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Prognostic Value of Posttreatment [18F] Fluorodeoxyglucose Uptake of Primary Non-small Cell Lung Carcinoma Treated with Radiation Therapy with or without Chemotherapy: A Brief Review

      In patients treated with radiation therapy for non-small cell lung carcinoma, positron emission tomography and computed tomography are commonly used to assess response to treatment. Seven rather small single-institution series have documented the ability of posttreatment positron emission tomography to predict local control and survival through measurements of [18F] fluorodeoxyglucose uptake. The ability to make prognostic assessments using this information would be a major clinical breakthrough by allowing early alterations in patient management. Here, we review the current literature on the prognostic value of posttreatment [18F] fluorodeoxyglucose uptake in patients treated with radiation therapy with or without chemotherapy for non-small cell lung carcinoma.

      Key Words

      Traditionally, anatomic imaging modalities such as computed tomography (CT) have been used in the diagnosis, staging, and posttreatment assessment of non-small cell lung cancer (NSCLC).
      • Bruzzi JF
      • Munden RF
      PET/CT imaging of lung cancer.
      With the advent of [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET), it became possible to obtain functional assessments of tissue in addition to the anatomic information conveyed by CT.
      • Juweid ME
      • Cheson BD
      Positron-emission tomography and assessment of cancer therapy.
      Ultimately, these two modalities became integrated such that combined PET/CT scans could be obtained with a single examination.
      • Bruzzi JF
      • Munden RF
      PET/CT imaging of lung cancer.
      The biologic basis of FDG-PET for detecting malignancy is as follows: malignant cells display an over-expression of glucose transporter 1 receptors on their surface as well as up-regulated intracellular levels of the phosphorylating enzyme hexokinase when compared with healthy cells; the radioactive glucose analog [18F] FDG is administered and is preferentially taken up by tumor cells because of the aforementioned physiologic abnormalities.
      • Bruzzi JF
      • Munden RF
      PET/CT imaging of lung cancer.
      • Vansteenkiste J
      • Fischer BM
      • Dooms C
      • Mortensen J
      Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review.
      Since the radioactive [18F] FDG glucose analog is not able to enter the intracellular glycolytic pathways with the glucose-6-phosphate dephosphorylating enzyme phosphatase being down-regulated, the analog becomes sequestered within the cell.
      • Bruzzi JF
      • Munden RF
      PET/CT imaging of lung cancer.
      • Vansteenkiste J
      • Fischer BM
      • Dooms C
      • Mortensen J
      Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review.
      Positron emission tomography, in conjunction with CT, has gained an increasingly important role in the staging of NSCLC and the radiation treatment planning process. In terms of tumor staging, combined PET/CT has been shown to be more accurate than either modality alone in patients with NSCLC.
      • Lardinois D
      • Weder W
      • Hany TF
      • et al.
      Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography.
      Promising staging accuracy has also been reported in patients with SCLC.
      • Fischer BM
      • Mortensen J
      • Langer SW
      • et al.
      A prospective study of PET/CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone marrow analysis.
      Furthermore, combined PET/CT has also been shown to provide more accurate nodal staging than using either PET or CT alone.
      • Lardinois D
      • Weder W
      • Hany TF
      • et al.
      Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography.
      Improved primary target volume delineation
      • Erdi YE
      • Rosenzweig K
      • Erdi AK
      • et al.
      Radiotherapy treatment planning for patients with non-small cell lung cancer using positron emission tomography (PET).
      • Nestle U
      • Walter K
      • Schmidt S
      • et al.
      18F-deoxyglucose positron emission tomography (FDG-PET) for the planning of radiotherapy in lung cancer: high impact in patients with atelectasis.
      • Mah K
      • Caldwell CB
      • Ung YC
      • et al.
      The impact of (18)FDG-PET on target and critical organs in CT-based treatment planning of patients with poorly defined non-small-cell lung carcinoma: a prospective study.
      leading to enhanced sparing of normal tissue
      • De Ruysscher D
      • Wanders S
      • Minken A
      • et al.
