Management of Stage III, N2 NSCLC: A Virtual Thoracic Oncology Tumor Board Abstract Introduction Management of stage III non small-cell lung cancer (NSCLC) is complex and requires careful work-up, staging, and decision making. Stage III NSCLC comprises a heterogeneous population of patients, so accurate staging is important. Multiple treatment approaches are available, and appropriate selection must be individualized based on patient and tumor characteristics. Multidisciplinary evaluation is generally necessary in deciding between surgical and nonsurgical approaches and between chemotherapy or chemoradiation. In this webcast, a multidisciplinary virtual thoracic oncology tumor board reviews the case of a 55-year-old former smoker with stage III NSCLC. They review relevant data for treatment planning and debate the appropriate work-up and management of this case. Key messages from their discussions are summarized here. Diagnosis and Work-Up of Locally Advanced NSCLC Invasive procedures are, unfortunately, necessary to accurately diagnose nodal involvement. Positron emission tomography (PET) scan and other imaging tools are not sufficiently accurate to diagnose mediastinal lymph node positivity, so a positive PET scan merits further work-up before definitive treatment planning. Lymph node staging generally requires either mediastinoscopy or endobronchial ultrasound with transbronchial needle aspiration of the lymph nodes (EBUS-TBNA). Endoscopic esophageal ultrasound with needle aspiration is a less well-studied approach, but when combined with EBUS-TBNA, allows for evaluation of some additional groups of nodes that would otherwise not be accessible by EBUS-TBNA alone. Mediastinoscopy is the gold standard for lymph node staging, but EBUS-TBNA has shown good sensitivity and specificity in recent studies. It is also important to think ahead, because if restaging following induction therapy is likely to be needed, it is best to avoid performing two mediastinoscopies. In such cases, EBUS-TBNA would be preferred as the initial staging modality. Lymph node staging distinguishes stage IIIA from stage IIIB NSCLC, which is important in determining candidacy for surgery. Surgical Versus Nonsurgical Approaches Patients with stage IIIB NSCLC are generally not considered candidates for surgery and would therefore be treated with definitive chemoradiation. There is considerably more debate about resection for patients with stage IIIA NSCLC. Stage IIIA is potentially curable disease with 5-year survival rates of 20% to 30% or greater.
The only data available to drive decision making regarding whether to perform surgery for stage IIIA NSCLC are from the Intergroup 0139/RTOG 9309 study presented by Albain et al at the 2005 annual meeting of the American Society of Clinical Oncology. In this study, 396 patients with T1-3N2M0 NSCLC were randomized to receive chemoradiation followed by either surgery or continued radiation. Chemoradiation consisted of cisplatin, etoposide, and radiation therapy with 45 Gy. The nonsurgical group continued radiation to 61 Gy. Following surgery or continued radiation therapy, all patients received consolidative chemotherapy with two cycles of cisplatin/etoposide. The surgical arm had significantly better progression-free survival (PFS), which at 5 years was 22.4% versus 11.1% with chemoradiation alone (P =.017). However, no statistically significant difference in overall survival (OS) was observed. At 5 years, OS was 27.2% with surgery versus 20.3% without surgery (P <.1). Perioperative mortality may explain the lack of survival advantage for the surgical group in INT 0139/RTOG 9309. One quarter of the surgical patients died in the perioperative period, with the highest mortality rate in patients who underwent right pneumonectomy. A post hoc subgroup analysis did find a significant OS advantage for those who underwent lobectomy compared with matched patients in the chemoradiation group (36% versus 18% 5-year OS, respectively; P =.002). Based on this analysis, surgery would be the preferred management for patients who are candidates for lobectomy, especially those with single-station N2 disease. Appropriate candidates should be referred to high-volume centers with multidisciplinary tumor boards and surgeons experienced in lobectomy. Arguments in favor of a nonsurgical approach (ie, chemoradiation) are that: (1) no OS benefit was seen in the INT 0139/RTOG 9309 study in the overall study population; (2) no prospective randomized data show a survival advantage for surgery over concurrent chemoradiation; and (3) phase II studies of chemoradiation with current radiation techniques yield similar outcomes to studies combining chemoradiation and surgery. It should also be noted that many patients are not surgical candidates because lung cancer often occurs in patients with other pulmonary diseases, such as chronic obstructive pulmonary disorder. Pulmonary function testing should be performed, and predicted function postlobectomy should be calculated before deciding whether a patient is medically fit to undergo surgery. Preoperative Induction Therapy For patients who are considered surgical candidates, the next question is whether preoperative induction therapy should consist of chemotherapy alone or chemoradiation. No prospective randomized phase III study has been completed to address this issue. The rationale for using chemotherapy alone is that it has reduced toxicity compared with chemoradiation, and morbidity and mortality are particularly reduced in pneumonectomy patients. Furthermore, it is easier to perform mediastinoscopy for restaging and easier to perform surgery after chemotherapy than after chemoradiation. For these reasons, many cancer centers prefer to give induction chemotherapy alone and then postoperative chemoradiation. In a phase II RTOG study, docetaxel/cisplatin produced a pathologic
