Locally Advanced, Unresectable Non-Small Cell Lung Cancer

Locally Advanced, Unresectable Non-Small Cell Lung Cancer

Locally Advanced, Unresectable Non-Small Cell Lung Cancer* New Treatment Strategies David H. Johnson, MD Approximately 40% of non-small cell lung can...

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Locally Advanced, Unresectable Non-Small Cell Lung Cancer* New Treatment Strategies David H. Johnson, MD

Approximately 40% of non-small cell lung cancer (NSCLC) patients present with locally advanced, unresectable lesions. Treatment with thoracic radiotherapy yields survivals averaging just 9 to 10 months, and long-term survival at 5 years is poor. Recent studies indicate that chemotherapy followed by thoracic radiotherapy improves 5-year survival by threeto fourfold. Nevertheless, most patients do ultimately die of the underlying disease. New strategies designed to enhance local tumor control— use of radiation-sensitizing drugs, three-dimensional treatment planning techniques, or altered radiation fractionation schedules—may further improve survival outcome. In addition, newer cisplatin-based regimens containing either paclitaxel or vinorelbine improve survival over that achieved with older vinca alkaloid or podophyllotoxin combination regimens. Accordingly, the newer drug regimens combined with radiotherapy can be expected to further improve survival in this subset of NSCLC patients. Prospective studies are underway to test this conjecture. (CHEST 2000; 117:123S–126S) Key words: distant metastases; fractionation; local control; radiation sensitization; radiotherapy; three-dimensional planning Abbreviations: CHART ⫽ continuous hyperfractionated accelerated radiotherapy; NSCLC ⫽ non-small cell lung cancer

cell lung cancer (NSCLC) is a leading cause N on-small of cancer deaths worldwide. The high death rate is 1

due to the fact that NSCLC is usually in an advanced stage not amenable to surgical resection when first diagnosed. Although the outlook for NSCLC patients remains fairly dismal, there is reason for guarded optimism, as modest therapeutic advances have been realized in this disease over the course of the past 2 decades. For example, in stage IV disease, survival can be lengthened and symptom palliation is possible with cisplatin-based chemotherapy.2,3 Similarly, survival for individuals with locally advanced, stage III NSCLC has improved with combined-modality therapy.4 – 6 Historically, patients with locally advanced NSCLC were treated with thoracic radiotherapy alone. However, because so many patients develop recurrent disease outside the chest, chemotherapy was added to standard thoracic radiotherapy in an attempt to diminish this problem with a resultant fourfold increase in 2-year survival rates.4 – 6 Despite these noteworthy advances, the overwhelming majority of NSCLC patients continue to die *From the Division of Medical Oncology, Vanderbilt Cancer Center, Nashville, TN. Correspondence to: David H. Johnson, MD, Division of Medical Oncology, 1956 The Vanderbilt Clinic, Nashville, TN 37232-5536

of their underlying malignancy, leaving considerable room for further refinement in the management of this disease. This review will focus on strategies aimed at improving outcome in locally advanced NSCLC.

Current Management of Locally Advanced, Unresectable NSCLC Approximately 40% of patients with newly diagnosed NSCLC first present with locally advanced disease, and the majority are inoperable.1 Traditionally, these patients were treated with radiotherapy alone, resulting in a median survival of approximately 9 to 10 months and a 5-year survival rate of approximately 7%.7 These discouraging results were largely due to the eventual development of extrathoracic metastases. Several investigators have tried combining local therapy (ie, radiotherapy) with systemic therapy (ie, chemotherapy) in an attempt to overcome the obstacle of systemic recurrence. Although the initial results with this approach were somewhat disappointing,8,9 possibly due to the modest activity of chemotherapy regimens initially employed, there appeared to be a subset of patients with locally advanced disease who derived a modest survival benefit,4,10 particularly those with good performance status and little or no weight loss. Most thoracic oncologists now advocate the routine use of chemotherapy plus radiotherapy in this group of patients with locally advanced, unresectable NSCLC.

