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Induction Chemotherapy for Resectable Non–Small-Cell Lung Cancer

Induction Chemotherapy for Resectable Non–Small-Cell Lung Cancer

Drs. Patel, Blum, and Argiris have provided a detailed, thorough review of induction chemotherapy for non-smal--cell lung cancer (NSCLC). They also discuss staging and the relative merits of a variety of invasive and noninvasive techniques for staging lung cancer. Quite rightly, the authors point out that stage III lung cancer is a heterogeneous disease with survival rates ranging from below 5% to greater than 50%. Clearly, survival within stage III disease relates to the extent of mediastinal lymph node involvement. Bulky mediastinal lymph node involvement is associated with poor survival, and patients with microscopic deposits in a single lymph node may have excellent survival following surgery. It is, therefore, important that stage III be reclassified into subsets that will allow for more homogeneous preoperative classification and more accurate stratification for phase III trials. Previous phase II and III trials have frequently included patients with a variety of subsets within stage III, making the interpretation of the data difficult. Currently, a committee sanctioned by the International Association for the Study of Lung Cancer is working on the reclassification or, more accurately, the subclassification of stage III lung cancer. Role of PET, CT, and MRI
The authors also quite rightly point out that positron-emission tomography (PET) scanning has only 85% specificity in the mediastinum and that patients with positive mediastinal PET scans should have a confirmation by biopsy. It should also be pointed out that cervical mediastinoscopy has a false-negative rate of somewhere between 8% and 10%, and patients with negative cervical mediastinoscopy may be found to have positive mediastinal nodes at thoracotomy. In the past, patients with stage I/II lung cancer who did not have neurologic symptoms did not merit a computed tomography scan of the brain. However, it appears that magnetic resonance imaging (MRI) scans are more sensitive and that patients with stage II/III disease, although neurologically asymptomatic, may benefit from MRIs of the brain. This remains controversial. Clinical Trial Findings
The authors provide a comprehensive review of the phase II and III trials of neoadjuvant or induction chemotherapy. In phase III trials, patients treated with neoadjuvant therapy and surgery have a prolonged progression-free survival, but overall survival is usually not prolonged. This is quite similar to the old Lung Cancer Study Group trials in which adjuvant chemotherapy pro- longed progression-free survival significantly but did not have an impact on overall survival.[1] The authors point out that this could well be due to the greater morbidity and mortality associated with combined chemotherapy, radiation therapy, and surgery. Advantages of Induction Chemotherapy
Neoadjuvant chemotherapy has advantages over postoperative adjuvant chemotherapy. These include earlier treatment of micrometastatic disease and improved chemotherapy tolerance and compliance as compared to postoperative chemotherapy. In postoperative adjuvant trials, it is rare that more than 60% of the prescribed chemotherapy can be given. Preoperative or neoadjuvant chemotherapy is much better tolerated by the patient, and in almost all studies, all of the chemotherapy can be delivered preoperatively. Another advantage of neoadjuvant chemotherapy is the ability to clear disease from the mediastinal lymph nodes in a significant number of patients. It appears that complete clearance of disease from the mediastinal lymph nodes has a positive correlation with improved survival and appears to be a significant prognostic factor. Studies to date have shown that complete mediastinal lymph node dissection at the time of surgery produces superior survival results, compared to patients who receive lymph node sampling alone. [2] A randomized trial supported by the American College of Surgeons Oncology Group is currently looking at radical, complete lymph node dissection as opposed to lymph node sampling. Clearly there are advantages to neoadjuvant chemotherapy and there are certain subsets of patients who appear to benefit from its administration. With the development of better molecular markers, it also seems likely that molecular staging will prove to be useful in predicting which patients will benefit from multimodality therapy. Addition of Radiation Therapy
Other remaining issues include the fact that it is unclear whether the addition of radiation therapy to pre- operative chemotherapy improves survival. The general consensus is that the addition of radiation therapy to chemotherapy in the neoadjuvant setting increases toxicity considerably. This is especially true when paclitaxel and gemcitabine (Gemzar) are used in combination with radiation therapy.[3] Several studies have indicated that paclitaxel and gemcitabine are associated with an increase in pulmonary complications when combined with radiation therapy.[3-7] Our own experience at University of California, Los Angeles, has led us to avoid adding radiation therapy to any chemotherapeutic regimen containing paclitaxel or gemcitabine when surgery is planned. We feel that the incidence of acute respiratory distress syndrome associated with these chemotherapeutic regimens in combination with radiation therapy gives rise to unacceptable postoperative pulmonary toxicity and mortality. In the current paper, the phase III randomized trials listed in Table 2 do not include radiation therapy, which might lead one to assume that those experienced in neoadjuvant therapy for lung cancer do not feel that the benefits of preoperative radiation outweigh the risks. The North American Lung Cancer Intergroup is planning a phase II trial that will incorporate preoperative paclitaxel and radiation therapy. This randomized trial should answer questions as to the pulmonary toxicity of the combination of paclitaxel and radiation therapy followed by surgery.[8] Once again, however, in our own experience we have found this toxicity to be unacceptable. Surgical Complications
The authors address surgical complications, pointing out that in at least one study, mortality after right pneumonectomy was excessive.[9] There are, however, other studies in which there is no difference between the mortality of right pneumonectomy, left pneumonectomy, and other resections.[ 10] The original study noting the high mortality of right pneumonectomy involved MVP ther- apy (mitomycin [Mutamycin], vindesine, cisplatin [Platinol]).[9] This combination is known to cause pulmonary toxicity following surgery, as was pointed out by the Lung Cancer Study Group in a neoadjuvant study using MVP.[11] It may well be that the induction regimen determines whether or not right pneumonectomy carries a higher morbidity. Novel Agents
The authors review novel agents including the tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva), as well as the potential application of antiangiogenesis factors. Recent data have indicated that tyrosine kinase inhibitors may have an increased efficacy in bronchoalveolar carcinoma as well as in patients with lung cancer who are nonsmokers. In addition, recent publications have indicated that certain critical mutations (and not the presence of growth factor receptors such as the epidermal growth factor receptor or HER2/neu) predict responses to the tyrosine kinase inhibitors.[12,13] Therefore, it may be critical in applying the use of these new agents to look at genetic mutations as well as molecular markers. Conclusions
Much has been learned about the use of neoadjuvant chemotherapy in patients with resectable and unresectable lung cancer. We are wary of the combination of radiation therapy with certain chemotherapeutic agents, as they contribute to postoperative pulmonary toxicity. We have learned that it is possible to downstage these patients and to convert unresectable patients to resectable patients. We have also learned much about surgical techniques that need to be employed following induction therapy, and this has reduced the rate of surgical complications. Certainly, the evolution of molecular markers will have an impact in this area, allowing the oncologist to predict which NSCLC patients might benefit from neoadjuvant therapy.

