Locally advanced (stage IIIA) non–small cell lung cancer (NSCLC) is confined to the chest, but requires more than surgery to maximize cure. Therapy given preoperatively is termed neoadjuvant , whereas postoperative therapy is termed adjuvant . Trimodality therapy (chemotherapy, radiation, and surgery) has become the standard treatment regimen for resectable, locally advanced NSCLC. During the past 2 decades, several prospective, randomized, and nonrandomized studies have explored various regimens for preoperative treatment of NSCLC. The evaluation of potential candidates with NSCLC for neoadjuvant therapy as well as the currently available therapeutic regimens are reviewed.
Key points
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A complete evaluation of patients diagnosed with lung cancer should include a comprehensive medical history, physical examination, analysis of functional capacity, relevant imaging studies, pathological studies, and a discussion about the patients’ goals.
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A review of the tumor subtype and pathologic assessment of the lymph nodes enables the assignment of the most accurate clinical stage.
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Neoadjuvant chemoradiation is used to treat patients with resectable, locally advanced NSCLC with the following goals:
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Eliminate micrometastatic systemic disease
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Prevent tumor growth, achieve downstaging, and sterilize affected lymph nodes
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Provide time for an oncologic stress test, ensuring that during treatment, metastatic disease does not appear.
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The current recommended preoperative regimen is a concurrent platinum-based chemotherapy course with 54 Gy of thoracic radiation.
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After surgery, the pathologic stage can be informative as to prognosis and any need for additional therapy; after trimodality therapy, patients should have a regular follow-up with tobacco abstinence support and recurrence/metastasis screening.
Introduction
Lung cancer remains the leading cause of cancer death worldwide. It is quite heterogeneous and is subdivided into small cell lung cancer (20%) and non–small cell lung cancer (NSCLC), with the latter affecting 80% of patients. NSCLC itself is composed of several types, including adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and neuroendocrine tumors. In each of these histologic subtypes, cancer stage has a significant impact on the prognosis.
According to the International Association for the Study of Lung Cancer Staging Project, the overall 5-year survival for stage IA NSCLC is 66%, stage IB is 56%, stage IIA is 43%, stage IIB is 35%, and stage IIIA is 23%. Five-year survivals for stages IIIB and IV disease are lower than 10%. Treatment of NSCLC includes chemotherapy, radiation, and/or surgery, with different combinations and order of therapies depending on the stage of the disease. The steps of evaluating patients with suspected lung cancer, the current neoadjuvant therapies, and the evaluation of the therapeutic effect are reviewed herein.
Introduction
Lung cancer remains the leading cause of cancer death worldwide. It is quite heterogeneous and is subdivided into small cell lung cancer (20%) and non–small cell lung cancer (NSCLC), with the latter affecting 80% of patients. NSCLC itself is composed of several types, including adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and neuroendocrine tumors. In each of these histologic subtypes, cancer stage has a significant impact on the prognosis.
According to the International Association for the Study of Lung Cancer Staging Project, the overall 5-year survival for stage IA NSCLC is 66%, stage IB is 56%, stage IIA is 43%, stage IIB is 35%, and stage IIIA is 23%. Five-year survivals for stages IIIB and IV disease are lower than 10%. Treatment of NSCLC includes chemotherapy, radiation, and/or surgery, with different combinations and order of therapies depending on the stage of the disease. The steps of evaluating patients with suspected lung cancer, the current neoadjuvant therapies, and the evaluation of the therapeutic effect are reviewed herein.
Definition of neoadjuvant therapy
Neoadjuvant therapy is defined as either chemotherapy or radiotherapy given before the surgical excision of a malignant tumor. It often involves a combination of both treatment modalities, and it is used to treat some patients with locally advanced stages of NSCLC who have good performance status. Neoadjuvant therapy is given with the intent of
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Eradicating N2 nodal disease.
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Eliminating micrometastatic systemic disease.
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Controlling the tumor in intermediate stage lung cancer to provide a time period to ascertain that patients are not harboring metastatic disease that will appear after surgery.
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Sufficiently reducing the extent of tumor to enable a lesser resection (eg, converting a pneumonectomy to a lobectomy).
There may be better drug delivery of chemotherapy before alteration of vascular supply to the primary tumor during surgery. Another consideration is that a substantial number of patients are not able to complete adjuvant therapy after undergoing extensive surgery; giving chemotherapy upfront is more likely to provide access for both therapies to a larger number of patients. Finally, giving chemoradiotherapy preoperatively allows for the assessment of the effect at surgery. This judgment of efficacy is not possible if chemoradiotherapy is given postoperatively, after the tumor has been completely removed.
