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Follow-Up of Patients after Stereotactic Radiation for Lung Cancer: A Primer for the Nonradiation Oncologist

      Background

      The use of stereotactic ablative radiotherapy (SABR) as primary treatment for early stage non–small-cell lung cancer, or for ablation of metastases, has increased rapidly in the past decade. With local recurrence rates reported at approximately 10%, and a patient population that is becoming increasingly fit and amenable to salvage treatment, appropriate multidisciplinary follow-up care is critical. Appropriate follow-up will allow for detection and management of radiation-related toxicity, early detection of recurrent disease and differentiation of recurrence from radiation-induced lung injury.

      Methods

      This narrative review summarizes issues surrounding follow-up of patients treated with SABR in the context of a multidisciplinary perspective. We summarize treatment-related toxicities including radiation pneumonitis, chest wall pain, rib fracture, and fatal toxicity, and highlight the challenges of early and accurate detection of local recurrence, while avoiding unnecessary biopsy or treatment of benign radiation-induced fibrotic lung damage.

      Results

      Follow-up recommendations based on the current evidence and available guidelines are summarized. Imaging follow-up recommendations include serial computed tomography (CT) imaging at 3–6 months posttreatment for the initial year, then every 6–12 months for an additional 3 years, and annually thereafter. With suspicion of progressive disease, recommendations include a multidisciplinary team discussion, the use of high-risk CT features for accurate detection of local recurrence, and positron emission tomography/CT SUVmax cutoffs to prompt further investigation. Biopsy and/or surgical or nonsurgical salvage therapy can be considered if safe and when investigations are nonreassuring.

      Conclusions

      The appropriate follow-up of patients after SABR requires collaborative input from nearly all members of the thoracic multidisciplinary team, and evidence is available to guide treatment decisions. Further research is required to develop better predictors of toxicity and recurrence.
      Stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiotherapy (SBRT), has become a standard treatment for inoperable, early stage non–small-cell lung cancer (NSCLC). SABR uses highly conformal radiotherapy plans, with rigorous patient setup procedures, to deliver large, ablative doses of radiotherapy in only a few treatment sessions, often between 1 and 8 fractions (Fig. 1). SABR differs from older radiotherapy techniques in several regards: overall treatment time is much shorter (usually 1–2 weeks duration versus 4–6 weeks, respectively); the dose per fraction is much larger (often 18 Gy per day, rather than 2 Gy per day, respectively); and SABR treatment plans allow for large “hot spots” within the tumor, sometimes more than 150% of the prescribed dose.
      Figure thumbnail gr1
      FIGURE 190-year-old man with severe COPD (GOLD III) presents with a biopsy-proven left lung cancer, treated with stereotactic radiotherapy (54 Gy in three fractions). Representative axial images correspond to: A, PET/CT. B, Patient setup, with ConeBeam CT matched to planning CT to confirm setup accuracy. C, SABR treatment plan. COPD, chronic obstructive pulmonary disease; PET, positron emission tomography; CT, computed tomography; SABR, stereotactic ablative radiotherapy.
      These differences in treatment planning and delivery are associated with increased biologic potency: local control rates after SABR are often reported as ~90% at 3 years.
      • Senthi S
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      Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: A retrospective analysis.
      ,
      • Nguyen NP
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      Can stereotactic fractionated radiation therapy become the standard of care for early stage non-small cell lung carcinoma.
      In light of these promising outcomes, and the relative convenience of SABR delivery using only a few fractions in an outpatient setting, the use of SABR in clinical practice for treating primary lung cancers and oligometastatic disease has increased rapidly.

      Lewis S, Salama J, Nakamura N, et al. Stereotactic ablative radiotherapy (SABR) for extra-cranial oligometastatic disease: How do Canadian practice patterns compare to the rest of the world? [abstract]. 2013 Canadian Association of Radiation Oncology Annual Meeting

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      These high rates of local control have led to suggestions that SABR may be as effective as surgical resection for the primary treatment of T1N0 or T2N0 NSCLC,
      • Senan S
      • Paul MA
      • Lagerwaard FJ
      Treatment of early-stage lung cancer detected by screening: Surgery or stereotactic ablative radiotherapy?.
      a suggestion that has led to debate and the launch of randomized comparisons with lobectomy or wedge resection as primary treatment in operable patients.
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      Unfortunately, three such randomized trials have closed because of a lack of accrual; as a result, randomized comparisons with surgery will not be available in the near future.
      The assessment of patients after SABR is an increasingly common scenario for the multidisciplinary team: not only are increased numbers of inoperable patients receiving SABR for lung cancer or oligometastatic disease but the use of SABR for borderline or potentially operable patients is also increasing.
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      Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small cell lung cancer.
      SABR recipients are increasingly fit with longer life expectancies, resulting in increased opportunity for surgical or nonsurgical salvage. For patients with local progression detected after SABR, several options may be associated with long-term survival, including surgical resection, targeted agents for patients harboring oncogene mutations, or in selected cases, repeat irradiation.
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      Stereotactic ablative radiotherapy for reirradiation of locally recurrent lung tumors.
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      Surgical treatment of local recurrence after stereotactic body radiotherapy for primary and metastatic lung cancers.
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      Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases.
      These posttreatment decisions often require collaboration between members of the thoracic multidisciplinary team, including radiation oncologists, surgeons, radiologists, pulmonologists/respirologists, pathologists, and medical oncologists. This overview will discuss common clinical and radiologic findings after SABR to help guide these multidisciplinary decisions.

