Patterns of Recurrence and Predictors of Survival in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy, Surgery, and Radiation.

PURPOSE: Neoadjuvant chemotherapy (NAC) is standard of care for locally advanced breast cancer. There is wide variation in radiation therapy (RT) practice and limited data describing locoregional relapse (LRR) after NAC. We hypothesized a low LRR risk with modern NAC, surgery, and RT and aimed to elucidate patterns of LRR and predictors of disease-free survival (DFS) and overall survival (OS) in these patients. METHODS AND MATERIALS: Data from 416 patients with stage II/III breast cancer treated between 2008 and 2015 with NAC, surgery, and adjuvant RT were reviewed retrospectively. DFS and OS rates were calculated using the Kaplan-Meier method. The LRR rate was estimated using the cumulative incidence function, treating death as a competing risk. Multivariable survival analysis was performed using Cox regression. RESULTS: Median follow-up was 4.7 years. Most patients had cT2/3 (74%) cN1 (61%) disease and underwent mastectomy (75%) and axillary dissection (84%). Pathologic complete response (pCR) was achieved in 22% of patients. There were 27 LRRs (including 4 isolated LRRs) and 89 distant failures. Two patients developed LRR 2 months after surgery, before adjuvant RT. LRR could be mapped in 23 patients: most (20) recurred within the RT field; 1 in- and out-of-field; and 2 out-of-field. Five-year LRR, DFS, and OS were 6.4%, 77%, and 90%, respectively. On multivariable analysis, triple-negative subtype (hazard ratio [HR] 2.82; 95% confidence interval [CI], 1.78-4.47; P < .001), stage III disease (HR 1.72; 95% CI, 1.11-2.69; P = .016), and non-pCR (HR 4.76; 95% CI 2.13-10.0; P < .001) were associated with poor DFS and OS (HR 4.13 [95% CI, 2.21-7.72; P < .001]; HR 1.94 [95% CI, 1.001-3.75; P = .049]; and HR 2.38 [95% CI, 0.98-5.88; P = .055], respectively). CONCLUSIONS: Patients with breast cancer treated with modern NAC, surgery, and RT have a low 5-year LRR risk, with the majority occurring in-field. Triple-negative subtype, stage III disease, and non-pCR were associated with inferior DFS and OS.

Intermediate dose-volume parameters and the development of late rectal toxicity after MRI-guided brachytherapy for locally advanced cervix cancer.

PURPOSE: The dose delivered to the most exposed 2 cm3 [Formula: see text] of the rectum and bladder is predictive of late rectal and bladder toxicity in cervix cancer patients. We investigated the predictive value of intermediate doses to the rectum and bladder for late rectal/bladder toxicity after MRI-guided brachytherapy for patients with locally advanced cervix cancer. METHODS AND MATERIALS: Toxicity was prospectively graded using Common Toxicity Criteria for Adverse Events v4.0 and retrospectively verified for women with Stage IB-IVA cervix cancer treated consecutively with MRI-guided brachytherapy between 2008 and 2013. The minimum equivalent dose in 2 Gy fractions delivered to 0.1, 1, 2, 5, and 10 cm3 of the rectum and bladder and the absolute volume of the rectum receiving 55, 60, 65, 70, and 75 Gy3 (V55-75) were collected. The association between dose-volume parameters and Grade 2+ rectal/bladder toxicity was examined using logistic regression. RESULTS: With a median followup of 44 months, cumulative incidences of Grade 2+ rectal and bladder toxicity among the 106 patients were 29% and 15% at 3 years, respectively. All the dose-volume parameters were significantly associated with late Grade 2+ rectal and bladder toxicity (p < 0.05), except for bladder [Formula: see text] . On multivariable logistic regression, both [Formula: see text]  > 70 Gy3 and V55 > 11 cm3 (p < 0.05) were predictive of late Grade 2+ rectal toxicity, with improved model fitting and higher area under the curve compared with the model with [Formula: see text]  > 70 Gy3 alone. CONCLUSIONS: In this study, V55 was predictive of late Grade 2+ rectal toxicity. Adding V55 to  [Formula: see text] improved prediction accuracy.

