Journal of Thoracic Oncology:
State of the Art: Concise Review
A Systematic Review of Restaging After Induction Therapy for Stage IIIa Lung Cancer: Prediction of Pathologic Stage
de Cabanyes Candela, Sara MD*; Detterbeck, Frank C. MD†‡
*Hospital Clínico Universitario de Valladolid, Valladolid, Spain; †Yale Cancer Center Thoracic Oncology Program; and ‡Smilow Cancer Hospital at Yale-New Haven Hospital, New Haven, CT.
Disclosure: The authors have no conflicts of interest to report.
Address for correspondence: Frank C. Detterbeck, MD, Section of Thoracic Surgery, Yale University School of Medicine, 330 Cedar St., BB 205, New Haven, CT 06520-8062. E-mail: firstname.lastname@example.org
Background: Many clinicians use restaging after induction therapy as a way to select patients for surgery.
Methods: A systematic review was conducted to define the reliability of restaging tests after induction therapy for stage III(N2) lung cancer, when compared with pathologic findings at surgery.
Results: A complete response at all sites carries a false-negative (FN) rate of 50% for computed tomography and 30% for positron emission tomography. Mediastinal node involvement has FN and false-positive rates of 33% and 33% by computed tomography, and 25% and 33% by positron emission tomography. The FN rate of invasive restaging is 22% by repeat mediastinoscopy, 14% by esophageal ultrasound and needle aspiration in expert hands (reliable results are not yet available for endobronchial ultrasound), and 9% by primary mediastinoscopy done with optimal thoroughness. These results are not significantly affected by the type of induction therapy or the timing of restaging.
Conclusion: The ability to identify patients who have achieved mediastinal downstaging other than by a careful primary mediastinoscopy is poor.
Stage IIIa non-small cell lung cancer (NSCLC) accounts for approximately one third of patients presenting with this disease, and most of this stage group consists of patients with malignant involvement of the mediastinal lymph nodes (N2,3).1 Although the optimal management of these patients is unclear, a common practice has become to consider preoperative (“induction”) therapy (chemotherapy ± radiotherapy [RT]) and possible surgery. Which patients are most appropriate to select for this approach is also unclear,2 but it is clear that a major prognostic factor is whether induction therapy achieves clearance of N2,3 node involvement (downstaging).3–5 This observation is based on the stage as determined after resection and raises the question of how well preoperative restaging tests can predict the pathologic stage and thus serve to select patients for resection.
Many physicians have, in fact, adopted the management strategy for stage IIIa(N2) NSCLC of induction treatment, followed by resection of patients believed to have been downstaged. This approach is taken despite the fact that most of the questions remain unanswered. Whether surgical resection adds further benefit over chemoradiotherapy is controversial.2,3,6 Should patients with a good response to chemoradiotherapy undergo surgery because of a good response or not undergo surgery because of a good response (or should resection be avoided in those with a poor response or actually be pursued provided there is no disease progression)2? Finally, whether restaging tests accurately predict the final pathologic stage and which restaging test is best are unclear. This article seeks to shed light on this last question.
We have conducted a systematic review of literature on methods of restaging after induction therapy for patients with stage IIIa(N2) NSCLC. The specific question addressed is how reliably each method of restaging predicts the actual pathologic stage. Methods of restaging include imaging (i.e., computed tomography [CT] or positron emission tomography [PET]), needle-based biopsy techniques (e.g., esophageal ultrasound or endobronchial ultrasound and needle aspiration [EUS/EBUS-NA]), or surgical techniques (e.g.,1st time mediastinoscopy or repeat mediastinoscopy). The primary question is how well restaging tests predict persistence or clearance of tumor from mediastinal nodes, because this is often cited as a criterion for selection of patients for resection. A secondary question is how well restaging tests can predict complete clearance of tumor from all sites (a pathologic complete response [pCR]), potentially making surgery unnecessary.
