Radiation Oncology

Letter to the Editor concerning “Re-irradiation in gynaecological cancers, present experiences and future hopes”

Challenges in the re-irradiation of locally advanced head and neck cancers: outcomes and toxicities Abstract Purpose To retrospectively review outcomes and toxicities for patients with recurrent head and neck cancer (HNC) undergoing re-irradiation (re-RT). Methods Retrospective review of oncologic outcomes and toxicity data from patients who received head and neck (HN) re-RT with curative intent using intensity-modulated radiation therapy (IMRT) from 2011 to 2016. Common toxicities were scored using Common Terminology Criteria for Adverse Events (CTCAE) V4. Treatment outcomes included progression-free survival (PFS), locoregional control (LRC), and overall survival (OS). Results Twenty-one patients with HNC were re-irradiated with curative intent. The median follow-up after re-RT was 27.8 months. The median retreatment dose was 66 Gy (range, 60–70), and the median retreatment volume was 194.1 cm3(range, 52.4–1375.6). The median LRC, PFS, and OS were 10 months, 8.4 months, and 18.1 months, respectively. Patients treated with surgery as a component of primary HN cancer treatment had significantly worse PFS and OS when retreated compared with those initially treated with chemoradiation alone (p = 0.026 and p = 0.005, respectively). Those with stage IVA/B recurrent disease had worse LRC, PFS, and OS compared with stage II/III disease (p = 0.029, p = 0.049, and p = 0.020 respectively). Acute grade ≥ 3 toxicity and late grade ≥ 3 toxicity were 38% and 38%, respectively, with dysphagia being most common (24% acute and 14% late). Conclusion Re-irradiation with IMRT for locally advanced HN recurrences either definitively or after salvage surgery is feasible, but treatment-related toxicity remains significant. Patients who received surgery as a component of their initial treatment and those with more advanced stage disease may be more difficult to salvage with re-irradiation.

Correction to: Stereotactic body radiation therapy for non-small cell lung cancer patients with prior history of thoracic surgery and/or radiation therapy: the influence of smoking, size, and central location on risk of complications The article Stereotactic body radiation therapy for non-small cell lung cancer patients with prior history of thoracic surgery and/or radiation therapy: the influence of smoking, size, and central location on risk of complications.

Changes in prostate-specific antigen midway through salvage radiotherapy may be associated with long-term outcomes Abstract Objective To examine the relationship between changes in prostate-specific antigen (PSA) by midpoint of salvage radiotherapy (SRT) for biochemically recurrent prostate cancer and long-term clinical outcomes. Methods We conducted a retrospective study of men treated with SRT for biochemically recurrent prostate cancer at a single practice from 2004 to 2016. Patients were grouped based on PSA response at treatment midpoint: group 0, no change; group 1, decrease; group 2, increase. The primary endpoint was clinical failure measured from time of SRT completion and defined as serum PSA ≥ 0.2 ng/mL above post-radiotherapy nadir, initiation of androgen deprivation therapy, development of bone metastasis, or death from prostate cancer. The Kaplan-Meier method was used to estimate freedom from clinical failure for each group, and differences between groups were examined using pairwise multiple comparison. Results Median follow-up was 51.6 months (range, 3.3–138.0). Of 76 eligible men, 13.1% experienced no change in PSA at midpoint of SRT (group 0), 68.4% experienced a decrease (group 1), and 18.4% experienced an increase (group 2). Four-year freedom from clinical failure rates were as follows: group 0, 60.0%; group 1, 58.3%; and group 2, 41.7%. Median time to clinical failure was 71.7 months (95% confidence interval, 46.9–96.5) for group 1; 26.8 months (95% confidence interval, 0.0–55.9) for group 2; and was not reached for group 0. There was a significant difference in four-year freedom from clinical failure between groups 1 and 2 (p = 0.036). Conclusions PSA changes by the midpoint of SRT predict long-term prostate cancer control with increases in PSA associated with decreased freedom from disease progression.

Salvage radiation therapy following radical prostatectomy in Stockholm County in 2008–2016 Abstract Objective This is a large single-institution report including 714 consecutive prostate cancer patients who received salvage radiation therapy (SRT) between 2008 and 2016 in Stockholm, Sweden. The aim of the study was to determine the PSA outcomes of salvage radiotherapy in a cohort of prostate cancer patients after radical prostatectomy (RP). Methods All patients have been treated with 70 Gy during a 7-week period. STHLM-0 database was the source of all PSA test results in Stockholm. Results During a median follow-up of 48 months after radiotherapy treatment, 49% of patients had no signs of biochemical failure (BcF), 13% experienced BcF, and 38% never reached PSA nadir and subsequently progressed after SRT. Five-year biochemical free survival (bPFS) was 47%. Low PSA at SRT start as well as low preoperative Gleason score and T-stage were independently associated with favorable 5-year biochemical progression-free survival. Conclusions Patients who started SRT at PSA < 0.28 ng/ml had the best 5-year bPFS of 58%. Median pre-SRT PSA was 0.28 ng/l (0.2–0.45) indicating the good standard of salvage radiotherapy process from patient referral to start of radiotherapy in Stockholm County.

