Neha Vapiwala

Importance of the treatment package time in surgery and postoperative radiation therapy for squamous carcinoma of the head and neck

To determine the effect of treatment time‐related factors on outcome in patients treated with surgery and postoperative radiation therapy (RT) for locally advanced squamous cell carcinoma of head and neck (SCCHN)

Radiation and immunotherapy: a synergistic combination

Immunotherapy can be an effective treatment for metastatic cancer, but a significant subpopulation will not respond, likely due to the lack of antigenic mutations or the immune-evasive properties of cancer. Likewise, radiation therapy (RT) is an established cancer treatment, but local failures still occur. Clinical observations suggest that RT may expand the therapeutic reach of immunotherapy. We examine the immunobiologic and clinical rationale for combining RT and immunotherapy, two modalities yet to be used in combination in routine practice. Preclinical data indicate that RT can potentiate the systemic efficacy of immunotherapy, while activation of the innate and adaptive immune system can enhance the local efficacy of RT.

An Individual Person Data Meta-Analysis of Preoperative Magnetic Resonance Imaging and Breast Cancer Recurrence

PURPOSE There is little consensus regarding preoperative magnetic resonance imaging (MRI) in breast cancer (BC). We examined the association between preoperative MRI and local recurrence (LR) as primary outcome, as well as distant recurrence (DR), in patients with BC. METHODS An individual person data (IPD) meta-analysis, based on preoperative MRI studies that met predefined eligibility criteria, was performed. Survival analysis (Cox proportional hazards modeling) was used to investigate time to recurrence and to estimate the hazard ratio (HR) for MRI. We modeled the univariable association between LR (or DR) and MRI, and covariates, and fitted multivariable models to estimate adjusted HRs. Sensitivity analysis was based on women who had breast conservation with radiotherapy. RESULTS Four eligible studies contributed IPD on 3,180 affected breasts in 3,169 subjects (median age, 56.2 years). Eight-year LR-free survival did not differ between the MRI (97%) and no-MRI (95%) goups (P = .87), and the multivariable model showed no significant effect of MRI on LR-free survival: HR for MRI (versus no-MRI) was 0.88 (95% CI, 0.52 to 1.51; P = .65); age, margin status, and tumor grade were associated with LR-free survival (all P < .05). HR for MRI was 0.96 (95% CI, 0.52 to 1.77; P = .90) in sensitivity analysis. Eight-year DR-free survival did not differ between the MRI (89%) and no-MRI (93%) groups (P = .37), and the multivariable model showed no significant effect of MRI on DR-free survival: HR for MRI (v no-MRI) was 1.18 (95% CI, 0.76 to 2.27; P = .48) or 1.31 (95% CI, 0.76 to 2.27; P = .34) in sensitivity analysis. CONCLUSION Preoperative MRI for staging the cancerous breast does not reduce the risk of LR or DR.

Incidence and Patterns of Distant Metastases for Patients With Early-Stage Breast Cancer After Breast Conservation Treatment

BACKGROUND Breast conservation treatment (BCT), consisting of breast conservation surgery followed by definitive radiation therapy (RT), has been shown to be effective for early-stage breast cancer. Patterns of metastatic failure by specific anatomic site are not well described in the literature. METHODS A total of 1754 patients with stage I or II invasive carcinoma of the breast treated with BCT between 1977 and 2003 were identified. Patients were scored based on first site of metastasis: bone, brain, lung, liver, or other. Non-breast cancer deaths, contralateral breast cancer, and second malignancies were treated as competing risks events. Cumulative incidence functions for each competing event were calculated using competing risk methodology. Univariate analysis was performed to determine the hazard ratio (HR) associated with patient and tumor characteristics. RESULTS The most common event was non-breast cancer death (16.5% at 15 years; 95% confidence interval [CI], 13.9%-19.4%). The most common exclusive first site of metastasis was bone (5.9% at 15 years). The 4 most common anatomic sites of distant metastases as the first exclusive event were bone (41.1%), lung (22.4%), liver (7.3%), and brain (7.3%). CONCLUSION The present study has demonstrated the site-specific risks of metastases. These data support current clinical practice of screening for site-specific metastatic disease after BCT based on concerning patient-specific signs or symptoms.

Outcome After Breast Conservation Treatment with Radiation for Women with Triple-Negative Early-Stage Invasive Breast Carcinoma