      Effects of radiotherapy planning with a dedicated combined PET-CT-simulator of patients with non-small cell lung cancer on dose limiting normal tissues and radiation dose-escalation: a planning study.
      • van Der Wel A
      • Nijsten S
      • Hochstenbag M
      • et al.
      Increased therapeutic ratio by 18FDG-PET CT planning in patients with clinical CT stage N2–N3M0 non-small-cell lung cancer: a modeling study.
      has also been demonstrated using PET/CT with critical impact on patient management.
      • Bradley J
      • Thorstad WL
      • Mutic S
      • et al.
      Impact of FDG-PET on radiation therapy volume delineation in non-small-cell lung cancer.
      • Mac Manus MP
      • Hicks RJ
      • Ball DL
      • et al.
      F-18 fluorodeoxyglucose positron emission tomography staging in radical radiotherapy candidates with nonsmall cell lung carcinoma: powerful correlation with survival and high impact on treatment.
      The use of CT alone in the past for assessment of treatment response has been problematic because of the difficulty interpreting tumor response with the concomitant radiation effect in the lung.
      • Movsas B
      • Raffin TA
      • Epstein AH
      • Link Jr, CJ
      Pulmonary radiation injury.
      The integration of the metabolic assessment by PET with the anatomic assessment by CT may mitigate this difficulty.
      The prospect of using PET/CT to predict clinical outcomes including local control and survival in patients treated with radiation therapy for unresectable and medically inoperable NSCLC has immense implications. Patients deemed to have a poor prognosis based upon a posttreatment scan could have their management altered and thus avoid the cost and morbidity of further ineffective treatment. Likewise, those patients deemed to have favorable prognosis by PET/CT imaging could receive further aggressive treatment to obtain a durable response. Thus, clinicians and investigators alike would have objective data to use when making management decisions in individual patients or in adjustment of clinical protocols. Previous reviews have addressed the prognostic value of FDG uptake in patients with lung cancer.
      • Vansteenkiste J
      • Fischer BM
      • Dooms C
      • Mortensen J
      Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review.
      • Pillot G
      • Siegel BA
      • Govindan R
      Prognostic value of fluorodeoxyglucose positron emission tomography in non-small cell lung cancer: a review.
      Nevertheless, these reviews did not specifically focus on posttreatment scans
      • Pillot G
      • Siegel BA
      • Govindan R
      Prognostic value of fluorodeoxyglucose positron emission tomography in non-small cell lung cancer: a review.
      or specifically on patients treated with radiation therapy.
      • Vansteenkiste J
      • Fischer BM
      • Dooms C
      • Mortensen J
      Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review.
      • Pillot G
      • Siegel BA
      • Govindan R
      Prognostic value of fluorodeoxyglucose positron emission tomography in non-small cell lung cancer: a review.
      Furthermore, some of the more recent published studies included in the present work were not examined in the two previous reviews. In this review, we examine the current literature on the prognostic value of posttreatment FDG uptake in patients treated with radiation therapy with or without chemotherapy for NSCLC.

      Clinical Studies Examining Prognostic Value of FDG Uptake

      One small early series examined the PET findings of 12 patients after radiation therapy for NSCLC.
      • Hebert ME
      • Lowe VJ
      • Hoffman JM
      • Patz EF
      • Anscher MS
      Positron emission tomography in the pretreatment evaluation and follow-up of non-small cell lung cancer patients treated with radiotherapy: preliminary findings.
      Each of these patients also had FDG-PET scanning performed before radiation therapy. This study had FDG uptake assessed in patients using both quantitative regions of interest (ROIs) (n = 7) as well as using visual assessment (n = 5). The authors examined the suspected tumor volumes on anatomic imaging and correlated them to PET images where they identified regions in which FDG uptake was most avid visually. As noted above, seven of the patients had ROIs placed in these areas and the average activity was measured numerically within the ROI. The remaining patients did not have data to perform numerical evaluations of FDG uptake and thus were assessed visually. The timing of PET after radiation therapy was not reported. Of these 12 patients, four achieved a complete metabolic response (CMR) (defined as a reduction in FDG uptake to background level) on PET. After a range of 7 to 16 months follow-up postradiation therapy for these four patients, none had developed local recurrence although one patient expired secondary to brain metastasis. The authors concluded that “a complete response by PET scan appears to indicate a true local remission of disease.” They noted, however, that longer follow-up was needed to validate this statement.