      Radiation Pneumonitis after SABR

      With older conventional radiotherapy techniques for lung cancer, reported rates of radiation pneumonitis (RP) often ranged from 13% to 37%.
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      • Lock M
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      • Yu E
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      Prediction of radiation pneumonitis by dose - volume histogram parameters in lung cancer–a systematic review.
      Symptomatic RP is characterized by cough or dyspnea, often accompanied with fever, chest discomfort and pleuritic pain, sometimes requiring oxygen or hospitalization. Alternative diagnoses include infection, chronic obstructive pulmonary disease (COPD) exacerbation, recurrent tumor, lymphangitic carcinomatosis, among other entities,
      • Choi YW
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      Effects of radiation therapy on the lung: Radiologic appearances and differential diagnosis.
      and in approximately 50% of cases, accurate diagnosis of RP is difficult.
      • Yirmibesoglu E
      • Higginson DS
      • Fayda M
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      Challenges scoring radiation pneumonitis in patients irradiated for lung cancer.
      The standard first-line treatment of symptomatic RP is oral corticosteroid therapy. Response is usually rapid, and response rates of up to 80% have been reported.
      • Movsas B
      • Raffin TA
      • Epstein AH
      • Link Jr, CJ
      Pulmonary radiation injury.
      Less commonly, intravenous corticosteroids, oxygen support, and hospitalization may also be required. When discontinuing steroid therapy, slow tapering of corticosteroid is important to prevent relapse of symptoms.
      • Makimoto T
      • Tsuchiya S
      • Hayakawa K
      • Saitoh R
      • Mori M
      Risk factors for severe radiation pneumonitis in lung cancer.
      Because of the relatively small lung volumes irradiated to high doses during SABR, the development of dyspnea or RP after SABR is uncommon. In a multicenter prospective trial of 55 patients with inoperable stage I NSCLC receiving SABR (RTOG 0236),
      • Timmerman R
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      • Galvin J
      • et al.
      Stereotactic body radiation therapy for inoperable early stage lung cancer.
      the rate of grade 3 or 4 pulmonary or respiratory-tract-specific toxicity was 16%, and the rate of protocol-specified hypoxia or pneumonitis was 8%. In a meta-analysis of 11 observational studies of SABR (mostly prospective), the rate of severe (grade ≥ 3) RP following SABR was only 2%, with 0.8% of patients developing irreversible dyspnea.
      • Grutters JP
      • Kessels AG
      • Pijls-Johannesma M
      • De Ruysscher D
      • Joore MA
      • Lambin P
      Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: A meta-analysis.
      A recent randomized trial of 102 patients with T1 or T2N0 NSCLC compared stereotactic radiotherapy (66 Gy in three fractions) versus high-dose conventional radiotherapy (70 Gy in 35 fractions over 7 weeks). In the conventional arm, a 2 cm margin (compared with 0.5 cm for SABR) was added around the tumor to account for targeting uncertainties with the older technique. The trial, reported thus far in abstract form only, demonstrated that with these large margins, conventional RT was able to achieve similar local control as SABR, but with increased toxicity (RP rates 16% in the SABR arm versus 34% in the conventional arm). SABR was favored due to lower toxicity and much shorter treatment duration.

      Nyman J, Hallqvist A, Lund JA, et al. SPACE - A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC [abstract]. 2014 European Society for Radiotherapy and Oncology Annual Meeting

