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S. Watanabe

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    GR01 - Surgery and the New Stage IIIA (ID 16)

    • Event: WCLC 2013
    • Type: Grand Round Session
    • Track: Surgery
    • Presentations: 1
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      GR01.3 - Role of Neoadjuvant and Adjuvant Therapies (ID 448)

      14:00 - 15:30  |  Author(s): S. Watanabe

      • Abstract
      • Presentation
      • Slides

      1. Introduction Lung cancer has remained to be the leading cause of cancer-related death in many countries. Most patients are diagnosed at an advanced stage, stage III or IV. A way to improve surgical outcome would be the administration of chemotherapy before or after the surgical procedure. 2. Neoadjuvant therapy The preoperative induction therapy offers several benefits: (1) an increased percentage of patients completing the planned dose of chemotherapy, (2) the probability to treat micrometastatic tumor dissemination preoperatively, (3) the ability to assess response to the chemotherapy as a prognostic indicator, and (4) the probability to increase resectability by the tumor regression. 2.1. Induction chemotherapy Numbers of phase II trial using induction chemotherapy can be found in the previous literatures. Phase III neoadjuvant trial results including stage IIIA disease are summarized in Table1. Two studies reported by Roth (1994) and Rosell (1994) suggested that induction therapy followed by surgery could lead to improved outcomes, however, recent large scale studies did not show the improvement of survival in stage IIIA patients received neoadjuvant chemotherapy.  2.2. Induction chemotherapy with third-generation agents Results of previous studies, all of them are phase II study, evaluating the efficacy of induction chemotherapy with third-generation agents are shown in the table 2. These trials showed the feasibility and potential benefit of induction chemotherapy with combination or cisplatin and third-generation agents for stage III patients. Since the data of phase III trial with large sample size are lacking, the adequate regimen of induction chemotherapy has yet to be defined. 2.3. Induction chemotherapy or induction chemoradiotherapy? Whether induction radiotherapy adds benefit when surgery is planned is an important clinical question, because the addition of each modality increase the possibility of morbidity and mortality of treatment. To investigate the benefit of neoadjuvant radiation therapy, Shah (2012) conducted systematic review and meta-analysis. None of the studies demonstrated a survival benefit to adding induction radiotherapy to induction chemotherapy versus induction chemotherapy alone. The meta-analysis performed on randomized studies demonstrated no benefit in survival from adding radiation (HR: 0.93; p=0.81), nor did the meta-analysis performed on retrospective studies (HR: 0.77; p=0.24). The most promising use of induction chemoradiotherapy is to treat the superior sulcus tumor (SST) where preoperative local tumor regression is a key to achieving complete resection. Rush (2007) reported the results of SWOG 9416 (Intergroup 0160) phase II trial, which tested the feasibility of induction chemoradiotherapy for SST, on the basis of improved outcomes in other subsets of stage III NSCLC. Pathologic complete response (CR) or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Kunitoh (2008) reported the similar results of Japan Clinical Oncology Group (JCOG) phase II trial (JCOG 9806), which was conducted for testing the feasibility of induction chemoradiotherapy for NSCLC-SST patients. There were 12 patients with pathologic CR. The disease-free and overall survival rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively. They concluded that the trimodality approach was safe and effective for the treatment of patients with SST 3. Adjuvant therapy 3.1. Adjuvant chemotherapy The NSCLC Collaborative Group (1995) reported a meta-analysis of 14 clinical trials addressing the role of adjuvant chemotherapy for resected NSCLC. There was no statistically significant survival benefit in group of patients received adjuvant chemotherapy, but a trend toward better survival prompted further studies. Subsequently, the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis based on individual patient data collected from the 5 largest trials (4,584 patients) of cisplatin-based adjuvant chemotherapy in completely resected patients with NSCLC was performed. This analysis also showed a significant survival benefit with adjuvant chemotherapy, with an overall hazard ratio (HR) of 0.89, translating into a 5-year absolute survival benefit of 5.4%. Then in 2010, the NSCLC Meta-analyses Collaborative Group reported a meta-analysis of 34 clinical trials with 8,447 patients (3,323 deaths) addressing the benefit of adjuvant chemotherapy for resected NSCLC. Among those, the overall hazard ratio to survival in patients received cisplatinum-based adjuvant chemotherapy by stage suggests absolute improvements in 5-year survival of 5% for stage III disease (from 30% to 35%). 3.2. Adjuvant radiotherapy In 1988, postoprative radiotherapy (PORT) Meta-analysis Trialists Group collected individual data on 2,128 patients from nine available randomized trials of PORT versus surgery alone. They reported a 21% relative increase in the risk of death, which was equivalent to an absolute detriment of 7% at 2 years, with PORT reducing overall survival from 55% to 48% after resection. Subgroup analysis suggested that the adverse effect on overall survival was most notable for patients with stage I/II (N0-N1) tumors, whereas there was no clear evidence of either adverse effect or benefit for stage III disease. The results of the PORT meta-analysis, however, are probably not applicable to current therapy because of recent major improvements in radiation treatment planning and delivery. 4. Neoadjuvant or adjuvant chemotherapy? Which is the better treatment, induction or adjuvant chemotherapy? Some concern has also arisen regarding adjuvant chemotherapy compliance, with most trials using cisplatin doublets reporting delivery of only 60% of planned treatment. Induction chemotherapy seems better tolerated, more than 80% of the patients received the full planned treatment at the difference of adjuvant chemotherapy. In the LACE meta-analysis, 33% of patients in the chemotherapy arm did not start or finish the planned chemotherapy regimen, reflecting the difficulty of adjuvant chemotherapy administering such taxing therapies to a postoperative population. 6. Conclusions Although definitive chemoradiation remains a standard of care for stage IIIA NSCLC, alternative approaches such as induction chemotherapy and surgery for a selective group of patients can be considered. When surgical resection after induction therapy can be performed with low risk and a good chance of complete resection, it might provide an optimal outcome. The decision to proceed with resection after induction therapy must include a detailed preoperative pulmonary function evaluation as well as a critical intraoperative assessment of the feasibility of complete resection. Figure 1Figure 2

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