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Ann Thorac Surg 1998;65:208-211
© 1998 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Neoadjuvant and Adjuvant Trials in Non–Small Cell Lung Cancer

Division of Hematology and Oncology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, USA

Accepted for publication July 23, 1997.

Dr Einhorn, Indiana Cancer Pavilion, 535 Barnhill Dr, Rm 473, Indianapolis, IN 46202-5289.

Presented in part at the Tenth Annual General Thoracic Surgical Club Meeting, Captiva, FL, March 7–9, 1997.

	Abstract

Top Abstract Introduction Preoperative or Postoperative... Postoperative Adjuvant... Neoadjuvant Therapy Conclusions References

 
Adjuvant therapy in non–small cell lung cancer has become a controversial topic during this present decade. Postoperative thoracic irradiation has the potential to decrease local recurrence and lessen the probability of postobstructive pneumonia or atelectasis. However, as a single modality, in several randomized studies, it has failed to have a favorable impact on survival. Most postoperative adjuvant chemotherapy studies, likewise, have not improved survival compared with operation alone. Recently, there has been a resurgence of interest in preoperative (neoadjuvant) chemotherapy in clinical stage IIIA disease, based on two very positive, albeit small, phase III studies. Improved chemotherapy in stage IV disease using newer and more effective agents, such as vinorelbine (Navelbine), paclitaxel (Taxol), or gemcitabine (Gemzar), is now available. It is hoped that the modest gains in stage IV disease can translate to more significant improvement in earlier stage disease.

	Introduction

Top Abstract Introduction Preoperative or Postoperative... Postoperative Adjuvant... Neoadjuvant Therapy Conclusions References

 
In 1996, there were approximately 175,000 newly diagnosed cases of lung cancer and 161,000 deaths. Approximately 75% of these cases will consist of non–small cell lung cancer (NSCLC) histopathologically. Lung cancer deaths in the United States exceed the second (colorectal cancer), third (prostate cancer), and fourth (pancreatic cancer) most common causes of cancer mortality combined. Deaths as a result of lung cancer account for 28% of all cancer-related mortality.

Ten years ago, I had the honor and privilege of presenting a lecture regarding neoadjuvant therapy of NSCLC to the General Thoracic Surgery Club, with subsequent publication in 1988 in The Annals of Thoracic Surgery [1]. Other reviews have also been published [2]. However, since publication of these reviews, new data have appeared in the literature concerning adjuvant and neoadjuvant therapy of NSCLC.

	Preoperative or Postoperative Radiation Therapy

Top Abstract Introduction Preoperative or Postoperative... Postoperative Adjuvant... Neoadjuvant Therapy Conclusions References

 
Twenty years ago, several nonrandomized studies suggested improved survival of patients with preoperative radiation therapy (XRT) compared with historic control data with operation alone. Fifteen percent to 50% of resected patients had pathologically sterile specimens. However, three large phase III studies, involving a total of 1,195 patients, failed to identify any survival advantage for preoperative XRT compared with operation alone. Although these older studies could be criticized based on inadequate staging and inferior XRT techniques, the size of the patient population makes it unlikely that preoperative XRT by itself can produce any major survival advantage.

Similarly, there have been several studies extolling the value of postoperative XRT in resected N1–2 disease (stage II or IIIA) compared with historical controls of operation alone. Squamous cell lung cancer is the histologic subtype most likely to benefit from postoperative XRT because locoregional (rather than distant) postoperative recurrences are more common than with other cell types. Kirsh and colleagues [3] reported a 34% 5-year survival in 32 patients with squamous cell carcinoma with postoperative XRT compared with 0% of 20 patients with N2 disease treated with operation alone. Green and colleagues [4] had a 21% 5-year survival in 28 patients with resected N1–2 squamous cell lung cancer who received postoperative XRT compared with a survival of only 1 of 16 with operation alone. Although these results were intriguing, they were retrospective, nonrandomized studies with unknown biases concerning who did and did not receive postoperative XRT. The Lung Cancer Study Group (LCSG) performed a phase III random prospective study in 210 eligible patients with stage II or resectable T1–3 N2 M0 (stage IIIA) lung cancer who were treated by operation alone or operation followed by 5,000 cGy postoperatively. Patients were stratified by stage, presence or absence of weight loss, age, and institution. Postoperative XRT achieved a significant reduction in recurrences to the ipsilateral lung and mediastinum (p = 0.001). Unfortunately, this reduction in local recurrence did not translate to any advantage in overall survival (p = 0.678) [5].

More recently, the Medical Research Council Lung Cancer Working Party in the United Kingdom conducted a phase III study between 1986 and 1993 [6]. Three hundred eight patients (63% N1 and 37% N2) were randomized to no postoperative therapy versus 40 Gy in 15 fractions postoperatively. There was no advantage in survival with the addition of postoperative irradiation.