Like all other therapies, neoadjuvant therapy is not without its risks. Disease can progress during neoadjuvant treatment, and some patients may never undergo surgery. Functional status can decline as a result of adverse reactions to therapy, delaying surgery. Neoadjuvant radiation therapy is also associated with scarring and can increase the risk of needing larger pulmonary resections (pneumonectomy).
Early studies on neoadjuvant therapy
The results of several prospective phase II clinical trials have demonstrated that neoadjuvant therapy is effective in downstaging NSCLC, with some studies reporting an increase in the length of survival. In 1992, Strauss and colleagues completed a phase II study evaluating the response of patients with stage IIIA NSCLC to concurrent neoadjuvant cisplatin/vinblastine/fluorouracil and radiation therapy followed by surgery and adjuvant radiation therapy. As one of the first trials with trimodality therapy, this study showed that 66% of the patients had a complete clinical response to neoadjuvant chemoradiation and 17% had a partial response. Thirty-one of 41 patients in the study underwent surgery, and 25 patients had surgical resection. Trimodality therapy was demonstrated to be effective, but there was substantial treatment toxicity in this study with a 15% (6 deaths) treatment-related mortality rate and only modest improvement in median length of survival to 15.5 months.
The Southwest Oncology Group (SWOG) 8805 study by Albain and colleagues also evaluated trimodality therapy with cisplatin and etoposide, radiotherapy, and surgery (or additional chemotherapy and radiation instead of surgery for unresectable disease) in patients with stage IIIA(N2) and IIIB(N2/N3) disease. This study reported encouraging survival rates, particularly for patients with no residual N2 disease at surgery. The median survival was 30 months for patients with no residual N2 disease versus 9 months for patients with residual N2 disease ( P = .002). A multicenter phase II study by Sugarbaker and colleagues in 1995 (Cancer and Leukemia Group B [CALGB] 8935) assessed the effectiveness of neoadjuvant cisplatin and vinblastine followed by surgery and adjuvant chemotherapy and radiation (54 Gy) for complete resection or followed by 59.4 Gy of radiation after incomplete/no resection in patients with stage IIIA(N2) NSCLC. This study reported longer lengths of median survival for patients able to undergo complete resection as compared with those with incomplete resection or no resection (20.9 months vs 17.8 months vs 8.5 months, respectively).
In addition to demonstrating a therapeutic effect, both the SWOG 8805 and CALGB 8935 studies reported lower mortality rates than previous studies: 13 (10.0%) and 4 (5.4%) treatment-related deaths, respectively. Of the 13 patients in the SWOG 8805 study, 5 died preoperatively and 8 died postoperatively (5 had intrapericardial pneumonectomy, 1 had a standard pneumonectomy, and 2 had lobectomies). In the CALGB 8935 study, 1 patient died preoperatively, 2 died postoperatively, and 1 died during treatment with adjuvant chemotherapy. Along with lower mortality rates, these studies also reported acceptable morbidity rates, demonstrating better treatment tolerance.
In 1994, single-center phase III studies compared neoadjuvant chemotherapy followed by surgery with surgery alone. The study by Rosell and colleagues compared patients with stage IIIA(N0-2) NSCLC treated with neoadjuvant mitomycin/ifosfamide/cisplatin, surgery, and adjuvant radiation with those treated with surgery and adjuvant radiation. This study found an improved median survival of 26 months versus 8 months, in favor of treatment with neoadjuvant chemotherapy ( P <.001). Roth and colleagues conducted a similar study comparing treatment with neoadjuvant cyclophosphamide/etoposide/cisplatin followed by surgery and adjuvant chemotherapy with surgery alone in patients with stage IIIA(N0-2) NSCLC. This study also reported an improved median survival of 64 months versus 8 months, in favor of neoadjuvant chemotherapy treatment ( P <.008).