Lymphopenia as a predictor of survival in chemoradiation-treated stage III non-small-cell lung cancer (NSCLC): a multi-center retrospective analysis Abstract Background Concurrent chemoradiation (CRT) with a platinum-containing regimen is considered standard of care for eligible unresectable stage III non-small-cell lung cancer (NSCLC) patients. Attempts to improve locoregional control, and thereby enhance overall survival (OS), by increasing the dose of radiation failed to do so in a contemporary phase III trial. Better understanding of the effects of radiation on the immune system, particularly absolute lymphocyte counts (ALC), may explain the poorer survival seen with high-dose (HD) radiation compared to low dose (LD). We hypothesized that treatment-induced lymphopenia affects outcomes in stage III NSCLC patients treated with concurrent CRT. Methods The study is a retrospective multi-institution study. Stage III NSCLC patients who received CRT between 1994 and 2014 were categorized into LD RT (≤ 66 Gy) and HD RT (> 66 Gy) groups. Overall survival was assessed using Kaplan-Meier method with log-rank test and Cox proportional hazard regression model to estimate the effect of radiation dose (LD vs. HD groups) on OS. Hematologic values including ALC were evaluated at diagnosis and at intervals during treatment. Patients with pre-existing immunodeficiency states and autoimmune disease were excluded from the analysis. Results Of the patients, 182 were included in the analysis. Median age was 62 years (range 37–82). Seventy-seven percent were males, 67% Caucasians. Most common types of histology were adenocarcinoma (52%) and squamous cell carcinoma (41%). One-hundred-fifty-four patients received LD RT and 28 received HD RT. Medians (ranges) of pre-treatment ALC were 1730/mm3 (384, 4300) vs. 2065/mm3 (600, 4580) (p = 0.58) between LD and HD groups. Medians (ranges) of nadir ALC were 324/mm3 (20, 2410) vs. 279.5/mm3 (20–930) (p = 0.11) between LD and HD groups. Kaplan-Meier survival curves showed that LD has better OS than the HD group (median survival 31.2 months vs. 13.9 months, p < 0.001). No significant association was detected between RT dose and lymphocytes nadirs or with lymphocyte count prior to RT. Conclusions HD RT in stage III NSCLC patients is associated with worse survival. Lower nadir lymphocyte counts, independent of dose of radiation, were not associated with decrease in survival. These findings need further validation in larger studies and in patients treated with immune therapy.

The systemic immunostimulatory effects of radiation therapy producing overall tumor control through the abscopal effect Abstract Objective Emerging studies show that radiation therapy produces an important out of field (distant) effect known as the ‘‘abscopal effect” in nonirradiated tumor sites. The objective of this study was to provide an overview of the current state of knowledge and clinical experience of radiation therapy producing abscopal effects in the management of different types of malignant diseases. Methods Peer-reviewed published clinical evidence on the abscopal effect of radiation therapy was collected using electronic databases such as Medline via PubMed and Google Scholar. The reference lists were searched in the publications that we obtained in an attempt to find additional relevant publications. Non-indexed peer-reviewed journals were manually searched and relevant information was extracted. The search was restricted to English language articles. The clinical data on the abscopal effect of radiation therapy were reviewed and the outcomes have been summarized. Results Currently, only clinical case reports and anecdotes have slowly converted into solid clinical data and interest is building in the field of radiation therapy, specifically on how local radiation can produce the abscopal effects for the management of different types of malignant tumors. Extensive clinical evidence suggests that the radiation therapy induced abscopal antitumor effects are mediated by immune cells such as the T-lymphocytes. This forms a basis for using radiation therapy in combination with immunotherapy to augment the abscopal response rates in cancer patients. Current evidence demonstrates that radiation therapy induces abscopal responses across many tumor types. Conclusion Together, the clinical outcomes from published reports suggest that localized radiation therapy is capable of inducing abscopal effects in a wide variety of malignant tumors. With the advent of novel immunotherapies, the potential for immune activation by radiation defines a novel role for radiation therapy in the treatment of systemic disease. A clinical consideration of the abscopal effects produced by radiation therapy could lead to a revolutionary change in the current management of patients including radiation treatment strategies and immunotherapies for various malignant tumors.

