J.J. Cuaron

Role of FDG-PET scans in staging, response assessment, and follow-up care for non-small cell lung cancer

The integral role of positron-emission tomography (PET) using the glucose analog tracer fluorine-18 fluorodeoxyglucose (FDG) in the staging of non-small cell lung cancer (NSCLC) is well established. Evidence is emerging for the role of PET in response assessment to neoadjuvant therapy, combined-modality therapy, and early detection of recurrence. Here, we review the current literature on these aspects of PET in the management of NSCLC. FDG-PET, particularly integrated 18F-FDG-PET/CT, scans have become a standard test in the staging of local tumor extent, mediastinal lymph node involvement, and distant metastatic disease in NSCLC. 18F-FDG-PET sensitivity is generally superior to computed tomography (CT) scans alone. Local tumor extent and T stage can be more accurately determined with FDG-PET in certain cases, especially in areas of post-obstructive atelectasis or low CT density variation. FDG-PET sensitivity is decreased in tumors <1 cm, at least in part due to respiratory motion. False-negative results can occur in areas of low tumor burden, e.g., small lymph nodes or ground-glass opacities. 18F-FDG-PET-CT nodal staging is more accurate than CT alone, as hilar and mediastinal involvement is often detected first on 18F-FDG-PET scan when CT criteria for malignant involvement are not met. 18F-FDG-PET scans have widely replaced bone scintography for assessing distant metastases, except for the brain, which still warrants dedicated brain imaging. 18F-FDG uptake has also been shown to vary between histologies, with adenocarcinomas generally being less FDG avid than squamous cell carcinomas. 18F-FDG-PET scans are useful to detect recurrences, but are currently not recommended for routine follow-up. Typically, patients are followed with chest CT scans every 3–6 months, using 18F-FDG-PET to evaluate equivocal CT findings. As high 18F-FDG uptake can occur in infectious, inflammatory, and other non-neoplastic conditions, 18F-FDG-PET-positive findings require pathological confirmation in most cases. There is increased interest in the prognostic and predictive role of FDG-PET scans. Studies show that absence of metabolic response to neoadjuvant therapy correlates with poor pathologic response, and a favorable 18F-FDG-PET response appears to be associated with improved survival. Further work is underway to identify subsets of patients that might benefit individualized management based on FDG-PET.

Early toxicity in patients treated with postoperative proton therapy for locally advanced breast cancer.

PURPOSE To report dosimetry and early toxicity data in breast cancer patients treated with postoperative proton radiation therapy. METHODS AND MATERIALS From March 2013 to April 2014, 30 patients with nonmetastatic breast cancer and no history of prior radiation were treated with proton therapy at a single proton center. Patient characteristics and dosimetry were obtained through chart review. Patients were seen weekly while on treatment, at 1 month after radiation therapy completion, and at 3- to 6-month intervals thereafter. Toxicity was scored using Common Terminology Criteria for Adverse Events version 4.0. Frequencies of toxicities were tabulated. RESULTS Median dose delivered was 50.4 Gy (relative biological equivalent [RBE]) in 5 weeks. Target volumes included the breast/chest wall and regional lymph nodes including the internal mammary lymph nodes (in 93%). No patients required a treatment break. Among patients with >3 months of follow-up (n=28), grade 2 dermatitis occurred in 20 patients (71.4%), with 8 (28.6%) experiencing moist desquamation. Grade 2 esophagitis occurred in 8 patients (28.6%). Grade 3 reconstructive complications occurred in 1 patient. The median planning target volume V95 was 96.43% (range, 79.39%-99.60%). The median mean heart dose was 0.88 Gy (RBE) [range, 0.01-3.20 Gy (RBE)] for all patients, and 1.00 Gy (RBE) among patients with left-sided tumors. The median V20 of the ipsilateral lung was 16.50% (range, 6.1%-30.3%). The median contralateral lung V5 was 0.34% (range, 0%-5.30%). The median maximal point dose to the esophagus was 45.65 Gy (RBE) [range, 0-65.4 Gy (RBE)]. The median contralateral breast mean dose was 0.29 Gy (RBE) [range, 0.03-3.50 Gy (RBE)]. CONCLUSIONS Postoperative proton therapy is well tolerated, with acceptable rates of skin toxicity. Proton therapy favorably spares normal tissue without compromising target coverage. Further follow-up is necessary to assess for clinical outcomes and cardiopulmonary toxicities.