High-dose intravenous steroid regimen for radiation-induced hypoglossal nerve palsy.

BACKGROUND: Hypoglossal nerve palsies are infrequent complications of head and neck radiotherapy. Treatments focus on maintaining function and prevention of abnormal airway-related swallowing events. METHODS: A patient with longstanding cranial neuropathies, including bilateral hypoglossal involvement, secondary to chemoradiotherapy for nasopharyngeal carcinoma, experienced repeated episodes of life-threatening complications. Initially, 2 courses of 2 weekly 24-hour intravenous methylprednisolone (IVMP) infusions were administered 2 years apart. We report the results of a third course comprising 5 weekly cycles. RESULTS: Patient-reported outcomes revealed significant improvement in swallowing function, speech, and psychosocial status. Airway invasion during swallowing and pharyngeal retention were assessed videofluoroscopically and evaluated using the Penetration-Aspiration Scale (PAS) and a residue rating scale, respectively. PAS ratings after infusions 2 and 5, improved dramatically from baseline and were maintained at 1-year follow-up. CONCLUSION: High doses of IVMP may improve radiation-induced neuropathies. Further testing in similar patients is needed to prove reproducibility. © 2016 Wiley Periodicals, Inc. Head Neck 39: E23-E28, 2017.

A prospective study of DWI, DCE-MRI and FDG PET imaging for target delineation in brachytherapy for cervical cancer.

BACKGROUND AND PURPOSE: We examined the utility of dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DWI), and FDG-PET imaging for brachytherapy target delineation in patients with locally advanced cervical cancer. MATERIALS AND METHODS: Twenty-two patients had DWI, DCE-MRI, and FDG-PET/CT scans after brachytherapy applicator insertion, in addition to standard T2-weighted (T2w) 3T MRI. Gross tumor volume (GTVB) and high-risk clinical target volume (HRCTV) were contoured first on T2w images, and then modified if indicated upon review of DWI/DCE-MRI/FDG-PET images by two observers. The primary endpoint was utility, determined by the number of patients whose volumes were modified, and interobserver variability. RESULTS: Eleven patients' T2w-GTVB were modified based on DWI/DCE-MRI/FDG-PET by observer 1, due to clearer demarcation (7) and residual disease not well visualized on T2w MRI (4). GTVB was modified in 17 patients by observer 2 (11 and 6, respectively). Incorporation of functional imaging improved the conformity index (CI) for GTVB from 0.54 (T2w alone) to 0.65 (P=0.003). HRCTV was modified in 3 and 8 patients by observers 1 and 2, respectively, with a trend toward higher CI using functional imaging (0.71 to 0.76, P=0.06). CONCLUSIONS: DWI/DCE-MRI/FDG-PET imaging as a supplement to T2w MRI decreased interobserver variability in GTVB delineation.

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

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.

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.

Predictors of breast radiotherapy plan modifications: quality assurance rounds in a large cancer centre.

BACKGROUND AND PURPOSE: This study describes the process and outcomes of breast radiotherapy (RT) quality assurance (QA) rounds, seeking to identify variables associated with plan modifications. MATERIALS AND METHODS: Real-time data were prospectively collected over 2 years. Descriptive statistics determined the proportion of cases requiring no (A), minor (B), or major (C) modifications, which were then subjected to univariate and multivariate analyses. RESULTS: A total of 2223 breast cancer QA cases were reviewed; 47 cases (2.1%) underwent a minor, and 52 cases (2.3%) required a major modification. Common changes included boost, volume, seroma, and bolus. On univariate analysis, regional nodal irradiation (RNI), tumour size, and axillary node dissection were significantly associated with major modifications. Upon multivariate analysis, the only independent predictor was RNI (OR 2.12, p=0.0075). For patients with no RNI, <2 cm tumours, no axillary lymph node dissection, and no boosts (n=420); the likelihood of category C was only 1.4%. CONCLUSIONS: It is feasible to conduct QA review for all breast cancer cases prior to commencing RT. Patients undergoing RNI had a higher likelihood of plan modifications; a group with low risk of modification was identified, which could direct future re-structuring of QA rounds.

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

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.

