Newer chemotherapy drugs have shown encouraging activity in advanced non-small-cell lung cancer. Based on these improved outcomes, as well as the high rate of distant relapse in patients with locally advanced disease, several recent studies have evaluated the use of systemic therapy in patients with earlier-stage disease.
ABSTRACT: Newer chemotherapy drugs have shown encouraging activity in advanced non-small-cell lung cancer. Based on these improved outcomes, as well as the high rate of distant relapse in patients with locally advanced disease, several recent studies have evaluated the use of systemic therapy in patients with earlier-stage disease. Chemotherapy has prolonged survival when given in addition to radiation therapy or used as induction therapy in patients with locally advanced, resectable non-small-cell lung cancer. Other work has shown improved survival when chemotherapy has been added to radiation therapy in patients with locally advanced, unresectable disease. Evaluations of the optimal sequencing of these two modalities have established the feasibility of delivering systemically active doses of chemotherapy concurrently with thoracic radiation. The mechanism of benefit is likely related in part to the radiosensitizing properties of certain chemotherapeutic agents, such as vinorelbine (Navelbine) and cisplatin (Platinol). To further evaluate the use of concomitant chemoradiation, our group designed a phase I, dose-escalation study of vinorelbine plus cisplatin and standard thoracic irradiation in patients with advanced chest neoplasms. Data from 37 patients showed that myelosuppression was the acute dose-limiting toxicity of this regimen. Early responses have been observed, and future analyses will document response rates both inside and outside the radiation field. [ONCOLOGY 11(Suppl 12)39-43, 1997]
Despite recent progress, locally advanced non-small-cell lung cancer (NSCLC) represents an ongoing treatment challenge. With more than 140,000 new cases annually, non-small-cell lung cancer remains the leading cause of cancer-related mortality in the United States. Of these new cases, nearly one-third present with locally advanced, unresectable disease (stages IIIA and IIIB).
Despite efforts to reduce smoking, the previously declining percentage of Americans who smoke seems to have reached a plateau at approximately 25%, with some evidence of an increase in the number of young smokers. This trend, along with the aging of the baby-boom generation, will certainly foreshadow a continuation of high lung cancer rates during the coming years.
Despite trials of chemoprevention of lung cancer and efforts to establish better screening strategies to identify earlier-stage cancers, non-small-cell lung cancer continues to be one of the major challenges facing the practicing oncologist. The use of radiation therapy alone has been the traditional treatment for unresectable stage III disease; however, this approach has led to few cures, with a dismal long-term survival rate of £ 10%.
This article will review the evolving role of chemotherapy in the treatment of both advanced and earlier-stage non-small-cell lung cancer, as well as recent work pointing toward the additive benefits of combined treatment with chemotherapy and radiation therapy. These observations provided the rationale for a phase I study, in which we assessed chemotherapy and concurrent chest irradiation as a means of ultimately improving both local and systemic control of non-small-cell lung cancer. Preliminary results of this investigation are reported here.
In view of the fact that a majority of patients with non-small-cell lung cancer will die of distant disease progression, better systemic therapy is needed. A few of the older standard chemotherapy drugs have demonstrated encouraging activity in non-small-cell lung cancer; these include cisplatin (Platinol), ifosfamide (Ifex), etoposide (VePesid), mitomycin (Mutamycin), vinblastine, and vindesine (Eldisine).
Using these drugs alone or in combination, several randomized studies have compared chemotherapy to best supportive care alone in the palliative setting.[5-11] Although these studies have often been too small to demonstrate statistically significant differences, or have employed older, less-efficacious chemotherapy regimens, a universal trend favoring patients treated with chemotherapy has been evident. In addition, four meta-analyses have now been performed using data from these trials; all have shown significantly longer survival among patients treated with chemotherapy than in those receiving supportive care alone for metastatic non-small-cell lung cancer.[12-15]
In the most recent meta-analysis, the 1-year survival rate improved from 15% to 25% (P < .0001) and the median survival was prolonged by 6 weeks in patients receiving cisplatin-based chemotherapy. Thus, chemotherapy has proved beneficial in the management of advanced non-small-cell lung cancer.
Several new chemotherapeutic drugs have been identified and studied in the treatment of non-small-cell lung cancer during the past several years. Those with encouraging activity have included vinorelbine (Navelbine), paclitaxel (Taxol), docetaxel (Taxotere), irinotecan (Camptosar), and gemcitabine (Gemzar); as single agents, each has produced a response rate of at least 15%. Phase II and III trials are currently evaluating these drugs, both as single agents and in combination therapy, to document their activity in non-small-cell lung cancer. These newer chemotherapeutic agents may offer improved efficacy with fewer toxic side effects, or a better therapeutic index, in the management of this disease.
