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7
Routine Mediastinoscopy for Clinical Stage I Lung Cancer
Karl Fabian L. Uy and Thomas K. Waddell
operative staging in many countries, we will discuss this topic with and without the availabil- ity of PET as clinical scenarios.
7.1. Limitations
The available literature on this specifi c topic is limited. Although there is a modest collection of data on mediastinoscopy in general, few focus narrowly on this topic. The majority of reporting series contain the clinical stage I subgroup of patients, but this data is not reported separately and is not extractable. In addition to heteroge- neous populations, reports over the last two decades contain nonconsecutive patients and inconsistent screening criteria. The confusion is furthered by the varying qualities of the imaging equipment used for clinical staging. Because the present evidence has considerable faults and lim- itations, formulating a straightforward answer to this specifi c question is impossible. There is a greater volume of literature on chest CT and PET scanning, which has been summarized in a well- done meta-analysis,6 and to which we refer to rather than quoting each study separately.
7.2. Definition of Benefit
When a procedure or test is said to be “of benefi t,”
what is meant exactly, and how does this defi ni- tion affect the conclusions drawn? There are a few possible measures of benefi t from a strategy of routine mediastinoscopy. Survival, whether mea- Cervical mediastinoscopy is a widely used proce-
dure in the invasive staging of non-small cell lung cancer (NSCLC). It is a safe invasive diag- nostic procedure that has been shown to have a morbidity rate of 1.7%, a mortality rate of 0.07%, and an emergency thoracotomy rate of 0.12%.1–5 Most commonly, it is done after noninvasive staging modalities have demonstrated no advanced disease, and is the fi nal step in the determination of the benefi t of surgical resection. Mediastinos- copy policies differ among countries, institu- tions, and surgeons, but generally it is done either selectively or routinely. There is a strong consen- sus for performing this in patients with enlarged mediastinal lymph nodes, but there is less than widespread acceptance for performing it in the setting of normal-sized nodes. Certainly, the prevalence of N2 or N3 disease is lower when both hilar and mediastinal lymph nodes are not enlarged on anatomical studies like chest com- puted tomography (CT), and/or have no increased uptake on a metabolic imaging modality like positron emission tomography (PET). Yet, how low should this prevalence be before mediasti- noscopy no longer provides benefi t? This chapter discusses the issue of whether routine cervical mediastinoscopy is of benefi t when noninvasive studies have demonstrated clinical stage I disease.
Because our recommendations in large part depend on the performance characteristics of chest CT scan and PET scan, data pertaining to their use in this patient population is included;
however, we do not address the issue of whether PET should be included in the staging workup.
Also, because PET is not part of the routine pre-
sured absolutely or by quality-adjusted life-years (QALYs) is the most obvious. These can be used to factor cost effectiveness or cost utility, while costs are very sensitive to local system issues and diffi cult to widely translate. Another possible measure of benefi t that has been used in some studies is the rate of avoidance of “unnecessary”
thoracotomy.7 For example, some investigators might defi ne this as situations where N2 disease is discovered at thoracotomy in a cN0 patient, in which case an outright lung resection is deemed of no survival advantage compared to no resec- tion. We would contend that this defi nition and concept is at present being challenged by new evidence, such as large phase III trials of adjuvant chemotherapy.8,9
The decision to perform routine mediastinos- copy for clinical stage I lung cancer depends in large part on the treating physician’s opinion of how N2 disease is best treated. Specifi cally, what is the best treatment for clinical T1-2 N0 non- small cell lung cancer that turns out to be patho- logic N2? The options include routine surgical resection followed by adjuvant chemotherapy, neoadjuvant chemotherapy with or without radi- ation followed by surgery, or chemoradiation without surgery. Although mediastinoscopy does detect N3 disease and could contribute signi- fi cantly by excluding stage IIIB patients from surgery, the incidence of mediastinoscopy- detected N3 disease in the clinical stage I group is suffi ciently low – 0% to 1%10–12 – that it will not impact on our recommendations.
The best treatment for this very specifi c subset of patients is unknown. For those who feel that N2 disease is best treated without surgery at all, routine mediastinoscopy would clearly have some advantages. However, there is very little specifi c literature available on this subset of patients who are treated with chemoradiation alone. Thus, it is diffi cult to work out the cost savings per patient with this approach. Our view is that surgery is appropriate in many patients and has the potential to offer some improvement in survival. For example, we may make some inferences based on how overall N2 disease is best treated, and answers to this question are now emerging. The North American Intergroup 0139 trial is a multicenter randomized, controlled trial that explored the utility of preoperative chemo-
radiation followed by surgery versus chemoradi- ation alone for T1-3 N2 non-small cell lung cancer.
