8 Management of Unexpected N2 Disease Discovered at Thoracotomy

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8

Management of Unexpected N2 Disease Discovered at Thoracotomy

Hyde M. Russell and Mark K. Ferguson

incomplete and often inaccurate. Arguments for aborting a planned resection when N2 nodal disease is discovered intraoperatively include:

the morbidity of an exploratory thoracotomy is substantially less than that of a formal lung resection; preoperative systemic therapy is more effective in prolonging survival than is postoperative adjuvant therapy; and not all patients with N2 nodal disease should be subjected to resection. There is no direct comparison of outcomes of the two choices to guide decision making in this setting, and conclusions must be extrapolated from several different data sets.

8.1. Published Data

The current practice pattern among most thoracic surgeons who discover involved ipsilateral mediastinal nodes at the time of formal lung resection is to proceed with the planned resection.³ Determining the optimal therapy for such patients requires examining all available options, including surgery alone, surgery with postoperative therapy, induction therapy followed by resection, and chemoradiotherapy alone. In order to obtain data for comparison of these four choices, published outcomes from a variety of studies were reviewed. A Medline search of English lan- guage publications from 1990 to 2005 using the criteria “lung resection” and “lung neoplasm”

and “stage III” or “mediastinal adenopathy” or

“N2” yielded 744 results. One hundred twenty abstracts were reviewed and an article search was performed on selected abstracts. Additional The appropriate therapy for stage IIIa (N2) non-

small cell lung cancer (NSCLC) is not clearly established. Recent randomized trials demonstrate that preoperative chemoradiotherapy followed by resection improves long-term and disease-free survival compared with surgery alone.^1,2 These results have bolstered the interest in multimodality treatment for patients with resectable N2 disease. Furthermore, the literature suggests that neoadjuvant therapy followed by surgery is superior to resection and subsequent adjuvant treatment, although such a comparison has not been deﬁ nitively studied. Based on these results, patients who are found to have N2 nodal metastasis prior to thoracotomy, using methods such as mediastinoscopy, thoracoscopy, endoscopic ultrasonography, transbronchial needle aspiration, or possibly positron emission tomography (PET) scanning, should receive neoadjuvant treatment prior to resection.

A therapeutic dilemma arises when unsuspected N2 nodal disease is encountered intraoperatively during a planned formal lung resection for clinical stage I or II NSCLC. The management options include proceeding with resection or aborting the planned resection to allow for neoadjuvant treatment with possible subsequent reoperation and resection. The prevailing practice pattern favors initial resection for several reasons: the patient has already been subjected to the morbidity of a thoracotomy; intraoperative mediastinal nodal staging is time consuming and is unlikely to change the long-term outcome; and many surgeons perform only sampling of suspi- cious nodal stations at best, making nodal staging

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references from article bibliographies were included as appropriate.

8.1.1. Surgery Alone for N2 Disease

The reported outcomes of surgically resected N2 disease are uniformly poor, with 5-year survival ranging from 10% to 27%, with most articles reporting 20% survival at 5 years and median survival times of 18 to 24 months.^4–8 (Table 8.1).

Despite these low numbers, surgery remains a common therapeutic option because the outcomes for resected patients are still signiﬁ cantly better than for those who do not undergo operation, in whom 5-year survival is 0%. While this difference may largely be due to a selection bias that eliminates patients with advanced age, poor performance status, and clinical N2 disease from consideration for resection, surgery clearly has an impact in some patients. A Japanese study⁶ evaluated the prognosis of N2 NSCLC in 222 patients who had undergone resection. Overall, 5-year survival was 27%, but in subgroup analyses survival varied markedly from 0% to over 50%. Prognostic factors found to be particularly important were clinical N2 nodal status, multiple diseased N2 nodes, tumor size, and complete resectability. Patients with clinical N2 disease, often described as bulky stage IIIa disease, and multiple pathologic mediastinal nodes had a 5- year survival of 5%; in those who exhibited neither of those factors survival was 57% at 5 years. The site of N2 disease was also signiﬁ cant:

patients with involved inferior N2 nodes fared worse (5-year survival 12%, p < 0.05) than others.