      SABR appears to be well tolerated in patients with severe COPD, regardless of oxygen dependence. In a retrospective study of 265 patients treated with SABR, the risk of RP ≥ Grade 1 was lower in patients with severe COPD, defined as a Global Initiative for Chronic Obstructive Lung Disease (GOLD) score of III or IV (odds ratio [OR] of RP 0.37 for GOLD III, compared with patients with GOLD 0, p < 0.01).
      • Takeda A
      • Kunieda E
      • Ohashi T
      • et al.
      Severe COPD is correlated with mild radiation pneumonitis following stereotactic body radiotherapy.
      Treatment-related mortality is also low: a systematic review of the literature comparing surgery to SABR in 176 patients with severe COPD (defined as GOLD score III or IV or a predicted postoperative forced expiratory volume in 1 second (FEV1) of ⩽ 40%), showed a 30-day mortality of 10% versus 0% respectively, favoring SABR. Local and locoregional control rates were excellent in all identified studies with either surgery or SABR (≥ 89%).
      • Palma D
      • Lagerwaard F
      • Rodrigues G
      • Haasbeek C
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      Curative treatment of stage I non-small-cell lung cancer in patients with severe COPD: Stereotactic radiotherapy outcomes and systematic review.
      Certain subgroups of patients may be at higher risk of RP, including patients with large tumors, and those with interstitial lung disease (ILD). In a small study of 18 patients with large tumors (defined as a planning target volume greater than 80 cc) treated with SABR, the crude risk of RP was 26%, and was closely correlated with several factors, particularly the volume of contralateral lung receiving a low-dose bath (≥ 5 Gy) of radiation.
      • Ong CL
      • Palma D
      • Verbakel WF
      • Slotman BJ
      • Senan S
      Treatment of large stage I-II lung tumors using stereotactic body radiotherapy (SBRT): Planning considerations and early toxicity.
      In one study, ILD was associated with an increased risk of severe and fatal RP of 26% versus 3% (crude rates, p < 0.001).
      • Takeda A
      • Sanuki N
      • Enomoto T
      • Kunieda E
      Subclinical interstitial lung disease: Is it a risk factor for fatal radiation pneumonitis following stereotactic body radiotherapy?.
      Because many patients with ILD are also at high risk of operative morbidity and mortality, SABR can be reasonably considered with caution after a patient discussion regarding risks and benefits, and attempts to optimize a patient's baseline status before treatment.
      Studies reporting on effects of SABR on pulmonary function show only small declines in pulmonary function. A retrospective study of 141 patients treated with SABR who underwent pre- and posttreatment pulmonary function tests (PFTs) detected only small declines in FEV1 or forced vital capacity (FVC), with statistical significance limited to patients with good baseline pulmonary function (i.e., mild/moderate COPD).
      • Takeda A
      • Enomoto T
      • Sanuki N
      • et al.
      Reassessment of declines in pulmonary function ≥1 year after stereotactic body radiotherapy.
      Nonsignificant declines in FEV1 were reported in another study of 92 patients, with declines in FEV1 of 1.88% predicted and in carbon monoxide diffusion capacity (DLCO) of 2.59% predicted.
      • Stephans KL
      • Djemil T
      • Reddy CA
      • et al.
      Comprehensive analysis of pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients.
      In RTOG 0236 described above, the mean decline in percent predicted FEV1 was 5.8% and in DLCO was 6.3% at 2 years, which did not meet statistical significance. Furthermore, baseline PFTs did not predict pulmonary toxicity or overall survival.
      • Stanic S
      • Paulus R
      • Timmerman RD
      • et al.
      No clinically significant changes in pulmonary function following stereotactic body radiation therapy for early- stage peripheral non-small cell lung cancer: An analysis of RTOG 0236.
      Patient-reported quality-of-life data also confirms a lack of quality-of-life decline after SABR.
      • Lagerwaard FJ
      • Aaronson NK
      • Gundy CM
      • Haasbeek CJ
      • Slotman BJ
      • Senan S
      Patient-reported quality of life after stereotactic ablative radiotherapy for early-stage lung cancer.

      Radiographic Patterns of Lung Injury Following SABR

