One of the main purposes of the UICC International Lung Cancer Staging, promulgated in 1986 and revised in 1997, is to distinguish between potentially resectable lung cancer and unresectable lung cancer, with the dividing line between IIIA and IIIB with contralateral lymph node metastasis or tumor invasion of unresectable organ structures. With the development of modern multidisciplinary lung cancer treatment including surgery, radiotherapy, chemotherapy, etc., the unresolved question is what treatment is more appropriate for potentially resectable IIIA(N2) NSCLC, since the 5-year survival rate for surgery alone or surgery plus radiotherapy is less than 5%.
This has led to the investigation of multidisciplinary combination treatment options for IIIA(N2) NSCLC, which is a systemic lesion that may have systemic micrometastases at the time of initial treatment. Based on this understanding, the addition of chemotherapy along with local surgical treatment or radiotherapy is the direction of research. However, how to administer the drug, the time of administration and the amount of drug used still need to be further studied.
1.The development of preoperative induction therapy
Before 1980, the standard treatment for stage IIIA(N2) non-small cell lung cancer included three aspects: surgical treatment alone, radiotherapy alone or combined radiotherapy and surgical treatment. With the gradual recognition of lung cancer as a systemic disease, several phase III clinical trials comparing radiotherapy alone with combined radiotherapy for NSCLC showed the advantages of combined radiotherapy.
A meta-analysis of 2589 patients in 14 trial groups published by Pritchard in 1996 showed a 12% reduction in 1-year mortality and a 17% reduction in 3-year mortality with combination radiotherapy compared to radiotherapy alone. Another influential trial was Cancer and Leukemia Group B (CALGB)8433 published in the New England Journal of Medicine in 1990, in which 155 patients were divided into radiotherapy alone (60 Gy) and radiotherapy combined (60 Gy radiotherapy followed by cisplatin and vincristine chemotherapy), showing a statistically significant increase in the efficiency of combined radiotherapy compared to radiotherapy alone (56% vs. 43%) and a statistically significant increase in median survival and 5-year Survival rates were also significantly higher (13.7 months vs. 9.6 months, 17% vs. 6%).
This encouraging result has prompted increased interest in studying the addition of chemotherapy in regionally progressive NSCLC. There has also been a concomitant increase in the study of preoperative chemotherapy for NSCLC, combined with or without induction therapy with radiotherapy.
While it is difficult to fully agree on the conclusions of these trials because of differences in the amount of drugs used and the way they are administered, these trials have confirmed several important concepts.
First, clinically effective preoperative induction therapy increases the rate of surgical resection and, more importantly, increases the rate of complete surgical resection.
Second, complete resection on pathology contributes to patient survival.
Third, complete mediastinal lymph node dissection can significantly improve survival in cases. Fourth, preoperative chemotherapy reduces postoperative local recurrence or distant metastases.
In 1992, the National Cancer Institute first published the results of one of their phase 3 clinical trials [13]. 27 cases of pathologically confirmed IIIA(N2) NSCLC were then prospectively divided into two groups, one for preoperative chemotherapy → surgery → postoperative chemotherapy, and the other group was surgery → postoperative radiotherapy.
The efficiency of preoperative chemotherapy was 62%, and the complete surgical resection rate was 85% in both groups. Follow-up results showed a significant advantage in tumor-free survival and overall survival in the preoperative chemotherapy group versus the surgery-only group (13 months vs. 6 months and 29 months vs. 16 months), but were not statistically significant due to the small number of cases and the short follow-up period.
In 1994, two research units published the results of their prospective randomized controlled studies, the first being a Spanish study group from Barcelona with 60 patients randomized to the preoperative chemotherapy → surgery → postoperative mediastinal radiotherapy group and the surgery → postoperative mediastinal radiotherapy group [14]. The preoperative chemotherapy group had a chemotherapy efficacy rate of 60%, a median tumor-free period of 20 months vs. 5 months and an overall survival of 26 months vs. 8 months compared to the surgery alone group.
This trial updated its findings in 1999, but as always, showed a survival advantage in the chemotherapy group, with 3- and 5-year survival rates of 20% and 17%, respectively, compared with a 3-year survival rate of 5% and no 5-year survivors in the surgery-only group.
The second study, from the MD Anderson Cancer Center in 1999, was similar to the previous study in that 60 patients were randomized into two groups: chemotherapy followed by surgery and surgery alone, with 50% of patients in both groups receiving postoperative radiation therapy. The predicted outcome for the chemotherapy group was a median survival of 64 months for the chemotherapy group and 11 months for the surgery alone group.
The 1998 update showed a median survival of 21 months vs. 14 months for the chemotherapy and surgery alone groups with 3- and 5-year survival rates of 43% vs. 36% and 19% vs. 15%, respectively. However, there are many who believe that these two trials had some flaws especially for the Barcelona study: too few cases entered the trial, the duration was short, the survival rate for surgery alone was too low, and the biology of the patients in the two groups was not balanced.
Two other experiments 10 years later challenged this conclusion. One was a study by a French group in which 345 cases of 1A-3A NSCLC were divided into a preoperative chemotherapy group and a surgery-only group, and all T3 and N2 patients received radiation therapy. The trial results showed better overall survival in the preoperative chemotherapy group than in the surgery-only group (37 months vs. 26 months).