These studies raise doubt about the validity of postoperative XRT in resected N1–2 disease. In our current era of healthcare cost constraints, it is perhaps time to question the continued use of postoperative XRT. The benefits of reduced incidence of local recurrence (atelectasis and obstructive pneumonia) have to be weighed against the cost and toxicity of a treatment that does not, by itself, improve survival.

Preoperative or postoperative XRT has sometimes, but not always, been a component of recent phase III multimodality treatment strategies in patients with stage II or IIIA disease [7]. In this setting, if chemotherapy is effective, there might be a potential survival benefit with the addition of XRT and reduced local recurrence.

	Postoperative Adjuvant Chemotherapy or Combined Chemotherapy and Radiotherapy

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There is little, if any, controversy about the management of resected stage I NSCLC, as these patients are treated with operation alone. There is one study suggesting benefit with postoperative chemotherapy. Investigators from Helsinki, Finland, randomized 110 patients to operation alone versus operation followed by CAP (cyclophosphamide, 400 mg/m², + doxorubicin, 40 mg/m², + cisplatin, 40 mg/m², every 4 weeks for six cycles). Ninety-nine patients had pathologic stage I disease. The study was conducted from 1982 to 1987. There were 27 recurrences (48%) in the control arm compared with 7 (31%) with postoperative CAP (p = 0.01). The 5-year survival rate was 56% (control arm) versus 67% (p = 0.050). A potential problem in interpretation of these data was the disparity of clinical characteristics in these 110 patients. The CAP arm had 7 patients with a Karnofsky performance score less than 80 compared with 11 for the control arm, 19 (versus 15) had T1 disease, 7 (versus 14) had large cell histology, and 11 (versus 22) required pneumonectomy, all favoring the CAP arm [8].

The LCSG also evaluated adjuvant CAP in a phase III trial in resected stage I NSCLC [9]. The CAP regimen in this study used a dosage of cisplatin of 60 mg/m² (same doxorubicin and cyclophosphamide) and gave four courses every 3 weeks. Two hundred sixty-nine patients with stage I or T1 N1 M0 patients were randomized. With a mean follow-up of 3.8 years, there were no differences in time to recurrence (p = 0.53) or overall survival (p = 0.92) [9].

The LCSG evaluated CAP in a phase III trial in resected stage II–III adenocarcinoma and large cell lung cancer. The "control" arm consisted of intrapleural bacille Calmette-Guérin vaccine plus levamisole as an adjuvant to operation. The results revealed a significant increase in disease-free survival and overall survival for CAP [7]. However, this study is confounded by the inclusion of levamisole in the control arm. There are several phase III studies of levamisole in lung cancer demonstrating inferior survival with levamisole compared with control arms without levamisole.

Investigators from Memorial Sloan-Kettering Cancer Center published results from a phase III trial [10]. Seventy-two patients with T1–3 N2 M0 disease were randomized to operation plus postoperative XRT (4,600 cGy) or postoperative XRT plus vindesine (3 mg/m² weekly for five cycles then every 2 weeks for six cycles) and cisplatin (120 mg/m² on days 1, 29, 71, and 113). The median survival with chemotherapy was 17.5 months compared with 24.5 months for the control arm. Time to progression was 9 versus 9.2 months. The 1-, 2-, and 5-year survivals were 72%, 31%, and 17% with postoperative chemotherapy versus 66%, 44%, and 30% for the control arm [10]. There was no evidence of any benefit with the use of an aggressive postoperative chemotherapy regimen of cisplatin (120 mg/m²) + vindesine.

In Japan, a phase III study randomized 209 patients with completely resected stage IIIA NSCLC to postoperative cisplatin (80 mg/m²) + vindesine every 4 weeks for three cycles versus no postoperative therapy [11]. The 3-year survival was 37% with adjuvant chemotherapy and 42% with no postoperative therapy, with a median survival time of 31 months versus 37 months.

A multiinstitutional French study randomized 267 patients with resected NSCLC. Patients received either 60 Gy radiotherapy postoperatively or three courses of postoperative cyclophosphamide + doxorubicin + lomustine + vincristine + cisplatin (75 mg/m² every 4 weeks) followed by 60 Gy radiotherapy. Seventy percent had stage IIIA, 27% stage II, and 3% stage I. The minimal follow-up was 6 years. There was no difference in disease-free survival (p = 0.47) or overall survival (p = 0.68) [12].

	Neoadjuvant Therapy

Top Abstract Introduction Preoperative or Postoperative... Postoperative Adjuvant... Neoadjuvant Therapy Conclusions References

 
There have been numerous positive phase II neoadjuvant trials of chemotherapy or chemoradiotherapy in clinical stage II–III disease. Compared with historic controls, these studies demonstrated a higher rate of resectability, improved local control, some resected specimens with only necrotic tumor, and improved survival [1].