The benefit seen in prognostic improvement is likely due to downstaged disease, specifically, eradication of nodal disease. A retrospective review in 2000 evaluating the outcomes of 103 patients who underwent surgery after neoadjuvant therapy for stage IIIA(N2) NSCLC found that patients whose nodal disease was eradicated had significantly improved 35.8% 5-year survival compared with patients with persistent N1 and N2 nodal disease who had a 9% 5-year survival. Four patients died within 30 days of surgery, 2 of whom underwent pneumonectomies and 2 of whom underwent lobectomies. Analysis of nodal status after neoadjuvant therapy followed by surgery in the CALGB 8935 study also found that those patients with persistent N2 cancer had significantly decreased failure-free survival (median failure-free survival 8.2 months vs 47.8 months in patients with no residual N2 disease, P = .01). Therefore, the major goal for treating patients with neoadjuvant therapy for stage IIIA(N2) NSCLC became focused on eliminating nodal disease.
Neoadjuvant therapy versus adjuvant therapy
The SWOG S9900 phase III study evaluated neoadjuvant carboplatin and paclitaxel with surgery versus surgery alone in treating patients with stage IB, II, or select IIIA NSCLC (no superior sulcus tumors or tumors with N2 disease). The overall survival and progression-free survival was improved with neoadjuvant chemotherapy as compared with surgery alone (overall survival: median 62 months vs 41 months, respectively; progression-free survival: 33 months vs 20 months, respectively), but these results did not reach statistical significance. Furthermore, this study closed early after results were published demonstrating the nonsignificant but intriguing survival benefit from adjuvant therapy in patients with early stage NSCLC.
In 2003, a Japanese phase III study compared patients with completely resected stage I and II NSCLC who were treated with adjuvant uracil and tegafur versus those treated with surgery alone. No survival benefits were observed with the addition of the adjuvant regimen becauase the overall 5-year survival rate was found to be 79% for the adjuvant group and 75% for the control group (not statistically significant) and the disease-free survival rate was 78% and 71%, respectively (also not statistically significant). These survivals are higher than other reports and may represent a study of homogeneous early stage NSCLC tumors.
Alternatively, the International Adjuvant Lung Cancer Trial was a phase III trial that compared treating early stage NSCLC with postoperative cisplatin therapy versus observation and found that patients treated with adjuvant chemotherapy had significantly higher 5-year overall survival (44.5% vs 40.4%, hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.76–0.98, P <.03) and disease-free survival (39.4% vs 34.3%, HR 0.83, 95% CI 0.74–0.94, P <.003). These lower survival rates may reflect a larger population of participants with occult, higher-stage disease. The National Cancer Institute of Canada Clinical Trials Group JBR.10 trial was a phase III study that also reported significantly improved overall survival (94 vs 73 months, HR 0.69, P = .04) and disease-free survival (not reached vs 46.7 months, HR 0.60, P <.001) in patients with completely resected stage IB and II NSCLC who were treated with adjuvant vinorelbine and cisplatin versus observation. However, when the survival data on the subgroup with stage IB disease were analyzed, no significant benefit was associated with adjuvant chemotherapy. The Cancer and Leukemia Group B 9633 phase III trial specifically studied patients with stage I NSCLC and found that the only statistically significant survival advantage to adjuvant paclitaxel and carboplatin as compared with observation was seen in patients with tumors 4 cm or greater in diameter (HR 0.69, 95% CI 0.48–0.99, P = .043).
A prospective randomized trial by the Spanish Lung Cancer Group compared 3 treatment arms in 624 patients with early stage NSCLC: 201 patients underwent treatment with preoperative chemotherapy plus surgery (preoperative); 211 patients underwent treatment with surgery plus adjuvant chemotherapy (adjuvant); and 212 patients had surgery alone (control). Chemotherapies given either preoperatively or in the adjuvant setting were 3 cycles of paclitaxel (200 mg/m 2 intravenously [IV] over 3 hours) and carboplatin (area under the curve dose of 6 mg/mL/min IV over 30–60 minutes). The results of this trial found that there was no statistically significant difference in the 5-year disease-free survival between the preoperative and control arms (38.3% vs 34.1%, HR 0.92, P = .176) or between the adjuvant and control arms (36.6% vs 34.1%, HR 0.96, P = .74). The overall survival at 5-year was 46.6%, 45.5%, and 44.0% for the preoperative, adjuvant, and control arms, respectively, with no significant difference across the treatment arms.
The Spanish Lung Cancer Group study did not demonstrate that the addition of chemotherapy to surgery, either preoperatively or postoperatively, would improve disease-free survival; but the study was likely limited by the inclusion of a large number of patients with stage I NSCLC (74.3%, 77.6%, and 73.3% of the preoperative, adjuvant, and control cohorts, respectively). However, the investigators did note an advantage of giving chemotherapy preoperatively as opposed to postoperatively. They concluded that because the treatment decision was made before surgery by the randomization, more patients were able to receive chemotherapy preoperatively. Given that the percentage of patients who started chemotherapy preoperatively (97.0%) versus the percentage that began therapy in the adjuvant arm (66.2%) was higher, this study seems to indicate that chemotherapy may be better tolerated in a neoadjuvant setting.
