Using max standardized uptake value from positron emission tomography to assess tumor responses after lung stereotactic body radiotherapy for different prescriptions

Abstract Purpose To retrospectively investigate tumor responses of lung SBRT patients for different prescriptions. To analyze the relation between optimal biologically equivalent dose (BED) and tumor responses. Methods and Materials Tumor responses after lung SBRT were compared by examining 48 treatments used four prescriptions. This study used simplified tumor response criteria: (a) Complete Response (CR) — post max SUV (SUV post) after SBRT in the treated tumor region was almost the same as the SUVs in the surrounding regions; (b) Partial Response (PR) — SUV post was smaller than previous max SUV (SUV pre), but was greater than the SUVs in the surrounding regions; (c) No Response (NR) — SUV post was the same as or greater than SUV pre. Some SUV post reported as mild or favorable responses were classified as CR/PR. BED calculated using α/β of 10 Gy were analyzed with assessments of tumor responses for SBRT prescriptions. Results For the prescriptions (9 Gy × 5, 10 Gy × 5, 11 Gy × 5, and 12 Gy × 4) historically recommended by RTOG, we observed that higher BED 10 and lower tumor volume would achieve a higher complete response rate. The highest complete response rate was observed for smallest tumor volume (PTV ave = 6.8 cc) with higher BED 10 (105.6) of 12 Gy × 4 prescription. For 11 Gy × 5 prescription, the BED 10 (115.5) was the highest, but its complete response rate (58%) was lower than 79% of 12 Gy × 4 prescription. We observed the PTV ave of 11 Gy × 5 prescription was more than double of the PTV ave of 12 Gy × 4 prescription. For the same lung SBRT prescription (BED 10 > 100) earlier staging tumor had more favorable local control. Conclusion We demonstrated post max SUV read from PET/CT could efficiently and accurately assess tumor response after lung SBRT. Although SBRT with prescriptions resulting in a BED 10 > 100 experienced favorable tumor responses for early staging cancer, escalation of BED 10 to higher levels would be beneficial for lung cancer patients with later staging and larger volume tumors.


| INTRODUCTION
Positron Emission Tomography (PET) is an imaging technique that provides unique information about the molecular and metabolic changes associated with disease. The technology has existed for more than 50 years 1 but has only been used clinically after 18Ffluorodeoxyglucose (FDG) and other isotopes were synthesized 30 years ago. [2][3][4] In 2000 the Food and Drug Administration approved the use of 18F-FDG to assist in evaluation of malignancy in patients with known or suspected abnormalities found by other testing methods. In 2008 a multidisciplinary expert panel of oncologists, radiologists, and nuclear physicians recommended the use of 18F-FDG PET in oncology practice and determined the suitability of 18F-FDG PET in managing various forms of cancer. 5 18F-FDG PET has been recognized as an important tool for the initial staging of Non-Small-Cell Lung Cancer (NSCLC) 6 and for providing functional information in treatment planning. 7 The use of Standardized Uptake Values (SUV) has become more commonly accepted in clinical FDG-PET oncology imaging, and it has found a specific role in assessing patient response to cancer therapy. 8,9 Stereotactic body radiotherapy (SBRT) is an effective treatment for early-stage NSCLC and has been predominately used for medically inoperable patients. Most cancer centers in the United States follow guidelines based on Radiation Therapy Oncology Group (RTOG) protocols to evaluate lung SBRT treatment planning 10 and to assess clinical outcomes in patient follow-up. 11 Computed Tomography (CT) is used as a mandatory follow-up to assess tumor response after lung SBRT.
As an example, RTOG requires CT scans every 3 months during the first 2 years after SBRT; then every 6 months for 2 more years to assess outcomes. 18F-FDG PET scanning was used only if CT scans showed progressive soft tissue abnormalities. 12 Some cancer centers also use 18F-FDG PET/CT (simplified as PET/CT) for follow-up. There have been some pilot trials and studies using 18F-FDG PET to predict treatment outcomes before lung SBRT [13][14][15] or assess clinical outcomes after lung SBRT. [16][17][18][19][20][21][22][23][24] In this study we retrospectively investigated tumor responses of lung SBRT patients for different SBRT prescriptions, analyzed the relation between optimal biologically equivalent dose (BED) and tumor responses for SBRT prescriptions.

