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Stereotactic body radiation therapy for melanoma and renal cell carcinoma: impact of single fraction equivalent dose on local control

Stereotactic body radiation therapy for melanoma and renal cell carcinoma: impact of single... Background: Melanoma and renal cell carcinoma (RCC) are traditionally considered less radioresponsive than other histologies. Whereas stereotactic body radiation therapy (SBRT) involves radiation dose intensification via escalation, we hypothesize SBRT might result in similar high local control rates as previously published on metastases of varying histologies. Methods: The records of patients with metastatic melanoma (n = 17 patients, 28 lesions) or RCC (n = 13 patients, 25 lesions) treated with SBRT were reviewed. Local control (LC) was defined pathologically by negative biopsy or radiographically by lack of tumor enlargement on CT or stable/declining standardized uptake value (SUV) on PET scan. The SBRT dose regimen was converted to the single fraction equivalent dose (SFED) to characterize the dose- control relationship using a logistic tumor control probability (TCP) model. Additionally, the kinetics of decline in maximum SUV (SUV ) were analyzed. max Results: The SBRT regimen was 40-50 Gy/5 fractions (n = 23) or 42-60 Gy/3 fractions (n = 30) delivered to lung (n = 39), liver (n = 11) and bone (n = 3) metastases. Median follow-up for patients alive at the time of analysis was 28.0 months (range, 4-68). The actuarial LC was 88% at 18 months. On univariate analysis, higher dose per fraction (p < 0.01) and higher SFED (p = 0.06) were correlated with better LC, as was the biologic effective dose (BED, p < 0.05). The actuarial rate of LC at 24 months was 100% for SFED ≥45 Gy v 54% for SFED <45 Gy. TCP modeling indicated that to achieve ≥90% 2 yr LC in a 3 fraction regimen, a prescription dose of at least 48 Gy is required. In 9 patients followed with PET scans, the mean pre-SBRT SUV was 7.9 and declined with an estimated half-life of max 3.8 months to a post-treatment plateau of approximately 3. Conclusions: An aggressive SBRT regimen with SFED ≥ 45 Gy is effective for controlling metastatic melanoma and RCC. The SFED metric appeared to be as robust as the BED in characterizing dose-response, though additional studies are needed. The LC rates achieved are comparable to those obtained with SBRT for other histologies, suggesting a dominant mechanism of in vivo tumor ablation that overrides intrinsic differences in cellular radiosensitivity between histologic subtypes. Background (RT) must be employed to achieve the same level of For at least three decades, renal cell carcinoma (RCC) clinical response produced with lower dose for most and melanoma have been considered to be relatively other histologies [1]. For the case of melanoma, labora- “radioresistant” tumors. In the case of RCC, this opinion tory studies in the early 1970s suggested that higher was initially based on observations that substantially radiation doses per fraction would be needed to achieve higher doses of conventionally fractionated radiotherapy effective cell kill [2]. Subsequently, clinical investigations of hypofractionated RT were initiated to evaluate this approach to enhance radiation cytotoxicity [3]. * Correspondence: David.Raben@ucdenver.edu University of Colorado Denver, School of Medicine, Aurora, Colorado, USA Full list of author information is available at the end of the article © 2011 Stinauer et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Stinauer et al. Radiation Oncology 2011, 6:34 Page 2 of 8 http://www.ro-journal.com/content/6/1/34 Clinical outcomes reported in the 1980s tended to Methods support the prevailing pessimistic viewpoints about RCC We retrospectively reviewed all patients with melanoma and melanoma response to RT. A dose-response rela- and RCC treated with SBRT to metastatic sites from tionship for palliative effect was observed by Onufrey October 2004 to November 2009 at the University of and Mohiuddin among 125 patients treated for meta- Colorado. This study was approved by the University of static RCC [4], though their results were somewhat at Colorado Institutional Review Board. All patient charts variance with those of Halperin and Harisidias [5]. Mul- were reviewed for clinical information including treat- tiple melanoma randomized studies were performed ments with systemic therapies. Patients were excluded both in Europe and in the United States to explore ways for review if they did not have any follow-up imaging to refine the use of RT in that setting: a Danish study after SBRT. Patients were considered to have oligometa- found equivalence between 27 Gy in 3 fractions and 40 static disease if they had three or fewer sites of metas- Gy in 5 fractions, and an RTOG study likewise found tases in which all sites were treated with aggressive local equivalence between 50 Gy in 20 fractions and 32 Gy in therapy with possible systemic therapy. Otherwise, 4 fractions in terms of response rate [6,7]. patients were classified as having extensive metastatic More recently, high single doses of radiation delivered disease. Patients with extensive disease had relatively during stereotactic radiosurgery (SRS) to brain and stable systemic disease with either painful lesions or spinal metastases have been studied in both melanoma growing lesions which were treated with SBRT. and RCC, with encouraging outcomes [8-13]. Pre-clini- SBRT was defined as a minimum total dose of 40 Gy cal evidence has likewise indicated that a multi-session, given in 5 or fewer fractions using stereotactic technique high dose per fraction regimen of the type commonly previously described [20]. Briefly, for treatment plan- used for stereotactic body radiation therapy (SBRT) is ning, the gross tumor volume (GTV) was considered effective in the treatment of RCC [14], an observation equal to the clinical target volume (CTV). The planning further supported by clinical observations [15,16]. To target volume (PTV) was typically constructed by adding our knowledge identical pre-clinical studies have not 5 mm radially and 5-10 mm in the superior-inferior been reported for melanoma. direction. The dose was prescribed to cover at least 95% The increasingly popular use of high dose per frac- of the PTV, normalized to the isodose line representing tion, SBRT-type regimens for not only melanoma and 60-80% of the maximum dose inside the PTV. The RCC but also for a variety of other lesions [17,18] has majority of plans were generated using multiple dynamic prompted a re-analysis of the traditional linear-quadra- conformal arcs with at least 1 non-coplanar arc or a tic (LQ) model-based formalism for predicting the combination of multiple static beams. Localization was radiation dose-response relationship for SBRT, since performed with KV orthogonal imaging fused to plan- there is reason to consider that the LQ model overesti- ning CT with the isocenter re-marked after shifts. mates radiation-induced cytotoxicity at high dose per Patients then underwent CT simulation for verification fraction [19]. To begin to understand the potential that the newly marked isocenter was within the GTV. In benefits of SBRT for these histologies, we undertook a recent years, after the acquisition of 4D CT simulation review of our institutional experience at the University technology, when significant breathing-related motion of Colorado involving the use of SBRT for RCC and was present, the PTV was constructed by enlarging the melanoma. internal target volume (ITV) defined on a 4D imaging The first objective was to analyze whether the local set by 5 mm in all directions. Patients underwent control rates reported for high dose per fraction cra- abdominal compression to limit respiratory motion. nial and spinal SRS for RCC and melanoma can be Toxicity was scored according to the Common Termi- replicated in other sites. Second, we attempted to nology Criteria for Adverse Events v3.0. The use of model the SBRT dose-response relationship. In this RECIST (Response Evaluation Criteria in Solid Tumors) context, we used both a traditional linear-quadratic criteria after SBRT is difficult in view of the expected par- model-based metric, the biological equivalent dose enchymal changes commonly seen in surrounding normal (BED), and a novel index proposed for modeling high tissue within the volume that receives approximately 20 dose per fraction RT, the single fraction equivalent Gy or higher. For this reason, we did not characterize dose (SFED)[19]. Finally, we reviewed the clinical lesions as having had a complete response or partial observations typically seen in terms of metabolic ima- response by RECIST criteria. Instead, local failure was ging following SBRT for RCC and melanoma and the scored when one of the following conditions were met: (1) overall survival of this population of patients, with the tumor viability as seen by an increase in SUV on follow- intent of offering guidance for proper patient up PET scan relative to the most recent prior PET; (2) selection. expansion of a solid mass with discrete borders within the Stinauer et al. Radiation Oncology 2011, 6:34 Page 3 of 8 http://www.ro-journal.com/content/6/1/34 treated PTV by 20% in longest dimension relative to the melanoma patients had 28 lesions, and 13 RCC patients most recent prior CT or MRI; or (3) tumor viability as evi- had 25 lesions available for review. Two patients with denced pathologically by biopsy. In questionable cases, the RCC did not have follow-up imaging and were not follow-up CT was fused with the planning CT to define included, one melanoma patient had an additional lesion in-field LC. If a patient with suspicious failure was subse- that was treated but did not have any follow-up imaging quently treated for that lesion with chemotherapy, the and this lesion was excluded from our analysis. Patient lesion was considered a failure. Overall survival (OS) was ages ranged from 36 to 83, with median age of 59. recorded from the date of treatment completion to last There were 17 males and 13 females treated with SBRT. follow-up or date of death. Seventeen patients had oligometastatic disease at time of The SBRT dose regimen used was then converted to treatment with all sites treated with SBRT, and 13 single fraction equivalent dose (SFED) using the follow- patients had extensive disease in which only selected ing equation: lesions were treated with SBRT. The median number of lesions treated per patient was 2 (range, 1-3). Among SFED = D − (n − 1) × D the tumor sited treated, lung was most common (n = 39), followed by liver (n = 11) and bone (n = 3). with D estimated at 1.8 from the Park analysis [19]. The SBRT regimens were 40-50 Gy delivered in 5 Local control curves were generated using Kaplan-Meier fractions (n = 23) or 42-60 Gy delivered in 3 fractions method. Comparisons between curves were performed (n = 30). The regimen applied was selected at the dis- using the log rank method. Candidate predictors for cretion of the treating physician in view of clinical local control (total dose, GTV, histology etc) were also objectives and normal tissue dose considerations for evaluated by log rank analysis. Univariate analysis was each lesion without regard to the histology. The aim performed with the median value using log rank com- was to safely deliver the highest dose possible while parisons (GraphPad Prism , GraphPad Software, Inc., La respecting the surrounding normal tissue tolerance. The Jolla California). most common regimen was 60 Gy in 3 fractions (n = The dose-response relationship was modeled using a 20) followed by 45 Gy in 5 fractions (n = 11) and 50 Gy logistic tumor control probability (TCP) formula [21]: in 5 fractions (n = 8). Median gross tumor volume (GTV) was 6.3cc (range, 1-275). Median follow-up for TCP = (1+ (TCD /D) ) 50 patients alive at the time of analysis was 28.0 months (range,4-68).See table1for treatment characteristics WhereDisthetotal dose,TCD is thedosethat including SFED and BED values for each regimen. achieves 50% tumor control, and k describes the slope of the curve. Doses to individual lesions were grouped into Tolerance and other therapies tertile bins, and the x-axis value was the mean dose given There were no acute side effects, only mild late toxici- in that bin, expressed as either BED or SFED, while the ties which were not dose dependent. Six patients experi- y-axis value was the probability of LC at twelve months. enced grade 1 toxicity (3 pain, 2 cough and 1 dyspnea). In patients undergoing surveillance with PET scans There was one incident of grade 3 toxicity of hypoxia at who had long term local control, we looked at the pattern 11 months after treatment in an asthmatic patient who of the maximal standardized uptake value (SUV) change. developed multiple pulmonary metastases requiring Only patients with a pre-treatment and at least one post- increased continuous oxygen use. One patient developed treatment PET scan were included for analysis. The PET grade 3 radiation pneumonitis successfully managed scans were performed intermittently for tumor surveil- with steroids. lance and regularly in patients undergoing chemotherapy for other sites of disease. The lesions were contoured Table 1 Treatment Characteristics using dedicated medical image analysis software (MIM- vista , MIM Software, Inc., Cleveland, Ohio). This was Fractionation Schedule # of pts SFED (Gy) BED (Gy) then fused to their follow up PET scans and the maxi- 60 Gy in 3 fractions 20 56.4 180 mum SUV (SUV ) was calculated for each lesion on max 54 Gy in 3 3 50.4 151.2 each PET scan performed. Nine patients with 12 lesions 50 Gy in 5 8 42.8 100 had a total of 43 PET scans prior to and after SBRT. 45 Gy in 3 5 41.4 112.5 42 Gy in 3 2 38.4 100.8 Results 45 Gy in 5 11 37.8 85.5 Patient population 40 Gy in 5 4 32.8 72 Thirty patients with 53 treated lesions met the study Fractionation schedules and conversion to single fraction equivalent dose inclusion criteria and were analyzed. Overall, 17 (SFED) and biological equivalent dose (BED). Stinauer et al. Radiation Oncology 2011, 6:34 Page 4 of 8 http://www.ro-journal.com/content/6/1/34 Seven patients were