Based on improved outcomes with chemotherapy in non-small-cell lung cancer, as well as the high rate of distant relapse in patients with locally advanced disease, several recent studies have attempted to apply the principle of systemic therapy to patients with earlier-stage disease. The Lung Cancer Study Group conducted a randomized trial of postoperative cyclophosphamide (Cytoxan, Neosar), doxorubicin (Adriamycin), and cisplatin plus radiation vs radiation alone in patients with completely resected stage IIIA disease.
The results suggested that adjuvant chemotherapy is associated with a survival advantage in patients with resected, locally advanced disease. Although the difference between groups did not reach statistical significance, the median duration of survival was longer in patients who received chemotherapy than in those who did not (20 vs 13 months).
Evidence that chemotherapy may have better efficacy in early-stage non-small-cell lung cancer also led researchers to pursue induction protocols in resectable, locally advanced disease. In a study by Rosell et al, patients with stage IIIA disease were randomized to receive either mitomycin, ifosfamide, and cisplatin or no chemotherapy before resection. All patients received adjuvant radiation therapy. The patients treated with chemotherapy had a remarkably superior median survival of 26 months, compared with 8 months in the control group (P < .001).
These results were confirmed by Roth et al, who randomized patients to receive either cyclophosphamide, etoposide, and cisplatin or no chemotherapy before surgical resection. Again, the median duration of survival was significantly better in the patients who received chemotherapy than in those who did not (64 vs 11 months; P < .008). These trials strongly support the role of induction chemotherapy as standard treatment for patients with resectable stage IIIA non-small-cell lung cancer.
Chemotherapy is also becoming standard treatment for unresectable stage IIIB non-small-cell lung cancer. Recently, investigators completed several studies that compared chemotherapy plus radiation to the previous standard of radiation alone. In a randomized trial conducted by the Cancer and Leukemia Group B (CALGB), the use of cisplatin and vinblastine followed by radiation was significantly superior to radiation alone with regard to both median survival (14 vs 10 months) and 5-year survival (19% vs 7%; P = .0066).
Sause et al confirmed these findings in another randomized trial that used the same regimen. Patients who received chemotherapy plus radiation had an improvement in median survival similar to those not receiving chemotherapy (14 vs 11 months) and a superior 1-year survival rate (60% vs 46%; P = .03). In a French study, Le Chevalier et al also found an improved 3-year survival rate with chemotherapy plus radiation vs radiation alone (12% vs 4%). Taken together, these studies confirm that chemotherapy prolongs survival when added to radiation in unresectable non-small-cell lung cancer.
With the evolving success of chemotherapy, it was logical to study optimal sequencing when this treatment is used in conjunction with radiation therapy. This line of investigation was also sparked by evidence that the simultaneous use of chemotherapy can sensitize tumor cells to the cytotoxic effects of radiation.
Vinorelbine was shown to potentiate the effects of radiation on a human non-small-cell lung cancer line in vitro, with a fivefold decrease in surviving cells exposed to the drug and radiation compared with radiation alone. This is thought to occur by tumor-cell synchronization into the radiosensitive G2M phase of the cell cycle. In addition, preclinical in vitro and in vivo data support the role of cisplatin as a radiation sensitizer, causing increased damage to tumor cells.
The goal of this bimodality approach is to improve local control within the radiation field, while addressing systemic disease control through the use of effective chemotherapy. The mechanism of benefit may be based on simple physical cooperation of the two modalities, which work on different sites or cell populations.
An alternative mechanism would be biologic synergy, wherein one modality actually helps sensitize cells so that they become more responsive to the other therapy; this can occur by means of chemotherapy-induced synchronization of tumor cells to a radiation-sensitive phase, or by actual inhibition of repair of sublethal damage produced by radiation therapy, thereby augmenting cell death.[25-27]
A randomized study by Schaake-Koning et al demonstrated that the addition of radiosensitizing chemotherapy could improve survival in stage IIIB non-small-cell lung cancer. The 3-year survival rate was 16% in patients who received daily cisplatin and radiation therapy vs 3% in those treated with the latter modality alone. This effect was explained almost entirely by the improved local control (31% vs 19%, at 2 years) provided by the addition of cisplatin. Nonetheless, the study provided evidence that chemotherapy has a critical role in locally advanced non-small-cell lung cancer.