Postoperative radiotherapy improves local control and survival in patients with uterine leiomyosarcoma.

BACKGROUND: To examine the role of radiotherapy (RT) in uterine leiomyosarcomas (LMS) and to determine the patient population who may benefit from RT. METHODS: From 1998-2008, 69 patients with primary uterine LMS underwent hysterectomy with or without pelvic radiotherapy to a median dose of 45 Gy. Univariate analysis was performed using the Kaplan-Meier method and cumulative-incidence function, and multivariate analyses using Fine and Gray or Cox proportional hazard models. RESULTS: Following surgery, 32 out of 69 patients received RT. There was no evidence of any correlation between patient, disease and treatment characteristics and the use of RT. Median follow-up was 57 months. RT was associated with reduced local recurrence (3y LR 19% vs. 39%; Gray's p = 0.019) and improved overall survival (3y OS 69% vs. 35%; log-rank p = 0.025) on univariate analysis. Multivariate analysis demonstrated that RT reduced LR (HR: 0.28, CI: 0.11-0.69, p = 0.006) and increased OS (HR: 0.44, CI: 0.23-0.85, p = 0.014) independent of other clinical and pathologic factors. Positive surgical margins increased the odds of LR (HR: 5.6, CI: 2.3-13.4, p = 0.00012). Large tumor size and advanced stage (II-IV) were associated with the development of distant metastases and inferior OS. CONCLUSIONS: Postoperative pelvic RT reduces LR and improves OS of patients with uterine LMS.

Dosimetric and clinical impact of 3D vs. 2D planning in palliative radiotherapy for bone metastases.

PURPOSE: The incorporation of three-dimensional (3D) planning for the treatment of bone metastases has been embraced in many North American practices with assumed superior tumor targeting, sparing of normal structures, and improvement in patient outcomes. The goal of our project was to evaluate the dosimetric and clinical impact of 3D vs. two-dimensional (2D) planning for patients who require simple palliative radiotherapy techniques (≤ 2 beams) for bone metastases. METHODS: Patients undergoing palliative radiation therapy for bone metastases were eligible. The study oncologists first documented the intended treatment target, defined the treatment target/field using digital radiographs (2D), followed by using full 3D planning computerized tomography volumetric datasets. Treatment plans were compared dosimetrically, and patient-reported outcomes (pain, fatigue, anorexia, and nausea) were compared against a historical cohort treated with 2D plans. RESULTS: Eighty-five patients were enrolled in the study group. Review of the 3D datasets led to changes in the target area of interest in 44/85 (52 %) of cases, of which 21/85 (25 %) were clinically significant. 3D plans resulted in superior target coverage and normal tissue sparing. There was no significant difference in patient-reported outcomes however. CONCLUSION: 3D radiotherapy planning resulted in superior treatment plans but we were unable to demonstrate a significant benefit in clinical outcomes. Prospective study designs are needed to describe the contemporary expectation of palliative radiotherapy for bone metastases in the modern era of 3D planning.

Concomitant intensity modulated boost during whole breast hypofractionated radiotherapy--a feasibility and toxicity study.

BACKGROUND: Breast cancer sensitivity to large fraction size may be enhanced using hypofractionated concomitant boost radiotherapy (CBRT), thereby shortening overall treatment time. This ethics approved, prospective single cohort feasibility study was designed to evaluate the dosimetry and toxicity of CBRT using an intensity-modulated radiotherapy (IMRT) technique, compared with a standard sequential boost technique (SBT). METHODS: Fifteen women (11 right-sided; 4 left-sided) received 42.4 Gy to the whole breast and an additional 10.08 Gy to the tumor bed in 16 daily fractions, using IMRT and standard dose constraints. Each patient was replanned with the SBT, using mixed photon-electrons. Clinical target volume (CTV), dose evaluation volume (DEV), and organs at risk (OAR) dose distributions were compared with the SBT. Toxicity and treatment times were prospectively recorded. RESULTS: All 15 CBRT plans achieved the desired CTV (V(49.9Gy) ≥ 99%) and DEV (V(49.9Gy) ≥ 95%), coverage of the boost, compared with only 10 (66.7%, p=0.03), and 12 (80%, p=0.125) SBT plans, respectively. Ipsilateral lung (p<0.0001), and heart (right-sided, p=0.001; left-sided, p=0.13) doses were lower. Grade 3 acute toxicity occurred in 1 (6.7%) patient. At 1 year, two (13.3%) additional patients had overall grade 2 late toxicity, compared with baseline. No grade 3-4 late toxicity was observed. CONCLUSIONS: CBRT using IMRT improved boost coverage and lowered OAR doses, compared with SBT. Toxicities were acceptable using a daily boost of 3.28 Gy. While resource utilization was greater, overall treatment time was reduced.