treated with sorafenib, 5 before We generated TCP graphs using both SFED and BED SBRT and 2 after SBRT as well as 7 patients treated (Figure 2). Both SFED and BED had a strong coefficient with sunitinib. One patient underwent SBRT while suni- of determination to predict future outcomes (SFED R = tinib was held for 2 weeks before and after treatment, 3 0.999 and BED R = 0.996). Using the SFED TCP graph, patients were treated with sunitinib before SBRT and 3 a 90% chance of tumor control was calculated to an patients were treated after SBRT. There was no signifi- SFED of 44.3 Gy which translates into approximately 48 cant increase in toxicity seen in these 14 patients (two Gy in 3 fractions. Using BED, 90% chance of tumor con- grade 1 events and one late grade 3 pneumonitis). One trol was calculated at 126 Gy, which corresponds to approximately 49 Gy in 3 fraction regimen. patient with melanoma received CTLA4 antibody after radiation and did not experience any adverse side effects Median overallsurvivalforallpatientsinthisstudy from SBRT. Overall patients were pre-treated with a was 24.3 months. The median overall survival of variety of systemic therapies. The median number of patients with oligometastatic disease was not reached courses was 1 with range 0-3. Additionally, patients while patients with extensive metastatic disease had a went on to further systemic therapy with a median of median overall survival of only 12.3 months (p = 0.03) one course (range 0-5). (Figure 3). Median overall survival was not reached in patients with RCC, and was statistically longer than mel- Local control and overall survival anoma patients with median overall survival of 22.2 The actuarial rate of LC for all patients was 88% at 18 months (p = 0.015). months (Figure 1). Several factors were analyzed by uni- variate analysis in an effort to identify predictors of LC. In Metabolic imaging and kinetics of PET scan changes general, for quantitative parameters, the median value was The SUV was plotted and fitted with an exponential max chosen as an arbitrary cut-off for univariate analysis to equation. The median pre-treatment SUV was 7.9 max maximize the comparison cohorts. Log rank comparison (range 1.5 - 14.6). The calculated time for the SUV max revealed number of fractions (3 vs 5, p < 0.01) as well as valuetodecreasebyhalftheoriginal valuewas 3.8 dose per fraction (> 11 Gy/fraction vs <11 Gy/fractions, p months (Figure 4). We found that the calculated post- < 0.01) and BED ( > 100 Gy vs < 100 Gy, p < 0.01) to be treatment baseline SUV was 2.6, which was reached max significant predictors of LC. Histology (RCC vs melanoma, at approximately 7 months. The median post-treatment p = 0.06) total dose (≥50Gy vs <50Gy, p = 0.09) SFED (≥ SUV was 2.5 (range 1.8 - 3.2). max 45 Gy vs < 45 Gy, p = 0.06) and GTV (>7cc vs <7cc, p = 0.06) showed a strong trend towards significance. Site trea- Discussion ted (lung vs other) and disease burden (oligometastatic vs We have observed in a cohort of patients treated with widely metastatic) were not predictors of local control. SBRT for metastatic melanoma or RCC, a high rate of Given the small number of events available to analyze, a durable LC can be achieved, especially for patients with multivariate analysis was not performed. a 3 fraction SBRT total prescription dose on the order of 48-49 Gy or higher. It should be appreciated that this dose estimate represents the dose covering the periphery of the PTV and that substantial dose hotspots are always created in the GTV. Thus, the actual dose need to ablate the gross disease itself is higher than this estimate. Thedatawereevaluated intermsofSFEDand BED because these indices incorporate both the total dose deliveredaswellasthe dose perfraction. SFED was designed to analyze the effect of high dose per fraction exposure by using an equation for cell survival which, when plotted a logarithmic scale, initially curves down- ward with increasing dose in a similar way as an LQ- based curve but then straightens at higher doses, cor- recting for an overestimation of cell kill by BED in the SBRT/ablativedoserange[22].Thereareatleast two reasons why the BED might not characterize high dose effects as well as a model such as the SFED. First of all, Figure 1 Local Control. Actuarial local control for both melanoma there is the phenomenon recognized long ago whereby and RCC lesions for lengthy individual exposures of living cells to Stinauer et al. Radiation Oncology 2011, 6:34 Page 5 of 8 http://www.ro-journal.com/content/6/1/34 Figure 2 Tumor Control Probability. Tumor Control Probability graphs generated from dose response relationship modeling. Doses to individual lesions were grouped into tertile bins and the x-axis value was the mean dose given in that bin, expressed as either (a) SFED or (b) BED. The y-axis value was the probability of LC at 12 months. radiation, intra-exposure repair can occur, obliging a through oxygen dependent DNA damage with resulting correction to the simple LQ model that adjusts for this loss of clonogenicity, an effect seen in vitro and pre- process. This notion was advanced at least as long ago sumed to occur in vivo. However, pre-clinical studies as the 1940s, when Lea and Catcheside modeled radia- have suggested that the high doses of radiation delivered tion-induced chromosomal aberrations in a plant model in each session of SBRT might trigger an entirely differ- using a linear-quadratic formula that also could be mod- ent method of cell kill in vivo via an anti-angiogenic ified with a factor that accounted for the total time of pathway involving endothelial cell apoptosis [24]. Coin- exposure [23]. cidentally, apropos of the present clinical series, the pre- A second, more modern explanation of why BED clinical studies initially suggesting this mechanism might not precisely model high dose effects relates to a included studies of melanoma xenografts. Furthermore, mechanism of tumor cell kill at work in vivo that is not endothelial cell apoptosis appeared to be induced above active in vitro. With conventionally fractionated doses, a threshold dose of 11 Gy, and the present study simi- radiation cell kill is assumed to be largely mediated larly suggested significant improvement in tumor cell Stinauer et al. Radiation Oncology 2011, 6:34 Page 6 of 8 http://www.ro-journal.com/content/6/1/34 primary lung cancer. The SFED model would predict better LC with the 48 Gy arm, while BED modeling pre- dicts the single 34 Gy treatment to have superior LC. The present clinical observations of high LC after aggressive radiation treatment are consistent with what has been observed after single high dose SRS to brain and spinal metastases for both melanoma and RCC [8-10,26]. In these studies the LC for melanoma is typi- cally lower than for RCC [10,26], for which brain SRS can achieve very high LC [11]. Likewise, in the present study we observed a trend for lower 1 year LC for mela- noma than RCC (82% v. 95%), possibly intrinsic differ- Figure 3 Overall survival. Actuarial overall survival of patients based on disease state. Oligometastatic disease was defined as ences in radiosensitivity that are retained even in the three or less metastases in which all site of disease were treated high dose-per-fraction setting. In a study of SBRT in with aggressive local therapy. Extensive disease was defined as primary and metastatic RCC, the local control rate was patients with more than three sites of metastases. 