complete response in 19% of patients with stage IIIA pn2 NSCLC. The study was originally intended to have a concurrent chemoradiation arm using the same chemotherapy regimen, but was never completed due to inadequate accrual. The rationale for preoperative chemoradiation is that it is associated with an increased pathologic response and likelihood of nodal clearance or downstaging compared with chemotherapy alone. It may in fact be necessary for patients with bulky disease in order to facilitate resection. For those receiving chemoradiation, radiation doses of 45 to 74 Gy have been studied. Higher doses (74 Gy) are usually given with 3-D conformal approaches since they reduce the volume of normal tissue exposed to radiation and therefore are associated with less risk of toxicity. Outside of clinical trials, standard practice for those receiving chemoradiation is usually to treat with radiation to a total of about 66 Gy. Following induction therapy, it may be helpful to restage the patient before surgery, particularly if a pneumonectomy is planned. Restaging is less necessary before a lobectomy. The decision regarding whether to restage is influenced by not only the type of surgery to be performed but also by whether a mediastinoscopy was done previously. If restaging is performed, a mediastinoscopy is preferred if not previously performed because a needle biopsy has reduced sensitivity after induction therapy. However, if the patient had a prior mediastinoscopy, a repeat mediastinoscopy should be avoided because it has reduced sensitivity and specificity and increased safety risks. Whether or not mediastinal lymph nodes are restaged, assessment for distant disease with PET scan and brain MRI is warranted. Managing Residual Disease Currently, most patients are treated with a total of four cycles of chemotherapy, which includes the induction cycles. The INT 0139/RTOG 9309 protocol called for all patients to receive consolidative chemotherapy with two cycles of cisplatin/etoposide. Although not all patients were able to complete that regimen in the trial, it is still considered the standard of care, particularly since development of systemic metastases remains a concern. That said, it has not been definitively demonstrated that postoperative chemotherapy or chemoradiation adds additional benefit over induction therapy and surgery. The Hoosier Oncology Group conducted a study in patients with unresectable stage IIIA/B NSCLC. In this study, patients were treated with cisplatin/etoposide and concurrent chemoradiation, and those with no evidence of disease progression were then randomized to either three cycles of docetaxel or observation. Docetaxel added no survival benefit but considerable toxicity, including an increase in treatment-related death. It is not entirely clear that these data can be extrapolated to patients undergoing resection, but they at least point to the fact that this issue requires further study. Prevention of brain metastases is another concern in patients with stage III disease. Good results have been seen in small-cell lung cancer with prophylactic cranial irradiation
(PCI). A few small prospective randomized studies in NSCLC have shown a decrease in central nervous system (CNS) metastases with PCI. The recently completed RTOG 0214 study randomized patients with stage IIIA/B NSCLC to PCI or observation. Although targeted accrual was never met, and the study had to close early, it did show a significant decrease in the incidence of CNS metastases at 1 year in the PCI group (7.7%) compared with controls (18%; P =.004). On the other hand, there was no significant benefit seen in terms of disease-free survival (DFS) or OS at 1 year. Longer follow-up is needed to determine whether the difference in incidence of CNS metastases will ultimately translate into a significant DFS or OS benefit. Follow-up should include history, physical examination, and neurologic examination. It also typically includes chest computed tomography (CT) scan every 3 to 6 months, although there is no specific evidence to confirm that regular CT scanning affects longterm outcomes. Patients should be evaluated for new primary as well as recurrent tumors. Managing Isolated Brain Metastases Isolated brain metastases can be treated with whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), a combination of WBRT and SRS, or craniotomy and resection. SRS is most appropriate for patients with disease that is limited in size and involves no more than three lesions because it is associated with good locoregional control and the least amount of morbidity. The addition of SRS to WBRT may also improve outcomes in patients with low-volume CNS disease. RTOG 9508 showed increased mean survival time in patients treated with WBRT and SRS compared with WBRT alone (6.5 versus 4.9 months; P =.0393). An ongoing RTOG study will help determine whether the addition of targeted biologic therapy (erlotinib) or chemotherapy (temozolomide) adds benefit to WBRT + SRS. Patients with brain metastases may also need treatment for symptom relief, for example, with steroids, particularly if vasogenic edema is present. Managing Systemic Relapse There is some debate as to whether systemic relapse following neoadjuvant chemoradiation therapy should be managed with traditional first-line or second-line options for metastatic NSCLC, given the prior exposure to chemotherapy. First-line therapy would consist of retreatment with a platinum doublet chemotherapy regimen, usually favoring carboplatin over cisplatin in the United States, often coupled with pemetrexed. One-year survival with these regimens is now 30% to 40%. Long duration between neoadjuvant therapy and the appearance of metastases would favor treating the metastases with first-line platinum-based therapy. Based on ECOG 4599 by Sandler et al, it would also be appropriate to consider adding bevacizumab for patients who do not have brain metastases or requirements for ongoing anticoagulation. Second-line options would be either docetaxel, pemetrexed, or erlotinib. It would also be appropriate to enroll patients with systemic relapse after neoadjuvant therapy in clinical