      In the other eight patients, six achieved a partial metabolic response (PMR) (defined as >50% reduction in FDG uptake but not resolution to background) by PET while two displayed no metabolic response (defined as <50% reduction in FDG uptake). After a range of 11 to 24 months follow-up postradiation therapy for these eight patients, three of the six partial responders developed local recurrence and another partial responder died after surgery with pathologic evidence of residual tumor. The other two partial responders had stable lesions and at last follow-up had no clinical evidence of disease. The two patients who had no metabolic response on PET also had no clinical evidence of disease at last follow-up. Time to local recurrences, metastasis, and death were not reported. For these eight patients with partial or no metabolic response, the authors concluded that “there was no consistent correlation between clinical response and changes on PET scan in this group of patients.”
      • Hebert ME
      • Lowe VJ
      • Hoffman JM
      • Patz EF
      • Anscher MS
      Positron emission tomography in the pretreatment evaluation and follow-up of non-small cell lung cancer patients treated with radiotherapy: preliminary findings.
      Ichiya et al.
      • Ichiya Y
      • Kuwabara Y
      • Sasaki M
      • et al.
      A clinical evaluation of FDG-PET to assess the response in radiation therapy for bronchogenic carcinoma.
      examined the prognostic value of FDG-PET in 30 patients with bronchogenic carcinoma, treated with radiation therapy alone (n = 13) or with chemoradiation (n = 17). Each of these patients received a pretreatment PET scan “within 1 week before the initiation of the therapy” while 20 (19 of whom had NSCLC) also received posttreatment PET “within 3 weeks after completion of therapy.” Uptake of FDG was measured using the tumor to muscle ratio (TMR). To obtain the TMR value, the authors placed ROIs on areas of tumor with the most avid FDG uptake. They also placed 5 or 6 ROIs on different portions of the muscle and used the mean value of these numbers. Using this mean muscle value and the value obtained from the tumor ROI, the TMR was calculated. Follow-up imaging using both chest x-rays and CT was used to define treatment response (either partial response, n = 13 or no change, n = 7) based on lesion size and these responses were compared with the changes in TMR. On anatomic imaging, a decrease in tumor size of greater than 50% was defined as a partial response while a decrease less than 50% or an increase of less than 25% was defined as no change. None of the patients had complete response or progressive disease. Also, patients were designated as either relapsed or nonrelapsed at 6 months after treatment. After treatment, patients who had a partial response tended to have greater decreases in TMR compared with patients who had no change, although the difference was not statistically significant. Furthermore, a TMR greater than 5 after treatment was associated with a significantly higher risk of relapse (p < 0.05).
      • Ichiya Y
      • Kuwabara Y
      • Sasaki M
      • et al.
      A clinical evaluation of FDG-PET to assess the response in radiation therapy for bronchogenic carcinoma.
      In 2002, Choi et al.
      • Choi NC
      • Fischman AJ
      • Niemierko A
      • et al.
      Dose-response relationship between probability of pathologic tumor control and glucose metabolic rate measured with FDG PET after preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer.
      studied 29 patients with locally advanced NSCLC treated with preoperative chemoradiotherapy and assessed the prognostic value of FDG uptake in these patients. They examined the dose–response relationship between the probability of tumor control using pathologic tumor response (pTCP) of the surgical specimen as the reference standard and posttreatment FDG uptake using the residual metabolic rate of glucose (MRglc). The area of tumor with the highest activity was determined visually, an ROI was placed in this area, and the maximal MRglc value in the ROI was then calculated. In this study, PET was obtained “a few days before treatment” as well as 2 weeks after the completion of preoperative chemoradiation. The authors found that a probability cutoff of 0.5 had an accuracy of 83% in predicting pathologic response (sensitivity, 86% and specificity, 81%). They also found an inverse dose–response relationship between gradient of residual MRglc after chemoradiotherapy and pTCP with their fitted logistic model showing the following relationship: residual MRglc corresponding to pTCP 50% was 0.076 while pTCP ≥95% was ≤0.040 μmol/min/g.