90-98% [16] which is in line with our own and other institutional local control rates across a broad range of kill with a fraction size above that level. Of course, mel- histologic subtypes [16-18,27,28]. anoma and RCC have also been shown to have a large The oligometastatic hypothesis suggests that tumors initial shoulder on the cell survival curve [25], and the early in systemic disease progression may present with a present study’s favorable results might also be at least limited number of discrete lesions without extensive partly explained by the fact that doses in the SBRT occult spread of disease, thus a condition amenable to range exceed that of the initial shoulder region. Both potentially curative intervention if the identifiable BED and SFED proved to be a reliable predictor for LC. lesions can be eradicated [29]. Studies of liver metaste- Further studies will be needed to resolve whether one is ctomy in patients with RCC reveal that there are long truly superior to the other, and it will be informative to term survivors and chance for cure with a 5 year OS see the results of RTOG 0915 in which a single 34 Gy rate of 39% [30]. The argument for using ablative local fraction is compared to 48 Gy in 4 fraction regimen for therapy for isolated metastases is strengthened if effec- tive systemic therapy is available to complement it [31]. And in recent years, for both melanoma and RCC there have been new systemic agents developed that provide clinical benefit, including the anti-CTLA-4 antibody, ipi- limumab, and multi-targeted agents such as sunitinib and sorafenib. Properly selected patients with metastatic RCC undergoing lung resection have a chance for long term survivorship [32], as do patients with liver metastases from RCC, where a 5 year OS of approximately 40% has been reported for a group of well selected patients [30]. Patients with liver metastases from RCC tend to fare better than patients with liver metastases from melanoma [33], once again suggesting basic differences in the typical degree of aggressiveness between these cancer types. In the present series, melanoma patients likewise had shorter median survival than RCC patients. In this series the arbitrary cutoff point applied to char- acterize patients as having oligometastatic vs. extensive metastatic disease was the presence of 3 or fewer indivi- Figure 4 Change in SUV for controlled lesions. The Standardized dual sites of disease. The superior outcome of patients uptake values were plotted with pre-treatment PET used for planning as time 0. Follow-up PET/CT’s were fused and SUV was defined as oligometastatic by this definition was generated for each treated lesion that was controlled. An expected, and this or a similar cutoff level of sites of dis- exponential equation was generated revealing a post-treatment ease would appear to be appropriate as a stratification baseline level of activity of 2.6 at 7 months. variable for future studies of SBRT in the treatment of Stinauer et al. Radiation Oncology 2011, 6:34 Page 7 of 8 http://www.ro-journal.com/content/6/1/34 metastatic disease. However, the difference in outcome Conclusions between the cohorts defined in this manner does not The present study demonstrates that an aggressive rule out the possibility that patients with more extensive SBRT regimen is an effective modality for controlling disease might still benefit from a general reduction in metastatic melanoma and RCC. The LC rates achieved their systemic disease burden, whether achieved by sys- in our series are comparable to those obtained with temic therapy or local therapy. Indeed, for the case of SBRT for other tumor histologies, suggesting a domi- RCC in particular, two independent phase III studies nant mechanism of in vivo tumor ablation after high indicate that a reduction in a patient’s total burden of dose fractions that largely overrides intrinsic differences disease via nephrectomy lengthens OS for patients with in cellular radiosensitivity between histologic subtypes of known metastatic disease, even though not all sites of tumor. SFED TCP modeling indicates that to achieve a disease were locally treated [34]. Thus, as studies are high rate of durable LC in a 3 fraction regimen of designed in the future, it is important to avoid the SBRT, a dose of at least 48 Gy is required. overly narrow assumption that only patients with oligo- metastatic disease can potentially benefit from ablation Author details of metastatic sites of disease via local therapy, though University of Colorado Denver, School of Medicine, Aurora, Colorado, USA. certainly patients with more limited disease will have a Exempla St. Joseph Hospital, Denver, Colorado, USA. better prognosis overall. Authors’ contributions PET scans are now widely available to monitor MAS conceived of the study, carried out data collection, performed a response to cancer therapy in a variety of setting, and literature search, and drafted the manuscript. BK participated in the design, literature research, statistical analysis, and drafting the manuscript. TES we have here reported on the kinetics of change in participated in study design and data retrieval. RG, KL, WR, MG, and MC metabolic activity following SBRT for RCC and mela- contributed to the clinical management of patients and data collection. TF noma. In our cohort of locally controlled patients, the contributed to patient management and in drafting the manuscript. DR participated in the design, clinical patient management, and manuscript decrease to a steady post-treatment baseline SUV max writing. All authors read and approved the final manuscript. took approximately 7 months. The post-treatment baseline level averaged 2.6 and was consistent with Competing interests The authors declare that they have no competing interests. findings of Henderson et al, who showed that almost half of primary non-small cell lung cancer lesions have Received: 5 January 2011 Accepted: 8 April 2011 Published: 8 April 2011 moderately elevated SUV at 12 months without max local failure [35]. 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Thelen A, Jonas S, Benckert C, Lopez-Hanninen E, Rudolph B, Neumann U, Submit your next manuscript to BioMed Central Neuhaus P: Liver resection for metastases from renal cell carcinoma. and take full advantage of: World J Surg 2007, 31:802-807. 31. Yang JC, Abad J, Sherry R: Treatment of oligometastases after successful • Convenient online submission immunotherapy. Semin Radiat Oncol 2006, 16:131-135. 32. Assouad J, Petkova B, Berna P, Dujon A, Foucault C, Riquet M: Renal cell • Thorough peer review carcinoma lung metastases surgery: pathologic findings and prognostic • No space constraints or color figure charges factors. Ann Thorac Surg 2007, 84:1114-1120. • Immediate publication on acceptance 33. Sherry RM, Pass HI, Rosenberg SA, Yang JC: Surgical resection of metastatic renal cell carcinoma and melanoma after response to • Inclusion in PubMed, CAS, Scopus and Google Scholar interleukin-2-based immunotherapy. Cancer 1992, 69:1850-1855. • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Stereotactic body radiation therapy for melanoma and renal cell carcinoma: impact of single fraction equivalent dose on local control

