Stereotactic Body Radiotherapy for Kidney Cancer: Ready for Prime Time?

The standard treatment for renal cell carcinoma (RCC) is surgery. However, a number of patients will not be candidates for surgical treatment or will reject this therapeutic approach. Therefore, alternative approaches are required. Historically, radiotherapy has been considered an ineffective treatment for RCC due to the radioresistance of renal tumour cells to conventional fractionation and the increased rate of toxicity. Stereotactic body radiotherapy (SBRT) is a radiotherapy technique that provides a non-invasive ablative treatment with remarkable rates of local control in both primary tumours and metastases in several locations, with a low associated morbidity due to the highly conformal dose and the use of image-guided techniques. Current evidence shows that a higher dose per fraction, achieving a higher biological effective dose, can overcome the radioresistance of RCC cells. Therefore, SBRT, as well as the combination of SBRT and new emerging immune therapies, has a potential role in the local treatment of primary RCC and oligometastatic RCC patients.     

Are We Ready for the 10% Solution?

The limitations of the Response Evaluation Criteria in Solid Tumors (RECIST) for the assessment of molecularly targeted agents have been increasingly recognized with the advance of new therapies. The current study and others focusing on vascular endothelial growth factor-pathway inhibitors in advanced renal cell carcinoma highlight that tumor shrinkage below the RECIST threshold can be associated with significant clinical benefit, and flexibility in size change categorization should be considered in future modification of the criteria.The Response Evaluation Criteria in Solid Tumors (RECIST) criteria, which categorize quantitative tumor size changes into complete response, partial response (PR), stable disease (SD), or progressive disease (PD) [1], provide standardized, objective measurements of tumor response to therapy and have been used extensively over the last decade for early to late drug development and regulatory approvals, as well as for treatment decisions in individual patient care. The RECIST criteria were generated based on data from cytotoxic chemotherapy trials; their limitations for the assessment of molecularly targeted agents have been increasingly recognized with the advance of new therapies. In particular, the cutoff of 30% change in the sum of longest diameters (ΔSLD) as the criterion of response has been criticized for not adequately capturing potentially effective therapies. As exemplified by antiangiogenic therapies, such as sorafenib in renal cell carcinoma (RCC) and hepatocellular carcinoma, drugs with very low rates of RECIST-defined responses (10% or less) can still succeed and confer significant clinical benefit. For that reason, many clinical trials also use SD as an additional indicator of therapeutic effect. However, inclusion of SD and progression-free survival (PFS) in the efficacy readout often requires randomized trials to distinguish the drug effect from the natural course of the tumor. For patients receiving therapy, the implication of SD is often uncertain, because the criterion encompasses a wide range of tumor size changes, from 29% reduction to 19% increase. Exploration and validation of optimal criteria of tumor burden changes or functional imaging parameters as markers of drug effect and/or clinical benefit have the promise to improve the efficiency of both development of new therapeutics and therapeutic management of individual patients.A study published in this issue of The Oncologist [2] represents one of the many retrospective analyses of the relation between tumor size changes and clinical outcomes in patients treated with vascular endothelial growth factor (VEGF) pathway-targeting agents, focusing on a specific patient care question: what degree of tumor size change early in the course of therapy may predict the clinical outcome in the patient and therefore provide guidance for decisions on further treatment? The analysis was based on 66 patients treated with 1 of the 6 different VEGF-pathway inhibitors, and thresholds of −30% (as in RECIST) or −10% ΔSLDs were tested for their ability to classify patients with good or poor outcomes. This analysis concluded that ≥10% reduction in SLD (responders) at the first scan was associated with significantly better outcomes, compared with that of nonresponders (those who did not achieve 10% SLD reduction). Time to treatment failure was 8.4 months versus 4.1 months, and overall survival was 35 months versus 15 months, both with p values < .01. In contrast, the RECIST threshold of −30% ΔSLDs at the first scan failed to predict patient outcome (TTF of 6.9 months versus 5.5 months). It further suggested that −10% ΔSLDs at first scan could be used for treatment decisions as to whether the anti-VEGF therapies should be continued, although the negative predictive value of “nonresponse,” by either the −10% or −30% cutoffs, was not discussed.As already recognized by the authors, there are multiple limitations of this series, including limited sample size and small numbers in each marker subgroup, heterogeneity of the VEGF-targeting therapies ranging from tyrosine-kinase inhibitors (TKIs) to monoclonal antibodies, and inconsistency in the timing of first scans (20–170 days from start of therapy) on which the cutoff optimization was based. Despite the limitations, this study joined a large body of independent retrospective studies that collectively demonstrated a significant correlation between tumor size changes at the first scan and the clinical outcome [3–5]. One of the largest series was reported by Thiam et al. [5] based on 334 patients with advanced