The postinduction therapy pathologic stage is, in reality, merely a surrogate end point for the real outcome measure of interest: long-term survival without recurrence. One can also pose the question of how well restaging tests predict survival and use the answers to select patients for a particular treatment approach. These issues are not addressed in this article but are the subject of another investigation. This review only addresses the end point of the correlation between restaging tests and actual pathologic stage, because many physicians already use restaging to select patients for surgery, without really knowing how well the restaging techniques actually perform.
PATIENTS AND METHODS
A systematic review was conducted of data defining parameters of reliability (sensitivity, specificity, false-negative [FN], and false-positive [FP] rates) of methods of restaging of the mediastinum or the primary tumor after induction therapy for NSCLC. The study question in this review was to what extent the restaging test correlates with actual pathologic findings. Studies reporting on restaging with an end point of survival rather than a microscopic assessment of nodal involvement were excluded; such studies were saved separately and comprise the subject of a separate review.
The point of the study question is to assess the ability to select individual patients for a particular treatment approach. For example, if the absence of viable tumor at all sites could be reliably predicted, such patients could avoid surgery. On the other hand, if persistent N2 involvement is used to preclude surgery (or clearance of the mediastinum is used to select for surgery), then the FP rate (or the FN rate) in the mediastinum is the key measure of a restaging test's value. These parameters allow assessment of a negative or positive restaging test result in an individual patient. In contrast, sensitivity and specificity are less clinically relevant because they assess the test performance in a population of patients in whom the true final result (presence or absence of cancer) is already known. It must be emphasized that sensitivity and specificity cannot be used to estimate the FN or FP rate because they are calculated by entirely different formulas (the only exception is perfect sensitivity or specificity [100%] which does predict a FN or FP rate of 0, respectively, in most cases). The parameter accuracy is avoided. Although this term satisfies a desire for simplicity, condensing to a single measure omits so much information that the number is not useful to interpret test results either for an individual patient or in comparison with other tests, and it varies with prevalence of disease. Furthermore, it is misleading because it implies accuracy of a test result for a patient, which it does not.
Restaging tests that were considered are CT, PET, any method of needle aspiration (i.e., EBUS, EUS, and transbronchial needle aspiration [TBNA]) or mediastinoscopy. The gold standard against which a restaging test was compared was microscopic assessment of mediastinal nodes or of the primary tumor. A positive microscopic result was considered acceptable, regardless of the technique used (e.g., mediastinoscopy, EUS/EBUS-NA, or thoracotomy), but a negative result was not counted unless based on surgical exploration. The thoroughness of intraoperative surgical evaluation may vary,7 and unfortunately few studies defined this. The intent appears to have been a lymphadenectomy in most studies, but details of what was actually done were generally not provided.
A Medline search was conducted using the search terms: lung cancer, non-small cell lung cancer, induction, neoadjuvant, mediastinal staging, restaging, CT, computed tomography, PET, PET-CT, positron emission tomography, endobronchial ultrasound, esophageal ultrasound, needle aspiration, mediastinoscopy, and remediastinoscopy. The search was limited to English language peer-reviewed articles published between 1980 and 2009. In addition, the reference lists of retrieved articles and reviews and guidelines addressing induction therapy and restaging were reviewed. The programs of major lung cancer meetings from 2000 to 2009 were scanned, and authors of pertinent unpublished studies were contacted. Articles were selected that involved either prospective or retrospective clinical studies reporting on restaging (before resection) after induction treatment (chemotherapy, RT, or a combination) if data on at least 20 patients was reported. Because of the paucity of articles on needle aspiration methods of restaging, this was expanded to articles reporting on these techniques in at least 10 patients. We intended to limit the review to patients with biopsy-proven stage III (N2,3) NSCLC, but many studies did not adhere to this strictly. Therefore, we accepted all studies involving induction therapy and restaging for NSCLC. However, we excluded articles that focused primarily on Pancoast tumors. Furthermore, we excluded articles that did not allow calculation of test parameters.