trials of targeted agents, such as vandetanib, gefinitib, erlotinib, cetuximab, and newer agents targeting Akt, mtor, and Ras pathways. Molecular markers are now being used as a way of identifying patients most likely to respond to certain therapies. For example, ERCC1 mutations may predict platinum resistance, and RRM1 is a molecular determinant of gemcitabine efficacy. The MADe IT Study by Simon et al used both of these markers to guide choice of either docetaxel/vinorelbine, gemcitabine/docetaxel, carboplatin/docetaxel, or carboplatin/gemcitabine and reported a 1-year survival rate of 59%. In addition, epidermal growth factor receptor mutations are known to be predictive of response to tyrosine kinase inhibitors, such as erlotinib. Positive findings with molecular markers point to the need to preserve tissue when samples are obtained, including early in the work-up, such as during an EBUS-TBNA. Conclusion There are many controversies regarding optimal management of patients with stage III NSCLC. Numerous options for work-up and treatment are available, and data to guide decision making are somewhat limited. A multidisciplinary review of options is generally needed to determine the best management plan for individual patients. Suggested Readings Albain KS, Swann RS, Rusch VR, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) nonsmall cell lung cancer (NSCLC): outcomes update of North American intergroup 0139 (RTOG 9309). Abstract 7014. Presented at: 42nd annual meeting of the American Society of Clinical Oncology; May 13-17, 2005; Orlando, Fla. Allen AM, Mentzer SJ, Yeap BY, et al. Pneumonectomy after chemoradiation. The Dana-Farber Cancer Institute/Brigham and Women s Hospital Experience. Cancer. 2008;112:1106-1113. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363:1665-1672. Betticher DC, Schmitz S-F H, Totsch M, et al. Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pn2 non small-cell lung cancer: a multicenter phase II trial. J Clin Oncol. 2003;21:1752-1759. Bradley JD, Graham M, Suzanne S, et al. Phase I Results of RTOG L-0117; a phase I/II dose intensification study using 3DCRT and concurrent chemotherapy for patients with inoperable NSCLC. Abstract 7063. Presented at: 42nd annual meeting of the American Society of Clinical Oncology; May 13-17, 2005; Orlando, Fla.
Curran WJ, Scott CB, Langer CJ, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemoradiation for patients with unresected stage III nsclc: RTOG 9410. Abstract 2499. Presented at: 39th annual meeting of the American Society of Clinical Oncology; May 29-June 3, 2003; Chicago, Ill. Fournel P, Robinet G, Thomas P, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non small-cell lung cancer: groupe Lyon-Saint-Etienne d Oncologie Thoracique Groupe Francais de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol. 2005;23:5910-5917. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 1999;17:2692-2699. Gore EM, Bae K, Wong S, et al. A phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small cell lung cancer: initial analysis of Radiation Therapy Oncology Group 0214. Abstract 7506. Presented at: 45th annual meeting of the American Society of Clinical Oncology; May 29-June 2, 2009; Orlando, Fla. Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non small-cell lung cancer: The Huber RM, Schmidt M, Flentje M, et al. Induction chemotherapy and following simultaneous radio/chemotherapy versus induction chemotherapy and radiotherapy alone in inoperable NSCLC (Stage IIIA/IIIB). Abstract 2501. Presented at: 39th annual meeting of the American Society of Clinical Oncology; May 29-June 3, 2003; Chicago, Ill. Mina L, Neubauer MA, Ansari R, et al. Phase III trial of cisplatin (P) plus etoposide (E) plus concurrent chest radiation (XRT) with or without consolidation docetaxel (D) in patients (pts) with inoperable stage III non-small cell lung cancer (NSCLC): HOG LUN 01-24/USO-023 updated results. Abstract 5719. Presented at: 44th annual meeting of the American Society of Clinical Oncology; May 30-June 3, 2008; Chicago, Ill. Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest. 1997;111:1718-1723. Sandler A, Gray R, Perry MC, et al. Paclitaxel carboplatin alone or with bevacizumab for non small-cell lung cancer. N Engl J Med. 2006;355:2542-2550. Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated non small-cell lung cancer. N Engl J Med. 2005;353:123-132. Simon GR, Williams CC, Chiappori AA, et al. Molecular analysis-directed individualized therapy (MADeIT) in advanced non-small cell lung cancer (NSCLC). Abstract 7502.
Presented at: 43rd annual meeting of the American Society of Clinical Oncology; June 1-5, 2007; Chicago, Ill Socinski MA, Blackstock AW, Bogart JA, et al. Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non small-cell lung cancer: CALGB 30105. J Clin Oncol. 2008;26:2457-2463. Sonnet JR, Suntharalingam M, Edelman MJ, et al. Pulmonary resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small-cell lung cancer. Ann Thorac Surg. 2004;78:1200-1205. Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-small cell lung cancer. Chest. 2003;123:137S-146S.