      Although symptomatic RP after SABR is uncommon, radiographic radiation-induced lung injury (RILI) occurs frequently, as a result of the ablative doses of radiotherapy delivered to the peritumoral region. RILI can mimic a local recurrence (Fig. 2) both in morphologic appearance and time course, leading to an important clinical dilemma: how to accurately distinguish recurrence from fibrosis and determine when a biopsy or other intervention is warranted. This distinction is particularly important for an increasingly fit SABR patient population, where salvage options may still be considered, including surgical resection, reirradiation, combined chemoradiotherapy, or palliative local or systemic therapy. Inaccurate classification as benign radiation lung injury can confound timely detection and delay treatment of disease progression. Alternatively, inaccurate classification of RILI as local recurrence can lead to unnecessary biopsy or even salvage treatment with its associated risk of morbidities; biopsy or resection of pseudoprogression has been reported in several case studies in the literature.
      • Takeda A
      • Kunieda E
      • Takeda T
      • et al.
      Possible misinterpretation of demarcated solid patterns of radiation fibrosis on CT scans as tumor recurrence in patients receiving hypofractionated stereotactic radiotherapy for lung cancer.
      • Stauder MC
      • Rooney JW
      • Neben-Wittich MA
      • Garces YI
      • Olivier KR
      Late tumor pseudoprogression followed by complete remission after lung stereotactic ablative radiotherapy.
      • Taira N
      • Kawabata T
      • Ichi T
      • et al.
      Salvage operation for late recurrence after stereotactic body radiotherapy for lung cancer: Two patients with no viable cancer cells.
      Figure thumbnail gr2
      FIGURE 2SABR plan and follow-up imaging for the patient described in . Serial CT chest follow-up were scans obtained at 3, 9, 15, 22, 32, 35, and 39 months after radical treatment. The patient was not a candidate for salvage interventions and thus was monitored throughout without repeat biopsy. There was no change in RECIST measurement beyond 32 months. SABR, stereotactic ablative radiotherapy; CT, computed tomography.
      RILI can be classified as RP in the acute setting (within 6 months of treatment), and pulmonary fibrosis in the late setting (after 6 months and beyond). The degree of lung injury depends on multiple factors, including total dose and fractionation of irradiation, along with target size.
      • Palma DA
      • van Sörnsen de Koste J
      • Verbakel WF
      • Vincent A
      • Senan S
      Lung density changes after stereotactic radiotherapy: A quantitative analysis in 50 patients.
      RILI is reported to occur in 62% of patients treated with SABR in the acute setting, and in 91% of patients in the late setting, with the majority of patients remaining clinically asymptomatic.
      • Huang K
      • Dahele M
      • Senan S
      • et al.
      Radiographic changes after lung stereotactic ablative radiotherapy (SABR)–can we distinguish recurrence from fibrosis? A systematic review of the literature.
      Radiologic signs of fibrosis can potentially evolve even 2 years after treatment or beyond and does not follow a known predictable course.
      • Dahele M
      • Palma D
      • Lagerwaard F
      • Slotman B
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      Radiological changes after stereotactic radiotherapy for stage I lung cancer.
      Common patterns encountered on computed tomography (CT) radiographic imaging have been classified as, in the acute setting: consolidative or ground-glass opacity changes, each subdivided into diffuse (greater than 5 cm) or patchy (⩽ 5 cm), and in the late setting: modified conventional, mass-like, or scar-like patterns.
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      • Palma D
      • Lagerwaard F
      • Slotman B
      • Senan S
      Radiological changes after stereotactic radiotherapy for stage I lung cancer.
      • Palma DA
      • Senan S
      • Haasbeek CJ
      • Verbakel WF
      • Vincent A
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      Radiological and clinical pneumonitis after stereotactic lung radiotherapy: A matched analysis of three-dimensional conformal and volumetric-modulated arc therapy techniques.
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      • et al.
      Radiation injury of the lung after three-dimensional conformal radiation therapy.
      Despite this distinct range of morphologies, these categories are not generally used to predict recurrence. Furthermore, considerable interphysician variability in assessments can result from the subjective nature of the current image evaluation criteria.

