients. These features should be considered in the staging of patients and in the design of clinical trials.


International Journal of Radiation Oncology Biology Physics | 2008

Inter- and Intrafractional Tumor and Organ Movement in Patients With Cervical Cancer Undergoing Radiotherapy: A Cinematic-MRI Point-of-Interest Study

Philip Chan; R. Dinniwell; Masoom A. Haider; Y. Cho; David A. Jaffray; Gina Lockwood; Wilfred Levin; Lee Manchul; Anthony Fyles; Michael Milosevic

PURPOSE Internal tumor and organ movement is important when considering intensity-modulated radiotherapy for patients with cancer of the cervix because of the tight margins and steep dose gradients. In this study, the internal movement of the tumor, cervix, and uterus were examined using serial cinematic magnetic resonance imaging scans and point-of-interest analysis. METHODS AND MATERIALS Twenty patients with Stage IB-IVA cervical cancer underwent pelvic magnetic resonance imaging before treatment and then weekly during external beam radiotherapy. In each 30-min session, sequential T(2)-sagittal magnetic resonance imaging scans were obtained. The points of interest (cervical os, uterine canal, and uterine fundus) were traced on each image frame, allowing the craniocaudal and anteroposterior displacements to be measured. The mean displacements and trends were analyzed using mixed linear models. Prediction intervals were calculated to determine the internal target margins. RESULTS Large interscan motion was found for all three points of interest that was only partially explained by the variations in bladder and rectal filling. The intrascan motion was much smaller. Both inter- and intrascan motion was greatest at the fundus of the uterus, less along the canal, and least at the cervical os. The isotropic internal target margins required to encompass 90% of the interscan motion were 4 cm at the fundus and 1.5 cm at the os. In contrast, smaller margins of 1 cm and 0.45 cm, respectively, were adequate to encompass the intrascan motion alone. CONCLUSION Daily soft-tissue imaging with correction for interfractional motion or adaptive replanning will be important if the benefits of intensity-modulated radiotherapy are to be maximized in women with cervical cancer.


Cancer | 1998

Interstitial fluid pressure in cervical carcinoma

Michael Milosevic; A. Fyles; Raimond Wong; Melania Pintilie; Mary-Claire Kavanagh; Wilfred Levin; Lee Manchul; Thomas J. Keane; Richard P. Hill

Interstitial fluid pressure (IFP) is elevated in many animal and human tumors. The authors assessed tumor IFP and its relation to tumor oxygenation in a prospective clinical study of patients with cervical carcinoma.


Radiotherapy and Oncology | 1999

Tumour proliferation and apoptosis in human uterine cervix carcinoma II: correlations with clinical outcome

Richard W. Tsang; C.Shun Wong; A. Fyles; Wilfred Levin; Lee Manchul; Michael Milosevic; William Chapman; Yu-qing Li; Melania Pintilie

PURPOSE The prognostic value of tumour proliferation and apoptosis measurements were studied prospectively in patients with carcinoma of the uterine cervix, relative to other established clinical factors. MATERIALS AND METHODS The labelling index (LI) for bromodeoxyuridine was determined by flow cytometry (fc) and also by immunohistochemistry. Apoptosis was assessed histologically using morphological criteria. Patients were treated with radical radiation therapy (RT). RESULTS The median/mean LI-fc were 6.7%/7.9% (range 1.52-3.9%). The median/mean apoptosis index (AI) were 1.0%/1.6% (range 0-6.8%). To date, 27 patients have died of disease, and the median follow-up for alive patients is 3.2 years (range 0.4-6.0 years). Among 64 patients who completely responded to treatment, 25 patients have relapsed (six pelvic, 17 distant and two pelvic and distant). In univariate analysis, the most significant factors for disease-free survival (DFS) were large tumour size (P=0.0001), low haemoglobin (P=0.01 ), LI-fc (DFS 67% for LI < 7%, 33% for LI > or = 7%, P=0.03), and T(pot) (DFS 66% for T(pot) > 5 days, 35% for T(pot) < or = 5 days, P=0.04) Stage, overall treatment time (OTT), S-phase fraction, ploidy, T(s), LI by histology, mitotic index, and AI were not significant. Multivariate analysis (Coxs model) showed that the only significant prognostic factors for DFS were tumour size and OTT. However, for small tumours (diameter < 6 cm), either a high LI-fc ( > or = 7%) or a high AI ( > 1%) was associated with poorer DFS, whereas patients with larger tumours (diameter > or = 6 cm) fared poorly regardless of LI-fc and AI. CONCLUSIONS Tumour size was the most important prognostic factor in cervix carcinoma. Although none of the biologic parameters have independent prognostic significance when the effect of initial tumour size was taken into account, our data suggests that LI and AI may be useful in discriminating outcome for patients with smaller tumours when managed by radical RT. These findings support the hypothesis that rapidly proliferating tumours are less likely to be controlled with a conventional course of RT.