However, further subgroup analysis revealed that preoperative chemotherapy was only effective in stage I and II cases, but not in stage III cases. The second trial was from JCOG9209 in Japan.[18] Sixty-four patients were divided into two groups, preoperative chemotherapy and surgery alone, and the results showed no difference in survival between the two groups. Due to the absence of statistical differences and the lower survival rate, this trial has long been closed.
2. The risk of surgery after chemotherapy
In the early 1990s many phase II and III clinical trials showed an increased risk of surgery in conjunction with induction chemotherapy. In 1993, Fox Chase Cancer Center in Philadelphia reported that of 13 patients operated on after preoperative induction chemotherapy and high-dose radiotherapy, one ARDS occurred in six lobectomized patients, but there were no fatal cases. In contrast, ARDS occurred in 5 of the 7 total lung resection patients, including 2 deaths and 1 death due to bronchopleural fistula, with an overall mortality rate of 43%. Several other groups have reported a higher incidence of ARDS and bronchopleural floor in patients undergoing total pneumonectomy after preoperative chemotherapy.
Some recent reports have shown a significant improvement in outcomes due to the recognition of the potential risks of preoperative induction chemotherapy, especially for total pneumonectomy, and the adoption of some preventive measures. For example, airway pressure and air flow control in both lungs are restricted during anesthesia, and bronchial stumps are encapsulated with autologous muscle flaps during surgical procedures.
3. The place of surgery in the treatment of IIIA(N2) NSCLC
The results of trials over the last 20 years have shown that for fully resectable IIIA(N2) NSCLC, preoperative induction chemotherapy significantly increases the survival rate of patients. A dedicated analysis from the Dana Farber Cancer Institue [24] showed that the median survival after surgery for patients with a stage N0 reduction was 20 months, with a 5-year survival rate of 36%.
This was significantly better than those patients with N1 or N2 (median survival of 16 months and 5-year survival rate of 9%). Interestingly, there was no survival difference between patients who remained N1 or N2 after preoperative induction chemotherapy. Another report from Sweden [25] had similar findings, where two important factors affecting postoperative survival were complete surgical resection including lymph node dissection and post-chemotherapy step-down.
The Swiss group’s report also concluded that there was an improvement in survival in patients who were downgraded from N2 to N1. These studies, like others, guide thoracic surgeons and oncologists when operating to select those cases that have a step-down after induction therapy.
This leads to another question that arises as to whether surgery increases survival in those cases that respond after induction therapy. This is because of the increased surgical difficulties for patients after induction. There is a corresponding increase in mortality and the incidence of surgical complications. These questions were answered in the North American trial INT0139, which included 396 cases of IIIA(N2) NSCLC. Patients were divided into surgical and non-surgical groups, and all patients received two courses of induction chemotherapy (cisplatin + pedialyte glycosides) with 45 GY of concomitant radiotherapy.
All patients were re-graded after chemotherapy to estimate treatment response. Patients who had no disease progression after two cycles of chemotherapy underwent surgical treatment. The other non-surgical group was treated with two additional courses of chemotherapy followed by radiation therapy totaling no more than 61 GY. 46% of the surgical patients achieved mediastinal lymph node clearance and had a 3-year survival rate of 53%. Tumor-free survival was better in the surgical group than in the radiotherapy-leased group (median survival 13 months vs. 10 months, 5-year survival rate 22% vs. 11%). Although the overall survival rate was better in the surgical group than in the radiotherapy group, analysis of the survival curves showed that the difference in survival between the two groups started in the second half of the curve. This result was attributed to the higher surgical mortality rate, which was 7.9%.
Further analysis showed that the majority of these deaths were in patients with total pneumonectomy after induction chemotherapy (14/16). Therefore, the cases in the surgical group were divided into lobectomy and total pneumonectomy groups separately compared to the non-surgical group and it was found that the surgical lobectomy group had a better survival rate compared to the non-surgical group. In contrast, the total pneumonectomy group had unfavorable outcomes. These data suggest that lobectomy after induction chemotherapy is worth advocating for IIIA(N2) NSCLC, while eventual radiotherapy is recommended for those patients who require total pneumonectomy.
4. Optimal induction therapy regimen for IIIA(N2) NSCLC
Although three phase III clinical trials of preoperative induction chemotherapy versus surgery alone for lung cancer included only 147 patients, the obvious clinical benefits of preoperative chemotherapy have led to a change in the concept of treatment for IIIA(N2) NSCLC, and preoperative induction chemotherapy or radiotherapy has now become the standard of care for IIIA(N2) NSCLC.
In April 2005, The Radiation Therapy and Oncology Group (RTOG) and the Southwest Oncology Group (SWOG) initiated an ongoing clinical trial (RTOG 0412 /SWOG S0332).
The purpose of this trial involves radiotherapy as preoperative induction therapy for IIIA(N2) NSCLC. 547 patients were divided into two experimental groups, one with preoperative induction chemotherapy with cisplatin + doxorubicin and the other with the same chemotherapy regimen + radiotherapy at 50 Gy. All patients who did not progress were treated with surgery and continued with chemotherapy postoperatively. It is hoped that this trial will unravel the mystery of the role of preoperative induction radiotherapy.