Neoadjuvant chemotherapy and high-dose radiation using intensity-modulated radiotherapy followed by rectal sparing TEM for distal rectal cancer Abstract Purpose For distal rectal tumors, abdominoperineal resection may achieve local control but with significant morbidity. High-dose radiation can improve pathologic response and allow for full-thickness local excision (FTLE) with comparable outcomes and improved morbidity. We report 15 years of data on distal rectal cancer treated with chemotherapy, intensity-modulated radiotherapy (IMRT), and FTLE via transanal endoscopic microsurgery. Methods and materials Forty-four patients were treated for cT1–T3, N0, and M0 distal rectal cancer using IMRT at 5580 cGy with 5-FU chemotherapy, followed by FTLE. Local recurrence (LR), disease-free survival (DFS), and overall survival (OS) were reported. Results Median follow-up was 51 months. Three patients (6.8%) had LR, all salvaged surgically. Mean DFS and OS are 8.56 and 9.10 years, respectively. DFS and OS were strongly associated with pathologic response to chemoradiotherapy (p = 0.043 and p = 0.023, respectively). Thirty-four patients (77%) are alive with no disease. Postoperative grade I–II complications noted in 17 patients and grade III complications in 2 patients. No patients required a diverting colostomy. Conclusions High-dose IMRT and chemotherapy followed by FTLE to treat distal rectal cancers are well tolerated and effective. FTLE may improve outcomes and minimize complications in appropriately selected patients. Randomized clinical trials are needed to compare it with standard surgery.

Adjuvant chemoradiation in resected gallbladder cancer: a prognostic index model for predicting overall survival Abstract Purpose Patients with gallbladder cancer (GBC) have a dismal prognosis. We investigated outcomes and risk factors for overall survival (OS) in patients treated with radical surgery and adjuvant chemoradiotherapy (CRT). Materials/methods A total of 212 patients with LAGC (⩾pT3 59% and/or pN+ 52%) were studied. The primary endpoint of the analysis was OS. We constructed a risk scoring system in which points were assigned to each risk factor by dividing each β coefficient in the final model by the lowest β coefficient and rounding to the nearest integer. A risk score was assigned to each subject by adding up the points for each risk factor present. Subjects were then divided into three risk groups based on their risk scores (0 points = low risk, 1–2 points = intermediate risk, 3–6 points = high risk). Results Median follow-up was 46.2 months (2–235). Five-year OS for the entire cohort was 53%. In multivariate analysis, higher pT stage [HR, 2.43 (1.29–3.68); p = 0.01], R1 resection [HR, 5.06 (3.12–8.19); p < 0.001], and number of surgical procedures [HR, 1.41 (1.01–2.16); p = 0.05] were associated with an increased risk of death. Five-year OS for patients with low (n = 63), intermediate (n = 94), and high (n = 55) risk was 79.1%, 51.2%, and 9.5%, respectively. Conclusion Overall results after multimodality treatment of GBC are promising. A risk model was generated to determine a prognostic index for individual patients with GBC. Classification of risk factors for death has contributed to propose a prognostic index that could allow us to guide risk-adapted tailored treatment.

Fast in situ image reconstruction for proton radiography Abstract Objective Proton beam therapy is an emerging modality for cancer treatment that, compared to X-ray radiation therapy, promises to provide better dose delivery to clinical targets with lower doses to normal tissues. Crucial to accurate treatment planning and dose delivery is knowledge of the water equivalent path length (WEPL) of each ray, or pencil beam, from the skin to every point in the target. For protons, this length is estimated from relative stopping power based on X-ray Hounsfield units. Unfortunately, such estimates lead to 3 to 4% uncertainties in the proton range prediction. Therefore, protons in the Bragg peak may overshoot (or undershoot) the desired stopping depth in the target causing tissue damage beyond the target volume. Recent studies indicate that tomographic imaging using protons has the potential to provide directly more accurate measurement of RSPs with significantly lower radiation dose than X-rays. We are currently working on a proton radiography system that promises to provide accurate two-dimensional (2D) images of WEPL values for protons that pass through the body. These will be suitable for positioning and range verification in daily treatments. In this study, we demonstrate that this system is capable of rapidly achieving such accurate images in clinically meaningful times. Methods We have developed a software platform to characterize the potential performance of the prototype proton radiography system. We use Geant4 to simulate raw data detected by the device. An especially written software — pRad — was written to process these data as they are received and uses iterative methods to generate radiographs. The software has been designed to generate a radiograph from a few million protons in under a minute after receiving the first proton from the device. We used a head phantom with known chemical compositions that could be modeled quite accurately in Geant4 simulations of proton radiographs. The radiographs are displayed as pixelated WEPL values displayed on a 2D gray scale image of WEPL values. Results Rapid radiograph reconstruction of 3D phantoms using simulated proton pencil beams have been achieved with our software platform. On a modest desktop computer with a single central processing unit (CPU) and a single graphics processing unit (GPU), it takes about 11 s to reconstruct images using iterative linear algorithms to reconstruct a radiograph from 7.6 million protons. For the radiographic reconstructions of the head phantom described here, the mean WEPL errors, in the proton radiograph using a large majority of the pixels in the complete image were less than 1 mm when compared to images obtained without proton scattering and without detector resolution included. Conclusion We have demonstrated, through computer simulations of proton irradiation of a pediatric head phantom using the newly built pRad detector and image reconstruction software, that high-quality proton radiographs can be generated for patient alignment and verification of water equivalent thickness of the patient before each treatment.