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.

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.

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.

Reirradiation after radical radiation therapy: a survey of patterns of practice among Canadian radiation oncologists.

PURPOSE: The objective of this study was to survey the use of reirradiation (Re-RT) for in-field failures after previous radical radiation treatment (RT) among Canadian radiation oncologists (ROs). METHODS AND MATERIALS: An electronic survey was sent to 271 ROs in Canada. The completed surveys were received electronically via e-mail and the data were analyzed using SAS 9.1.3 software. RESULTS: A total of 183 ROs (67.5%) completed and returned the survey. The majority of the respondents were involved in the practice of either breast (48%) or genitourinary (43%) tumor sites. A total of 49% of the participants were interested in using Re-RT for the management of in-field recurrences. The goals of the therapy would be improvement of quality of life (99%), locoregional control (80%), or cure (32%). Most of the physicians believed that patients should have a minimum Karnofsky performance status of 50 or Eastern Cooperative Oncology Group performance status of 3, a minimum life expectancy of 3 months, and a minimum interval from initial treatment of 3 months if Re-RT were to be given with curative intent. CONCLUSIONS: This survey showed that a wide variation existed among ROs in their approach to Re-RT. Newer technologies in RT planning and delivery would be employed to facilitate normal tissue avoidance. The results of this study suggested that a consensus meeting was needed to establish guidelines for the practice and prospective evaluation of Re-RT.

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.

Cervical cancer regression measured using weekly magnetic resonance imaging during fractionated radiotherapy: radiobiologic modeling and correlation with tumor hypoxia.

PURPOSE: To measure regression of cancer of the uterine cervix during external beam radiotherapy using magnetic resonance imaging, derive radiobiologic parameters from a mathematical model of tumor regression, and compare these parameters with the pretreatment measurements of tumor hypoxia. METHODS AND MATERIALS: A total of 27 eligible patients undergoing external beam radiotherapy for cervical cancer underwent weekly magnetic resonance imaging scans. The tumor volume was assessed on each of these scans and the rate of regression plotted. A radiobiologic model was formulated to simulate the effect on tumor regression of the surviving proportion of cells after 2 Gy (SP(2)), the cell clearance constant (clearance of irreparably damaged cells from the tumor [T(c)]), and accelerated repopulation. Nonlinear regression analysis was used to fit the radiobiologic model to the magnetic resonance imaging-derived tumor volumes and to derive the estimates of SP(2) and T(c) for each patient. These were compared to the pretreatment hypoxia measurements. RESULTS: The initial tumor volume was 8-209 cm(3). The relative reduction in volume during treatment was 0.02-0.79. The simulations using representative values of the independent biologic variables derived from published data showed SP(2) and T(c) to strongly influence the shape of the volume-response curves. Nonlinear regression analysis yielded a median SP(2) of 0.71 and median T(c) of 10 days. Tumors with a high SP(2) >0.71 were significantly more hypoxic at diagnosis (p = 0.02). CONCLUSION: The results of our study have shown that cervical cancer regresses during external beam radiotherapy, although marked variability is present among patients and is influenced by underlying biologic processes, including cellular sensitivity to radiotherapy and proliferation. Better understanding of the biologic mechanisms might facilitate novel adaptive treatment strategies in future studies.

The difficulties of a randomized study in superior vena caval obstruction.