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Springer Journals
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Copyright © 2011 by Stinauer et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
DOI
10.1186/1748-717X-6-34
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21477295
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Abstract

Background: Melanoma and renal cell carcinoma (RCC) are traditionally considered less radioresponsive than other histologies. Whereas stereotactic body radiation therapy (SBRT) involves radiation dose intensification via escalation, we hypothesize SBRT might result in similar high local control rates as previously published on metastases of varying histologies. Methods: The records of patients with metastatic melanoma (n = 17 patients, 28 lesions) or RCC (n = 13 patients, 25 lesions) treated with SBRT were reviewed. Local control (LC) was defined pathologically by negative biopsy or radiographically by lack of tumor enlargement on CT or stable/declining standardized uptake value (SUV) on PET scan. The SBRT dose regimen was converted to the single fraction equivalent dose (SFED) to characterize the dose- control relationship using a logistic tumor control probability (TCP) model. Additionally, the kinetics of decline in maximum SUV (SUV ) were analyzed. max Results: The SBRT regimen was 40-50 Gy/5 fractions (n = 23) or 42-60 Gy/3 fractions (n = 30) delivered to lung (n = 39), liver (n = 11) and bone (n = 3) metastases. Median follow-up for patients alive at the time of analysis was 28.0 months (range, 4-68). The actuarial LC was 88% at 18 months. On univariate analysis, higher dose per fraction (p < 0.01) and higher SFED (p = 0.06) were correlated with better LC, as was the biologic effective dose (BED, p < 0.05). The actuarial rate of LC at 24 months was 100% for SFED ≥45 Gy v 54% for SFED <45 Gy. TCP modeling indicated that to achieve ≥90% 2 yr LC in a 3 fraction regimen, a prescription dose of at least 48 Gy is required. In 9 patients followed with PET scans, the mean pre-SBRT SUV was 7.9 and declined with an estimated half-life of max 3.8 months to a post-treatment plateau of approximately 3. Conclusions: An aggressive SBRT regimen with SFED ≥ 45 Gy is effective for controlling metastatic melanoma and RCC. The SFED metric appeared to be as robust as the BED in characterizing dose-response, though additional studies are needed. The LC rates achieved are comparable to those obtained with SBRT for other histologies, suggesting a dominant mechanism of in vivo tumor ablation that overrides intrinsic differences in cellular radiosensitivity between histologic subtypes. Background (RT) must be employed to achieve the same level of For at least three decades, renal cell carcinoma (RCC) clinical response produced with lower dose for most and melanoma have been considered to be relatively other histologies [1]. For the case of melanoma, labora- “radioresistant” tumors. In the case of RCC, this opinion tory studies in the early 1970s suggested that higher was initially based on observations that substantially radiation doses per fraction would be needed to achieve higher doses of conventionally fractionated radiotherapy effective cell kill [2]. Subsequently, clinical investigations of hypofractionated RT were initiated to evaluate this approach to enhance radiation cytotoxicity [3]. * Correspondence: David.Raben@ucdenver.edu University of Colorado Denver, School of Medicine, Aurora, Colorado, USA Full list of author information is available at the end of the article © 2011 Stinauer et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Stinauer et al. Radiation Oncology 2011, 6:34 Page 2 of 8 http://www.ro-journal.com/content/6/1/34 Clinical outcomes reported in the 1980s tended to Methods support the prevailing pessimistic viewpoints about RCC We retrospectively reviewed all patients with melanoma and melanoma response to RT. A dose-response rela- and RCC treated with SBRT to metastatic sites from tionship for palliative effect was observed by Onufrey October 2004 to November 2009 at the University of and Mohiuddin among 125 patients treated for meta- Colorado. This study was approved by the University of static RCC [4], though their results were somewhat at Colorado Institutional Review Board. All patient charts variance with those of Halperin and Harisidias [5]. Mul- were reviewed for clinical information including treat- tiple melanoma randomized studies were performed ments with systemic therapies. Patients were excluded both in Europe and in the United States to explore ways for review if they did not have any follow-up imaging to refine the use of RT in that setting: a Danish study after SBRT. Patients were considered to have oligometa- found equivalence between 27 Gy in 3 fractions and 40 static disease if they had three or fewer sites of metas- Gy in 5 fractions, and an RTOG study likewise found tases in which all sites were treated with aggressive local equivalence between 50 Gy in 20 fractions and 32 Gy in therapy with possible systemic therapy. Otherwise, 4 fractions in terms of response rate [6,7]. patients were classified as having extensive metastatic More recently, high single doses of radiation delivered disease. Patients with extensive disease had relatively during stereotactic radiosurgery (SRS) to brain and stable systemic disease with either painful lesions or spinal metastases have been studied in both melanoma growing lesions which were treated with SBRT. and RCC, with encouraging outcomes [8-13]. Pre-clini- SBRT was defined as a minimum total dose of 40 Gy cal evidence has likewise indicated that a multi-session, given in 5 or fewer fractions using stereotactic technique high dose per fraction regimen of the type commonly previously described [20]. Briefly, for treatment plan- used for stereotactic body radiation therapy (SBRT) is ning, the gross tumor volume (GTV) was considered effective in the treatment of RCC [14], an observation equal to the clinical target volume (CTV). The planning further supported by clinical observations [15,16]. To target volume (PTV) was typically constructed by adding our knowledge identical pre-clinical studies have not 5 mm radially and 5-10 mm in the superior-inferior been reported for melanoma. direction. The dose was prescribed to cover at least 95% The increasingly popular use of high dose per frac- of the PTV, normalized to the isodose line representing tion, SBRT-type regimens for not only melanoma and 60-80% of the maximum dose inside the PTV. The RCC but also for a variety of other lesions [17,18] has majority of plans were generated using multiple