In a feasibility study, the Southwest Oncology Group (SWOG) showed that patients could receive concomitant chemotherapy and radiation therapy before surgical resection for locally advanced non-small-cell lung cancer. Patients received two cycles of concomitant radiation therapy and full, systemically active doses of chemotherapy (50 mg/m2 of cisplatin on days 1 and 8 and 50 mg/m2 of etoposide on days 1 through 5) before planned resection.
Although the incidence of toxicity was high (with grade 4 toxicity in 13% of patients), more than 80% of the study group was able to undergo resection, with an impressive 3-year survival rate of 27% in stage IIIA disease (median survival, 13 months). This study helped establish the feasibility of delivering systemically active doses of chemotherapy concurrently with thoracic radiation.
A study evaluating the combination of cisplatin and vinorelbine demonstrated a response rate of 28% and a median survival duration of 40 weeks in advanced non-small-cell lung cancer. These findings, as well as the evidence of a radiosensitizing effect of these agents[23,28] and the results showing the clinical feasibility of concurrent combined-modality therapy, prompted our group to undertake a phase I dose-escalation study in patients with advanced chest neoplasms.
Our goal was to evaluate whether vinorelbine and cisplatin could be given safely and effectively with concurrent standard thoracic irradiation. If so, this combination could potentially lead to improved local control within the radiation field and better systemic control of disease in patients with locally advanced non-small-cell lung cancer.
Patients and Methods
To be eligible for this study, patients were required to have cytologic or histologic documentation of an advanced intrathoracic neoplasm requiring palliative or definitive radiation therapy to the chest. The standards for documentation were determined at a multidisciplinary chest oncology conference attended by thoracic surgeons, radiation oncologists, medical oncologists, radiologists, and pathologists.
Also eligible were patients who had undergone surgical resection and were believed to require adjuvant radiation because of a very high risk of local relapse. All patients were required to have a CALGB performance status £ 2, plus adequate hepatic, renal, and bone marrow function. Signed informed consent was obtained from all patients.
The objective of the study was to determine the maximum tolerated dose of vinorelbine when given in combination with cisplatin and concomitant standard thoracic radiation. Furthermore, the study sought to define the dose-limiting toxicities of this regimen.
Dose-limiting toxicities were defined as myelosuppression with grade 4 neutropenia or thrombocytopenia of more than 4 days duration, neutropenic fever, or the need for platelet transfusion. Nonhematologic dose-limiting toxicities consisted of grade 3 or greater toxicity lasting for more than 7 days (excluding alopecia, nausea, and vomiting). Dose escalation continued until two of three or three of six patients experienced dose-limiting toxicities. The maximum tolerated dose was defined as the dose immediately preceding this maximum administered dose.
Table 1 outlines the various dose levels used. Cisplatin was started at 100 mg/m2, given on days 1 and 22. Vinorelbine was started at 20 mg/m2, given on days 1, 8, 15, 22, 29, and 36. Standard chest irradiation was administered in single daily (Monday through Friday) fractions of 200 cGy for 6 weeks (30 doses), for a total of 6,000 cGy.
Pretreatment evaluations included blood counts, blood chemistry, chest x-ray, chest CT through the liver and adrenal glands, bone scan, and head CT or MRI. Follow-up evaluations were performed 4 to 6 weeks after the completion of therapy. Toxicity was graded on the standard CALGB scale. Complete response was defined as normalization of all radiologic evidence of disease, whereas partial response was defined as a ³ 50% reduction in the product of the greatest perpendicular dimensions of all measurable lesions, with no evidence of progression elsewhere.
Since accrual began in February 1994, the study has enrolled 37 patients (20 men and 17 women; median age, 62 years (range, 31 to 76 years). The characteristics of these patients are summarized in Table 2. A total of 22 patients had locoregionally advanced disease, and 15 had overt metastatic disease. Most patients (35) had non-small-cell lung cancer, nearly equally divided between adenocarcinoma (15) and squamous-cell carcinoma (12). Two patients had large-cell carcinoma, and six had other non-small-cell lung carcinomas. One patient had squamous-cell carcinoma of the esophagus, and one had follicular thyroid cancer. The median performance status was 1.
Initial chemotherapy (level I: 100 mg/m2 of cisplatin and 20 mg/m2 of vinorelbine) was well tolerated by the first cohort of patients. Subsequently, the vinorelbine dose was escalated to 25 mg/m2 (level II). This dose was not tolerated well; two of three patients developed dose-limiting neutropenia.