      Faruqi M, Giuliani M, Raziee H, et al. Inter-rater reliability of the categorization of late radiographic changes after lung stereotactic body radiation therapy [abstract]. 2013 CARO Annual Meeting

      However, familiarity with common patterns of RILI may help facilitate diagnosis of local recurrence.

      Challenges in Response Assessment

      All follow-up imaging modalities have limitations in response assessment in the post-SABR setting. With CT alone, benign changes may appear as an evolving mass-like opacity, easily mistaken for local recurrence.
      • Dahele M
      • Palma D
      • Lagerwaard F
      • Slotman B
      • Senan S
      Radiological changes after stereotactic radiotherapy for stage I lung cancer.
      ,
      • Matsuo Y
      • Nagata Y
      • Mizowaki T
      • et al.
      Evaluation of mass-like consolidation after stereotactic body radiation therapy for lung tumors.
      The standard evaluation of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 presents challenges in the post-SABR setting, because these criteria rely on diameter alone to classify response, and increasing areas of fibrosis may meet the criteria for progressive disease. RECIST measurements should be done in the plane of image acquisition (axial for body CT).
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      • Therasse P
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      • et al.
      New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).
      Positron emission tomography (PET) also has limitations: acute inflammatory reaction within lung parenchyma exposed to ablative doses of radiation can result in falsely elevated metabolic activity suggestive of malignancy.
      • Hoopes DJ
      • Tann M
      • Fletcher JW
      • et al.
      FDG-PET and stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer.
      ,
      • Matsuo Y
      • Nakamoto Y
      • Nagata Y
      • et al.
      Characterization of FDG-PET images after stereotactic body radiation therapy for lung cancer.
      PET is more costly than CT and is not often a routine posttreatment investigation at many centers; and standardized uptake value (SUV) measurements are not fully quantitative and are dependent on more complex standardization procedures.
      • Boellaard R
      Need for standardization of 18F-FDG PET/CT for treatment response assessments.
      Studies reporting on imaging predictors of response after SABR are limited by the lack of pathologic proof of recurrence for many patients, because of the relative frailty of the SABR patient population and/or the avoidance of biopsy where there is a lack of options for salvage in the event of a positive result. This lack of pathologic proof of recurrence may introduce bias, creating a circular argument whereby imaging is used to define the recurrence endpoint, and then the same imaging modality is investigated as a predictor of recurrence, overestimating the predictive ability of such tests.
      A systematic review has identified certain radiographic high-risk features (HRFs) suggestive of recurrence after SABR as per Table 1.
      • Huang K
      • Dahele M
      • Senan S
      • et al.
      Radiographic changes after lung stereotactic ablative radiotherapy (SABR)–can we distinguish recurrence from fibrosis? A systematic review of the literature.
      ,
      • Huang K
      • Senthi S
      • Palma DA
      • et al.
      High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer.
      To reduce the potential bias associated with imaging-defined recurrences, HRFs were validated using CT datasets from known pathology-proven recurrences, who were matched to nonrecurrences, in a blinded study.
      • Huang K
      • Senthi S
      • Palma DA
      • et al.
      High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer.
      The best HRFs in terms of both sensitivity and specificity were enlargement after 12 months and cranio-caudal growth of ≥ 5 mm and ≥ 20% (Table 1). The presence of three or more HRFs predicted local recurrence with high sensitivity and specificity (over 90%).
      Table 1High-Risk Features on CT Predictive of Local Recurrence
      • Huang K
      • Senthi S
      • Palma DA
      • et al.
      High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer.
       High-Risk FeatureSensitivity (%)Specificity (%)
       Enlarging opacity at primary site9267
       Sequential enlargement67100
       Enlargement after 12 months10083
       Bulging margin8383
       Linear margin disappearance42100
       Loss of air bronchogram6796
      • Cranio-caudal growth of ≥5 mm
      • and ≥20%
      9283
      CT, computed tomography.
      Functional imaging by FDG-PET can complement suspicious CT findings, although FDG avidity can appear transiently following SABR and even persist at a low value for over 12 months.
      • Huang K
      • Dahele M
      • Senan S
      • et al.
      Radiographic changes after lung stereotactic ablative radiotherapy (SABR)–can we distinguish recurrence from fibrosis? A systematic review of the literature.
      Lung injury following ablative radiotherapy can result in transiently increased metabolically activity resulting in false-positive FDG avidity. Such FDG avidity may lead to unnecessary biopsy of benign inflammatory tissue and has been described as “pseudoprogression” in several case reports.
      • Stauder MC
      • Rooney JW
      • Neben-Wittich MA
      • Garces YI
      • Olivier KR
      Late tumor pseudoprogression followed by complete remission after lung stereotactic ablative radiotherapy.
      ,
      • Frechette KM
      • Brown LC
      • Aubry MC
      • Wigle DA
      • Olivier KR
      Pseudoprogression after stereotactic body radiotherapy.
      Falsely elevated SUVmax readings of up to 7.0 has been detected shortly following SABR treatment in patients who ultimately were not classified as having progressive disease.
      • Feigenberg S
      • Yu J
      • Eade T
      FDG PET response by 3 months following stereotactic body radiotherapy for non-small cell lung cancer may be an early surrogate of local failure [abstract].
      Although the data is highly heterogeneous, a posttreatment SUVmax ≥ 5.0, or greater than the original pretreatment SUVmax appears most suggestive of recurrent disease.
      • Huang K
      • Dahele M
      • Senan S
      • et al.
      Radiographic changes after lung stereotactic ablative radiotherapy (SABR)–can we distinguish recurrence from fibrosis? A systematic review of the literature.
      ,
      • Essler M
      • Wantke J
      • Mayer B
      • et al.
      Positron-emission tomography CT to identify local recurrence in stage I lung cancer patients 1 year after stereotactic body radiation therapy.
      • Takeda A
      • Yokosuka N
      • Ohashi T
      • et al.
      The maximum standardized uptake value (SUVmax) on FDG-PET is a strong predictor of local recurrence for localized non-small-cell lung cancer after stereotactic body radiotherapy (SBRT).
      • Bollineni VR
      • Widder J
      • Pruim J
      • et al.
      Residual (1)(8)F-FDG-PET uptake 12 weeks after stereotactic ablative radiotherapy for stage I non-small-cell lung cancer predicts local control.
      In another study with 17 local recurrences, SUVmax cutoffs as low as 3.2 and 4.2 have been reported, with sensitivity and specificity of 100% and 96–98%, respectively; however, not all recurrences were pathologically proven.
      • Takeda A
      • Kunieda E
      • Fujii H
      • et al.
      Evaluation for local failure by 18F-FDG PET/CT in comparison with CT findings after stereotactic body radiotherapy (SBRT) for localized non-small-cell lung cancer.

