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Can metabolic activity predict response in early-stage lung cancer treated with stereotactic body radiation therapy?
Zachary D Horne*1 David A Clump1
Dwight E Heron1
“In light of recent evidence from multiple institutions, the maximum standardized uptake value has the potential to play a role in the risk stratification of early-stage non-small-cell lung cancer.” Lung cancer has been and continues to be a devastating disease, with projections for 2013 estimating 228,190 new cases, while 159,480 individuals will succumb to their disease [101]. Although intensive molecular studies have identified novel target therapies, such as that for ALK-mutated metastatic disease, there is relatively little new information for patients diagnosed with early-stage disease. This is especially important with the increased utilization of screening protocols to detect early-stage disease and the now relatively widespread implementation of stereotactic body radiation therapy (SBRT) for patients who are medically inoperable or elect for this promising treatment over that of more invasive therapies. With fluorodeoxyglucose-PET scanning being a part of the standard staging protocols [1], there is additional information on the metabolic activity of tumors, which, beyond diagnostic and planning purposes, is largely ignored. The question that has been asked is: can this information be used to identify a high-risk
cohort that may potentially benefit from more aggressive initial therapy? This question can in part be answered by extrapolating from the surgical literature, as both modalities are often used to treat early-stage disease. In a 2010 metaanalysis sanctioned by the International Association for the Study of Lung Cancer (IASLC), the maximum standardized uptake value (SUVmax) was found to be a useful marker for predicting overall survival in definitive surgical lung cancer patients [2]. Patients who receive SBRT as therapy, however, often lack a histological diagnosis and are treated based on interval changes in radiographic and PET findings, leaving the multidisciplinary team with relatively little information about the patient’s disease compared with those with pathological findings. Because it is expected that the patients have a similar disease process, a projection from the surgical literature would indicate that SUVmax may be a useful marker for patients treated with SBRT.
“…the maximum standardized uptake value may be a useful marker for patients treated with stereotactic body radiation therapy.”
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA *Author for correspondence:
[email protected] 1
10.2217/LMT.13.17 © 2013 Future Medicine Ltd
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Editorial Horne, Clump & Heron Unfortunately, the literature to date has been conflicting. The initial analysis on the utility of pretreatment SUVmax as a prognostic factor came from the University of Indiana (IN, USA) in 2006. The study, which analyzed 32 patients, found that while there was no predictive value for survival, SUVmax greater than the median value of 6.35 neared significance for local failure [3]. This was followed by a study from the Cleveland Clinic (OH, USA) in 2009 with congruent results [4]. Again, SUVmax failed to predict outcomes. In both of these studies, however, patients were treated with heterogeneous dosing regimens. In the University of Indiana study, 8% of patients received 50 Gy in ten fractions, and in the Cleveland Clinic study, 21% of patients received less than 48 Gy in four fractions [3,4]. Additionally, the numbers of events in each study were low enough to prevent significant results from emerging, relative to the number of patients analyzed.
“In our study, a unit increase in the maximum standardized uptake value conferred an 11% increased risk of relapse on multivariate analysis.” Two studies from Japan were the first to make a determination of outcome disparities for earlystage patients treated with SBRT, stratified by low and high pretreatment tumor metabolic activity. The first study stratified 26 patients by a SUVmax of 5.0 and found it to be the only significant predictor of local control, which differed by 53% between the two groups at 15 months’ follow-up [5]. In this study, tumor size was controlled for, with highly metabolic large tumors (>3 cm) having a 15‑month local control rate of 50%, compared with the smaller tumors with increased metabolic activity having a 0% 15‑month local control rate [5]. The second, larger study of 95 patients utilized a pretreatment cutoff SUVmax value of 6.0 and demonstrated decreased local control rates at 2 years of 93 versus 42% between the two cohorts [6]. On multivariate analysis, SUVmax was the strongest predictor of local control [6]. This study again controlled for tumor size, and found that within each T-stage, local control rates were better for tumors with lower SUVmax [6]. Treatment dose was also controlled for, as patients received either 40 or 50 Gy, with less metabolically active tumors achieving higher control rates, regardless of treatment dose [6].