International Journal of Radiation Oncology Biology Physics | 2009

Magnetic Resonance Imaging-Guided Intracavitary Brachytherapy for Cancer of the Cervix

Daniel R. Zwahlen; J. Jezioranski; Philip Chan; Masoom A. Haider; Y. Cho; Ivan Yeung; Wilfred Levin; Lee Manchul; Anthony Fyles; Michael Milosevic

PURPOSE To determine the feasibility and benefits of optimized magnetic resonance imaging (MRI)-guided brachytherapy (BT) for cancer of the cervix. METHODS AND MATERIALS A total of 20 patients with International Federation of Gynecology and Obstetrics Stage IB-IV cervical cancer had an MRI-compatible intrauterine BT applicator inserted after external beam radiotherapy. MRI scans were acquired, and the gross tumor volume at diagnosis and at BT, the high-risk (HR) and intermediate-risk clinical target volume (CTV), and rectal, sigmoid, and bladder walls were delineated. Pulsed-dose-rate BT was planned and delivered in a conventional manner. Optimized MRI-based plans were developed and compared with the conventional plans. RESULTS The HR CTV and intermediate-risk CTV were adequately treated (the percentage of volume treated to >or=100% of the intended dose was >95%) in 70% and 85% of the patients with the conventional plans, respectively, and in 75% and 95% of the patients with the optimized plans, respectively. The minimal dose to the contiguous 2 cm(3) of the rectal, sigmoid, and bladder wall volume was 16 +/- 6.2, 25 +/- 8.7, and 31 +/- 9.2 Gy, respectively. With MRI-guided BT optimization, it was possible to maintain coverage of the HR-CTV and reduce the dose to the normal tissues, especially in patients with small tumors at BT. In these patients, the HR percentage of volume treated to >or=100% of the intended dose approached 100% in all cases, and the minimal dose to the contiguous 2-cm(3) of the rectum, sigmoid, and bladder was 12-32% less than with conventional BT planning. CONCLUSION MRI-based BT for cervical cancer has the potential to optimize primary tumor dosimetry and reduce the dose to critical normal tissues, particularly in patients with small tumors.


International Journal of Radiation Oncology Biology Physics | 2002

Stage II endometrial carcinoma: prognostic factors and risk classification in 170 patients

Graham Pitson; Terence J. Colgan; Wilfred Levin; Gina Lockwood; Lee Manchul; Michael Milosevic; Joan Murphy; Anthony Fyles

PURPOSE Factors affecting outcome in patients with surgicopathologic Stage II endometrial cancer are poorly defined. The purpose of this study was to determine prognostic factors in a series of patients treated according to standardized protocols at a single institution. METHODS AND MATERIALS One hundred and seventy patients referred to Princess Margaret Hospital after hysterectomy between 1984 and 1995 were retrospectively reviewed. One hundred and twenty patients received postoperative external beam radiotherapy and brachytherapy, 18 received external beam radiotherapy alone, five received brachytherapy alone, and 27 had no radiotherapy. RESULTS With a median follow-up of 5.1 years, overall and disease-free survival (DFS) at 5 years was 77% and 68%, respectively, and 24% of patients had relapsed. Significant independent adverse factors for DFS included age >65 (p = 0.0001), FIGO Stage IIB (p = 0.02), and capillary-lymphatic space (CLS) involvement (p = 0.0007). Prognostic factors for relapse were age (p = 0.0008), histologic grade (p = 0.01), and CLS (p = 0.01). A prognostic model based on the number of adverse prognostic factors (0-3) revealed that the 5-year survival rates for the four groups were as follows: 0%-85%, 1%-77%, 2%-55%, and 3%-11%. Combining the groups with 0 or 1 adverse factors resulted in a three-group variable that was strongly related to DFS (p < 0.0001). CONCLUSIONS Patient age, stage, and CLS were significant factors for DFS, and age, grade, and CLS predicted time to relapse in Stage II endometrial cancer. A prognostic model for DFS using these factors can provide clinically meaningful outcome predictions.


International Journal of Radiation Oncology Biology Physics | 2000

Interrelationship of proliferation and hypoxia in carcinoma of the cervix.

Richard W. Tsang; A. Fyles; Michael Milosevic; A. Syed; Melania Pintilie; Wilfred Levin; Lee Manchul

PURPOSE In human cervix cancer treated with radiotherapy, we have previously shown from separate groups of patients that tumor hypoxia and proliferation rate as measured by bromodeoxyuridine (BrdU) labeling index (LI) are important determinants of clinical outcome. We now examine the relationship of these two pre-treatment predictive assays in 43 patients studied prospectively from 1994-98 where both tests were performed for each patient. MATERIAL AND METHODS Newly diagnosed patients with carcinoma of the cervix were examined under anesthesia for staging purposes. Patients were given BrdU (200 mg) by intravenous route prior to the procedure. Tumor oxygenation was measured with the Eppendorf pO2 histograph. Biopsy of tumor was then performed and the BrdU LI was obtained by flow cytometry. The degree of tumor hypoxia for each tumor was expressed as median pO2 values, and as the percentage of pO2 readings <5 mm Hg (HP5). RESULTS The median age was 53 years (range 23-79 years). There were 32 squamous, and 11 non-squamous carcinomas. FIGO stages were: IB and IIA, 8; IIB, 17; IIIB, 18; with a median tumor size of 6 cm (range 2-10 cm). The patients received uniform treatment with radical radiation therapy. There were 22 diploid and 21 aneuploid tumors. The median LI, pO2, and HP5 were 8.0%, 5.4 mm Hg, and 46.8%, respectively. Tests for linear associations showed no significant correlation between median pO2 vs. LI (r = 0.078, p = 0.62), and HP5 vs. LI (r = -0.14, p = 0.38). CONCLUSIONS The clinical outcome in this group of patients is immature, but these results suggest that tumor hypoxia and proliferation measurements are independent and potentially complementary predictive assays in cervix carcinoma. Further investigations are required to examine the distribution of proliferating tumor cells and its relationship with hypoxic tumor cells in tissue sections with the use of immunohistological techniques and image analysis systems.