A meta-analysis of the results of 15 randomized controlled trials showed that neoadjuvant chemotherapy provided a 13% reduction in the relative risk of death (HR 0.87, 95% CI 0.78–0.96, P = .007), which represents an absolute survival improvement of 5% at 5 years (40% to 45%) for patients with resectable stage IB to IIIA NSCLC, regardless of the chemotherapy regimen (most were platinum based). The same study also found that recurrence-free survival (HR 0.85, 95% CI 0.76–0.94, P = .002) and time to distant recurrence (HR 0.69, 95% CI 0.58–0.82, P <.0001) was improved by preoperative chemotherapy. These findings show that neoadjuvant chemotherapy followed by surgery is an effective treatment approach, particularly for locally advanced disease.
Studies have also addressed the sequence in which to give radiation therapy in the multimodality treatment of NSCLC. A phase III study by the German Lung Cancer Cooperative Group (GLCCG) compared treatment with cisplatin and etoposide, then concurrent radiation and carboplatin and vindesine, followed by surgery (intervention group) to treatment with cisplatin and etoposide followed by surgery and adjuvant radiation (control group) in patients with stage IIIA and IIIB NSCLC. A similar number of patients in the intervention (142 patients of 264 eligible) and control (154 patients of 260 eligible) groups were able to undergo surgery and a similar number in either group had complete resection (98 and 84, respectively). Of the patients who had a complete resection, the ones receiving neoadjuvant chemoradiation were more likely to have a pathologic response (60% vs 20%, P <.0001) and mediastinal downstaging (46% vs 29%, P = .02). Although the overall survival and progression-free survival were not significantly different between both groups, neoadjuvant radiation was proven effective for decreasing disease burden to allow for a lesser resection.
Patient evaluation overview
Early stage NSCLC includes stage I and II cancer and is treated with surgical resection. Current practice standards are to evaluate patients with resected stage IB tumors 4 cm or greater or stage II disease for postoperative chemotherapy and potential clinical trials. Patients with a higher risk of recurrence based on features, such as lymphovascular invasion, poor tumor differentiation, and potentially unfavorable molecular prognostic tests, may also be considered for adjuvant chemotherapy. Neoadjuvant and adjuvant radiation are currently not recommended for stage I and II NSCLC unless the goals are to downstage the tumor to allow for a lesser resection or to sterilize positive margins. A study by Wang and colleagues found that postoperative radiotherapy is associated with improved overall survival in patients with incomplete resection of their stage II or III(N0-2) tumor.
Neoadjuvant concurrent chemoradiation is a part of the standard treatment of resectable stage IIIA NSCLC (and select cases of localized IIIB disease). Adjuvant therapy is also considered in the postoperative management of these patients. Advanced disease, which includes stages IIIB and IV NSCLC, is usually treated with definitive or palliative chemotherapy with or without radiation therapy. There are special cases of advanced disease, such as local invasion of the trachea, esophagus, blood vessels, heart or spine, or oligometastatic disease affecting the brain or adrenal gland, that can be technically resected. Adjuvant therapy should also be considered after surgical resection in these cases ( Table 1 ).
