Wilfred Levin

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

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.

Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: Data from a phase III trial

PURPOSE The objective of this study was to determine whether the thermal dose delivered during hyperthermia treatments and other thermal factors correlate with outcome after combined radiation and hyperthermia of breast carcinoma recurrences. Data were from the combined hyperthermia and radiation treatment arms of four Phase III trials, which when pooled together, demonstrated a positive effect of hyperthermia. METHODS AND MATERIALS Four Phase III trials addressing the question of whether hyperthermia could improve the local response of superficial recurrent breast cancer to radiation therapy were combined into a single analysis. Thermal dosimetry data were collected from 120 of the 148 breast cancer recurrence patients who received hyperthermia. The data were analyzed for correlations between thermal parameters as well as important clinical parameters and outcome (complete response rate, local disease free survival, time to local failure, and overall survival). RESULTS Five thermal parameters were tested, all associated with the low regions of the measured temperature distributions. Max(TDmin) and Sum(TDmin) were associated with complete response where TDmin is the minimum thermal dose measured by any of the tumor temperature sensors during a treatment: Max(TDmin) is the maximum of TDmin over a series of treatments. Using a categorical relationship with a cutoff of 10 min for Sum(TDmin), the complete response rate was 77% for Sum(TDmin) > 10 min and 43% for Sum(TDmin) < or = 10 min (p = 0.022, adjusted for study center and significant clinical factors). The overall complete response rate for hyperthermia and radiation was 61% compared to 41% for radiation alone. Either Max(TDmin) or Sum(TDmin) were also associated with local disease free survival, time to local failure and overall survival. CONCLUSIONS An earlier report of this trial demonstrated a significant benefit when hyperthermia was added to radiation in the treatment of breast cancer recurrences. The analysis of thermal factors demonstrates that parameters representative of the low end of the measured temperature distributions are associated with initial complete response rate, local disease-free survival, time to local failure and overall survival.

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

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.

Late radiation-related fibrosis: pathogenesis, manifestations, and current management

Radiation-induced fibrosis (RIF) represents one of the most common long-term adverse effects of curative radiotherapy. Current cancer treatment approaches, involving more intensive radiotherapy regimens, used in combination with systemic agents, will likely be associated with a higher incidence and greater degree of damage to normal tissues, especially RIF. Traditionally, the development of fibrosis after radiation therapy has been considered static and irreversible. Contemporary understanding recognizes RIF as a continuum of responses mediated by molecular pathways that may be amenable to interventions. Preliminary evidence suggests that pharmacological or other interventions may be possible to reverse the manifestation of the injury and restore function to tissues. A variety of strategies have been tested for the management of RIF, although formal trials of these therapies that permit treatment comparisons are unavailable at this time. It is critical that we formally evaluate new management approaches for RIF with larger patient accrual. To this end, it is also important to develop a means of registering its occurrence for outcome analysis and to refer these patients to colleagues familiar with optimal management and enrollment in clinical trials.

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

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.

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

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.

Optical coherence tomography platform for microvascular imaging and quantification: initial experience in late oral radiation toxicity patients

Abstract. An optical coherence tomography (OCT) microvascular imaging platform, consisting of Doppler (DOCT) and speckle variance (svOCT) modalities, and microvascular image quantification tools are developed. The quantification methods extract blood flow-related parameters from DOCT images and vessel morphological parameters from svOCT images. This platform is used to assess the microvascular (DOCT and svOCT) images obtained during a clinical study on late oral radiation toxicity. This specific pathology was considered a suitable scenario for verifying the performance of the developed quantification platform because late oral radiation toxicity is known to involve microvascular damage. The derived parameters are compared between several DOCT and svOCT images from one patient and one healthy volunteer as proof-of-principle, and the significance of the observed differences is discussed. Given the low number of OCT clinical studies that measure and quantify microvascular images and considering the importance of such quantification in a number of pathologies, this newly developed platform can serve as a useful tool in studying diseases and treatments with microvascular involvement.