A statistically signifi cant 50% increase in median survival was found for those patients whose tumors were amenable to a lobectomy.13 However, patients who required pneumonectomy had a high operative mortality, and, in this group, the addition of surgery had no advantage to chemo- radiation alone in terms of overall survival. The patient population in this trial consisted of all categories of N2, but the subset of lobectomy patients probably represents a group with a lower tumor burden and therefore more similar to our patients of interest.
A cost-effectiveness analysis has been done, addressing the question of whether thoracotomy- discovered N2 disease is best managed by out- right resection or by aborting the lung resection, administering neoadjuvant chemotherapy, and subsequently re-operating and performing the lung resection should there be no progression.14 The pertinence of this analysis is that the patient population is predominantly cN0-1 who were subsequently found out to be pN2, which is pre- cisely the subset which routine mediastinoscopy hopes to pick up. Does picking up N2 preopera- tively in this subset provide any advantage over outright resection and just giving chemotherapy postoperatively? The answer from this analysis is yes, in terms of better median survival, QALY, and cost-effectiveness (incremental cost-effec- tiveness ratio of $17,119 per QALY), even with a reoperation. In this context, then, routine medi- astinoscopy would be benefi cial in reducing the number of patients subjected to exploratory tho- racotomy and ensures that the maximum number of patients will undergo the preferred treatment – neoadjuvant chemotherapy. The drawback of this 2003 analysis, though, is that it used survival estimates from the 1990s for the adjuvant chemo- therapy group. We now have mature results of two large phase III trials8,9 that demonstrate a larger survival benefi t for adjuvant cisplatin- based chemotherapy for stage IIIA; however, these studies combined T3N0 with cN2, and many of the patients did not have mediastinoscopy before treatment, so the clinical staging was not rigorously done. A direct comparison between pre- and postoperative chemotherapy adminis- tration will only be available when a phase III
trial comparing these two administration regi- mens matures in a few years (the NATCH trial – neoadjuvant taxol-carboplatin HOPE trial).
Our choice as to whether pre- or postoperative administration is better is central to our decision for choosing or rejecting a routine mediastinos- copy strategy. The survival advantages mentioned above are diffi cult to compare at present – however, it is a well-established fact that patients are far more compliant with preoperative (90%
completion) rather than postoperative (25%–65%
completion) chemotherapy,13,15–17 which alone would sway the balance towards preoperative administration. Our own experience with a stan- dardized regimen of induction chemoradiation followed by surgery for cN2 over the last 7 years resulted in a median survival of 40 months, which we consider very favorable compared to our pre- vious experiences with adjuvant chemotherapy.
This experience, along with a higher completion rate with preoperative chemotherapy, has fi rmly entrenched our belief that neoadjuvant is better than adjuvant administration for N2 disease.
If it is accepted that induction treatment is a benefi cial management strategy for N2 disease, then it would be useful to discuss routine medi- astinoscopy. The next issue then is the prevalence of N2 disease in CT with or without PET- determined N0 and the performance characteris-
tics of mediastinoscopy. The prevalence of N2 disease after successive steps in the preoperative workup is listed in Table 7.1.
7.3. Routine Mediastinoscopy in Clinical Stage I after a Negative PET Scan
Postiron emission tomography for staging of lung cancer has become widely used, particularly in the United States. After a negative PET scan, the prevalence of involved mediastinal nodes in clini- cal stage I is 4.8% to 11.7% (Table 7.1). There have been only two studies to our knowledge that address the specifi c issue of mediastinoscopy after PET.11,18 One study18 has more than double the prevalence of the other, in part because this paper refl ects a T2-3 population rather than T1-2 N0, and the paper did not clearly state the clinical N status so it is possible that there are some cN1 patients included in this series. The quoted preva- lence of 11.7%, therefore, is the mediastinoscopy- detected prevalence of involved mediastinal nodes in patients with cT2-3 and a negative PET scan. The incidence of thoracotomy-discovered N2 was not stated, so the post-PET + mediastinos- copy prevalence is unknown. In the other paper,11 which specifi cally considers our population of TABLE 7.1. Prevalence (false-negative rate) of N2 disease in clinical stage I non-small cell lung cancer.