Exponential Increase in Relative Biological Effectiveness Along Distal Edge of a Proton Bragg Peak as Measured by Deoxyribonucleic Acid Double-Strand Breaks

PURPOSE To quantify the relative biological effectiveness (RBE) of the distal edge of the proton Bragg peak, using an in vitro assay of DNA double-strand breaks (DSBs). METHODS AND MATERIALS U2OS cells were irradiated within the plateau of a spread-out Bragg peak and at each millimeter position along the distal edge using a custom slide holder, allowing for simultaneous measurement of physical dose. A reference radiation signal was generated using photons. The DNA DSBs at 3 hours (to assess for early damage) and at 24 hours (to assess for residual damage and repair) after irradiation were measured using the γH2AX assay and quantified via flow cytometry. Results were confirmed with clonogenic survival assays. A detailed map of the RBE as a function of depth along the Bragg peak was generated using γH2AX measurements as a biological endpoint. RESULTS At 3 hours after irradiation, DNA DSBs were higher with protons at every point along the distal edge compared with samples irradiated with photons to similar doses. This effect was even more pronounced after 24 hours, indicating that the impact of DNA repair is less after proton irradiation relative to photons. The RBE demonstrated an exponential increase as a function of depth and was measured to be as high as 4.0 after 3 hours and as high as 6.0 after 24 hours. When the RBE-corrected dose was plotted as a function of depth, the peak effective dose was extended 2-3 mm beyond what would be expected with physical measurement. CONCLUSIONS We generated a highly comprehensive map of the RBE of the distal edge of the Bragg peak, using a direct assay of DNA DSBs in vitro. Our data show that the RBE of the distal edge increases with depth and is significantly higher than previously reported estimates.

Stereotactic Body Radiation Therapy for Primary Lung Cancers >3 Centimeters

Introduction: A retrospective analysis of the outcomes of stereotactic body radiation therapy (SBRT) in the treatment of large (>3 cm) non–small-cell lung cancers (NSCLCs). Methods: Between February 2007 and November 2011, 63 patients with T2-T4N0 NSCLC were treated with SBRT. Toxicity was graded per Common Terminology Criteria for Adverse Events, version 4.0. Local failure-free survival (LFFS), recurrence-free survival, and overall survival curves were estimated using the Kaplan–Meier method and univariate analysis was performed using Cox regression. Results: Median follow-up was 16.9 months. One- and 2-year LFFS was 88.8% and 75.7%, 1- and 2-year recurrence-free survival was 59.0% and 41.6%, and 1- and 2-year overall survival was 77.1% and 57.6%, respectively. Planning target volume less than 106 cm3 was associated with a significantly higher 1- and 2-year LFFS (p =0.05). Grade 2 or higher acute and late pulmonary toxicities occurred in 19.3% and 19.3% of patients, respectively, and were not associated with common dose–volume parameters; 22.8% of patients developed grade 2 or higher chest wall pain, which was significantly associated with chest wall V30 70 cm3 or more (p = 0.03). Conclusions: SBRT for larger NSCLC tumors achieves high LFFS with acceptable toxicity. LFFS was worse with planning target volume 106 cm3 or more. Grade 2 or higher chest wall pain was associated with chest wall V30 70 cm3 or more.

Anterior-oriented proton beams for prostate cancer: A multi-institutional experience.

Abstract Background. Proton beam therapy (PBT) for prostate cancer generally involves the use of two lateral beams that transverse the hips. In patients with hip replacements or a previously irradiated hip, this arrangement is contraindicated. The use of non-lateral beams is possible, but not well described. Here we report a multi-institutional experience for patients treated with at least one non-lateral proton beam for prostate cancer. Material and methods. Between 2010 and 2014, 20 patients with organ-confined prostate cancer and a history of hip prosthesis underwent proton therapy utilizing at least one anterior oblique beam (defined as between 10° and 85° from vertical) at one of three proton centers. Results. The median follow-up was 6.4 months. No patients have developed PSA failure or distant metastases. The median planning target volume (PTV) D95 was 79.2 Gy (RBE) (range 69.7–79.9). The median rectal V70 was 9.2% (2.5–15.4). The median bladder V50, V80, and mean dose were 12.4% (3.7–27.1), 3.5 cm3 (0–7.1), and 14.9 Gy (RBE) (4.6–37.8), respectively. The median contralateral femur head V45 and max dose were 0.01 cm3 (0–16.6) and 43.7 Gy (RBE) (15.6–52.5), respectively. The incidence of acute Grade 2 urinary toxicity was 40%. There were no Grade ≥ 3 urinary toxicities. There was one patient who developed late Grade 2 rectal proctitis, with no other cases of acute or late ≥ Grade 2 gastrointestinal toxicity. Grade 2 erectile dysfunction occurred in two patients (11.1%). Mild hip pain was experienced by five patients (25%). There were no cases of hip fracture. Conclusion. PBT for prostate cancer utilizing anterior oblique beam trajectories is feasible with favorable dosimetry and acceptable toxicity. Further follow-up is needed to assess for long-term outcomes and toxicities.