RCC treated on the sunitinib arm in a phase III trial for sunitinib versus interferon-α. It tested a series of ΔSLD thresholds at the first scan at 6 weeks (−45%, −30%, −20%, −10%, 0%, +10%) for their correlations with PFS and found that ΔSLDs of −10% provided the optimal cutoff that distinguished the PFS outcomes (median PFS of 5.6 months versus 11 months). The −10% cutoff was also examined in a number of other retrospective studies in independent patient cohorts and was consistently found to be significantly associated with outcomes ([5–7] and this study).What is the clinical utility of this finding? Although ≥10% shrinkage is clearly associated with significantly better outcome, the practical concern for a given patient is the likelihood of benefiting from therapy if that threshold is not reached. As an inherent limitation of post-treatment biomarkers, it is not possible to distinguish between predictive and prognostic markers because all marker subgroups would have received the same therapy. PFS of 5 months was often selected as an arbitrary landmark to estimate presence or lack of therapeutic benefit from VEGF-pathway inhibitors in first-line metastatic RCC. In several studies, including Thiam et al. [5] and the current study, median PFS values in nonresponders by the −10% criterion were 5–6 months, indicating that although these patients did not do well on average, 50% of the patients were progression-free for longer than 5–6 months. Furthermore, in tumors in which the target pathways remain relevant through progression, continuation of therapy may be beneficial whichever PD criteria are used. Given that the treatment benefit in an individual patient cannot be ruled out with high certainty, the value of this early post-treatment marker would depend on the availability of better, less toxic treatment options.Is this new criterion of response (≥10% SLD reduction) better than RECIST in guiding treatment decisions? The answer depends on how RECIST is used. It is clear that objective response (≥30% SLD reduction) is not a good predictor of outcomes. However, treatment decisions in general practice are not based on response, but rather on progression. Patients not achieving PR, but in SD, by RECIST definition (ΔSLDs in the range of −29% to +19%) would continue therapy until PD. To demonstrate the potential advantage of the −10% cutoff over the current practice, outcome differences using the cutoffs of RECIST PR/SD versus −10% should be compared. However, such comparisons are not always feasible because the numbers of patients with PD on first scans are usually very small, at least for anti-VEGF therapies in RCC. On the other hand, the use of the SD category as a basis for continuing therapy is conceivably problematic, because the tumor size could have increased by up to 19%. Indeed, lack of tumor shrinkage (0% SLD reduction) or +10% SLD at the first scan was associated with an extremely poor outcome in patients treated with sunitinib, with a median PFS of 1.5 months [5]. Further studies with sufficient power would be required to confirm this finding.What is the general implication of the findings on the use of tumor imaging in drug development? This study, among many others, reinforced the notion that clinically viable targeted agents may have low response rates as defined by RECIST, but tumor shrinkage with smaller magnitudes is common. These studies further suggest that modification of the response criteria to capture and categorize minor responses may provide a more sensitive readout of the therapeutic effect and potentially improve the accuracy of early drug evaluation. On the other hand, finding the optimal cutoff can be challenging, because the threshold may differ for the same agents in different indications or for different agents in the same indication. For example, although studies on VEGFR TKIs in metastatic RRC identified 10% as the optimal cutoff, similar tests for everolimus in second-line metastatic RCC failed to identify any cutoffs (from −45% to +20%) that separate better and poorer outcomes [8]. Technical limitations, such as measurement variability, may also limit the choice of thresholds that can be adopted. Efforts are under way by the RECIST committee to expand the database to include large randomized clinical trials of targeted agents, as well as studies using molecular imaging with fluorodeoxyglucose-positron emission tomography (FDG-PET), with the plan to evaluate and update the guidelines and criteria to meet the needs of drug development and patient care in the era of novel therapies.In summary, the current study and others focusing on VEGF-pathway inhibitors in advanced RCC highlight the observation that tumor shrinkage below the threshold of RECIST can be associated with significant clinical benefit, and that flexibility in the size change categorization should be considered in future modification of the response criteria. However, whether −10% or other cutoffs would be optimal for treatment decisions in individual patients is uncertain and would require further, sufficiently powered, prospective studies. It should be noted that criteria for one agent or one disease setting may not be generalizable to others. As newer therapeutic agents become available in various clinical settings, it may be necessary to further modify existing tumor size-based response criteria, verify promising molecular and functional imaging methods, and investigate new technologies. Finally, before optimal criteria are defined for dichotomous characterization of tumor responses, it would be desirable to collect tumor size measurements as a continuous variable and evaluate the reporting of antitumor activity based on several cutoffs, rather than just one, for responses or progression.     