      Other Adverse Effects of SABR

      Patients receiving SABR are also at risk of nonpulmonary adverse effects. Approximately one-third of patients will experience fatigue,
      • Lagerwaard FJ
      • Aaronson NK
      • Gundy CM
      • Haasbeek CJ
      • Slotman BJ
      • Senan S
      Patient-reported quality of life after stereotactic ablative radiotherapy for early-stage lung cancer.
      which is usually self-limiting. Uncommon acute or sub-acute adverse effects can include skin toxicity, chest wall pain (CWP), and nausea, whereas late effects can include ongoing CWP, rib fracture, and rarely, injury to the mediastinal structures when SABR is delivered to centrally located tumors.
      The incidence of CWP and rib fracture can be mitigated using a risk-adapted treatment strategy, whereby the risk of toxicity for tumors adjacent to the chest wall can be minimized by giving SABR over more fractions (i.e., using a smaller daily dose). Based on radiobiological modeling, smaller daily fraction sizes can substantially decrease the risk of late side effects.
      • Yang J
      • Lamond J
      • Fowler J
      • Lanciano R
      • Feng J
      • Brady L
      Effect of fractionation in stereotactic body radiation therapy using the linear quadratic model.
      In a study cohort of 42 patients treated with stereotactic radiotherapy doses of 54–60 Gy delivered over only three fractions to all patients regardless of tumor location, high rates of chest wall toxicity were observed, with nine patients developing rib fracture.
      • Voroney JP
      • Hope A
      • Dahele MR
      • et al.
      Chest wall pain and rib fracture after stereotactic radiotherapy for peripheral non-small cell lung cancer.
      Alternatively, using a risk-adapted radiation treatment scheme as described above and delivering 55 Gy over five fractions (two additional fractions) for tumors abutting the chest wall, lower toxicity rates have been achieved, with reported CWP and rib fracture of only 11.4% and 1.6%, respectively.
      • Bongers EM
      • Haasbeek CJ
      • Lagerwaard FJ
      • Slotman BJ
      • Senan S
      Incidence and risk factors for chest wall toxicity after risk-adapted stereotactic radiotherapy for early-stage lung cancer.
      A separate study of 69 patients used a similar risk-adapted approach, delivering either 54 Gy in three fractions, or 50–60 Gy in five fractions, the latter in patients with significant chest wall dose. The authors report a low incidence of chest wall toxicity at 20 months posttreatment, with chest wall pain in six patients (8.3%; one [1.4%] grade 3, as per CTCAE version 4.0) and rib fracture in five patients (6.9%).
      • Coroller TP
      • Mak RH
      • Lewis JH
      • et al.
      Low incidence of chest wall pain with a risk-adapted lung stereotactic body radiation therapy approach using three or five fractions based on chest wall dosimetry.
      Fatal toxicity has been reported in the treatment of central tumors or tumors located within 2 cm of major structures such as the bronchial tree, trachea, or major vessels—accordingly termed the “no fly zone” in SABR—particularly when such tumors are treated with three-fraction regimens. These excessive toxicities were most notably reported in a prospective phase II trial of medically inoperable early stage lung cancer of 70 patients, where patients were treated with the equivalent of approximately 54 Gy in three fractions, and the 2-year freedom from severe toxicity was 83% for patients with peripheral tumors and only 54% for patients with central tumors.
      • Timmerman R
      • McGarry R
      • Yiannoutsos C
      • et al.
      Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer.
      In a 4-year update, severe toxicities occurred in 10.4% of patients with peripheral tumors and 27.3% of patients with central tumors (p = 0.088).
      • Fakiris AJ
      • McGarry RC
      • Yiannoutsos CT
      • et al.
      Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: Four-year results of a prospective phase II study.
      A case of central airway necrosis following SABR treatment to a central tumor has also been well described.
      • Corradetti MN
      • Haas AR
      • Rengan R
      Central-airway necrosis after stereotactic body-radiation therapy.
      The risk of severe toxicity appears to be closely related to dose and fractionation. In a systematic review of 315 patients with centrally located tumors treated by SABR using various fractionation schemes, overall treatment-related mortality rate was reported at 2.7% and rates of Grade 3 or 4 toxicities were less than 9%.
      • Senthi S
      • Haasbeek CJ
      • Slotman BJ
      • Senan S
      Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review.
      The authors observed a dose–response relationship for toxicity, with a 75% reduction in treatment-related mortality (from 2.7% to 1%) when patients receive a lower biologically effective dose, ⩽ 210 Gy

      Lewis S, Salama J, Nakamura N, et al. Stereotactic ablative radiotherapy (SABR) for extra-cranial oligometastatic disease: How do Canadian practice patterns compare to the rest of the world? [abstract]. 2013 Canadian Association of Radiation Oncology Annual Meeting

      (a measure of the biologic effect of radiation on a particular tissue, taking into account radiation dose per fraction and total dose). In a recent study of 100 patients with centrally located tumors, the most common toxicity was chest wall pain (18% grade 1, 13% grade 2) followed by RP (11% grade 2, 1% grade 3) with no grade 4–5 toxicity noted.
      • Chang JY
      • Li QQ
      • Xu QY
      • et al.
      Stereotactic ablative radiation therapy for centrally located early stage or isolated parenchymal recurrences of non-small cell lung cancer: How to fly in a “no fly zone”.
      For a more in-depth review of the issues regarding treatment of central tumors with stereotactic radiation, the reader is referred to the relevant article in this IASLC series.

      Chang J, Bezjak A. Stereotactic radiation for central tumors. J Thoracic Oncol. 2014 in press

      Toxicities related to SABR in a reirradiation scenario, either as primary or salvage treatment for local recurrence, a secondary lung primary, or metastases, has been described in a limited number of small retrospective studies and in a systematic review. In a study of 39 patients who were treated with salvage SABR following conventional radiotherapy, 23% of patients had grade 2–3 RP, 3% had grade 4 skin toxicity, and no grade 5 toxicity was reported.
      • Reyngold M
      • Wu AJ
      • McLane A
      • et al.
      Toxicity and outcomes of thoracic re-irradiation using stereotactic body radiation therapy (SBRT).
      In a similar larger study of 72 patients, salvage SABR following prior radiotherapy resulted in 20.8% of patients with severe RP (≥ grade 3), with one grade 5 fatality (~1%). Grade 5 toxicity rates, however, vary greatly among studies and fatality has been reported in as high as 12% of patients.