      • Choi NC
      • Fischman AJ
      • Niemierko A
      • et al.
      Dose-response relationship between probability of pathologic tumor control and glucose metabolic rate measured with FDG PET after preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer.
      In the same year, Ryu et al.
      • Ryu JS
      • Choi NC
      • Fischman AJ
      • Lynch TJ
      • Mathisen DJ
      FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology.
      assessed the ability of lesion standard uptake value (SUV) to detect a pathologic complete response. The authors calculated the SUV by visually determining the tumor region with greatest FDG uptake and finding the mean value within a 12-mm diameter ROI in this tumor region. CT data was used to position the ROI when FDG uptake was absent on posttreatment studies. In addition to using SUV, the lesions were evaluated qualitatively using visual inspection. In this study, patients with stage III NSCLC were imaged using FDG-PET and then treated with preoperative concurrent chemoradiotherapy. Two weeks after completion of chemoradiotherapy, the patients were reimaged using FDG-PET. Patients were then scheduled to undergo surgical resection of their lesions on day 57. For each PET scan, SUVs were calculated for the primary tumors and later correlated with histopathologic findings from surgical specimens. Using an SUV of 3.0 as an arbitrary cut-off for differentiating between residual cancer and pathologic complete response, they reported a sensitivity of 88% and specificity of 67% in a cohort of 23 patients.
      • Ryu JS
      • Choi NC
      • Fischman AJ
      • Lynch TJ
      • Mathisen DJ
      FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology.
      In a larger series published in 2005, Mac Manus et al.
      • Mac Manus MP
      • Hicks RJ
      • Matthews JP
      • Wirth A
      • Rischin D
      • Ball DL
      Metabolic (FDG-PET) response after radical radiotherapy/chemoradiotherapy for non-small cell lung cancer correlates with patterns of failure.
      examined the ability of PET and CT to predict survival in 88 patients after radical radiation therapy alone (n = 15) or chemoradiotherapy (n = 73). In this study, patients underwent imaging before treatment and were then reimaged at a median of 70 days after radiation therapy. Rather than using SUV to quantify FDG uptake with PET, the authors used a visual assessment of tumor response with a CMR defined as “no abnormal tumor FDG uptake; activity in the tumor absent or similar to mediastinum.” PMR was defined as “any appreciable reduction in intensity of tumor FDG uptake or tumor volume. No disease progression at other sites.” Stable metabolic disease (SMD) was defined as “no appreciable change in intensity of tumor FDG uptake or tumor volume: no new sites of disease.” Finally, the authors defined progressive metabolic disease (PMD) as any “appreciable increase in tumor FDG uptake or volume of known tumor sites and/or evidence of disease progression at other intrathoracic or distant metastatic sites.”
      • Mac Manus MP
      • Hicks RJ
      • Matthews JP
      • Wirth A
      • Rischin D
      • Ball DL
      Metabolic (FDG-PET) response after radical radiotherapy/chemoradiotherapy for non-small cell lung cancer correlates with patterns of failure.
      Using the definitions of metabolic response noted above, 40 of the 88 patients achieved a CMR, 32 had a PMR, 5 SMD, and 11 patients developed PMD. On univariate analysis, patients with PMD, SMD or PMD, and non-CMR had significantly worse survival (p = 0.0001, hazard ratio (HR) = 4.47; p = 0.0001, HR = 3.56; p = 0.0004, HR = 2.40, respectively). After adjusting for Eastern Cooperative Oncology Group performance status, weight loss and PET stage at the beginning of treatment, patients with SMD or PMD, and non-CMR patients still had significantly worse survival (p = <0.0001, HR = 4.06; p = 0.0001, HR = 2.71; respectively). In terms of distant metastasis, patients with CMR had significantly lower risk than non-CMR patients on both univariate (p = 0.0044, HR = 2.69) and multivariate analysis (p = 0.0075, HR = 2.53). Finally, patients who had SMD demonstrated a significantly greater risk of primary tumor progression on both univariate (p = 0.0042, HR = 2.80) and multivariate analysis (p = 0.0086, HR = 2.49).