dynamic prompted a re-analysis of the traditional linear-quadra- conformal arcs with at least 1 non-coplanar arc or a tic (LQ) model-based formalism for predicting the combination of multiple static beams. Localization was radiation dose-response relationship for SBRT, since performed with KV orthogonal imaging fused to plan- there is reason to consider that the LQ model overesti- ning CT with the isocenter re-marked after shifts. mates radiation-induced cytotoxicity at high dose per Patients then underwent CT simulation for verification fraction [19]. To begin to understand the potential that the newly marked isocenter was within the GTV. In benefits of SBRT for these histologies, we undertook a recent years, after the acquisition of 4D CT simulation review of our institutional experience at the University technology, when significant breathing-related motion of Colorado involving the use of SBRT for RCC and was present, the PTV was constructed by enlarging the melanoma. internal target volume (ITV) defined on a 4D imaging The first objective was to analyze whether the local set by 5 mm in all directions. Patients underwent control rates reported for high dose per fraction cra- abdominal compression to limit respiratory motion. nial and spinal SRS for RCC and melanoma can be Toxicity was scored according to the Common Termi- replicated in other sites. Second, we attempted to nology Criteria for Adverse Events v3.0. The use of model the SBRT dose-response relationship. In this RECIST (Response Evaluation Criteria in Solid Tumors) context, we used both a traditional linear-quadratic criteria after SBRT is difficult in view of the expected par- model-based metric, the biological equivalent dose enchymal changes commonly seen in surrounding normal (BED), and a novel index proposed for modeling high tissue within the volume that receives approximately 20 dose per fraction RT, the single fraction equivalent Gy or higher. For this reason, we did not characterize dose (SFED)[19]. Finally, we reviewed the clinical lesions as having had a complete response or partial observations typically seen in terms of metabolic ima- response by RECIST criteria. Instead, local failure was ging following SBRT for RCC and melanoma and the scored when one of the following conditions were met: (1) overall survival of this population of patients, with the tumor viability as seen by an increase in SUV on follow- intent of offering guidance for proper patient up PET scan relative to the most recent prior PET; (2) selection. expansion of a solid mass with discrete borders within the Stinauer et al. Radiation Oncology 2011, 6:34 Page 3 of 8 http://www.ro-journal.com/content/6/1/34 treated PTV by 20% in longest dimension relative to the melanoma patients had 28 lesions, and 13 RCC patients most recent prior CT or MRI; or (3) tumor viability as evi- had 25 lesions available for review. Two patients with denced pathologically by biopsy. In questionable cases, the RCC did not have follow-up imaging and were not follow-up CT was fused with the planning CT to define included, one melanoma patient had an additional lesion in-field LC. If a patient with suspicious failure was subse- that was treated but did not have any follow-up imaging quently treated for that lesion with chemotherapy, the and this lesion was excluded from our analysis. Patient lesion was considered a failure. Overall survival (OS) was ages ranged from 36 to 83, with median age of 59. recorded from the date of treatment completion to last There were 17 males and 13 females treated with SBRT. follow-up or date of death. Seventeen patients had oligometastatic disease at time of The SBRT dose regimen used was then converted to treatment with all sites treated with SBRT, and 13 single fraction equivalent dose (SFED) using the follow- patients had extensive disease in which only selected ing equation: lesions were treated with SBRT. The median number of lesions treated per patient was 2 (range, 1-3). Among SFED = D − (n − 1) × D the tumor sited treated, lung was most common (n = 39), followed by liver (n = 11) and bone (n = 3). with D estimated at 1.8 from the Park analysis [19]. The SBRT regimens were 40-50 Gy delivered in 5 Local control curves were generated using Kaplan-Meier fractions (n = 23) or 42-60 Gy delivered in 3 fractions method. Comparisons between curves were performed (n = 30). The regimen applied was selected at the dis- using the log rank method. Candidate predictors for cretion of the treating physician in view of clinical local control (total dose, GTV, histology etc) were also objectives and normal tissue dose considerations for evaluated by log rank analysis. Univariate analysis was each lesion without regard to the histology. The aim performed with the median value using log rank com- was to safely deliver the highest dose possible while parisons (GraphPad Prism , GraphPad Software, Inc., La respecting the surrounding normal tissue tolerance. The Jolla California). most common regimen was 60 Gy in 3 fractions (n = The dose-response relationship was modeled using a 20) followed by 45 Gy in 5 fractions (n = 11) and 50 Gy logistic tumor control probability (TCP) formula [21]: in 5 fractions (n = 8). Median gross tumor volume (GTV) was 6.3cc (range, 1-275). Median follow-up for TCP = (1+ (TCD /D) ) 50 patients alive at the time of analysis was 28.0 months (range,4-68).See table1for treatment characteristics WhereDisthetotal dose,TCD is thedosethat including SFED and BED values for each regimen. achieves 50% tumor control, and k describes the slope of the curve. Doses to individual lesions were grouped into Tolerance and other therapies tertile bins, and the x-axis value was the mean dose given There were no acute side effects, only mild late toxici- in that bin, expressed as either BED or SFED, while the ties which were not dose dependent. Six patients experi- y-axis value was the probability of LC at twelve months. enced grade 1 toxicity (3 pain, 2 cough and 1 dyspnea). In patients undergoing surveillance with PET scans There was one incident of grade 3 toxicity of hypoxia at who had long term local control, we looked at the pattern 11 months after treatment in an asthmatic patient who of the maximal standardized uptake value (SUV) change. developed multiple pulmonary metastases requiring Only patients with a pre-treatment and at least one post- increased continuous oxygen use. One patient developed treatment PET scan were included for analysis. The PET grade 3 radiation pneumonitis successfully managed scans were performed intermittently for tumor surveil- with steroids. lance and regularly in patients undergoing chemotherapy for other sites of disease. The lesions were contoured Table 1 Treatment Characteristics using dedicated medical image analysis software (MIM- vista , MIM Software, Inc., Cleveland, Ohio). This was Fractionation Schedule # of pts SFED (Gy) BED (Gy) then fused to their follow up PET scans and the maxi- 60 Gy in 3 fractions 20 56.4 180 mum SUV (SUV ) was calculated for each lesion on max 54 Gy in 3 3 50.4 151.2 each PET scan performed. Nine patients