Patterns of failure in patients with head and neck carcinoma of unknown primary treated with radiation therapy

The purpose of this study was to examine patterns of failure and the relationship to radiation doses in patients with head and neck carcinoma of unknown primary (HNCUP).

Statin use not associated with improved outcomes in patients treated with brachytherapy for prostate cancer.

PURPOSE To investigate the association between statin use and prostate cancer outcomes in intermediate- and high-risk patients treated with brachytherapy for prostate cancer. METHODS AND MATERIALS Between 1998 and 2010, 754 men with National Comprehensive Cancer Network intermediate- (n = 627) and high-risk (n = 127) prostate cancer were treated with prostate brachytherapy at our institution. Patients received either low-dose-rate or high-dose-rate brachytherapy as monotherapy or in combination with supplemental external beam radiotherapy. Two hundred eighty-five patients (37.8%) also received androgen-deprivation therapy. Two hundred seventy-three men (36.2%) were identified as taking statin medication before initiating radiation therapy. Prostate-specific antigen relapse-free survival (PSA-RFS), distant metastasis-free survival (DMFS), and overall survival were compared using log-rank tests. Associations of patient and treatment characteristics with outcomes were analyzed with univariate and multivariate regression. The median followup was 48 months. RESULTS The 8-year PSA-RFS for intermediate-risk, high-risk, and all patients was 92.2%, 64.1%, and 87.7%, respectively. The 8-year DMFS was 97.1%, 82.9%, and 94.9%, respectively. The 8-year overall survival for the entire cohort was 86.6%. There were no significant differences between statin users and nonusers when stratified by risk group, nor when analyzed as a full cohort. On multivariate analysis, Gleason score 4 + 3 = 7 and >7 were significantly associated with worse PSA-RFS (p ≤ 0.003 and <0.001, respectively). Gleason score > 7 (p = 0.008) and the use of neoadjuvant androgen-deprivation therapy (p = 0.03) was associated with worse DMFS. Statin use did not significantly impact PSA-RFS or DMFS. CONCLUSIONS Pretreatment statin use is not associated with improved outcomes in intermediate- and high-risk patients undergoing prostate brachytherapy-based regimens for prostate cancer.

Novel applications of proton therapy in breast carcinoma

This review will focus on the indications, clinical experience, and technical considerations of proton beam radiation therapy in the treatment of patients with breast cancer. For patients with early stage disease, proton therapy delivers less dose to non-target breast tissue for patients receiving partial breast irradiation (PBI) therapy, which may result in improved cosmesis but requires further investigation. For patients with locally advanced breast cancer requiring treatment to the regional lymph nodes, proton therapy allows for an improved dosimetric profile compared with conventional photon and electron techniques. Early clinical results demonstrate acceptable toxicity. The possible reduction in cardiopulmonary events as a result of reduced dose to organs at risk will be tested in a randomized control trial of protons vs. photons.

Stereotactic body radiation vs. intensity-modulated radiation for unresectable pancreatic cancer

Abstract Background: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for unresectable pancreatic cancer, and is postulated to be more effective and less toxic than conventionally fractionated intensity modulated radiation therapy (IMRT). Material and methods: We retrospectively reviewed unresectable stage I–III pancreatic adenocarcinoma treated from 2008 to 2016 at our institution with SBRT (five fractions, 30–33 Gy) or IMRT (25–28 fractions, 45–56 Gy with concurrent chemotherapy). Groups were compared with respect to overall survival (OS), local and distant failure, and toxicity. Log-rank test and Cox proportional hazards regression model, and competing risks methods were used for univariate and multivariate analysis. Results: SBRT patients (n = 44) were older than IMRT (n = 226) patients; otherwise there was no significant difference in baseline characteristics. There was no significant difference in OS or local or distant failure. There was no significant difference in rates of subsequent resection (IMRT =17%, SBRT =7%, p = .11). IMRT was associated with more acute grade 2+ gastrointestinal toxicity, grade 2+ fatigue, and grade 3+ hematologic toxicity (p = .008, p < .0001, p = .001, respectively). Conclusions: In this analysis, SBRT achieves similar disease control outcomes as IMRT, with less acute toxicity. This suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen may suggest a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity.

Physics Essentials of Particle Therapy

The history and rationale for light ion therapy is provided. Light ions are generated in cyclotrons and synchrotrons. Light ions have no exit dose and a sharper penumbra, permitting improved shaping of the radiation dose compared to photons. In tissue, the distribution will be affected by inhomgeneities which create scatter resulting in dose variations at interfaces and affect distal fall off. Margins of ~3% of the range are used to account for range uncertainties that result from mapping of the CT numbers to the stopping power. While many factors (e.g. tissue type, range) may affect the biological response, a clinical relative biological effectiveness (RBE) of 1.1 has been adopted for protons while for carbon, RBE has a stronger dependence and this dependence is incorporated into the planning process.