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The findings from these two studies were further supported by a recent study from Princess Margaret Hospital (ON, Canada), which found pretreatment SUVmax to be the most significant prognostic factor for predicting distant failures in patients with early-stage disease who received SBRT. This study utilized a cutoff SUVmax value of 4.75, but also analyzed SUVmax as a continuous variable [7]. With the longest median follow-up of 2 years for all analyses of the relationship between tumor metabolism and patient outcomes, the study found pretreatment tumor metabolism to be correlated with poorer local, distant and overall tumor control [7]. On multivariate analysis, pretreatment SUVmax was a strong predictor of relapse, with each unit increase conferring an increased risk of 9% [7]. Additionally, this was the first study to show that increased tumor metabolic activity may confer a decreased survival advantage [7]. Data from our institution, presented at this year’s Cancer Imaging and Radiotherapy Symposium in Orlando (FL, USA), further support the prognostic value of pretreatment SUVmax in patients with early-stage non-small-cell lung cancer who are treated with SBRT. This study included 95 patients with biopsy-confirmed stage I disease treated with a homogenous dosing regimen of 60 Gy delivered in three fractions on nonconsecutive days [8]. SUVmax proved to be a powerful predictor of recurrence both as a dichotomous (5.0 cutoff ) and, more importantly, a continuous variable in multivariate analysis, which has been previously suggested [7,9]. In our study, a unit increase in SUVmax conferred an 11% increased risk of relapse on multivariate analysis. Similar to the Princess Margaret Hospital study, low pretreatment SUVmax was shown to confer a survival advantage as both a dichotomous and a continuous variable [7]. Additionally, the SUVmax stratification groups were found to be significantly associated with tumor histology, with more metabolically active tumors more often being of squamous cell histology and adenocarcinomatous tumors being less metabolically active. This may indicate that fluorodeoxyglucosePET findings may be a surrogate for histology and associated risks in the absence of pathological confirmation, which has been suggested previously by Vesselle et al. [10]. In light of recent evidence from multiple institutions, SUVmax has the potential to play a role in the risk stratification of early-stage
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Can metabolic activity predict response in early-stage lung cancer treated with SBRT? non-small-cell lung cancer. With relatively little literature on the subject, the next step in evaluating its place in the radiation oncologist’s armamentarium is to conduct a multiinstitutional pooled study to achieve greater study power, in patients both with and without biopsy-confirmed disease, in order to determine the most appropriate pretreatment SUVmax cutoff value, as well as to strengthen the association between histology and metabolic activity. Subsequently, randomized trials to evaluate the impact of adjuvant chemotherapy and/or dose escalation for patients deemed to be high risk
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Vansteenkiste JF, Stroobants SS. PET scan in lung cancer: current recommendations and innovation. J. Thorac. Oncol. 1, 71–73 (2006). Paesmans M, Berghmans T, Dusart M et al.; on behalf of the ILCSP. Primary tumor standardized uptake value measured on fluorodeoxyglucose positron emission tomography is of prognostic value for survival in non-small cell lung cancer: update of a systematic review and meta-analysis by the European Lung Cancer Working Party for the International Association for the Study of Lung Cancer Staging Project. J. Thorac. Oncol. 5, 612–619 (2010). Hoopes DJ, Tann M, Fletcher JW et al. FDG‑PET and stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer. Lung Cancer 56, 229–234 (2007). Burdick MJ, Stephans KL, Reddy CA, Djemil T, Srinivas SM, Videtic GM. Maximum standardized uptake value from staging FDG‑PET/CT does not predict treatment
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based on tumor metabolic function may be conducted. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. outcome for early-stage non-small-cell lung cancer treated with stereotactic body radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 78, 1033–1039 (2010).
References
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Hamamoto Y, Sugawara Y, Inoue T et al. Relationship between pretreatment FDG uptake and local control after stereotactic body radiotherapy in stage I non-small-cell lung cancer: the preliminary results. Jpn J. Clin. Oncol. 41, 543–547 (2011).
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Takeda A, Yokosuka N, Ohashi T et al. The maximum standardized uptake value (SUVmax) on FDG-PET is a strong predictor of local recurrence for localized non-small-cell lung cancer after stereotactic body radiotherapy (SBRT). Radiother. Oncol. 101, 291–297 (2011).
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Clarke K, Taremi M, Dahele M et al. Stereotactic body radiotherapy (SBRT) for non-small cell lung cancer (NSCLC): is FDG-PET a predictor of outcome? Radiother. Oncol. 104, 62–66 (2012). Horne ZD. Pretreatment SUVmax as a marker for progression-free survival in stage 1
NSCLC treated with SBRT. Presented at: 2013 Cancer Imaging and Radiation Therapy Symposium. Orlando, FL, USA, 8–9 February 2013. 9
Coon D, Gokhale AS, Burton SA, Heron DE, Ozhasoglu C, Christie N. Fractionated stereotactic body radiation therapy in the treatment of primary, recurrent, and metastatic lung tumors: the role of positron emission tomography/computed tomographybased treatment planning. Clin. Lung Cancer 9, 217–221 (2008).
10 Vesselle H, Salskov A, Turcotte E et al.
Relationship between non-small cell lung cancer FDG uptake at PET, tumor histology, and Ki-67 proliferation index. J. Thorac. Oncol. 3, 971–978 (2008). Website 101 ACS. What are the key statistics about lung
cancer? (2013). www.cancer.org/cancer/lungcancer-nonsmallcell/detailedguide/non-small-cell-lungcancer-key-statistics
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