      Huang K, Rodrigues GB, Yaremko B, et al. Stereotactic ablative radiotherapy (SABR) and pulmonary re-irradiation: A systematic review of the literature assessing safety and oncologic outcomes [abstract]. 2014 American Society for Radiation Oncology 56th Annual Meeting

      In a repeat SABR scenario, Peulen et al. reported on 32 lesions in 29 patients, with 17% grade 4–5 toxicity and 10% (n = 3) grade 5 toxicity consisting of massive hemoptysis. Notably, all patients with severe toxicity had centrally located tumors. Overall in the systematic review, of 19 studies involving 466 patients that reported on SABR in various reirradiation scenarios, the rates of grade 1–3 RP, grade 4 toxicity and fatal toxicity was reported in 124 (27%), 2 (less than 1%) and 8 patients (1.7%), respectively.

      Huang K, Rodrigues GB, Yaremko B, et al. Stereotactic ablative radiotherapy (SABR) and pulmonary re-irradiation: A systematic review of the literature assessing safety and oncologic outcomes [abstract]. 2014 American Society for Radiation Oncology 56th Annual Meeting

      The data suggests that toxicity may be increased in a repeat reirradiation scenario and repeat SABR should be considered with caution. Given most fatal toxicities occurred in patients treated for centrally located tumors, repeat irradiation of such lesions should be avoided or given with caution.
      Toxicities following the treatment of multiple primary lung cancers by SABR have also been reported. In one study, synchronous lesions treated to a dose of 54–60 Gy in 3–8 fractions were described in 56 patients, and no Grade 4–5 toxicities were observed after a median follow-up of 44 months.
      • Griffioen GH
      • Lagerwaard FJ
      • Haasbeek CJ
      • et al.
      Treatment of multiple primary lung cancers using stereotactic radiotherapy, either with or without surgery.
      Given a favorable toxicity profile, and 85% lesional control rates, the authors conclude multiple SABR treatments for multiple primary lung cancers without nodal metastasis can be considered as a radical treatment option. Another study where SABR represented the second treatment after an index/dominant tumor was treated by any modality, grade ≥ three RP was also low, reported in 2 of 71 patients (3%).
      • Chang JY
      • Liu YH
      • Zhu Z
      • et al.
      Stereotactic ablative radiotherapy: A potentially curable approach to early stage multiple primary lung cancer.