Description | Treatment | |
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Stage I | T1a-2aN0M0 | Surgical resection (lobectomy vs sublobar resection based on size/location) Consider SBRT for medically inoperable patients or patients who decline surgery Consider adjuvant therapy for tumors >4 cm in diameter |
Stage II | T1a-3N0-1M0 | Surgical resection Consider concurrent chemoradiation for medically inoperable patients Consider adjuvant therapy |
Stage IIIA | T1a-4N0-2M0 | Neoadjuvant therapy Restaging (lack of downstaging may warrant definitive chemoradiotherapy rather than proceeding to surgery) Surgical resection Consider adjuvant therapy |
Stage IIIB | T1a-4N2-3M0 | Neoadjuvant therapy in select cases, chemotherapy, radiation therapy, palliative surgery in special circumstances |
Stage IV | T1a-4N0-3M1a-b | Chemotherapy, radiation therapy, palliative surgery (no neoadjuvant therapy) |
Specific Indications for Neoadjuvant Therapy
The current clinical standard for the treatment of resectable stage IIIA NSCLC is neoadjuvant chemotherapy with/without concurrent radiation therapy, followed by surgical resection, and with/without adjuvant therapy. Stage IIIA disease is a heterogeneous category. It consists of tumors with metastasis to the ipsilateral mediastinal or subcarinal lymph nodes. The primary tumor may have invaded the parietal pleura, the chest wall, the diaphragm, or the main bronchus. A stage IIIA NSCLC tumor can also have no mediastinal lymph node metastasis but have invasion into other mediastinal structures, the great vessels, the carina/trachea, or a vertebral body; alternatively, it may consist of 2 or more tumor nodules in separate ipsilateral lobes. Mediastinal nodal involvement in NSCLC (stage IIIA[N2]) is associated with a worse outcome. Patients with stage IIIA disease are at higher risk than patients with early stage NSCLC for both local tumor progression and occult metastases. Thus, the disease management must be designed to treat both local and metastatic disease. No studies to date definitively prove the superiority of using neoadjuvant chemotherapy versus neoadjuvant chemoradiation. The National Comprehensive Cancer Network’s (NCCN) recommendation is for neoadjuvant chemotherapy to treat metastatic disease and concurrent neoadjuvant radiation to treat local disease.
Nonbulky stage IIIA disease is defined as involving only one lymph node station and a small lymph node size, such as less than 3 cm, or the likely presence of microscopic disease (not detected preoperatively). Bulky disease refers to metastatic disease in multiple mediastinal lymph node stations and large lymph nodes. In 2007, the American College of Chest Physicians (ACCP) conducted a literature search focusing on randomized trials treating stage IIIA NSCLC and concluded that neoadjuvant therapy followed by surgery for known stage IIIA disease is not recommended. They instead recommended combination chemoradiotherapy for all stage IIIA NSCLC with all extents of mediastinal lymph node involvement at preoperative evaluation. However, the trial results available at the time were limited by significant study population heterogeneity, a lack of randomization, or a lack of reliable pretreatment staging. The 3-stage American Joint Committee on Cancer staging system that existed before 1990 was less prognostically accurate, often limited by the prior inclusion of T3N0 with T1-2N2 cancers in the stage IIIA category. Additionally, less emphasis was placed on obtaining a pathologic confirmation of suspected mediastinal nodal disease, and the radiographic imaging used was not sensitive or specific enough for accurate staging of the disease.
In contrast, the guidelines recommended by the NCCN since 2010 support the use of chemoradiation for bulky mediastinal disease but recommend surgery for those patients with single-station N2 disease involvement who respond to neoadjuvant chemotherapy. This NCCN guideline is supported by studies that reported different survival outcomes for patients with bulky nodal disease versus nonbulky nodal disease. In 2000, a retrospective review was conducted by Andre and colleagues of 702 patients with stage IIIA(N2) NSCLC who underwent surgical resection. This study reported that there are subgroups, including clinically detected N2 disease (bulky) and minimal N2 disease (nonbulky, not detected preoperatively), which have different prognoses. Patients who had clinically detectable N2 disease had 5-year survival rates of 18% when treated with preoperative chemotherapy compared with 5% without preoperative chemotherapy ( P <.0001). The 5-year overall survival rates for patients with clinically detectable N2 disease versus those with minimal N2 disease was 7% and 29%, respectively, when both groups of patients were treated with surgery alone ( P <.0001, in multivariate analysis). This finding indicated that the extent of mediastinal lymph node involvement should be considered in the treatment of stage IIIA(N2) NSCLC and that different multimodality therapy regimens may be used depending on the stage IIIA disease subgroup.
Bulky disease can also refer to a large primary tumor burden (T3/T4). The phase II SWOG 9416 trial found that the combined modalities of induction chemoradiation (cisplatin and etoposide) and surgical resection led to high rates of complete resection and pathologic complete response in a particular subset of patients with stage IIIA(T3-4N0-1) NSCLC: those with superior sulcus tumors. High rates of complete response or minimal microscopic disease were observed (56% of resection specimens), with better survival in patients with pathologic complete response as compared with survival in patients with residual disease ( P = .02). These tumors are difficult to resect because they involve the brachial plexus, vertebral bodies, or subclavian vasculature. Neoadjuvant therapy can improve the prognosis of patients with superior sulcus tumors by improving the likelihood of complete surgical resection ( Box 1 ).