Miller and associates⁷ at the Mayo Clinic performed a retrospective analysis of 167 patients

who were found to have N2 disease at thoracotomy. Multivariate analysis revealed that younger age, negative inferior lymph nodes, fewer involved nodal stations, postoperative radiotherapy, and lobectomy rather than pneumonectomy all had a signiﬁ cant positive impact on survival. Their patients’ 5-year survival rates following lobectomy and pneumonectomy were 31% and 17%.

These outcomes demonstrate the heterogeneity of this population of patients and reveal that, while some patients clearly derive beneﬁ t from surgery, others are subjected to the risks of lung resection without an appreciable impact on the course of their disease.

8.1.2. Adjuvant Therapy

Postoperative (or adjuvant) chemotherapy has been the subject of many randomized, controlled trials, seven of which speciﬁ cally address stage III disease (Table 8.2), and two of which focus solely on patients with N2 metastases.^9–15 The results of these studies as a whole have largely been disappointing, as six of seven studies failed to ﬁ nd an advantage to the use of adjuvant chemotherapy. A phase III trial conducted at Memorial Sloan-Kettering in 1994 randomized seventy-two patients with stage IIIa N2 disease to surgery with or without adjuvant chemotherapy.

Median and 5-year survivals were 16.5 months and 17% in the treatment arm compared with 19.1 months and 30% in the control group, leading the investigators to conclude that there was no evidence of beneﬁ t from the postoperative chemotherapy that was administered.

The Japan Clinical Oncology Group reported results of a phase III study in 1993 in which they randomized 181 patients with completely resected stage III disease to receive postoperative chemotherapy (cisplatin + vindesine) or no further treatment. They also failed to demonstrate any beneﬁ t to the postoperative regimen. Three-year disease-free survival rates were 37% versus 42%, and median survivals were 31 months and 37 months for the treated and untreated group, respectively.

More recently in Japan, Tada and colleagues looked speciﬁ cally at patients with N2 metastases. One hundred nineteen patients with completely resected N2 disease were randomized to TABLE 8.1. Outcomes of surgery alone for N2 disease.

Median

No. survival 5-year

Reference Year patients (months) survival (%) EBM grade

Van 1993 44 12 10% 3

Klaveren³

Ishida⁴ 1990 115 n/a 18% 3

Suzuki⁵ 1999 222 30 27% 3

Miller⁶ 1994 167 18 21% 3

Nakanishi⁷ 1997 53 25 21% 3

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adjuvant chemotherapy versus no further treatment. Five-year survivals were 28% in the treatment group and 36% in the control arm. Median disease-free survivals were 18 months versus 16 months respectively, and no statistical difference was found between the two groups.

The International Adjuvant Lung Cancer Trial Collaborative Group produced the one study that did fi nd a statistically signifi cant survival advantage to postoperative chemotherapy. One thou- sand eight hundred sixty-seven patients with stage I-IIIa disease who underwent complete resection were randomized to chemotherapy versus observation. At fi ve years, 45% of treatment arm patients were alive compared with 40%

of the control group (p < 0.03). Patients with N2 disease constituted 26% of the study population.

Among this subgroup, 32% of patients in the chemotherapy group were alive at the end of the study compared with 28% in the control group.

No statistical information is given regarding the N2 subgroup, but the ﬁ nding represents a mar- ginal improvement at best.

The lack of beneﬁ t demonstrated by postoperative chemotherapy in patients with N2 nodal metastasis has made its application controversial

among providers. With regard to the clinical problem of N2 nodal disease discovered at the time of surgery, there is no evidence that the availability of postoperative adjuvant therapy should alter the decision of whether or not to proceed with resection.