      • Mac Manus MP
      • Hicks RJ
      • Matthews JP
      • Wirth A
      • Rischin D
      • Ball DL
      Metabolic (FDG-PET) response after radical radiotherapy/chemoradiotherapy for non-small cell lung cancer correlates with patterns of failure.
      In 2006, one group reported on 50 patients with stage IIIA/IIIB NSCLC treated with neoadjuvant chemoradiotherapy.
      • Pottgen C
      • Levegrun S
      • Theegarten D
      • et al.
      Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy.
      Initial PET/CT scans were obtained 3 days before induction chemotherapy. Posttreatment scans were then obtained after completion of concurrent chemoradiation (median of 83 days after start of induction chemotherapy). The authors visually identified focal areas of increased FDG uptake and calculated the maximum SUV (SUVmax) in these regions. Forty-three of the original 50 patients had PET performed after chemoradiotherapy, while 37 of the 50 patients went on to have surgical resection after chemoradiation.
      Using a definition of <10% residual tumor cells as a histopathologic response, the authors reported that in tumors less than or equal to the median volume in the study (7.5 cm3), the absolute SUVmax after chemoradiotherapy was significantly smaller in patients with histopathologic response than in those without response (area under the receiver operating characteristic [ROC] curve, 0.8 [95% confidence interval (CI), 0.55–1.0], p = 0.03). An SUVmax cutoff point of 3.3 produced a maximum sum of sensitivity and specificity (0.8 for each). In addition to absolute SUV after chemoradiation, the authors assessed the ratio of the posttreatment and pretreatment SUV for prognostic significance on histopathologic response. Sensitivities ranging from 70 to 94% and specificities ranging from 71 to 86% could be obtained using SUV ratio cutoff values between 0.38 and 0.55 with an area under the ROC curve of 0.86 (95% CI, 0.63–1.00; p = 0.008). The authors used ROC analysis to determine if the ratio of the posttreatment and pretreatment SUV was predictive of freedom from extracerebral relapse and found an area under the curve of 0.74 (95% CI, 0.49–0.98; p = 0.045) with SUV ratio cutoff values between 0.45 and 0.55 producing the largest sum of sensitivity and specificity. In terms of survival, SUVs showed no prognostic value.
      • Pottgen C
      • Levegrun S
      • Theegarten D
      • et al.
      Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy.
      In a recent study, 20 patients with medically inoperable or advanced NSCLC were assessed with PET/CT at a median of 71 days after radiation therapy and their metabolic response as determined by PET was examined for prognostic value. Of these 20 patients, 18 also received induction chemotherapy. Before the posttherapy scans, the patients had undergone PET/CT before the initiation of therapy, on day 7 of radiation therapy, and also on day 14 of radiation therapy. The authors assessed PET response by calculating the SUVmax within an ROI in the primary tumor region where high FDG uptake was noted. Using European Organization for Research and Treatment of Cancer criteria, patients were categorized as having CMR, PMR, SMD, or PMD. Patients who had either a CMR or PMR 70 days after radiation therapy had a significantly longer overall survival than patients with SMD or PMD (estimated survival of 100% versus 63% after 9 months of follow-up, p = 0.005).
      • van Baardwijk A
      • Bosmans G
      • Dekker A
      • et al.
      Time trends in the maximal uptake of FDG on PET scan during thoracic radiotherapy. A prospective study in locally advanced non-small cell lung cancer (NSCLC) patients.

      DISCUSSION

      In patients with unresectable clinical stage III and medically inoperable stage II NSCLC, concurrent chemoradiation therapy has become the standard of care. Despite improvements in outcomes with modern treatment protocols, reported median survival and 3-year survival rates of these patients remain relatively low. As new therapeutic regimens have been developed, it has become imperative to accurately assess patients’ early response to treatment. One of the most promising methods of posttreatment assessment is combined PET/CT. The structural information provided by CT is helpful in this regard. Nevertheless, posttreatment pulmonary radiation effect can create diagnostic uncertainty when trying to determine the presence of active tumor when CT alone is used in the assessment of treatment response.