We then observed cumulative esophageal toxicity in patients treated at dose level I; three of six patients experienced dose-limiting esophagitis requiring narcotics for odynophagia and enteral or parenteral nutritional support. We therefore lowered the vinorelbine dose to 20 mg/m2 on 2 of 3 weeks (days 1 and 8 of each cycle). Esophagitis was still observed at this dose level, and the next cohort of patients was treated at reduced doses of both drugs: 80 mg/m2 of cisplatin on days 1 and 22 of radiation therapy, and 15 mg/m2 of vinorelbine on days 1, 8, 22, and 29 of therapy.
Further follow-up will clarify the tolerability of this regimen at these doses. Early responses have been observed, and future analyses will include documentation of response rates inside and outside the radiation field. We will also study the tolerability of this regimen when vinorelbine is given on consecutive days (days 1 and 2) at the beginning of each cycle.
The goal of this study in patients with advanced solid tumors of the chest was to attempt to combine full-dose systemic chemotherapy using cisplatin and vinorelbine (one of the best-studied and most active regimens to date) with full-dose, standard thoracic irradiation. The combination of cisplatin and vinorelbine has been shown to produce a response rate of nearly 30% in patients with advanced non-small-cell lung cancer, with a median survival duration of 40 weeks.
No regimen studied in a large-scale, phase III trial has yielded more encouraging results. In a previous study of patients with advanced non-small-cell lung cancer, we had also demonstrated the efficacy of these two drugs as part of a multidrug regimen that also included fluorouracil (5-FU) and leucovorin. Because both of these drugs have shown preclinical or clinical evidence of radiation enhancement,[23-28] we believed that this two-drug regimen could augment the local activity of radiation to provide an improved response within the radiation field. In addition, the systemic activity of this regimen should have been helpful in the management of systemic metastases, whether microscopic or overt.
In summary, this regimen can be given safely with an acute dose-limiting toxicity of neutropenia and a chronic dose-limiting toxicity of esophagitis. Our results to date have shown that toxicity is additive when this regimen is used with concomitant radiation therapy. Furthermore, the total dose of vinorelbine that can be administered in combination with cisplatin and concurrent chest irradiation is diminished because of acute myelotoxicity and cumulative esophagitis. Further analysis of the data from this study will help delineate additional toxicities and define the maximum tolerated doses.
In addition, we hope to study the feasibility of administering vinorelbine on a consecutive-day basis (ie, on days 1 and 2) to see whether improved tolerability or efficacy is possible. We have previously studied the feasibility of giving both vinorelbine and ifosfamide on three consecutive days in patients with advanced non-small-cell lung cancer.
Based on the early results of our study of vinorelbine, cisplatin, and concomitant chest irradiation, the CALGB has recently undertaken a trial comparing three different cisplatin-based regimens (cisplatin plus vinorelbine, paclitaxel, or gemcitabine) given as two cycles of induction chemotherapy followed by concomitant chemotherapy and radiation therapy (at reduced drug doses) in patients with stage III non-small-cell lung cancer. This randomized, phase II trial will help further define the response rates and toxicities associated with these regimens. This study, and other ongoing studies of combined-modality therapy, will continue to broaden our knowledge of the optimal management of locally advanced non-small-cell lung cancer and build on the small, but significant, advances achieved to date.
1. Boring C, Squires TN, Tong T, et al: Cancer statistics. CA Cancer J Clin 44:7-27, 1994.
2. American Thoracic Society: Cigarette smoking and health. Am J Respir Crit Care Med 153:861-865, 1996.
3. Crino L, Latini P, Meacci M, et al: Induction chemotherapy plus high-dose radiotherapy vs. radiotherapy alone in locally advanced non-small cell lung cancer. Ann Oncol 4:847-851, 1993.
4. Masters GA, Vokes EE: Should non-small cell carcinoma of the lung be treated with chemotherapy? Pro: Chemotherapy is for non-small cell lung cancer. Am J Respir Crit Care Med 151:1285-1287, 1995.
5. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer: Report of a Canadian multicenter randomized trial. J Clin Oncol 6:633-641, 1988.
6. Woods RL, Williams CJ, Levi J, et al: A randomized trial of cisplatin and vindesine versus supportive care only in advanced non-small cell lung cancer. Br J Cancer 61:608-611, 1990.
7. Quoix E, Dietermann A, Charbonneau J, et al: La chimiotherapie comportant du cisplatine est-elle utile dans le cancer bronchique non microcellulaire au stade IV? Resultants dune etude randomisee. Bull Cancer 78:341-346, 1991.