8.1.3. Induction Therapy

In contrast to the lack of beneﬁ t observed with adjuvant therapy in stage III N2 disease, preoperative or neoadjuvant chemotherapy shows more promise. Four prospective randomized studies comparing induction chemotherapy to surgery alone were published from 1992 to 2005 (Table 8.3).

Roth and colleagues¹ at MD Anderson randomized 60 patients with resectable stage IIIa NSCLC to either preoperative chemotherapy (PCT) followed by surgery or surgery alone (SA).

Eighty-three percent of the patients had histo- logically conﬁ rmed N2 disease and they were equally distributed between the two groups.

The operations (lobectomy, bi-lobectomy, and pneumonectomy) were similar between the two groups, as was the rate of resectability. The TABLE 8.2. Outcomes of randomized, controlled studies of adjuvant postoperative therapy.

Stages No. patients Median survical months: 5-year overall survival: EBM Reference Year included (%N2) Regimen treatment vs. control treatment vs. control p value grade Pisters⁹ 1994 IIIa, N2 72 (100%) CT/RT vs. RT 16.3 vs. 19.1 17% vs. 30% 0.42 1− Tada¹¹ 2003 IIIa, N2 119 (100%) CT vs. observation 18.3 vs. 16.1 28.2% vs. 36.1% 0.89 1+ Ohta¹⁰ 1993 III 181 (66%) CT vs. observation 31 vs. 37 35% vs. 41% 0.595 1+ Dautzenberg¹³ 1995 I–IIIa 267 (51%) CT/RT vs. RT N2: 15.3 vs. 8 N2: 19% vs. 6% 0.003 1+ ECOG¹⁴ 2000 II–III 488 (54%) CT/RT vs. RT 38 vs. 39 33% vs. 39% 0.56 1++

IALT¹² 2000 I–IIIa 1867 (25%) CT/RT vs. RT na N2: 32% vs. 28% na 1++

Scagliotti¹⁵ 2003 I–IIIa 1209 (25%) CT vs. Obs w/wo 55.2 vs. 48 Stage IIIa 20% ns 1++

RT (43% with) vs. 19%

Abbreviations: na, not applicable; ns, not significant.

TABLE 8.3. Outcomes of randomized studies of preoperative therapy.

Median survival (months): 5-year overall survival:

Reference Year No. patients treatment vs. control treatment vs. control p value EBM grade

Roselle⁸ 1999 60 22 vs. 10 17% vs. 0% <0.001 1−

Roth⁷ 1998 60 64 vs. 11 36% vs. 15% 0.056 1−

Pass ¹⁹ 1992 27 28 vs. 15 nd 0.095 1−

Nagai⁹ 2003 62 17 vs. 16 10% vs. 22% 0.53 1+

Abbreviation: nd, not determined.

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median survival of preoperative chemotherapy group was 64 months compared to the surgery- only group’s 11 months. A long-term follow-up to this study was published in 1998¹⁶: 5-year survival was 36% in the PCT group and 15% in the SA group. When analysis was limited to those patients who were able to be resected, the median survival in the PCT group had not yet been reached, and the median survival of the SA group was 18 months. Five-year survival rates among resected patients were 53% versus 24%, favoring the PCT group.

These impressive results were supported the following year by a Spanish study conducted by Roselle and others,² which randomized 60 patients to PCT + surgery or surgery alone. Both groups received postoperative radiotherapy. In the PCT group, 17% of patients were alive at 5 years compared with none in the surgery alone group.¹⁷ Median survival was 26 months for PCT patients versus 8 months for the SA patients. This study was criticized on several issues: small size (60 patients), lack of biological equivalence between the two arms according to K-ras muta- tions and aneuploidy favoring the treatment arm, and unexpectedly low control group results.

Those criticisms aside, the evidence remains compelling enough to recommend preoperative therapy to patients with documented N2 disease.