A Multicenter Assessment of the Adequacy of Cancer Pain Treatment Using the Pain Management Index

PURPOSES Determine adequacy of management of pain secondary to bone metastases by physicians referring to specialized outpatient palliative radiotherapy (RT) clinics in Canada; compare geographic differences in adequacy of pain management and pain severity between these cohorts; compare results with published international literature. METHODS Prospectively collected data from three participating centers were used to calculate the Pain Management Index (PMI) by subtracting the patient-rated pain score at time of initial clinic visit from the analgesic score. Scores were 0, 1, 2, and 3 when patients reported no pain (0), mild (1-4), moderate (5-6), or severe pain (7-10), respectively, on the Edmonton Symptom Assessment System or Brief Pain Inventory. Analgesic scores of 0, 1, 2, and 3 were assigned for no pain medication, nonopioids, weak opioids, and strong opioids respectively. A negative PMI suggests inadequate pain management. RESULTS Overall incidence of negative PMI and moderate to severe pain was 25.1% and 70.9% respectively for 2011 patients. Comparing the three participating centers, the incidence of negative PMI was 31.0%, 20.0%, and 16.8% (p < 0.0001), and severe pain was 55.5%, 48.2% and 43.4% (p < 0.0001), these correlated with a negative PMI. Patients referred to our clinics were less likely to be undertreated for their pain when compared to study results from international countries. CONCLUSION Geographic differences in adequacy of analgesic management for painful bone metastases exist between Canadian specialized outpatient palliative RT clinics and between centers globally. Investigating reasons for these differences may provide insight into solutions to improve quality of life for these patients.

ROLE OF ADJUVANT RADIOTHERAPY IN GRANULOSA CELL TUMORS OF THE OVARY

PURPOSE To review the role of adjuvant radiotherapy (RT) in the outcome and recurrence patterns of granulosa cell tumors (GCTs) of the ovary. METHODS AND MATERIALS The records of all patients with GCTs referred to the Princess Margaret Hospital University Health Network between 1961 and 2006 were retrospectively reviewed. The patient, tumor, and treatment factors were assessed by univariate and multivariate analyses using disease-free survival (DFS) as the endpoint. RESULTS A total of 103 patients with histologically confirmed GCTs were included in the present study. The mean duration of follow-up was 100 months (range, 1-399). Of the 103 patients, 31 received adjuvant RT. A total of 39 patients developed tumor recurrence. The tumor size, incidence of intraoperative rupture, and presence of concurrent endometrial cancer were not significant risk factors for DFS. The median DFS was 251 months for patients who underwent adjuvant RT compared with 112 months for patients who did not (p=.02). On multivariate analysis, adjuvant RT remained a significant prognostic factor for DFS (p=.004). Of the 103 patients, 12 had died and 44 were lost to follow-up. CONCLUSION Ovarian GCTs can be indolent, with patients achieving long-term survival. In our series, adjuvant RT resulted in a significantly longer DFS. Ideally, randomized trials with long-term follow-up are needed to define the role of adjuvant RT for ovarian GCTs.

Stage I granulosa cell tumours: A management conundrum? Results of long-term follow up

UNLABELLED Optimal management of women with early stage granulosa cell tumours (GCT) presents a management conundrum - they have excellent prognosis but a third will relapse. Advances uncovering the molecular characteristics of GCT have not been matched by improvements in our understanding and treatment. METHODS Stage I GCT patients referred to Auckland City Hospital (1955-2012) and Princess Margaret Cancer Centre (1992-2012) were identified. Baseline characteristics, histopathology and outcomes were recorded retrospectively. RESULTS One hundred and sixty stage I GCT patients were identified with a median age of 49 years. Median follow-up was 7.0 years (range 0.1-44.2 years). Fifty-one patients (32%) relapsed with a median time to relapse (TTR) of 12.0 years (1.3-17.7 years) - 20 initial relapses occurred 10 years post-diagnosis. Higher relapse rates (43% vs. 24% p=0.02) and shorter TTR (10.2 vs. 16.2 years p=0.007) were seen with stage Ic versus stage Ia disease. Cyst rupture was associated with increased relapse (p=0.03). Surgery was the main therapeutic modality at relapse. Eighty six percent of patients received non-surgical management at least once post-relapse. Clinical benefit rate was 43% with chemotherapy, 61% with hormonal therapy and 86% with radiation. Five- and 10-year overall survival (OS) were 98.5 and 91.6%, respectively. Median OS was similar in patients with (24.3 years) and without relapse (22.3 years). CONCLUSION Surgery remains fundamental at diagnosis and relapse. Caution should be exercised in recommending adjuvant chemotherapy at initial diagnosis given median OS was greater than 20 years even with relapse. Hormonal therapy at relapse appears encouraging but needs further assessment. Novel treatment strategies need exploration with international collaboration essential for this.