8. Cellerino R, Tummarello D, Guidi F, et al: A randomized trial of alternating chemotherapy versus best supportive care in advanced non-small cell lung cancer. J Clin Oncol 9:1454-1461, 1991.
9. Kaasa S, Lund E, Thorud E, et al: Symptomatic treatment versus combination chemotherapy for patients with extensive non-small cell lung cancer. Cancer 67:2443-2447, 1991.
10. Cormier Y, Bergeron D, La Forge J, et al: Benefits of polychemotherapy in advanced non-small cell bronchogenic carcinoma. Cancer 50:845-849, 1982.
11. Ganz PA, Figlin RH, Haskell CM, et al: Supportive care vs supportive care and combination chemotherapy in metastatic non-small cell lung cancer. Cancer 63:1271-1278, 1989.
12. Grilli R, Oxman AD, Julian JM: Chemotherapy for advanced non-small cell lung cancer: How much benefit is enough? J Clin Oncol 11:1866-1872, 1993.
13. Souquet PJ, Chauvin F, Boissel JP, et al: Polychemotherapy in advanced non-small cell lung cancer: A meta-analysis. Lancet 342:19-21, 1993.
14. Marino P, Pampallona S, Preatoni A, et al: Chemotherapy versus supportive care in advanced non-small cell lung cancer: Results of a meta-analysis of the literature. Chest 106:861-865, 1994.
15. Non-Small Cell Lung Cancer Collaborators Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 311:899- 909, 1995.
16. Lilenbaum RC, Green MR: Novel chemotherapeutic agents in the treatment of non-small-cell lung cancer. J Clin Oncol 11:1391-1402, 1993.
17. Lad T: The comparison of CAP chemotherapy and radiotherapy to radiotherapy alone for resected lung cancer with positive margin or involved highest sampled paratracheal node (stage IIIA): LCSG 791. Chest 106(suppl S):302S-306S, 1994.
18. Roth JA, Fossella S, Komaki R, et al: A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer. J Natl Cancer Inst 86:673- 689, 1994.
19. Rosell R, Gomez-Codina J, Camps C, et al: A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 330:153-158, 1994.
20. Dillman RO, Seagren SL, Propert KJ, et al: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small cell lung cancer. N Engl J Med 323:940-945, 1990.
21. Sause W, Scott C, Taylor S, et al: RTOG 8808/ECOG 4588, preliminary analysis of a phase III trial in regionally advanced unresectable non-small cell lung cancer. Proc Am Soc Clin Oncol 13:325, 1994.
22. Le Chevalier T, Arriagada R, Quoix E, et al: Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer. J Natl Cancer Inst 84:85, 1992.
23. Edelstein MP, Wolfe LA, Duch DS: Potentiation of radiotherapy by Navelbine (NVB) in a human non-small cell lung cancer (NSCLC) line. Proc Am Assoc Cancer Res 36:611, 1995.
24. Dewit L: Combined treatment of radiation and cisdiammine dichloroplatinum (II): a review of experimental and clinical data. Int J Radiat Oncol Biol Phys 13:403-426, 1987.
25. Vokes EE: Interactions of chemotherapy and radiation. Semin Oncol 20:70-79, 1993.
26. Vokes EE, Weichselbaum RR: Concomitant chemoradiotherapy: Rationale and clinical experience in patients with solid tumors. J Clin Oncol 8:911-934, 1990.
27. Masters GA, Vokes EE: Radiotherapy and concomitant chemotherapy, in Bertino J (ed): Encyclopedia of Cancer. San Diego, California, Academic Press, 1997.
28. Schaake-Koning C, van den Bogaert W, Dalesio O, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 326:524-530, 1992.
29. Albain KS, Rusch VW, Crowley JJ, et al: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: Mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13:1880-1892, 1995.
30. Le Chevalier T, Brisgand D, Douillard JY, et al: Randomized study of vinorelbine and cisplatin vs vindesine and cisplatin vs vinorelbine alone in advanced non-small cell lung cancer: Results of a European multicenter trial including 612 patients. J Clin Oncol 12:360-367, 1994.
31. Masters GA, Drinkard LC, Hoffman PC, et al: A phase I/phase II study of vinorelbine (Navelbine) with cisplatin, 5-fluorouracil, and leucovorin for advanced non-small cell lung cancer. Cancer J Sci Am 1:288-294, 1995.
32. Masters GA, Hoffman PC, Hsieh A, et al: A phase I study of vinorelbine and ifosfamide in advanced non-small cell lung cancer. J Clin Oncol 15:884-882, 1997