BACKGROUND Triple-negative breast carcinoma is defined by a primary tumor that is estrogen receptor negative, progesterone receptor negative, and HER2 negative. The current study was performed to determine the relationship of triple-negative tumor status to outcome after breast conservation treatment with radiation. PATIENTS AND METHODS A total of 519 women with early-stage invasive breast carcinoma underwent breast conservation treatment with radiation. Of the 519 primary breast carcinomas, 90 (17%) were triple negative and 429 (83%) were not triple negative. The median follow-up after treatment was 3.9 years. RESULTS Compared with the patients without a triple-negative tumor, the patients with a triple-negative tumor had a higher 8-year rate of any local failure (8% vs. 4%, respectively; P = .041) and a lower 8-year rate of freedom from distant metastases (81% vs. 92%, respectively; P = .0066). There were no differences between the 2 groups for local-only first failure, overall survival, or contralateral breast cancer (all P >or= .3). On multivariate analysis, triple-negative tumors had an increased risk for any local failure (hazard ratio, 2.58), although this difference was not statistically significant (P = .097). CONCLUSION After breast conservation treatment with radiation, women with a triple-negative tumor had a higher rate of local failure compared with women without a triple-negative tumor. However, the absolute difference in local failure between the 2 groups was relatively small and therefore does not preclude breast conservation treatment with radiation for triple-negative early-stage invasive breast carcinoma.

Real-time study of prostate intrafraction motion during external beam radiotherapy with daily endorectal balloon.

PURPOSE To prospectively investigate intrafraction prostate motion during radiofrequency-guided prostate radiotherapy with implanted electromagnetic transponders when daily endorectal balloon (ERB) is used. METHODS AND MATERIALS Intrafraction prostate motion from 24 patients in 787 treatment sessions was evaluated based on three-dimensional (3D), lateral, cranial-caudal (CC), and anterior-posterior (AP) displacements. The mean percentage of time with 3D, lateral, CC, and AP prostate displacements>2, 3, 4, 5, 6, 7, 8, 9, and 10 mm in 1 minute intervals was calculated for up to 6 minutes of treatment time. Correlation between the mean percentage time with 3D prostate displacement>3 mm vs. treatment week was investigated. RESULTS The percentage of time with 3D prostate movement>2, 3, and 4 mm increased with elapsed treatment time (p<0.05). Prostate movement>5 mm was independent of elapsed treatment time (p=0.11). The overall mean time with prostate excursions>3 mm was 5%. Directional analysis showed negligible lateral prostate motion; AP and CC motion were comparable. The fraction of time with 3D prostate movement>3 mm did not depend on treatment week of (p>0.05) over a 4-minute mean treatment time. CONCLUSIONS Daily endorectal balloon consistently stabilizes the prostate, preventing clinically significant displacement (>5 mm). A 3-mm internal margin may sufficiently account for 95% of intrafraction prostate movement for up to 6 minutes of treatment time. Directional analysis suggests that the lateral internal margin could be further reduced to 2 mm.

The Role of Primary Androgen Deprivation Therapy in Localized Prostate Cancer

BACKGROUND Primary androgen deprivation therapy (PADT) is frequently used as a sole modality of treatment in men with localized prostate cancer, despite a lack of clinical trial data supporting its use. OBJECTIVE To measure the impact of treatment with PADT compared to observation on overall survival in men with organ-confined prostate cancer. DESIGN, SETTING, AND PARTICIPANTS The design was for an observational cohort from Surveillance, Epidemiology, and End Results (SEER) Medicare data. The cohort consisted of 16,535 men aged 65-80 yr at diagnosis with organ-confined well-differentiated or moderately differentiated prostate cancer who survived >1 yr past diagnosis and did not undergo treatment with prostatectomy or radiation therapy within 6 mo of diagnosis. They were diagnosed between 1991 and 1999 and followed until death or until the end of the study period (December 31, 2002). INTERVENTION Study subjects were selected to receive PADT alone if they received luteinizing hormone-releasing hormone agonists or bilateral orchiectomy in the first 6 mo after diagnosis, and they were selected to be observed if they did not have claims for PADT during the same interval. MEASUREMENTS Overall survival. RESULTS AND LIMITATIONS After adjusting for potential confounders (ie, tumor characteristics, comorbidities, and demographics), patients who received ADT had a worse overall survival rate than patients who were observed (hazard ratio: 1.20; 95% confidence interval: 1.13-1.27). In observational studies there may be unmeasured differences between the treated and untreated groups. The SEER database does not provide information on prostate-specific antigen levels. CONCLUSIONS This large, population-based study suggests that PADT did not improve survival in men with localized prostate cancer, but it suggests that PADT may instead result in worse outcomes compared with observation. Patients and physicians should be cognizant of the potential long-term side effects of ADT in a patient population for which expectant observation is an acceptable treatment strategy.

