Concurrent Chemoradiation Therapy Followed by Surgery
Preoperative concurrent chemoradiation therapy is another important consideration for locally advanced NSCLC, especially in cases of bulky primary disease and with superior sulcus tumors. The intent of this preoperative therapy in cases of bulky disease is to decrease the disease burden and eradicate mediastinal lymph node involvement to enable a surgical resection. It is also an important consideration in patients with superior sulcus tumors, where decreasing the disease burden enables a more successful surgical resection.
The SWOG 8805 trial[15] was a phase II study looking at the concurrent use of chemotherapy and radiation followed by surgery in locally advanced NSCLC. Of the 126 eligible patients, 75 had stage IIIA disease with N2 involvement and 51 had stage IIIB disease. Patients underwent induction chemotherapy consisting of two cycles of cisplatin and etoposide with concurrent radiation to 45 Gy. Patients with improved or stable disease after induction went on to surgical resection, whereas those with persistent unresectable disease continued to receive further chemotherapy with radiation. The overall 3-year survival rate was 26% with the trimodality approach. Of those who underwent surgery, the 3-year survival rate was 44% in patients whose mediastinal lymph node disease was eradicated by induction chemoradiotherapy, compared to 18% who had persistent mediastinal disease.
The design of SWOG 8805 was based on a study by Friess et al,[16] where patients with locally advanced NSCLC underwent four 1-month cycles of cisplatin and etoposide along with concurrent radiotherapy to 60 Gy, achieving a median survival of 16 months with a 30% 2-year survival rate. As seen in the SWOG 8805 study, the addition of surgery to induction chemoradiotherapy does provide a survival benefit, with improved overall 2- and 3-year survivals rates. However, the benefit is derived mostly in patients who do not have mediastinal lymph node disease following induction therapy.
In the Intergroup 0139 study,[17] 396 eligible patients with stage IIIA (pN2) NSCLC were randomized to two arms, one receiving induction cisplatin/etoposide with concurrent radiation to 45 Gy followed by surgery, then two more cycles of cisplatin/etoposide; and the other receiving cisplatin/etoposide with radiotherapy to 61 Gy, followed by two more cycles of chemotherapy. Progression-free survival was superior with the trimodality approach (12.8 vs 10.5 months, P = .017) compared to chemoradiotherapy alone. However, there was only a marginal benefit in the 5-year survival rate with the trimodality approach (27.2% vs 20.3%). Similar to the SWOG 8805 study, the pN0 at the time of surgery predicted long-term survival. The 5-year survival rate was 41% in patients with pN0 disease at the time of surgery, compared to 24% in those with residual mediastinal disease.
One of the most notable findings of the Intergroup 0139 study was the increase in mortality associated with pneumonectomy following induction chemoradiotherapy. Approximately 7.9% of patients in the trimodality arm had treatment-related deaths, compared to 2.1% in the chemoradiotherapy-only arm. Approximately 5% of the deaths in the trimodality arm were within the 30-day postoperative period, and 9 of the 10 deaths were related to pneumonectomy. These findings indicated an increased risk and mortality with pneumonectomy following induction chemoradiotherapy. When evaluating patients who underwent pneumonectomy vs lobectomy in the study, those in whom a lobectomy was performed did better. At 5 years, 36% of patients who had undergone lobectomy were alive, compared to 22% of those who underwent pneumonectomy. Other trials[18,19] have also noted increased mortality with pneumonectomy when followed by chemoradiotherapy.
On the other hand, Gaissert et al[20] reported that pneumonectomy is a feasible option following induction chemoradiotherapy in carefully selected patients. In a retrospective study, they reviewed 183 patients who had undergone pneumonectomy, 46 of whom had received concurrent neoadjuvant chemoradiation and 137 who had only undergone a resection. The 46 patients had disease ranging from stage IIB to IV. However, they were also younger and had better pulmonary and cardiac function. Hospital mortality was 4.3% after preoperative therapy and 6.6% after resection only. They concluded that induction therapy with chemoradiation did not increase operative mortality after pneumonectomy in carefully selected patients.
Patients with superior sulcus tumors may also benefit from concurrent chemoradiation. These tumors usually arise in the apex of the lung and may invade the brachial plexus, second or third rib, the subclavian vessels, the stellate ganglion, or the adjacent vertebral bodies. Traditionally, these tumors were treated with radiation followed by surgery,[21,22] which produced a 5-year survival rate of around 30%. The phase II SWOG 9416 trial[23] studied the use of concurrent chemoradiation followed by surgery. A total of 110 patients with a T3-4, N0-1 superior sulcus tumor received two cycles of cisplatin and etoposide concurrently with radiation to 45Gy. Patients with stable or responding disease then underwent resection followed by two more cycles of chemotherapy. The 5-year survival rate was 44% for all patients and 54% after complete resection. This trial showed that a combined-modality approach was feasible, with improvement in overall survival, in patients with superior sulcus tumors.
Induction chemoradiotherapy may be a good option for selected patients with bulky nodal disease, particularly N2 disease. Patients who have a dramatic response to combined-modality therapy and are able to tolerate a surgical resection may benefit from surgery. The risk of pneumonectomy after concurrent chemoradiotherapy needs to be considered prior to surgical planning. Concurrent chemoradiation is also indicated in patients with superior sulcus tumors, where a combined-modality approach is feasible and allows for a better surgical outcome.
Definitive Concurrent Chemoradiation Therapy
As compared to induction concurrent chemoradiation therapy, definitive concurrent chemoradiation is given with the intention of being the sole combined-modality treatment, without a surgical option. The dose of radiation therapy in this setting is usually > 60 Gy. These patients are usually either unable to withstand surgery due to poor lung function or too many comorbid conditions, or have disease that is too advanced to enable a resection. Radiation alone was the sole treatment modality used in the 1980s. Earlier studies initially used sequential chemotherapy followed by radiation compared to radiation alone, showing a survival advantage with the combination. Subsequent studies demonstrated a survival benefit for concurrent rather than sequential use of chemotherapy and radiation.
The Cancer and Leukemia Group B (CALGB) 8433 trial[24] was one of the first studies to show a survival advantage for chemotherapy and radiation compared to radiation alone. The trial randomized 155 patients with stage III NSCLC to two groups: 78 patients were randomized to receive cisplatin and vinblastine followed by radiation at 60 Gy, and 77 patients were randomized to receive 60-Gy radiation only. The median survival was 13.7 months with chemotherapy and radiation used sequentially, compared to 9.6 months for radiation alone (P = .012).
An Intergroup trial[25] also studied the addition of chemotherapy to radiation and confirmed the results of the CALGB trial. Sause et al randomized 458 patients with stage II, IIIA, or IIIB disease to receive 2 months of cisplatin/vinblastine followed by 60 Gy of radiation, or hyperfractionated radiation delivered twice daily for a total of 69.6 Gy, or once-daily radiation with 60 Gy. Overall survival was statistically superior for the patients who received chemotherapy followed by radiation. The median survival was 13.2 months for chemotherapy plus radiation vs 12 months for hyperfractionated radiation vs 11.4 months for standard radiation. This trial also proved the benefit of adding chemotherapy to radiation.