Prevalence after
Staging examinations Reference N negative examinations Level of evidence After CT CLOG7 183 23% 1b De Leyn20 235 20% 4 Suzuki22 342 17% 4 Pieterman21 54 18.5% 1b Gould6 1119 20% 2a Choi12 291 15.5% 4
Average 19.2%
After CT + mediastinoscopy De Leyn20 235 10.6% 4 Choi12 291 9.2% 4
Kim23 343 6% 4
Average 8.3%
After CT + PET Gould6 479 6% 2a Viney10 42 4.8% 1b Meyers11 248 5.6% 2b
Gonzalez- 137 11.7% 4 Stawinski18
Average 6.7%
After CT + PET + mediastinoscopy Meyers11 178 4.5% 2b
interest, the post–negative PET, premediastinos- copy prevalence of N2 disease was 5.6%, and mediastinoscopy was able to reduce this to 4.5%.
The sensitivity of mediastinoscopy in this exten- sively screened population was thus 38%. This 1.1% reduction in prevalence was subjected to a cost-effectiveness analysis in the same paper, with two-way sensitivity analyses to examine the impact of changes in the prevalence of N2 and the benefi t of induction over adjuvant chemotherapy.
The results showed that routine mediastinoscopy would add an average 0.01 years (3.65 days) of life at a cost of $201,918 per life-year gained. Although cost is indeed relative, most payers (public or private) may fi nd this rather high. Sensitivity analyses showed that the prevalence of N2 would have to exceed 10% to reduce the cost to below
$100,000 per life-year gained. We cannot recom- mend routine mediastinoscopy after a negative PET if it only achieves a 1.1% reduction in N2 prevalence, with or without consideration of the high cost of this strategy (grade C recommenda- tion). The issue is not yet settled, however, as the above data on the value of mediastinoscopy in the context of a negative PET scan is derived from only one case series. Although this analysis was performed in a center of excellence where the diagnostic accuracy of PET and mediastinoscopy is probably above average, the data cannot be considered of suffi ciently high quantity and quality to resolve the issue, and the question of routine mediastinoscopy after negative PET scan- ning should be considered an unanswered one.
chest CT shows no enlarged hilar or mediastinal lymph nodes (N0). This prevalence has been reported to be 15.5% to 23%, in contrast to 4.8%
to 11.7% after PET (Table 7.1). The specifi city of mediastinoscopy has been repeatedly shown to be 100%, with a more variable sensitivity rate that averages 84%.19 However, these values were computed based on large series of patients with and without enlarged mediastinal lymph nodes, and its sensitivity should decrease as the preva- lence decreases. There are very few studies that specifi cally address the issue of routine medias- tinoscopy in cT1-2N0.12,23 The largest case series of 291 patients with this exact patient population found N2 disease in 9.2% of mediastinoscopy- negative patients.12 The sensitivity of mediasti- noscopy in this study was 44.4%, in an institution where mediastinoscopy was done for all surgical candidates, regardless of nodal status by imaging.
Another retrospective study done for economic analysis purposes reported a postmediastinos- copy prevalence of 6% despite including some cN1 patients.23
A reduction in N2 prevalence from an average 19.2% to 8.3% is not large, but we contend it is enough for surgeons to decide to routinely perform mediastinoscopy (grade C recommen- dation). Routine mediastinoscopy in the post-CT setting is also cost effective. As mentioned in the cost-effectiveness analysis paper that studied post-PET routine mediastinoscopy,11 a prevalence of N2 of 10% results in an expense of $100,000 per life-year gained. A 20% prevalence will reduce the cost per life-year gained even more.
Routine mediastinoscopy is not recommended in the context of a negative PET; current data suggest it only achieves a 1.1% reduction in N2 prevalence (level of evidence 1b to 4; recom- mendation grade C).
7.4. Routine Mediastinoscopy in Clinical Stage I after a Negative Chest CT Scan
In institutions where PET is not readily available, the argument for or against routine mediastinos- copy depends on the prevalence of N2 after a
In the absence of PET and in the context of normal mediastinal lymph nodes on CT, routine mediastinoscopy is recommended because it reduces N2 prevalence from 19% to 8% (level of evidence 1b to 4; recommendation grade C).
7.5. Perspective
Surgeons who choose to do selective mediasti- noscopy on post-CT clinical stage I patients usually base their decisions on histology, location of tumor (central versus peripheral), and tumor
size. Table 7.2 summarizes the prevalence of pN2 in papers that had data for clinical stage I patients.