2.A | Lung SBRT patients and treatment
In our clinics pre-SBRT evaluations consisted of history and physical examinations, contrast-enhanced CT scans of the chest, PET/CT scans, and pulmonary function testing. Biopsies were performed unless medically contraindicated. Regular follow-ups with CT imaging were performed on all patients. Post-SBRT PET/CT was not mandated and was typically ordered at the discretion of the treating physician and upon concern for disease recurrence. For four SBRT prescriptions (9 Gy × 5, 10 Gy × 5, 11 Gy × 5, and 12 Gy

2.C | Biologically equivalent dose
Biologically equivalent dose (BED) has been introduced into optimal doses and fractionation schedules of SBRT. 28-32 BED 10 , BED calculated using α/β of 10 Gy in the linear quadratic model, is used to predict of local control in lung SBRT. showed similar max SUVs in surrounding regions for patients treated with SBRT in this study. Tumor response for these patients was classified as CR after SBRT. Some SUV post ≤ 2.5 was indicated as mild or favorable responses in some PET/CT diagnosis reports, we classified 1.9 < SUV post ≤ 2.5 as CR/PR.

3.C | Tumor response for different prescriptions
For patients treated with these four prescriptions (9 Gy × 5, Max SUVs are plotted in Fig. 3. Tumor responses were classified into four categories: (a) CR − SUV post-3 month was at or below 1.9; (b) CR/PR − SUV post-3 month was between 2.0 and 2.5, inclusive; (c) PR − SUV post-3 month was at or above 2.6 but smaller than SUV pre ; and (d) No NR − SUV post-3 month was the same as or greater than SUV pre .
Using CT, it may require more than 2 years to completely assess tumor responses, 34 and so CT alone may be unable to accurately assess tumor response early enough to allow for some salvage treatment modalities. 9 PET measures biochemical changes using 18F-FDG rather than evaluating tumor size differences from images as CT does, 9,35 and so PET is able to assess tumor response sooner than CT. PET/CT    Fig. 2. Max SUV taken around 3 months after SBRT completion has also been applied to assess tumor responses in recent studies. 23,24 In this study we used a SUV post at or below 1.9 as CR criteria. It should be noted that this value only applies to our clinic. SUV depends on patient size and the amount of injected FDG, as well as the duration of the uptake time between FDG injection and scan start. 8 Even if the same PET/CT scanning protocol was followed, there could still be some variability introduced by differing calibrations of scanners and performing readings on different workstations.
However, each clinic should have some thresholds of SUV post for different tumor responses.
CT/X-ray imaging were performed as the regular follow-up on all patients at our clinic. Post-SBRT PET/CT usually ordered at the discretion of the treating physician. Biopsies were also performed for confirming tumor recurrences. Table 3 compared the PET tumor responses defined in this study to the patient follow-ups based on the CT/X-ray imaging and biopsy data. Local Control (LC) is defined as a tumor shrinkage shown in the CT/X-ray images after SBRT, Regional Failure (RF) is defined as an enlarging nodule adjacent to the treated area observed on the CT images, and all tumor recurrences were confirmed by biopsies before re-treatments. Although our SBRT program followed RTOG protocols' prescriptions and normal tissue constraints, the patient follow-up did not follow any protocol. The individual follow-up interval and period varied on each patient. All the patients in this study had 1-year CT/X-ray imaging follow-ups, while only 23 (48%) patients had documented 2-year or longer follow-ups. In Table 3, 2-year a was the follow-up time documented in the period of 2-5 years after SBRT. Table 3 shown there was only one (4%) RF after 2 years follow-up for 26 CR cases; 3 (27%) RF after 2 years for 11 CR/PR cases; 5 (63%)  4.B | What is an optimal prescription for a lung SBRT patient?
In Table 2 we observed that higher BED 10 and lower tumor volume would achieve higher complete response (tumor control) rates. The highest complete response rate was observed for smallest tumor volume (PTV ave = 6.8 cc) with higher BED 10 (105.6) of 12 Gy × 4 prescription. For 11 Gy × 5 prescription, the BED 10 (115.5) was the highest in these four groups, but its complete response rate (58%) was lower than 79% of 12 Gy × 4 prescription. We found the average tumor volume of 11 Gy × 5 group was more than double of the volume

| CONCLUSION
We defined a tumor response criterion using post max SUV from PET/CT taken around 3 months after treatment to assess the tumor T A B L E 3 PET Tumor response vs patient follow-up.

CONF LICTS OF INTEREST
The authors do not have any conflicts of interest to declare.