with 12 lesions 50 Gy in 5 8 42.8 100 had a total of 43 PET scans prior to and after SBRT. 45 Gy in 3 5 41.4 112.5 42 Gy in 3 2 38.4 100.8 Results 45 Gy in 5 11 37.8 85.5 Patient population 40 Gy in 5 4 32.8 72 Thirty patients with 53 treated lesions met the study Fractionation schedules and conversion to single fraction equivalent dose inclusion criteria and were analyzed. Overall, 17 (SFED) and biological equivalent dose (BED). Stinauer et al. Radiation Oncology 2011, 6:34 Page 4 of 8 http://www.ro-journal.com/content/6/1/34 Seven patients were treated with sorafenib, 5 before We generated TCP graphs using both SFED and BED SBRT and 2 after SBRT as well as 7 patients treated (Figure 2). Both SFED and BED had a strong coefficient with sunitinib. One patient underwent SBRT while suni- of determination to predict future outcomes (SFED R = tinib was held for 2 weeks before and after treatment, 3 0.999 and BED R = 0.996). Using the SFED TCP graph, patients were treated with sunitinib before SBRT and 3 a 90% chance of tumor control was calculated to an patients were treated after SBRT. There was no signifi- SFED of 44.3 Gy which translates into approximately 48 cant increase in toxicity seen in these 14 patients (two Gy in 3 fractions. Using BED, 90% chance of tumor con- grade 1 events and one late grade 3 pneumonitis). One trol was calculated at 126 Gy, which corresponds to approximately 49 Gy in 3 fraction regimen. patient with melanoma received CTLA4 antibody after radiation and did not experience any adverse side effects Median overallsurvivalforallpatientsinthisstudy from SBRT. Overall patients were pre-treated with a was 24.3 months. The median overall survival of variety of systemic therapies. The median number of patients with oligometastatic disease was not reached courses was 1 with range 0-3. Additionally, patients while patients with extensive metastatic disease had a went on to further systemic therapy with a median of median overall survival of only 12.3 months (p = 0.03) one course (range 0-5). (Figure 3). Median overall survival was not reached in patients with RCC, and was statistically longer than mel- Local control and overall survival anoma patients with median overall survival of 22.2 The actuarial rate of LC for all patients was 88% at 18 months (p = 0.015). months (Figure 1). Several factors were analyzed by uni- variate analysis in an effort to identify predictors of LC. In Metabolic imaging and kinetics of PET scan changes general, for quantitative parameters, the median value was The SUV was plotted and fitted with an exponential max chosen as an arbitrary cut-off for univariate analysis to equation. The median pre-treatment SUV was 7.9 max maximize the comparison cohorts. Log rank comparison (range 1.5 - 14.6). The calculated time for the SUV max revealed number of fractions (3 vs 5, p < 0.01) as well as valuetodecreasebyhalftheoriginal valuewas 3.8 dose per fraction (> 11 Gy/fraction vs <11 Gy/fractions, p months (Figure 4). We found that the calculated post- < 0.01) and BED ( > 100 Gy vs < 100 Gy, p < 0.01) to be treatment baseline SUV was 2.6, which was reached max significant predictors of LC. Histology (RCC vs melanoma, at approximately 7 months. The median post-treatment p = 0.06) total dose (≥50Gy vs <50Gy, p = 0.09) SFED (≥ SUV was 2.5 (range 1.8 - 3.2). max 45 Gy vs < 45 Gy, p = 0.06) and GTV (>7cc vs <7cc, p = 0.06) showed a strong trend towards significance. Site trea- Discussion ted (lung vs other) and disease burden (oligometastatic vs We have observed in a cohort of patients treated with widely metastatic) were not predictors of local control. SBRT for metastatic melanoma or RCC, a high rate of Given the small number of events available to analyze, a durable LC can be achieved, especially for patients with multivariate analysis was not performed. a 3 fraction SBRT total prescription dose on the order of 48-49 Gy or higher. It should be appreciated that this dose estimate represents the dose covering the periphery of the PTV and that substantial dose hotspots are always created in the GTV. Thus, the actual dose need to ablate the gross disease itself is higher than this estimate. Thedatawereevaluated intermsofSFEDand BED because these indices incorporate both the total dose deliveredaswellasthe dose perfraction. SFED was designed to analyze the effect of high dose per fraction exposure by using an equation for cell survival which, when plotted a logarithmic scale, initially curves down- ward with increasing dose in a similar way as an LQ- based curve but then straightens at higher doses, cor- recting for an overestimation of cell kill by BED in the SBRT/ablativedoserange[22].Thereareatleast two reasons why the BED might not characterize high dose effects as well as a model such as the SFED. First of all, Figure 1 Local Control. Actuarial local control for both melanoma there is the phenomenon recognized long ago whereby and RCC lesions for lengthy individual exposures of living cells to Stinauer et al. Radiation Oncology 2011, 6:34 Page 5 of 8 http://www.ro-journal.com/content/6/1/34 Figure 2 Tumor Control Probability. Tumor Control Probability graphs generated from dose response relationship modeling. Doses to individual lesions were grouped into tertile bins and the x-axis value was the mean dose given in that bin, expressed as either (a) SFED or (b) BED. The y-axis value was the probability of LC at 12 months. radiation, intra-exposure repair can occur, obliging a through oxygen dependent DNA damage with resulting correction to the simple LQ model that adjusts for this loss of clonogenicity, an effect seen in vitro and pre- process. This notion was advanced at least as long ago sumed to occur in vivo. However, pre-clinical studies as the 1940s, when Lea and Catcheside modeled radia- have suggested that the high doses of radiation delivered tion-induced chromosomal aberrations in a plant model in each session of SBRT might trigger an entirely differ- using a linear-quadratic formula that also could be mod- ent method of cell kill in vivo via an anti-angiogenic ified with a factor that accounted for the total time of pathway involving endothelial cell apoptosis [24]. Coin- exposure [23]. cidentally, apropos of the present clinical series, the pre- A second, more modern explanation of why BED clinical studies initially suggesting this mechanism might not precisely model high dose effects relates to a included studies of melanoma xenografts. Furthermore, mechanism of tumor cell kill at work in vivo that is not endothelial cell apoptosis appeared to be induced above active in vitro. With conventionally fractionated doses, a threshold dose of 11 Gy, and the present study simi- radiation cell kill is assumed to be largely mediated larly suggested significant improvement in tumor cell Stinauer et al. Radiation Oncology 2011, 6:34 Page 6 of 8 http://www.ro-journal.com/content/6/1/34 primary lung cancer. The SFED model would predict better LC with the 48 Gy arm, while BED modeling pre- dicts the single 34 Gy treatment to have superior LC. The present clinical observations of high LC after aggressive radiation treatment are consistent with what has been observed after single high dose SRS to brain and spinal metastases for both melanoma and RCC [8-10,26]. In these studies the LC for melanoma is typi- cally lower than for RCC [10,26], for which brain SRS can achieve very high LC [11]. Likewise, in the present study we observed a trend for lower 1 year LC for mela- noma than RCC (82% v. 95%), possibly intrinsic differ- Figure 3 Overall survival. Actuarial overall survival of patients based on disease state. Oligometastatic disease was defined as ences in radiosensitivity that are retained even in the three or less metastases in which all site of disease were treated high dose-per-fraction setting. In a study of SBRT in with aggressive local therapy. Extensive disease was defined as primary and metastatic RCC, the local control rate was patients with more than three sites of metastases. 