Breast Journal | 2004

Use of alternative therapy in postmenopausal breast cancer patients treated with tamoxifen after surgery.

Karen P.L. Yap; David R. McCready; Anthony Fyles; Lee Manchul; Maureen E. Trudeau; Steven A. Narod

Abstract:  The goal of this study was to determine the frequency of alternative therapy use in postmenopausal women with early stage breast cancer who were enrolled in a randomized clinical trial designed to determine the value of breast irradiation after treatment with breast‐conserving surgery and tamoxifen. A questionnaire was given to 300 patients, ages 52 to 90 years, after completion of radiation therapy (if any). Of the 290 respondents, 78 (27%) had used some form of alternative therapy. Of these, 60.3% started after the diagnosis of breast cancer. Users of alternative therapies were significantly younger than nonusers (67.0 ± 8.4 years versus 70.0 ± 8.7 years, p = 0.009) and they used a median of one type of therapy per person (range 1–13). Users of alternative therapies were more likely to have experienced symptoms (stiffness, pain, numbness, or swelling) in the ipsilateral shoulder or arm after treatment of their breast cancers compared to nonusers (odds ratio [OR] = 2.0, p = 0.02). This relationship between alternative therapy use and symptoms was strongest in the group who started alternative therapies after breast cancer diagnosis (OR = 2.1, p = 0.05). On multivariate analysis, younger age and radiotherapy treatment were related to alternative therapy use. In conclusion, 27% of patients with early stage breast cancer used alternative therapy. Users were more likely to be younger and to experience shoulder or arm symptoms after breast‐conserving surgery with radiation. 


Radiology | 2016

Association of Apparent Diffusion Coefficient with Disease Recurrence in Patients with Locally Advanced Cervical Cancer Treated with Radical Chemotherapy and Radiation Therapy

Adam Gladwish; Michael Milosevic; Anthony Fyles; J. Xie; Jaydeep Halankar; Ur Metser; Haiyan Jiang; Nathan Becker; Wilfred Levin; Lee Manchul; Warren D. Foltz; Kathy Han

PURPOSE To investigate whether volumetrically derived apparent diffusion coefficient (ADC) from pretreatment diffusion-weighted (DW) magnetic resonance (MR) imaging is associated with disease recurrence in women with locally advanced cervical cancer treated with chemotherapy and radiation therapy. MATERIALS AND METHODS An ethics board-approved, retrospective study was conducted in 85 women with stage IB-IVA cervical cancer treated with chemo- and radiation therapy in 2009-2013. All patients underwent MR imaging for staging, including T2-weighted and DW MR imaging series, by using a 1.5- or 3.0-T imager. The mean, median, 75th, 90th, and 95th percentile ADCs (ADCmean, ADC50, ADC75, ADC90, and ADC95, respectively) of all voxels that comprised each tumor were extracted and normalized to the mean urine ADC (nADCmean, nADC50, nADC75, nADC90, and nADC95, respectively) to reduce variability. The primary outcome was disease-free survival (DFS). Uni- and multivariable Cox regression analyses were used to evaluate the association of ADC parameters and relevant clinical variables with DFS. RESULTS Of the 85 women included, 62 were free of disease at last follow-up. Median follow-up was 37 months (range, 5-68 months). Significant variables at univariable analysis included T2-weighted derived tumor diameter, para-aortic nodal involvement, advanced stage, ADC90 and ADC95, nADC75, nADC90, and nADC95. Normalized parameters were more highly associated (hazard ratio per 0.01 increase in normalized ADC, 0.91-0.94; P < .04). Because nADC75, nADC90, and nADC95 were highly correlated, only nADC95 (which had the lowest P value) was included in multivariable analysis. At multivariable analysis, absolute and normalized ADC95 remained associated with DFS (hazard ratio, 0.90-0.98; P < .05). CONCLUSION The volumetric ADC95 may be a useful imaging metric to predict treatment failure in patients with locally advanced cervical cancer treated with chemo- and radiation therapy.

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Anthony Fyles

Princess Margaret Cancer Centre

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Michael Milosevic

Princess Margaret Cancer Centre

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Melania Pintilie

Princess Margaret Cancer Centre

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Wilfred Levin

Princess Margaret Cancer Centre

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A. Fyles

University Health Network

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W. Levin

University of Toronto

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M. Milosevic

University Health Network

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