      • Movsas B
      • Raffin TA
      • Epstein AH
      • Link Jr, CJ
      Pulmonary radiation injury.
      • Werner-Wasik M
      • Xiao Y
      • Pequignot E
      • Curran WJ
      • Hauck W
      Assessment of lung cancer response after nonoperative therapy: tumor diameter, bidimensional product, and volume. A serial CT scan-based study.
      • Libshitz HI
      • Sheppard DG
      Filling in of radiation therapy-induced bronchiectatic change: a reliable sign of locally recurrent lung cancer.
      • Lever AM
      • Henderson D
      • Ellis DA
      • Corris PA
      • Gilmartin JJ
      Radiation fibrosis mimicking local recurrence in small cell carcinoma of the bronchus.
      The metabolic information provided by PET, when combined with the anatomic information provided by CT, has provided clinicians and investigators with a new tool to evaluate response to treatment. The ability to predict clinical outcomes on the basis of posttreatment PET scans would represent a major breakthrough in the management of patients with NSCLC. Clinicians could alter treatment regimens and pursue salvage therapy in patients shown to have poor prognosis on posttreatment PET. Similarly, those patients with disease demonstrating a favorable prognosis could be given additional aggressive treatment with customized dose escalation to potentially obtain a durable response. In the research setting, investigators would be able to discontinue protocols deemed to be ineffective before the accumulation of long-term survival data.
      To our knowledge, seven studies have examined the prognostic value of posttreatment FDG uptake in patients with NSCLC treated with radiation therapy (Table 1). Each of these studies was a relatively small, single-institution study and all demonstrated that posttreatment PET had some prognostic value. Nevertheless, the studies used several different ways of measuring FDG uptake including: average activity (nCi/mL) within manually designated ROI
      • Hebert ME
      • Lowe VJ
      • Hoffman JM
      • Patz EF
      • Anscher MS
      Positron emission tomography in the pretreatment evaluation and follow-up of non-small cell lung cancer patients treated with radiotherapy: preliminary findings.
      ; TMR
      • Ichiya Y
      • Kuwabara Y
      • Sasaki M
      • et al.
      A clinical evaluation of FDG-PET to assess the response in radiation therapy for bronchogenic carcinoma.
      ; MRglc
      • Choi NC
      • Fischman AJ
      • Niemierko A
      • et al.
      Dose-response relationship between probability of pathologic tumor control and glucose metabolic rate measured with FDG PET after preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer.
      ; SUV
      • Ryu JS
      • Choi NC
      • Fischman AJ
      • Lynch TJ
      • Mathisen DJ
      FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology.
      • Pottgen C
      • Levegrun S
      • Theegarten D
      • et al.
      Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy.
      • van Baardwijk A
      • Bosmans G
      • Dekker A
      • et al.
      Time trends in the maximal uptake of FDG on PET scan during thoracic radiotherapy. A prospective study in locally advanced non-small cell lung cancer (NSCLC) patients.
      ; and visual assessments of tumor response.
      • Hebert ME
      • Lowe VJ
      • Hoffman JM
      • Patz EF
      • Anscher MS
      Positron emission tomography in the pretreatment evaluation and follow-up of non-small cell lung cancer patients treated with radiotherapy: preliminary findings.
      • Ryu JS
      • Choi NC
      • Fischman AJ
      • Lynch TJ
      • Mathisen DJ
      FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology.
      • Mac Manus MP
      • Hicks RJ
      • Matthews JP
      • Wirth A
      • Rischin D
      • Ball DL
      Metabolic (FDG-PET) response after radical radiotherapy/chemoradiotherapy for non-small cell lung cancer correlates with patterns of failure.