The search strategy yielded a list of 170 articles. These titles were scanned, and the abstracts of relevant article were reviewed. Articles potentially meeting the inclusion criteria were selected for full review. Together with the manual search this produced a total of 129 articles that were reviewed in full. In the case of duplicate articles, only one was chosen that contained the most information. Articles were excluded if a later, updated publication contained data on the same patients. However, if overlapping series contained some unique patients, both were included. This process resulted in the selection of 32 articles, which met the study criteria, and provided data addressing the study questions. Data extracted included the number of patients, the method of restaging, type of induction therapy, interval between completion of induction therapy and restaging, and the feasibility of performing the restaging test (i.e., how often where adequate results obtained when the technique was attempted).
Test parameters are defined in the usual manner: sensitivity = true positive/(true positive + FN); specificity = true negative/(true negative + FP); FN rate = FN/(true negative + FN); FP rate = FP/(true positive + FP).8,9 We prefer the more straightforward terms FN rate and FP rate rather than negative predictive value (= 1 − FN rate) or positive predictive value (= 1 − FP rate). Because the FN and FP rates are markedly affected if the prevalence is very low or very high,8,9 we excluded these values from calculation of averages if the prevalence was <10% or >90%., respectively. The specificity and FP rate of restaging was often not evaluable because further confirmatory testing was not generally done if microscopic evidence of N2,3 involvement was found. In contrast, the requirement of confirmation by thoracotomy of a negative restaging result allowed accurate assessment of the FN rate and sensitivity. All results are consistently reported relative to detecting the presence of cancer; this involved recalculation of parameters from some studies that reported results relative to the presence of a response (i.e., the lack of cancer). Test parameters are calculated based only on patients in whom the test was feasible, so that test results can be interpreted. (However, in comparing sensitivity, the reader must also take into account the feasibility.)
Summary results involved simple averages without weighting according to the study size. A formal meta-analysis was not done because of the limited number of patients and articles, the variety of induction treatments, and the variety of subjective or objective criteria used to classify restaging test results. Instead, details of these characteristics are included in the tables and footnotes, so that the consistency and heterogeneity of the studies can be qualitatively assessed by the reader. The quality of the articles was not rated, but use of an appropriate confirmatory standard (as defined above) was strictly required of included studies. However, the thoroughness of the restaging procedures was rated according to a proposed classification.7 An analysis of publication bias was not done. The entire project including the search, data analysis, and writing was conducted independently by the authors.
Prediction of pCR at All Sites
If complete clearance of tumor at all sites could be reliably predicted, then these patients could be spared surgical resection. Studies of induction therapy have indeed shown that a pCR is achieved in some patients, although the proportion is low (<20%).3,10–15 Studies that have evaluated imaging tests for a pCR are summarized in Tables 1 and 2. The prevalence of persistent disease is high in these studies, consistent with the low pCR rates achieved after induction therapy. Most importantly, though, the FN rate of a complete response by imaging is high (approximately 50% by CT and 30% by PET).
The rate of pCR can also be related to the degree of radiographic response. In studies of >20 patients who have reported such data, a pCR was noted in approximately 57% of patients (range, 0–100%) who had a radiographic CR,13,15–20 in 16% of patients (range, 0–35%) with a radiographic PR,13,15–21 and in 0 to 10% of patients with radiographic stable disease.13,15–18,20,21
The studies involving CT have shown a great deal of variability (range of FN rate 0–100%). It is not clear why this is the case; details of the CT imaging were often not provided. Nevertheless, this variability does not inspire confidence in the use of CT to predict a pCR. The FN rate for CT appears particularly high after chemoradiotherapy, which is disappointing, because there is little confidence that chemotherapy alone can curelung cancer.