Disclosures

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

1. Lung Cancer Study Group: Final analysis. Chest 106(6 suppl):2795-4105, 1994.
2. Keller S, Sudschna A, Wagner H, et al: Mediastinal lymph node dissection improves survival in patients with stages II and IIIa nonsmall cell lung cancer. Ann Thorac Surg 70:358-366, 2000.
3. Slimack N, Klinge V, Singh T, et al: Gemcitabine associated interstitial pneumonitis: Comprehensiveness and clinical characteristics of FDA and medical literature cases (abstract 7229). Proc Am Soc Clin Oncol 23:670, 2004.
4. Van Zandwijik N, Smit EF, Kramer GW, et al: Gemcitabine and cisplatin as induction regimen for patients with biopsy proven stage IIIa N2 non-small cell lung cancer: Phase II study of the European organization for research and treatment of lung cancer (Cooperative Group EORTC 08955). J Clin Oncol 18:2658- 2664, 2000.
5. Choy H, Safran H, Akerly W: Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer. Clin Cancer Res 4:1931-1936, 1998.
6. Choy H, Akerley H, Safran S, et al: Multiinstitutional phase II trial of paclitaxel, carboplatin and concurrent radiation for locally advanced non-small cell lung cancer. J Clin Oncol 16:3316-3322, 1998.
7. Takeda K, Negro T, Tamura T, et al: Docetaxel (D) versus docetaxel plus gemcitabine (DG) for second-line treatment of non small cell lung cancer (NSCLC): Results of a JCOG randomized trial (JCOG0104) (abstract 7034). Proc Am Soc Clin Oncol 23:622, 2004.
8. Gandara D, West H, Albain K, et al: Defining the role of radiation therapy in combination with preoperative chemotherapy in stage III non-small cell lung cancer: Rationale and design of a new intergroup trial, pp 458-462. Alexandria, Va, ASCO Education Book, 2004.
9. Martin J, Ginsberg R, Abolhoda A, et al: Morbidity and mortality after neoadjuvant therapy for lung cancer: The risks of right pneumonectomy. Ann Thorac Surg 72:1149-1154, 2001.
10. Patel AN, Leuketich JD, Fernando HC, et al: Mortality of pneumonectomy in the age of neoadjuvant therapy for lung cancer (abstract 7176). Proc Am Soc Clin Oncol 23:657, 2004.
11. Wagner H, Lad T, Prantidosi S, et al: Randomized phase II evaluation of pre-operative radiation therapy and preoperative chemotherapy with mitomycin, vinblastine and cisplatin in patients with unresectable stage IIIA and IIIB non-small cell lung cancer. Chest 106:3495-3545, 1994.
12. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004.
13. Paez JG, Janne P, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004.
 
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