      TABLE 1Summary of Seven Studies Assessing the Prognostic Value of Posttreatment [18F] Fluorodeoxyglucose Uptake in Patients with Primary Non-small Cell Lung Carcinoma Treated with Radiation Therapy
      Author, YearPatients Receiving Posttreatment PETTiming of PET After TreatmentAssessment of FDG UptakeReference StandardMajor Findings
      Hebert, 19961512Not reportedQuantitative regions of interest; visual assessmentSerial imagingPrognostic value present: “complete response by PET scan appears to indicate a true local remission of disease”
      Ichiya, 19961620“Within 3 wk after completion of therapy”TMRFollow-up imagingPrognostic value present: TMR >5 after treatment associated with a significantly greater risk of relapse
      Choi, 20021729Two weeks after preoperative chemoradiationMRglcpTCP of surgical specimenPrognostic value present: for MRglc 0.5, accuracy predicting pathologic response was 83%; sensitivity and specificity were 86% and 81%, respectively; MRglc corresponding to pTCP 50% was 0.076 while for pTCP ≥95% it was ≤0.040
      Ryu, 20021823Two weeks after preoperative chemoradiationSUV; visual assessment of tumor responsePathologic findings from surgical specimensPrognostic value present: an SUV of 3.0 as a cut-off for differentiating between residual cancer and pathologic complete response had a sensitivity of 88% and specificity of 67%
      Mac Manus, 20051988Median of 70 d after completion of radiation therapyVisual assessment of tumor responseClinical follow-up; serial imaging; biopsyPrognostic value present: patients with PMD, SMD or PMD, and non-CMR had significantly shorter survival
      Pottgen, 20062043Median of 83 d after start of induction chemotherapySUVPathologic findings from surgical specimensPrognostic value present: an SUVmax cutoff point of 3.3 produced a maximum sum of sensitivity and specificity (0.8 for each) for predicting histopathologic response
      van Baardwijk, 20072120Median of 71 d after radiation therapySUVClinical follow-upPrognostic value present: patients who had either a CMR or PMR 70 d after radiation therapy had a significantly longer overall survival than patients with SMD or PMD
      PET, positron emission tomography; FDG, fluorodeoxyglucose; CT, computed tomography; TMR, tumor to muscle ratio; MRglc, residual metabolic rate of glucose; pTCP, pathologic tumor response; SUV, standardized uptake value; NR, no response; PD, progressive disease; CR, complete response; PR, partial response; CMR, complete metabolic response; PMR, partial metabolic response; SMD, stable metabolic disease; PMD, progressive metabolic disease.
      Clearly, standardized methods of FDG-uptake assessment need to be defined before widespread implementation. Another important issue is the optimal timing of PET after treatment. Performing PET scans too early after treatment can lead to over-estimation of FDG uptake since inflammation in treated tissue may still be active and residual glycolytic metabolism may still be occurring. However, obtaining PET scans after an excessively long interval may allow tumor recurrence.
      • Vansteenkiste J
      • Fischer BM
      • Dooms C
      • Mortensen J
      Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review.
      Some authors have noted that it may take lethally damaged cancer cells of NSCLC 8 to 12 weeks to undergo lysis after radiation therapy and FDG-PET may be more useful during this time period to assess response to therapy.
      • Choi NC
      • Fischman AJ
      • Niemierko A
      • et al.
      Dose-response relationship between probability of pathologic tumor control and glucose metabolic rate measured with FDG PET after preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer.
      Yet these authors also point out that if a boost dose predicated upon FDG uptake is planned, allowing such an interval may have a significantly adverse impact in obtaining tumor control because of the prolonged break in fractionated radiation therapy. In the aforementioned studies, posttreatment PET was performed 2 weeks to 71 days after completion of treatment. In the four more recent studies, where PET was generally performed later after treatment, the posttreatment PET had more prognostic value suggesting that the optimal timing of posttreatment PET may be 2 to 3 months after the completion of therapy. This requires further investigation.
      The seven studies have demonstrated that posttreatment FDG uptake of primary NSCLC treated with radiation therapy with or without chemotherapy has some prognostic value in terms of both overall survival and local control. Unfortunately, the heterogeneity of the studies precludes definitive statements regarding the prognostic value of posttreatment PET. Clearly, a large, multi-institution prospective study using standard quantitative methods of FDG-uptake assessment as well as standardized time-to-reimaging protocols is needed before posttreatment PET response can be used as an early proxy for the efficacy of treatment regimens.

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