Improving Local Tumor Control Although combined-modality treatment with chemotherapy and radiotherapy has improved survival in some patients with stage III NSCLC, most still succumb to the underlying disease.1 Tumor progression remains problematic, both locally within the chest and in extrathoracic sites. We will first examine the problem of local tumor control. It is commonly estimated that radiotherapy alone affords intrathoracic control in up to 50% of NSCLC cases, provided a total dose ⱖ 60 Gy is employed.11 However, such estimates are based on studies conducted ⬎ 20 years ago, which are probably not very accurate. The signs and symptoms associated with an extrathoracic lesion usually so dominate the clinical picture that even if local progression is present, it is commonly overlooked. Indeed, a patient who progresses outside of the chest rarely undergoes a thorough restaging. Consequently, the true incidence of local failure is almost certainly much higher than is commonly believed. In those rare circumstances where a careful reevaluation has been performed, the frequency of local control is disappointingly low, even when total radiotherapy doses are ⬎ 60 Gy.12 Fewer than 20% of irradiated patients undergoing repeat bronchoscopy have evidence of complete tumor control at the site of the primary lesion.12,13 Does this lack of local control really matter given our failure to adequately control systemic disease? The available data suggest improved local control is worthwhile. Strategies employed in recent years to further improve local tumor control include the use of radiation-sensitizing drugs, altered radiotherapy fractionation schedules, and the use of three-dimensional treatment planning techCHEST / 117 / 4 / APRIL, 2000 SUPPLEMENT

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Table 1—Concomitant Cisplatin Plus Radiotherapy in Locally Advanced NSCLC* Survival, % Radiotherapy Alone

Variables Duration 1-Yr 2-Yr 3-Yr Progression Local Distant

Radiotherapy and Weekly Cisplatin

Table 3—CHART vs Conventional TRT in the Treatment of Unresectable NSCLC* Variables

Radiotherapy and Daily Cisplatin

46 13 2

54 26 16

44 19 13

54 46

44 36

41 48.5

*Adapted from Schaake-Koning et al.18

niques. Several antineoplastic agents including cisplatin, topoisomerase-inhibiting agents, paclitaxel, and gemcitabine all have radiation-sensitizing potential.14 –17 This approach was tested in a European randomized trial showing that concomitant cisplatin and irradiation improved survival compared with radiotherapy alone.18 The survival benefit was clearly attributable to improved local tumor control because the rate of distant failure was not affected (Table 1). Although this approach warrants additional study, it is worth noting that the simultaneous use of radiation and drugs can be a double-edged sword. Administering chemotherapy and radiotherapy concomitantly may increase host toxicities, necessitating dose reductions in one or both treatment modalities. Esophagitis and pulmonary toxicities are particularly worrisome in this regard.19 –21 There appears to be a linear correlation between radiotherapy dose and local control of NSCLC.7,22 Accordingly, one theoretically could improve control at the primary tumor merely by increasing the dose of radiotherapy. However, it is difficult to increase the radiation dose ⬎ 60 Gy, due to toxicities engendered in normal tissues. Threedimensional treatment planning may permit use of increasing total radiation doses without causing excessive host toxicity.23 Preliminary studies indicate radiotherapy doses can be escalated to as high as 85 to 90 Gy without causing major damage to normal tissues with this technique.24 –27 Yet another means of increasing radiotherapy dose while minimizing normal tissue toxicity is the use of multiple daily radiation fractions.28 Pilot studies indicate this approach also is feasible.29,30 In fact, the results of

Patients, No. Median survival, mo 2-yr survival, %

CHART

Standard TRT

338 ⬃ 15

225 ⬃ 12

33

19

*Adapted from Saunders et al.34 TRT ⫽ thoracic radiation therapy.