The end points for combined modality studies include response rate to preoperative chemotherapy, resectability rate, pathologic complete remission rate, and median and 5-year survival. Most studies attained a 40% to 70% response rate. However, it was noted that there was often poor correlation between radiographic and pathologic results. About 70% of patients were resectable and 20% had no tumor after neoadjuvant therapy. However, the most important factor was whether this combined modality approach improved survival compared with operation alone for stage IIIA disease.

Two recently published phase III studies have demonstrated a dramatic benefit of preoperative chemotherapy in patients with stage IIIA disease. Rossell and colleagues [13] in Spain randomized 60 patients to operation alone versus three courses of mitomycin-C + ifosfamide + cisplatin (50 mg/m²) followed by operation. Both arms received postoperative thoracic irradiation. The median survival was 8 versus 26 months (p < 0.001) and median disease-free survival 5 versus 20 months. Despite the very positive results in this randomized study, there were some problems with this study: (1) small sample size (30 patients per arm), (2) unusual chemotherapy regimen, at least for this country, with just 50 mg/m² cisplatin, (3) control arm had unusually poor results (disease-free survival of just 5 months and median survival time 8 months) for the operation-alone arm for operable stage IIIA disease (these results are more typical for stage IV disease), (4) K-ras mutations in only 3 of 20 (15%) preoperative chemotherapy patients versus 10 of 24 (42%) in the control group (p = 0.05), and (5) only 5 of 17 (29%) preoperative chemotherapy tumors were aneuploid compared with 14 of 20 (70%) in the control arm (p = 0.02).

Roth and colleagues [14] at M.D. Anderson also randomized 60 patients with stage IIIA disease to three courses of preoperative (and three postoperative) chemotherapy with cisplatin (100 mg/m²) + VP-16 + cyclophosphamide versus operation alone. The estimated median survival time was 64 versus 11 months (p = 0.008). The estimated 1-, 2-, and 3-year survivals were 75%, 60%, and 56% for the chemotherapy arm versus 45%, 25%, and 15% for surgery alone [14]. A third (and even smaller) National Cancer Institute study also demonstrated benefit for neoadjuvant therapy [15].

Although provocative, these results are so good that they defy logic and raise the question about small sample size and disparity of patients randomized to chemotherapy plus operation versus operation alone. There is no reason why drugs that are ineffective postoperatively should have such dramatic results preoperatively. A large phase III breast cancer study randomized 1,523 patients to preoperative versus postoperative adjuvant chemotherapy. Despite the theoretical appeal of neoadjuvant therapy, there was no difference in disease-free or overall survival [18].

There are two negative neoadjuvant studies in stage III NSCLC. Japanese investigators have also evaluated neoadjuvant therapy for clinical stage III NSCLC. Eighty-three patients were randomized to operation versus preoperative cisplatin + vindesine + XRT. Despite a 72% response rate to neoadjuvant therapy with 11% pathologic complete responses, there was no difference in survival between the two arms [16].

Neoadjuvant chemotherapy was also studied by the Cancer and Leukemia Group B in a phase III study. Fifty-seven patients with stage IIIA N2 NSCLC were randomized to XRT + operation versus two cycles of preoperative cisplatin (35 mg/m² for three cycles) + VP-16 (200 mg/m² for three cycles) followed by operation and XRT. There was no difference in disease-free survival (p = 0.98) or overall survival (p = 0.64) [17].

Patient heterogeneity can complicate conclusions from small studies in stage III disease. Recent revisions in the staging system have now been published (Table 1). Patients with T3 N0 disease are now classified as having stage IIB disease [19]. This new staging system will facilitate subsequent adjuvant trials.

	Conclusions

Top Abstract Introduction Preoperative or Postoperative... Postoperative Adjuvant... Neoadjuvant Therapy Conclusions References

	References

Top Abstract Introduction Preoperative or Postoperative... Postoperative Adjuvant... Neoadjuvant Therapy Conclusions References

 

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14. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA NSCLC. J Natl Cancer Inst 1994;86:673-680.[Abstract/Free Full Text]
15. Pass HI, Pogrebniak HW, Steinberg SM, Mulshine J, Minna J Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 1992;53:992-998.[Abstract]
16. Yoneda S, Hibino S, Gotoh I, et al. A comparative trial on induction chemoradiotherapy followed by surgery or immediate surgery for stage III NSCLC [Abstract]. Proc Am Soc Clin Oncol 1995;14:367.
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18. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative therapy for primary breast cancer on local-regional disease, disease-free survival and survival: results from NSABP B-18 [Abstract]. Proc Am Soc Clin Oncol 1997;16:127.
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