In contrast to the dramatic results of these two studies, two negative studies have been published more recently. Nagi and associates¹⁸ with the Japan Clinical Oncology Group released data on 62 patients, all with N2 nodal metastasis, who were randomized to PCT or surgery alone with a median follow-up period of 6.2 years. Median survival was 17 months for the PCT group and 16 months for surgery alone. Five-year survival esti- mates were 10% [95% conﬁ dence interval (CI), 0%–20%] for the induction patients and 22%

(95% CI, 7%–37%) for the surgery-alone group.

Pass and colleagues at the National Institutes of Health (NIH) published their data on a small randomized study comparing preoperative etoposide–platinum chemotherapy followed by surgery versus surgery with postoperative radiotherapy. Twenty-seven patients were randomized with a median follow-up of 30 months. Median survival for the preoperative chemotherapy group

was 29 months versus 16 months for the control group. Although the difference was remarkable, this result did not reach statistical signiﬁ cance (p = 0.095).¹⁹

Despite these confl icting results in studies of small sample sizes, the magnitude of benefi t in the Roth and Roselle studies is compelling. In addition, a meta-analysis of four neoadjuvant studies was performed in 2004.²⁰ Quantitative analysis of the pooled survival curves found a nonsignifi cant hazard ratio (HR) of 0.65 (95% CI, 0.41–1.04) in favor of neoadjuvant chemotherapy in stage III disease.

8.1.4. Chemoradiotherapy Alone

Surgery has traditionally been the mainstay of potentially curative treatment for resectable disease. Given recent improvements in chemotherapy outcomes which rival those of surgery, the role of resection in the treatment of stage III N2 disease is increasingly a topic of debate. The North American Intergroup 0139 trial released interim data in abstract form at the 2005 Ameri- can Society of Clinical Oncology (ASCO) meeting.²¹ This trial included 484 patients with stage III N2 disease who were considered potentially resectable. Induction chemoradiotherapy was given to all patients followed by a re- evaluation and subsequent randomization of surgery eligible patients to either resection or observation. Both arms received consolidation chemotherapy (postoperatively in the surgery arm). There were 16 treatment-related deaths in the surgery arm, 14 of which occurred in pneumonectomy patients (26% of all pneumo- nectomies). In contrast, there were only four treatment-related deaths in the control group.

The pattern of recurrence was signiﬁ cantly different between the two groups with 10% local relapse in the surgery group and 22% in the control arm. There was no difference in the devel- opment of distant metastasis between the two groups (37% vs. 42%). Tumor downstaging was evident with 46% of all resected specimens reveal- ing N0 status. Five-year progression-free survival (PFS) was statistically different between the two groups favoring surgery (22% resected group vs.

11% observation group). There was a trend towards superior overall survival at 5 years in the

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surgery group (27% vs. 20%) but this difference did not reach statistical signiﬁ cance. Tumor downstaging appeared to affect overall survival:

patients who were pN0 had a 41% 5-year survival compared with 24% in pN1–3 patients.

To clarify the effect of the pneumonectomy- related deaths on the study, an exploratory subgroup analysis was performed based on surgical procedure. Chemoradiotherapy followed by lobectomy had a statistically signiﬁ cant improvement in survival compared with matched con- trols in the non-operative arm (median, 34 vs. 22 months, 5-year, 36% vs. 18%). In contrast, neoadjuvant treatment followed by pneumonectomy resulted in no beneﬁ t over chemoradiotherapy alone (median, 19 vs. 29 months, 5-year, 22% vs.

24%).

This survival difference between pneumonectomy and lobectomy has been noted in previous studies of patients with N2 disease.^4,6,7 In one of these studies, the survival curves diverged even after the ﬁ rst year, suggesting that perioperative mortality may not be solely responsible for the long-term differences. Regardless of the cause, the ﬁ nding raises the question of whether resection should be offered to a patient with N2 metastasis if a pneumonectomy is required.