several studies suggest hyperfractionated irradiation yields a survival benefit comparable to that achieved with combined-modality therapy (Table 2).29,31,32 These tantalizing data lend strong support to the notion that improving local tumor control is a worthwhile goal, even in the absence of improved control of extrathoracic disease. In further support of this position are the results of a recently completed British trial in which continuous hyperfractionated accelerated radiotherapy (CHART) was compared with standard daily radiotherapy (total dose, 60 Gy in 30 fractions) for the treatment of patients with unresectable NSCLC.33,34 CHART consisted of thricedaily 1.5-Gy fractions of irradiation given for 12 consecutive days to a total dose of 54 Gy (36 fractions). Median and long-term survival favored the CHART-treated group (Table 3), as did local control group rates. If these results are validated in confirmatory trials, the impact on the practice of NSCLC treatment could be profound.

Improved Control of Systemic Disease Several meta-analyses clearly showed that cisplatinbased chemotherapy can improve survival in patients with NSCLC.2,35,36 The modest survival advantage benefits primarily those patients treated with cisplatin-based combination regimens, although there is a trend toward improved survival with regimens containing vinca alkaloids or etoposide.2 Within the past few years, several new drugs have shown excellent activity against NSCLC, including the taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and irinotecan.37 Importantly, some of these agents possess unique mechanisms of action and, with rare exception, appear to be less toxic than many of the older agents used in the management of NSCLC. In recently completed randomized studies, the combinations of cisplatin plus paclitaxel or cisplatin plus vinorelbine yielded modest survival advantages over older cisplatin-based combination regimens.38,39 Given these observations, it is

Table 2—Radiotherapy Plus Chemotherapy and Hyperfractionated Radiotherapy in Locally Advanced NSCLC* Author Dillman et al Sause et al5

4

Cox et al29 Jeremic et al32

Radiotherapy, Gy

Chemotherapy

Median Survival, Mo

2-Yr Survival, %

4-Yr Survival, %

60 60 69.6 (bid) 69.6 (bid) 69.6 (bid)

CDDP ⫹ Vbl CDDP ⫹ Vbl – – –

13.7 13.6 12.3 13.0 14.0

26 31 24 29 26

19 11 9 9 9

*CDDP ⫽ cisplatin; Vbl ⫽ vinblastine. 124S

Multimodality Approach to Lung Cancer

reasonable to anticipate these newer regimens will provide similar (or greater) survival benefit in locally advanced NSCLC. Already there is considerable preliminary data to suggest this is likely to be true, and randomized trials are in progress. Furthermore, combining chemotherapy with newer techniques of thoracic radiotherapy may well provide additional survival benefit as suggested by the results of several pilot studies 19 and at least one recently reported randomized trial.40

Summary In summary, better local control, as well as greater control of extrathoracic micrometastases, should result in improved survival among patients with locally advanced NSCLC. The methods of improving local control are quite varied, and each merits continued investigation. Potentially, these techniques will lead to further improvement in the survival of NSCLC patients with locally advanced disease.

References 1 Ginsberg RJ, Vokes EE, Raben A. Non-small cell lung cancer. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: Lippincott-Raven, 1997:858 –910 2 Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311:899 –909 3 Ellis PA, Smith IE, Hardy JR, et al. Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 1995; 71:366 –370 4 Dillman RO, Herndon J, Seagren SL, et al. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 1996; 88:1210 –1215 5 Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88 – 08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-smallcell lung cancer. J Natl Cancer Inst 1995; 87:198 –205 6 Johnson DH. Combined-modality therapy for unresectable, stage III non-small-cell lung cancer: caveat emptor or caveat venditor. J Natl Cancer Inst 1996; 88:1175–1177 7 Sause WT, Turrisi AT. Principles and application of preoperative and standard radiotherapy for regionally advanced non-small cell lung cancer. In: Pass HI, Mitchell JB, Johnson DH, et al, eds. Lung cancer: principles and practice. Philadelphia, PA: Lippincott-Raven; 1996:697–710 8 Mattson K, Holsti L, Holsti P, et al. Inoperable non-small cell lung cancer: radiation with or without chemotherapy. Eur J Cancer 1988; 24:477– 482 9 Morton R, Jett J, McGinnis W, et al. Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer: a randomized, phase III trial. Ann Intern Med 1991; 115:681– 686 10 Dillman R, Seagren S, Propert K, 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 1990; 323:940 –945 11 Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiother-