The reliability of PET to detect residual tumor is more consistent but still carries an unacceptably high FN rate (∼30%). Most of the PET studies addressed only detection of residual cancer at the primary site. Subgroup analysis does not identify a group in which a negative PET is reliable (Table 2). The FP rate appears to be quite low in studies involving induction chemotherapy without radiation and in studies involving quantitative PET assessment (by the standardized uptake value or SUV). Cerfolio et al.,22 using a quantitative change from pre to postinduction PET, found better prediction of pCR after chemotherapy than chemoradiotherapy and after lower than higher doses of RT. Review of the results in Table 2 suggests this may be driven by differences in the FP rather than the FN rate. It should be noted that despite its name, SUV is not standardized, and there is significant variation between scanners and scans due to multiple factors.23,24
One study has analyzed in detail both CT and PET to define quantitatively what degree of change after induction treatment best predicts a pCR.22 CT did not perform well, even with a >90% decrease in the size of the primary cancer (FN rate 60%, FP rate 31%).22 The optimal change in SUV in the primary lesion by PET was found to be a >80% reduction (FN rate 0%, FP rate 5%). Whether this can be duplicated in a validation dataset from another institution remains to be seen. In summary, CT imaging is unable to reliably predict complete eradication of all viable tumor, and PET is generally also not sufficiently reliable, although a quantitative change of >80% holds promise.
Mediastinal Restaging by Imaging (CT and PET)
The major focus of reassessment after induction therapy is whether there is malignant involvement of the mediastinal lymph nodes. Studies addressing this issue using imaging techniques are summarized in Table 3. Surprisingly, few studies have formally evaluated the reliability of restaging by CT (six studies involving 190 patients). The results support the general belief that CT is a poor restaging test (FN and FP rates of approximately 40%). Even if one focuses only on the patients without a radiographic response to induction therapy (stable disease), a substantial portion (9–36%) have, in fact, been downstaged to ypN0,1.16,25–27 Therefore, neither a complete response nor a complete lack of response in the mediastinum by CT is reliable in identifying those who have or have not been downstaged.
Ten studies involving 398 patients have evaluated the ability of PET to determine downstaging from N2,3 to ypN0,1 (Table 3). PET restaging is associated with a high FN (25%) and FP rate (33%). Subset analyses do not reveal a group in which PET performed sufficiently well to serve as a restaging test (Figure 1). The results for PET imaging are quite consistent among studies, with the exception of a low FP rate in one study28 and a low specificity in another.29 An explanation for these outliers is not readily apparent.
In a retrospective analysis, Cerfolio et al. found that approximately 1 month was the optimal timing of a restaging PET/CT after chemoradiotherapy. The end point in the analysis was both the overall stage and the mediastinal node status as suggested by restaging PET/CT versus the result of biopsy or resection. Subset analysis of all studies did not show a difference between PET restaging in less than or greater than 4 weeks. However, this included both studies involving chemoradiotherapy and chemotherapy alone. It is possible that this may make a difference in the optimal timing of PET. Others have suggested that an early PET response (after one dose of chemotherapy) is highly predictive of outcomes (but have not reported results of early PET with respect to mediastinal downstaging).30 We were not able to analyze an interaction between early versus late PET imaging and induction chemotherapy versus chemoradiotherapy further from the data reported.
Mediastinal Restaging by Invasive Procedures
Five studies involving 515 patients (Table 4) report results of repeat mediastinoscopy for restaging of stage III NSCLC (as well as other studies involving smaller overlapping cohorts of patients). All patients had undergone previous mediastinoscopy (not EBUS), which involved biopsy of stations 2R, 2L, 4R, 4L, and 7. All groups used a similar technique consisting of opening the previous scar and entering the mediastinum through the left paratracheal space, followed by extension of the dissection to the right paratracheal space. All authors used a traditional mediastinoscope except De Leyn et al., who used a videomediastinoscope. The thoroughness of the mediastinal evaluation in these studies is high.