INTRODUCTION: Superior vena caval obstruction (SVCO) is a not uncommon complication of malignant disease. Treatment may consist of radiation (RT) to the mediastinum, systemic therapy for chemosensitive tumors, and supportive measures such as oxygen and steroids. Advances in interventional radiology have allowed the introduction of expandable stents into the superior vena cava (SVC), with the theoretical advantage of providing symptom relief within hours, rather than the days and weeks over which RT exerts its effect. Although small case series have supported the use of stents in SVCO, there are no randomized data. METHODS: We set up a randomized study at Princess Margaret Hospital, Toronto. Patients were randomized to receive palliative RT to the mediastinum or immediate stenting of the SVC and then mediastinal RT within a week. The aim of the study was to compare symptom response between the two treatment arms. A second study, a prospective longitudinal study, was also set up to obtain information on symptom response and outcome regardless of the treatment given. RESULTS: In a 12-month period, we were unable to accrue any patients in the randomized study; of the 19 patients approached, 13 have agreed to participate in the longitudinal study. CONCLUSIONS: In this report, we present the problems that we have encountered with these studies.

A prospective phase I-II trial of the cyclooxygenase-2 inhibitor celecoxib in patients with carcinoma of the cervix with biomarker assessment of the tumor microenvironment.

PURPOSE: To evaluate the toxicity and effectiveness of celecoxib in combination with definitive chemoradiotherapy (CRT) in women with locally advanced cervical cancer. METHODS AND MATERIALS: Thirty-one patients were accrued to a phase I-II trial of celecoxib 400 mg by mouth twice per day for 2 weeks before and during CRT. Tumor oxygenation (HP(5)) and interstitial fluid pressure (IFP) were measured before and 2 weeks after celecoxib administration alone. The median follow-up time was 2.7 years (range, 1.1-4.4 years). RESULTS: The most common acute G3/4 toxicities were hematologic (4/31, 12.9%) and gastrointestinal (5/31, 16.1%) largely attributed to chemotherapy. Late G3/4 toxicity was seen in 4 of 31 patients (13.7% actuarial risk at 2 yr), including fistulas in 3 patients (9.7%). Within the first year of follow-up, 25 of 31 patients (81%) achieved complete response (CR), of whom 20 remained in CR at last follow-up. After 2 weeks of celecoxib administration before CRT, the median IFP decreased slightly (median absolute, -4.6 mm Hg; p = 0.09; relative, -21%; p = 0.07), whereas HP(5) did not change significantly (absolute increase, 3.6%; p = 0.51; median relative increase, 11%; p = 0.27). No significant associations were seen between changes in HP(5) or IFP and response to treatment (p = 0.2, relative HP(5) change and p = 0.14, relative IFP change). CONCLUSIONS: Celecoxib in combination with definitive CRT is associated with acceptable acute toxicity, but higher than expected late complications. Celecoxib is associated with a modest reduction in the angiogenic biomarker IFP, but this does not correspond with tumor response.

Computerized tomographic simulation compared with clinical mark-up in palliative radiotherapy: a prospective study.

PURPOSE: To evaluate the impact of computed tomographic (CT) planning in comparison to clinical mark-up (CM) for palliative radiation of chest wall metastases. METHODS AND MATERIALS: In patients treated with CM for chest wall bone metastases (without conventional simulation/fluoroscopy), two consecutive planning CT scans were acquired with and without an external marker to delineate the CM treatment field. The two sets of scans were fused for evaluation of clinical tumor volume (CTV) coverage by the CM technique. Under-coverage was defined as the proportion of CTV not covered by the CM 80% isodose. RESULTS: Twenty-one treatments (ribs 17, sternum 2, and scapula 2) formed the basis of our study. Due to technical reasons, comparable data between CM and CT plans were available for 19 treatments only. CM resulted in a mean CTV under-coverage of 36%. Eleven sites (58%) had an under-coverage of >20%. Mean volume of normal tissues receiving >/=80% of the dose was 5.4% in CM and 9.3% in CT plans (p = 0.017). Based on dose-volume histogram comparisons, CT planning resulted in a change of treatment technique from direct apposition to a tangential pair in 7 of 19 cases. CONCLUSIONS: CT planning demonstrated a 36% under-coverage of CTV with CM of ribs and chest wall metastases.