      General Follow-Up Recommendations

      Follow-up recommendations, including the frequency and duration of follow-up imaging for lung cancer survivors, are based nonrandomized studies. A retrospective study on the patterns of recurrence following SABR in a large cohort of 124 patients with disease recurrence from the Netherlands showed the vast majority of recurrences occurred within the first 3 years after treatment
      • Senthi S
      • Lagerwaard FJ
      • Haasbeek CJ
      • Slotman BJ
      • Senan S
      Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: A retrospective analysis.
      ; a corresponding posttreatment CT imaging follow-up has been proposed at 6-month intervals for the first 3 years, and annually thereafter.
      Published consensus guidelines are also available. The American Association for Thoracic Surgery guidelines, applicable to lung cancer survivors eligible for additional therapy, recommend high-resolution surveillance CT scans every 6 months during an initial 4-year surveillance period; in the absence of concerning signs of recurrent disease, the frequency of follow-up imaging can be reduced to an annual low-dose screening CT, to account for the risk for a second lung cancer diagnosis of 3% per year.
      • Jaklitsch MT
      • Jacobson FL
      • Austin JH
      • et al.
      The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups.
      National Comprehensive Cancer Network guidelines recommend imaging surveillance with a chest CT scan (contrast optional) every 6–12 months for 2 years, then a noncontrast-enhanced chest CT scan annually, in the absence of clinical/radiographic evidence of disease.
      Consolidating the various published guidelines as summarized above, a general approach to follow-up of patients following SABR treatment should include physical assessment every 3–6 months during the initial year following treatment, followed by every 6–12 months for 3 years, then annually thereafter. Exact frequency and duration of follow-up can be left to the discretion of the treating physician's clinical assessment. For example, the presence of CT findings on follow-up imaging may prompt more frequent imaging.
      In the setting of suspicious findings on imaging, guidelines for follow-up of patients after SABR are currently lacking. A systematic follow-up imaging algorithm based on HRFs and SUVmax thresholds based on current evidence is available for reference and provides literature-based guidelines for management until further evidence becomes available.
      • Huang K
      • Senthi S
      • Palma DA
      • et al.
      High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer.
      This algorithm combines high-risk CT features and FDG-PET as tools for the prediction and accurate diagnosis of local recurrence. Patients are categorized as having a low-, intermediate-, or high-risk of recurrence based on the number of high-risk CT features present (no HRFs, 1–2 HRFs, or ≥ 3 HRFs, respectively). Subsequent management is based on this risk stratification: low-risk patients with no HRFs can be imaged every 3–6 months for 1 year, after which an imaging interval of 6–12 months can be considered; intermediate-risk patients with the presence of 1–2 HRFs can benefit from an FDG-PET/CT if available and close follow-up; patients at high-risk of recurrence with the presence of more than three HRFs can be investigated with a biopsy or can proceed directly to salvage treatment. When available, SUVmax values that are either greater than five, or exceeding pretreatment SUVmax values, trigger additional interventions including biopsy, resection, or nonsurgical salvage. Applicability of this follow-up scheme depends on the specific clinical scenario, and recommendations are expected to change as more data becomes available. More rigorous follow-up and early investigation for any suspicion of disease progression may also be justified in patients with known pretreatment risk factors for local recurrence such as larger lesions (T2), suboptimal radiation dose, and perhaps high pretreatment SUVmax.
      • Takeda A
      • Yokosuka N
      • Ohashi T
      • et al.
      The maximum standardized uptake value (SUVmax) on FDG-PET is a strong predictor of local recurrence for localized non-small-cell lung cancer after stereotactic body radiotherapy (SBRT).
      ,
      • Dunlap NE
      • Larner JM
      • Read PW
      • et al.
      Size matters: A comparison of T1 and T2 peripheral non-small-cell lung cancers treated with stereotactic body radiation therapy (SBRT).
      ,
      • Zhang J
      • Yang F
      • Li B
      • et al.
      Which is the optimal biologically effective dose of stereotactic body radiotherapy for Stage I non-small-cell lung cancer? A meta-analysis.
      Whenever possible, lung cancer patients with suspicious findings on radiographic follow-up scans who are amenable to salvage treatment should be discussed by a multidisciplinary team. Salvage surgery after SABR appears to be safe: at least four small studies have reported on patients who have undergone surgery for salvage of a post-SABR recurrence.
      • Chen F
      • Matsuo Y
      • Yoshizawa A
      • et al.
      Salvage lung resection for non-small cell lung cancer after stereotactic body radiotherapy in initially operable patients.
      • Hamamoto Y
      • Kataoka M
      • Yamashita M
      • et al.
      Lung-cancer related chest events detected by periodical follow-up CT after stereotactic body radiotherapy for stage I primary lung cancer: Retrospective analysis of incidence of lung-cancer related chest events and outcomes of salvage treatment.
      • Neri S
      • Takahashi Y
      • Terashi T
      • et al.
      Surgical treatment of local recurrence after stereotactic body radiotherapy for primary and metastatic lung cancers.
      • Allibhai Z
      • Cho BC
      • Taremi M
      • et al.
      Surgical salvage following stereotactic body radiotherapy for early-stage NSCLC.
      Across these four studies, such surgery is generally well tolerated with a favorable toxicity profile, with only one patient sustaining a major toxicity (fistula requiring further surgery for correction).
      • Neri S
      • Takahashi Y
      • Terashi T
      • et al.
      Surgical treatment of local recurrence after stereotactic body radiotherapy for primary and metastatic lung cancers.
      Salvage repeat irradiation in the setting of SABR has shown good outcomes in terms of local control, and overall survival, although toxicity is likely higher, as described above. Reirradiation with SABR as either primary or salvage treatment resulted in local control rates ranging from 65.5% to 75% at 1 year.

      Huang K, Rodrigues GB, Yaremko B, et al. Stereotactic ablative radiotherapy (SABR) and pulmonary re-irradiation: A systematic review of the literature assessing safety and oncologic outcomes [abstract]. 2014 American Society for Radiation Oncology 56th Annual Meeting

      Future Directions

      The results of ongoing research in response assessment will continue to shape the optimal imaging and follow-up guidelines for lung cancer patients in the coming years. Large studies examining patients with pathologic proof of recurrence would be ideal to investigate and test new imaging biomarkers. Given the relative uncommon clinical scenario of local recurrence that is confirmed pathologically, multi-institutional efforts would be required to assemble such data. New quantitative methods such as CT image feature analysis and further characterization of posttreatment FDG-PET SUVs
      • Takeda A
      • Enomoto T
      • Sanuki N
      • et al.
      Reassessment of declines in pulmonary function ≥ 1 year after stereotactic body radiotherapy.
      and other biologic markers are emerging.
      • Yamashita H
      • Kobayashi-Shibata S
      • Terahara A
      • et al.
      Prescreening based on the presence of CT-scan abnormalities and biomarkers (KL-6 and SP-D) may reduce severe radiation pneumonitis after stereotactic radiotherapy.
      ,
      • Mattonen SA
      • Huang K
      • Ward AD
      • Senan S
      • Palma DA
      New techniques for assessing response after hypofractionated radiotherapy for lung cancer.
      Ultimately, further study is needed to help reduce physician uncertainties in imaging response assessment, which is becoming an increasingly critical aspect of survivorship for patients undergoing SABR for NSCLC and their physicians within the multidisciplinary team.

      ACKNOWLEDGMENT

      Dr. Palma is supported by a Clinician-Scientist Grant from the Ontario Institute for Cancer Research.

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