Remediastinoscopy has been found to be safe, although one death has been reported.31 The feasibility of remediastinoscopy was 87%. Remediastinoscopy was considered valid when all previously positive stations were biopsied, but two studies defined biopsy of any tissue as sufficient.32,33 There is no apparent difference in the feasibility whether RT was given or whether the procedure was performed earlier or later. It has been suggested that the low feasibility reported by De Leyn et al.28 was due to the use of the larger videomediastinoscope, although in general videomediastinoscopy performs better than traditional mediastinoscopy.34
Remediastinoscopy quite consistently carries a high FN rate (22%). This is not worse if induction therapy included RT; in fact, the FN rate is lower after induction chemoradiotherapy versus chemotherapy alone (15% versus 33%). Further subgroup analyses were not able to be performed from the data reported.
A prospective multicenter study has evaluated thoracoscopic restaging after previous mediastinoscopy and induction therapy in 70 patients,35 but only preliminary data are available. The feasibility of thoracoscopic restaging was 74%, although complete ipsilateral restaging was possible in only 57%. The reported test parameters are sensitivity 75%, specificity 100%, FN rate 24%, and FP rate 0%. However, it is not clear whether these values included all patients, all feasible procedures, or only procedures involving complete restaging.
Several authors have reported results of mediastinal restaging techniques that are based on needle aspiration, involving 191 patients (Table 4). This involves several smaller studies of EUS, a larger multiinstitutional study of EBUS and one study of TBNA without node visualization. The level of thoroughness of mediastinal staging in these studies is much more limited than for remediastinoscopy (average number of node stations sampled per patient of 1.2,36 1.4,37 and 1.638). The feasibility of performing an “adequate” EBUS/EUS evaluation of the mediastinum is high (97%).
The average FN rate of needle-based techniques of mediastinal restaging is surprisingly good (14%). This is surprising, because in general, needle-based mediastinal staging has been associated with a FN rate of approximately 20 to 25%,34,39 making it hard to believe it is better in the setting of restaging. The FN rate of 0 in the study of TBNA (without visualization) is particularly surprising and can perhaps be explained by the small study size and patient selection. Exclusion of this study results in a FN rate of 18%. Similarly, the study by Annema et al37 included selected patients with nodes in stations 7 or 4L that were easily accessible by EUS-NA. The study by Herth et al38 was prospective and very carefully done, but the unusually high prevalence of persistent mediastinal disease renders the FN rate unstable. However, this is the only study that allows assessment of the FP rate, because resection was carried out in all patients, regardless of the EBUS results. Although needle-based techniques have occasionally produced FP results,40–42 none were found.38 The limited number of studies did not allow subset analyses to be performed.
Two studies addressed the performance of first-time mediastinoscopy for restaging in a total of 85 patients.43,44 All these patients originally had mediastinal node involvement documented by a needle technique. These studies used either video-assisted mediastinoscopy or transcervical extended mediastinal lymphadenectomy and a very thorough mediastinal evaluation. Neither of the studies reported the interval between the conclusion of induction treatment and restaging, and most of patients underwent induction chemotherapy alone. Results of these studies are shown in Table 4.
Many physicians have adopted the treatment strategy of induction therapy followed by resection of those patients thought to be downstaged. However, many aspects of this are unclear, including whether the strategy itself is beneficial, what induction treatment should be given, or how patients should be selected for this approach. Perhaps most surprising is how convinced many are that the criteria for selection of patients for subsequent resection are well established. It is often forgotten that downstaged patients have been identified after resection. Use of downstaging to select patients for surgery requires a reliable method of identifying them before resection.
The most widely used method of selecting patients for surgery is the radiographic response by CT to induction therapy. This occurs despite the fact that virtually every study that has analyzed this has found little, if any, correlation between the response by CT and pathologic findings after resection. This review also confirms that a normal-appearing mediastinum after induction therapy carries a 30% FN rate and an abnormal mediastinum a 30% FP rate. Therefore, use of CT alone to either select patients for or exclude them from surgery is not justified, at least not if the goal is to only resect those patients who are downstaged. Furthermore, a complete response by CT cannot be used to justify avoidance of resection because of a 50% FN rate. Although a radiographic response makes the patient and the physician feel good, it provides little information about the presence of absence of viable tumor.