Although there is a trend towards a higher pN2 rate in T2 as opposed to T1 lesions, the two series comparing central and peripheral lesions had opposite fi ndings, and none of the differences are signifi cant enough to make a recommenda- tion for selective mediastinoscopy in a particular group. Of note, a large, well-analyzed series24 found a signifi cant difference between central and peripheral tumor locations; but when the T3- T4 tumors were excluded, the difference became more modest (9.2% vs. 5.8%).
Histology, if it is available, provides a better discriminant of pN2 rates, with metastases found in an average 14% of non-bronchioloalveolar car- cinoma adenocarcinomas versus 8.9% of squa- mous cell carcinomas. However, the surgeon still has to contend with the knowledge that there is an 8.9% chance of missing N2 disease if he/she does not perform mediastinoscopy in stage I squamous cell carcinoma. There is not much data for large cell carcinomas, but the suggested pre- valence rates of 33% to 40%25,27,30,31 mandate a mediastinoscopy if this diagnosis is obtained preoperatively.
At our institution, routine mediastinoscopy continues to be done on all patients, whether clinical stage I by chest CT only, or by chest CT with PET. Continuing this practice has a number of advantages at the present time. Routine medi- astinoscopy provides the most precise staging, whether cost effective or not. Precision of staging, aside from benefi ting the individual patient (and society, indirectly), adds to the worldwide fund of knowledge about lung cancer staging and treatment, which if collected properly will even- tually generate enough data to answer questions like “should routine mediastinoscopy be done in clinical stage I lung cancer?” It maximizes oppor- tunities to offer patients the chance to participate in neoadjuvant trials for N2 disease. We consider these trials important, and it is precisely the patients with microscopic N2 disease who we believe are most likely to benefi t from an aggres- sive approach. Another advantage is the mainte- nance of expertise in this operator-dependent diagnostic modality, which has uses other than for staging lung cancer. Depending on an institu- tion’s patient population and mediastinoscopy policy, 5% to 20% of patients undergo mediasti- noscopy for non-lung cancer indications, the most common of which is undiagnosed medias- tinal lymphadenopathy. Greater than 90% of these lesions (half of which are benign) can be diagnosed by mediastinoscopy.1,32,33 For most of these patients, mediastinoscopy obviates the need for a thoracoscopy or thoracotomy. Thus, training and maintenance of competence through frequent mediastinoscopy is another indirect benefi t of a routine mediastinoscopy policy.
We believe that the data is suffi cient for the recommendation of routine mediastinoscopy in patients staged as cT1-2 N0 after chest CT.
However, the issue is unresolved in the increasing number of post-PET patients. A randomized trial of mediastinoscopy versus no mediastinoscopy in post-PET clinical stage I patients certainly could be done, though there will probably be little interest in pursuing this. In the absence of a randomized trial, prospective data collection in institutions implementing routine mediastinos- copy will probably be what will determine future practice. Of greatest usefulness would be an anal- ysis of the prevalence of N2 disease in PET- negative patients according to histology, location TABLE 7.2. Prevalence of pN2 in clinical stage I lung cancer by tumor
characteristics.
Primary tumor Reference N characteristics
Central Peripheral Daly24 501 9.2% 5.8%
Suzuki22 379 11.1% 18.5%
Average 10.0% 11.3%
Adenocarcinoma Squamous cell Vallieres25 35 15.8% 10%
Lewis26 418 7.3% 6.1%
Funatsu27 164 10.7% 7.1%
De Leyn20 235 21.5% 16.8%
Suzuki22 379 20% 12%
Choi12 291 11.5% 3.3%
Average 14.0% 8.9%
T2 T1 McKenna28 47 18%
Vallieres25 35 13%
Lewis26 418 8.5% 7%
De Leyn20 235 17.7% 9.5%
Tahara29 30 11%
Choi12 291 6.1% 8.9%
Average 10.4% 8.4%
of tumor, and T status. As in the discussion on selective mediastinoscopy for post-CT cN0, this information will refi ne the decision-making process. It should help thoracic surgeons decide which of their PET-negative stage I patients require mediastinoscopy, should they choose not to do it routinely. For now, however, it is sug- gested that thoracic surgeons perform routine mediastinoscopy on their patients until a suffi - cient body of evidence accumulates to better answer this question.
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