90-98% [16] which is in line with our own and other institutional local control rates across a broad range of kill with a fraction size above that level. Of course, mel- histologic subtypes [16-18,27,28]. anoma and RCC have also been shown to have a large The oligometastatic hypothesis suggests that tumors initial shoulder on the cell survival curve [25], and the early in systemic disease progression may present with a present study’s favorable results might also be at least limited number of discrete lesions without extensive partly explained by the fact that doses in the SBRT occult spread of disease, thus a condition amenable to range exceed that of the initial shoulder region. Both potentially curative intervention if the identifiable BED and SFED proved to be a reliable predictor for LC. lesions can be eradicated [29]. Studies of liver metaste- Further studies will be needed to resolve whether one is ctomy in patients with RCC reveal that there are long truly superior to the other, and it will be informative to term survivors and chance for cure with a 5 year OS see the results of RTOG 0915 in which a single 34 Gy rate of 39% [30]. The argument for using ablative local fraction is compared to 48 Gy in 4 fraction regimen for therapy for isolated metastases is strengthened if effec- tive systemic therapy is available to complement it [31]. And in recent years, for both melanoma and RCC there have been new systemic agents developed that provide clinical benefit, including the anti-CTLA-4 antibody, ipi- limumab, and multi-targeted agents such as sunitinib and sorafenib. Properly selected patients with metastatic RCC undergoing lung resection have a chance for long term survivorship [32], as do patients with liver metastases from RCC, where a 5 year OS of approximately 40% has been reported for a group of well selected patients [30]. Patients with liver metastases from RCC tend to fare better than patients with liver metastases from melanoma [33], once again suggesting basic differences in the typical degree of aggressiveness between these cancer types. In the present series, melanoma patients likewise had shorter median survival than RCC patients. In this series the arbitrary cutoff point applied to char- acterize patients as having oligometastatic vs. extensive metastatic disease was the presence of 3 or fewer indivi- Figure 4 Change in SUV for controlled lesions. The Standardized dual sites of disease. The superior outcome of patients uptake values were plotted with pre-treatment PET used for planning as time 0. Follow-up PET/CT’s were fused and SUV was defined as oligometastatic by this definition was generated for each treated lesion that was controlled. An expected, and this or a similar cutoff level of sites of dis- exponential equation was generated revealing a post-treatment ease would appear to be appropriate as a stratification baseline level of activity of 2.6 at 7 months. variable for future studies of SBRT in the treatment of Stinauer et al. Radiation Oncology 2011, 6:34 Page 7 of 8 http://www.ro-journal.com/content/6/1/34 metastatic disease. However, the difference in outcome Conclusions between the cohorts defined in this manner does not The present study demonstrates that an aggressive rule out the possibility that patients with more extensive SBRT regimen is an effective modality for controlling disease might still benefit from a general reduction in metastatic melanoma and RCC. The LC rates achieved their systemic disease burden, whether achieved by sys- in our series are comparable to those obtained with temic therapy or local therapy. Indeed, for the case of SBRT for other tumor histologies, suggesting a domi- RCC in particular, two independent phase III studies nant mechanism of in vivo tumor ablation after high indicate that a reduction in a patient’s total burden of dose fractions that largely overrides intrinsic differences disease via nephrectomy lengthens OS for patients with in cellular radiosensitivity between histologic subtypes of known metastatic disease, even though not all sites of tumor. SFED TCP modeling indicates that to achieve a disease were locally treated [34]. Thus, as studies are high rate of durable LC in a 3 fraction regimen of designed in the future, it is important to avoid the SBRT, a dose of at least 48 Gy is required. overly narrow assumption that only patients with oligo- metastatic disease can potentially benefit from ablation Author details of metastatic sites of disease via local therapy, though University of Colorado Denver, School of Medicine, Aurora, Colorado, USA. certainly patients with more limited disease will have a Exempla St. Joseph Hospital, Denver, Colorado, USA. better prognosis overall. Authors’ contributions PET scans are now widely available to monitor MAS conceived of the study, carried out data collection, performed a response to cancer therapy in a variety of setting, and literature search, and drafted the manuscript. BK participated in the design, literature research, statistical analysis, and drafting the manuscript. TES we have here reported on the kinetics of change in participated in study design and data retrieval. RG, KL, WR, MG, and MC metabolic activity following SBRT for RCC and mela- contributed to the clinical management of patients and data collection. TF noma. In our cohort of locally controlled patients, the contributed to patient management and in drafting the manuscript. DR participated in the design, clinical patient management, and manuscript decrease to a steady post-treatment baseline SUV max writing. All authors read and approved the final manuscript. took approximately 7 months. The post-treatment baseline level averaged 2.6 and was consistent with Competing interests The authors declare that they have no competing interests. findings of Henderson et al, who showed that almost half of primary non-small cell lung cancer lesions have Received: 5 January 2011 Accepted: 8 April 2011 Published: 8 April 2011 moderately elevated SUV at 12 months without max local failure [35]. 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Radiation OncologySpringer Journals

Published: Apr 8, 2011

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