PET imaging is also commonly used to predict downstaging, although it is well recognized that RT can cause fluorodeoxyglucose uptake due to inflammation. Although PET performs somewhat better than CT, approximately one fourth of patients with a negative (“cleared”) mediastinum by PET still have pN2 involvement and approximately one third of those with persistent PET uptake in the mediastinum do not. Surprisingly, whether RT was given has no impact on these results. Indeed, no patient subsets could be identified in whom restaging PET is reliable. Finally, a complete response by PET in all sites cannot justify omitting resection: one third of such patients still have viable tumor. Perhaps more sophisticated assessments such as the percent change in PET activity can be used. However, it must be emphasized that such assessments require great attention to detail to ensure consistency in the measurements (i.e., the scanner, the region of interest, and the amount and timing of fluorodeoxyglucose).
Remediastinoscopy has been shown to be feasible and safe in experienced hands, but few institutions are comfortable with this technique. Because the results are disappointing (FN rate 25%), it is unlikely this will change. EBUS or EUS and needle aspiration are gradually becoming more widely available. The results seem to be slightly better than for remediastinoscopy (FN rate 15%), but the number of studies is limited, and it remains to be seen whether these will hold up as the procedure is practiced more widely (outside of the pioneering centers and in less well-selected patients). Primary mediastinoscopy performs fairly well, consistent with the performance of primary mediastinoscopy in general (especially the more thorough variations such as video-assisted mediastinal lymphadenectomy and transcervical extended mediastinal lymphadenectomy).39 However, this requires avoidance of mediastinoscopy in the initial staging. Often little thought is given to the eventual treatment strategy at the time that patients are first evaluated and staged.
A summary of the sensitivity and FN rates of various methods of restaging of the mediastinum is shown in Figures 2A, B. These results suggest that restaging to select only the patients who have been downstaged in the mediastinum for resection leaves much to be desired. Certainly, restaging by imaging alone is highly unreliable (both FN and FP rates are high). Furthermore, for those patients who have not been downstaged (by invasive restaging), it is unclear whether their survival is better with surgical resection or an alternative therapy (provided no distant metastases have appeared).2 It should be remembered that the majority of studies of induction therapy and resection took the approach of resection of all patients regardless of restaging (unless distant metastases had appeared). Restaging by EBUS/EUS is possibly acceptable if expertise is available or 1st time mediastinoscopy if thoughtful planning at presentation provided microscopic confirmation of N2,3 involvement without mediastinoscopy.
This review has only addressed the ability of restaging tests to reliably predict mediastinal downstaging (ypN0,1) and complete eradication of all tumor (pCR). This represents a surrogate end point that has been correlated with the ultimate goal of long-term cure. Studies linking characteristics of patients after induction therapy directly to long-term survival are beyond the scope of this review.
In summary, we have carried out a systematic review of studies addressing methods of restaging after induction therapy for stage III NSCLC, when compared with actual pathologic findings in the mediastinal nodes or primary site. Although these methods of restaging are commonly used to select or exclude patients from surgery, the data show them to be quite unreliable. In particular, mediastinal downstaging by CT, PET, or remediastinoscopy carry a FN rate of 20 to 30%. EUS and EBUS may perform slightly better, but data are limited. Primary mediastinoscopy seems to be the most reliable method of assessment. Ideally, initial invasive staging of the mediastinum should be done by a needle-based technique, so that primary mediastinoscopy can be used for restaging. Treatment approaches involving induction therapy and resection of downstaged patients should not be based on the assumption that imaging tests can predict the status of the mediastinal nodes.
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