8.2. Evidence Quality

The data discussed above come from multiple disparate sources of varying quality. The retrospective studies on surgery for N2 disease are case series and, as such, each receives a score of 3. The evidence regarding the effectiveness of adjuvant therapy is derived from prospective randomized, controlled trials and is graded between 1− and 1+. Likewise, the induction therapy studies also receive grades of 1− to 1+.

The meta-analysis of these level 1 studies is graded as 1++. Because none of these studies deals speciﬁ cally with the question at hand, data are extrapolated from them and applied to the problem. Finally, the Intergroup 0139 trial data has been released only in abstract form, which prevents assigning a formal grade.

Given the study design and number of patients enrolled, it will likely meet criteria for a grade of 1+.

8.3. Discussion

Unsuspected N2 nodal metastasis found at the time of exploratory thoracotomy for intended resection is a problem that arises in approximately 15% of cases. There have been no phase III trials performed specifi cally addressing this clinical situation, and the clinical decision to proceed versus abort relies on the interpretation of a com- bination of studies. Although it is diffi cult to directly compare the studies investigating neoadjuvant therapy with those looking at adjuvant therapy because of the heterogeneity of the patient population, neoadjuvant therapy appears to offer a survival benefi t that has not been matched with adjuvant treatment. Retrospective studies looking at this problem have attempted to identify factors that may help predict in which subgroup of patients it makes sense to continue with resection.

Multivariate analyses have shown that tumor size, the number of involved nodes, and completeness of resection all statistically impact survival.

However, fully evaluating lymph node status at the time of thoracotomy is generally not feasible.

In addition, these same factors (smaller tumor size, number of nodal stations, extent of resection) are characteristic of the best subgroups in the neoadjuvant therapy studies and only streng then the argument in favor of stopping the operation to intervene with chemoradiotherapy before returning for formal resection. We now know that there are clearly select patients with N2 disease who beneﬁ t from surgical resection. However, the current evidence suggests that providing this group with the best available cancer treatment requires preoperative chemoradiotherapy.

Given the oncologic superiority of induction therapy followed by subsequent resection, the cli- nician is then faced with the question of whether this approach makes sense for the individual patient from a quality-of-life and cost standpoint.

A meta-analysis of survival data from published reports of patients undergoing resection with unsuspected N2 disease plus data from neoadjuvant therapy trials was performed by Ferguson in 2003.²² Using decision analytic techniques, variables were weighted using a quality-of-life utility scale and costs of various treatment options cal- culated for a comparison of outcomes with the primary end points of median survival, QALY,

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and cost effectiveness. The results of this analysis favored aborting the initial resection to perform induction therapy followed by subsequent re- exploration and resection. As expected, median survival was higher in the induction therapy group (2.1 years vs. 1.7 years). Interestingly, despite prolonging the treatment time with induction therapy followed by a second operation and recovery, the QALY were greater (1.8 vs. 1.3) and the difference in cost per QALY was negligi- ble. The author suggested that the survival advantage is a reﬂ ection of both the beneﬁ t of induction therapy combined with the exclusion of patients with more aggressive disease who progressed during therapy and did not return for resection.

Given the importance of the weighted values assigned to the decision analysis variables, the results must be interpreted carefully. However, it is the ﬁ rst paper to quantify outcomes of the potential treatment choices in the setting of unsuspected N2 disease, and the conclusions are logical even if the inputs are subject to debate.

8.4. Recommendations

The accumulated data favor induction therapy over postoperative therapy for non-small cell lung cancer with N2 nodal involvement. When unsuspected N2 nodal disease is encountered during planned lung resection, our recommendation is to abort the operation to allow for neoadjuvant therapy. Provided the patient exhibits either a response to therapy or stable disease, subsequent redo thoracotomy and resection should be offered provided that the lesion is deemed completely resectable. Patients requiring pneumonectomy to achieve a complete resection should be selected with great care given the uncertainty of beneﬁ t in this population.

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