Comparing the Outcomes of Stereotactic Ablative Radiotherapy and Non-Stereotactic Ablative Radiotherapy Definitive Radiotherapy Approaches to Thoracic Malignancy: A Systematic Review and Meta-Analysis

Stereotactic ablative body radiotherapy (SABR) is popular because of the high rates of local control with low toxicity seen in lung cancer patients. In this study we compared clinically significant toxicity and overall survival for SABR and non-SABR definitive radiotherapy (conformal radiotherapy) patients. A PUBMED search of all human, English language articles on SABR and non-SABR radically treated early stage lung cancer patients was performed until June 2016. Results of these searches were filtered in accordance with a set of eligibility criteria and analyzed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eighty-seven SABR and 25 non-SABR articles were reviewed. There was no significant difference in pneumonitis rates between patients receiving SABR (11.4%; 95% confidence interval [CI], 9.7-13.3) and non-SABR treatment (14.4%; 95% CI, 10.6-18.8; P = .20). Esophagitis was the most common mediastinal toxicity reported with 15% of all non-SABR patients versus 1% of all SABR patients reporting developing Grade ≥2 toxicity. The proportion of patient surviving at 2 and 3 years was superior for SABR patients (P < .001). Treatment-related deaths were rare (approximately 1% for both treatments). Both radiotherapy approaches had low rates of pneumonitis, mediastinal toxicity, and treatment-related deaths. However, significant heterogeneity in the patient population and study regimens limit the power of direct comparison, showing that further high-quality studies are required to define the role of SABR in higher risk and operable patients.     

Single-Fraction Stereotactic Ablative Body Radiotherapy to the Lung – The Knockout Punch

This overview summarises the current evidence on efficacy and safety of single-fraction stereotactic ablative body radiotherapy (SABR) for primary lung cancers and lung metastases, in comparison with the more widely adapted multi-fraction SABR regimens. A literature search using the Medline database through PubMed was carried out using the following key words: (‘stereotactic’ or ‘sabr’ or ‘sbrt’), (‘radiotherapy’ or ‘radiation therapy’), (‘lung’ or ‘thorax’ or ‘thoracic’ or ‘chest’), (‘cancer’ or ‘metasta-’ or ‘oligometasta-’), alongside: (i) (‘single-fraction’ or ‘single-dose’) to identify trials and cohort studies with single-fraction SABR to lung malignant tumours and (ii) (‘fraction’ or ‘schedule’) limiting the search to ‘clinical trial’ and ‘randomized controlled trial’ to ensure thorough capture of lung SABR trials comparing different fractionations. The review discusses the radiobiological, technical and organ at risk considerations of single-fraction SABR to the lung.     

Stereotactic Ablative Radiotherapy in the Treatment of Early-Stage Lung Cancer – A Done Deal?

Stereotactic ablative radiotherapy (SABR) is an important curative-intent treatment option for early-stage non-small cell lung cancer. It offers good cancer control without invasive surgery and has become the standard of care for medically inoperable patients. The literature on SABR for early-stage non-small cell lung cancer is substantial and continues to grow. However, there remain areas of controversy where data are limited – notably the use of SABR in medically operable patients. Other areas of some debate include the treatment of central/ultra-central and large (>5 cm) lesions, as well as treatment with co-existing interstitial lung disease. This review article provides an overview of the current literature together with a discussion of future directions.     

Impact of Corticosteroid Administration on Outcomes Following Stereotactic Ablative Radiotherapy for Non–small-cell Lung Cancer