A Study to Quantify the Effectiveness of Daily Endorectal Balloon for Prostate Intrafraction Motion Management

PURPOSE To quantify intrafraction prostate motion between patient groups treated with and without daily endorectal balloon (ERB) employed during prostate radiotherapy and establish the effectiveness of the ERB. METHODS Real-time intrafraction prostate motion from 29 non-ERB (1,061 sessions) and 30 ERB (1,008 sessions) patients was evaluated based on three-dimensional (3D), left, right, cranial, caudal, anterior, and posterior displacements. The average percentage of time with 3D and unidirectional prostate displacements >2, 3, 4, 5, 6, 7, 8, 9, and 10 mm in 1-min intervals was calculated for up to 6 min of treatment time. The Kolmogorov-Smirnov method was used to evaluate the intrafraction prostate motion pattern between both groups. RESULTS Large 3D motion (up to 1 cm or more) was only observed in the non-ERB group. The motion increased as a function of elapsed time for displacements >2-8 mm for the non-ERB group and >2-4 mm for the ERB group (p < 0.05). The percentage time distributions between the two groups were significantly different for motion >5 mm (p < 0.05). The 3D symmetrical internal margin (IM) can be reduced from 5 to 3 mm (40% reduction), whereas the asymmetrical IM can be reduced from 3 to 2 mm (33% reduction) in cranial, caudal, anterior, and posterior for 6 min of treatment, when ERB is used. Beyond 6 min, the symmetrical 3D and asymmetrical cranial, caudal, anterior, and posterior IMs can be reduced from 9, 4, 7, 7, and 8 to 5, 2, 5, 3, and 4 mm, respectively (up to 57% reduction). CONCLUSION The percentage of time that the prostate was displaced in any direction was less in the ERB group for almost all magnitudes of motion considered. The directional analysis shows that the ERB reduced IMs in almost all directions, especially the anterior-posterior direction.

Bladder Cancer Patterns of Pelvic Failure: Implications for Adjuvant Radiation Therapy

PURPOSE Local-regional failures (LFs) after cystectomy with or without chemotherapy are common in locally advanced disease. Adjuvant radiation therapy (RT) could reduce LFs, but toxicity has discouraged its use. Modern RT techniques with improved normal tissue sparing have rekindled interest but require knowledge of pelvic failure patterns to design treatment volumes. METHODS AND MATERIALS Five-year LF rates after radical cystectomy plus pelvic node dissection with or without chemotherapy were determined for 8 pelvic sites among 442 urothelial bladder carcinoma patients. The impact of pathologic stage, margin status, nodal involvement, and extent of node dissection on failure patterns was assessed using competing risk analysis. We calculated the percentage of patients whose sites of LF would have been completely encompassed within various hypothetical clinical target volumes (CTVs) for postoperative radiation. RESULTS Compared with stage ≤pT2, stage ≥pT3 patients had higher 5-year LF rates in virtually all pelvic sites. Among stage ≥pT3 patients, margin status significantly altered the failure pattern whereas extent of node dissection and nodal positivity did not. In stage ≥pT3 patients with negative margins, failure occurred predominantly in the iliac/obturator nodes and uncommonly in the cystectomy bed and/or presacral nodes. Of these patients in whom failure subsequently occurred, 76% would have had all LF sites encompassed within CTVs covering only the iliac/obturator nodes. In stage ≥pT3 with positive margins, cystectomy bed and/or presacral nodal failures increased significantly. Only 57% of such patients had all LF sites within CTVs limited to the iliac/obturator nodes, but including the cystectomy bed and presacral nodes in the CTV when margins were positive increased the percentage of LFs encompassed to 91%. CONCLUSIONS Patterns of failure within the pelvis are summarized to facilitate design of adjuvant RT protocols. These data suggest that RT should target at least the iliac/obturator nodes in stage ≥pT3 with negative margins; coverage of the presacral nodes and cystectomy bed may be necessary for stage ≥pT3 with positive margins.

Validation and toxicity of PI3K/Akt pathway inhibition by HIV protease inhibitors in humans

PurposeActivation of the phosphatidylinositol 3-kinase/Akt pathway in tumors leads to radiation resistance, and inhibition of this pathway radiosensitizes tumors in laboratory models. Several first-generation human immunodeficiency virus (HIV) protease inhibitors (HPIs) inhibit Akt activation and are radiosensitizers. In order to validate a biomarker of Akt activity in anticipation of clinical trials using HPIs combined with radiotherapy, we sought to determine whether Akt activation was inhibited in leukocytes of HIV+ patients that were already taking these agents. Methods and MaterialsPeripheral blood mononuclear cells from HIV+ patients either taking radiosensitizing HPIs (nelfinavir, saquinavir, amprenavir) or not were analyzed by Western blotting for phospho-Akt. In order to determine whether these radiosensitizing HPIs increase the toxicity of radiotherapy, we performed a retrospective cohort study of HIV+ cancer patients treated with radiation and compared patients on radiosensitizing HPIs to controls not taking these agents. ResultsPatients taking these “active” radiosensitizing protease inhibitors had low levels of phospho-Akt compared to HIV+ patients taking either no medications or other anti-retroviral regimens. We found no significant differences in acute toxicities or in the ability to finish radiation treatment between 14 patients taking radiosensitizing HPIs and the 28 controls. ConclusionsThese results demonstrate the proof of principle that HPIs can inhibit Akt activation in patients taking normally prescribed anti-retroviral doses and are not associated with excessive toxicity. Radiosensitizing HPIs are excellent candidates for Phase I clinical trials as radiation sensitizers, and peripheral blood mononuclear cells can be used as a drug activity biomarker for Akt pathway inhibition.