IntroductionRadiotherapy produces immune-promoting effects, which may be blunted by the delivery of corticosteroids (CS). We thus aimed to evaluate the impact of CS use on recurrence and survival outcomes of patients with early stage non–small-cell lung cancer treated with stereotactic ablative radiotherapy (SABR).Materials and MethodsA prospectively registered database of patients with stage I to II (T1-3N0M0) stage non–small-cell lung cancer treated with SABR from 2004 to 2015 was queried. Concurrent CS administration was defined as receipt of CS within 2 days of the SABR course. Statistics included Kaplan-Meier survival analysis, Cox proportional hazards modeling, and cumulative incidence analysis utilizing death as a competing risk.ResultsOf 912 patients, 87 (9.5%) received CS with their SABR course. The most common agent was prednisone (64.4%). Indications for CS use were chronic obstructive pulmonary disease in 53 cases (60.9%), chemotherapy in 7 (8.0%), arthritis in 7 (8.0%), chronic pain in 4 (4.6%), transplant-related in 3 (3.4%), and “others” in 13 (14.9%; pneumonia, asthma, anemia, etc.). The median follow-up time was 59.3 months. Compared with patients who did not receive CS, receipt of CS was associated with poorer overall survival (P = .004). However, CS administration was not associated with worse time to progression (P = .766) or any recurrence when using death as a competing risk (local P = .119, regional P = .449, distant P = .847, and any recurrence P = .708). Toxicity rates were not statistically different between cohorts.ConclusionsThese data do not suggest increased recurrence rates when patients undergoing SABR are administered corticosteroids. However, owing to limitations of retrospective analyses, individualized judgment is still recommended.     

Oncotype DX for Colon Cancer: Are We Ready for Prime Time in Personalized Medicine?

Significant advances have been made in the treatment of patients with early-stage colon cancer during the last several decades. However, a substantial number of patients with early-stage disease will not be cured by surgery alone. Although adjuvant chemotherapy has been well accepted for the treatment of stage III disease, the precise role of adjuvant chemotherapy in stage II disease remains a subject of debate. Although patients with high-risk stage II disease derive significant benefit from adjuvant chemotherapy, it remains unclear whether patients with average or low-risk stage II disease should receive adjuvant therapy. Significant efforts have been made to develop molecular biomarkers to further define the subset of stage II disease patients who would derive a substantial benefit from adjuvant chemotherapy. Herein, we review the current status of molecular biomarker research in the treatment of colorectal cancer with respect to the specific role of the Oncotype DX gene expression profiling method in patients with stage II disease.     

Feasible Optimization of Stereotactic Ablative Radiotherapy Dose by Tumor Size for Stage I Non–small-cell Lung Cancer

Introduction

The purpose of this study was to assess the effect of dose escalation of stereotactic ablative radiotherapy (SABR) by investigating the long-term clinical outcomes of SABR for stage I non–small-cell lung cancer (NSCLC).

Imaging Features Associated With Disease Progression After Stereotactic Ablative Radiotherapy for Stage I Non–Small-Cell Lung Cancer

Introduction/BackgroundThe aim of this study was to identify imaging-based predictors of progression in patients treated with SABR for stage I NSCLC.Patients and MethodsBetween March 2003 and December 2012, 117 patients with stage I NSCLC meeting our study criteria were treated with SABR at Stanford University. Median follow-up was 17 months (range, 3-74 months) for all patients and 19 months for living patients (range, 3-74 months). Tumors were classified according to whether or not they contacted the pleura adjacent to the chest wall or mediastinum (MP), according to their maximum dimension based on computed tomography scans, and, for 102 patients who had archived pretreatment fluorine-18 fluorodeoxyglucose positron-emission tomography scans, according to SUVmax.ResultsTen patients (9%) developed local progression, 17 (15%) developed regional progression, and 19 (16%) developed distant metastasis. Two-year freedom from local progression, freedom from regional progression, and freedom from distant metastasis (FFDM) were 88%, 83%, and 83%, respectively. Overall survival was 70% at 2 years. FFDM was significantly associated with MP contact, maximum tumor dimension, and SUVmax, and these variables could be combined into an exploratory prognostic index that identified patients at highest risk for developing metastases.ConclusionIn our cohort, noninvasive, imaging-based features were associated with distant progression after SABR for early stage NSCLC. If validated, our prognostic index could allow identification of patients who might benefit from systemic therapy after SABR.     

An Impending Cancer Crisis in Developing Countries: Are We Ready for the Challenge?

Cancers affect all communities worldwide. There are, however, marked differences in the prevalence andtypes of cancers among communities. While the total cancer burden remains the highest in affluent societies,less developed economies are closing the gap very rapidly. As developing countries succeed in achieving lifestylessimilar to those in advanced economies, they will also encounter much higher cancer rates, particularly cancersof the breast, colon, prostate and uterus. The increased prevalence and incidence of cancers in developingcountries reflects a wider transition in the global burden of diseases from infectious to a greater frequency ofnon-communicable, chronic illnesses.