12

13

14 15 16 17 18 19

20

21

22

23 24

25 26 27

28

29

apy: report by the Radiation Oncology Therapy Oncology Group. Cancer 1987; 59:1874 –1881 LeChevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 1991; 83:417– 423 LeChevalier T, Arriagada R, Tarayre M, et al. Significant effect of adjuvant chemotherapy on survival in locally advanced non-small cell lung cancer [letter]. J Natl Cancer Inst 1992; 84:58 Dewit N. Combined treatment of radiation and cisdiamminedichloroplatinum: II. A review of experimental and clinical data. Int J Radiat Oncol Biol Phys 1987; 13:403– 426 Chang AYC, Gu Z, Keng P, et al. Radiation sensitizing effects of topoisomerase I and II inhibitors [abstract]. Proc Am Assoc Cancer Res 1991; 32:389 Liebmann J, Cook JA, Fisher J, et al. In vitro studies of taxol as a radiation sensitizer in human tumor cells. J Natl Cancer Inst 1994; 86:441– 446 Lawrence TS, Eisbruch A, Shewach DS. Gemcitabine-mediated radiosensitization. Semin Oncol 1997; 24(2Suppl7):S24 – S28 Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall cell lung cancer. N Engl J Med 1992; 326:524 –530 Choy H, Akerley W, Safran H, et al. Phase I trial of outpatient weekly paclitaxel and concurrent radiation therapy for advanced non-small-cell lung cancer. J Clin Oncol 1994; 12: 2682–2686 Reckzeh B, Merte H, Pfluger K-H, et al. Severe lymphocytopenia and interstitial pneumonia in patients treated with paclitaxel and simultaneous radiotherapy for non-small cell lung cancer. J Clin Oncol 1996; 14:1071–1076 Blanke C, DeVore R, Shyr Y, et al. A pilot study of protracted low-dose cisplatin and etoposide with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1997; 37:111–116 Perez CA, Stanley K, Rubin P, et al. Patterns of tumor recurrence after definitive irradiation for inoperable non-oat cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1980; 6:987–994 Lichter AS, Ten Haken RK. Three-dimensional treatment planning and conformal radiation dose delivery. Important Adv Oncol 1995:95–109 Hazuka MB, Turrisi A Jr, Martel MK, et al. Dose-escalation in non-small cell lung cancer (NSCLC) using conformal 3-dimensional radiation treatment planning (3DRTP): preliminary results of phase I study [abstract 1119]. Proc Am Soc Clin Oncol 1994; 13:243 Lichter AS, Lawrence TS. Recent advances in radiation oncology. N Engl J Med 1995; 332:371–379 Armstrong JG. Three-dimensional conformal radiotherapy: precision treatment of lung cancer. Chest Surg Clin North Am 1994; 4:29 – 43 Graham MV, Jain NL, Kahn MG, et al. Evaluation of an objective plan-evaluation model in the three dimensional treatment of nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 1996; 34:469 – 474 Peters LJ, Ang KK. Unconventional fractionation schemes in radiotherapy. In: DeVita VT, Hellman S, Rosenberg SA, eds. Important advances in oncology, 1986. Philadelphia, PA: JB Lippincott, 1986; 269 –286 Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with ⬎69.6 Gy in favorable patients with Radiation Therapy CHEST / 117 / 4 / APRIL, 2000 SUPPLEMENT

125S

30

31

32

33

34

Oncology Group stage III non-small cell lung carcinoma; report of Radiation Therapy Oncology Group 83–11. J Clin Oncol 1990; 8:1543–1555 Saunders MI, Dische S. Continuous hyperfractionated, accelerated radiotherapy (CHART) in non-small cell lung carcinoma of the bronchus. Int J Radiat Oncol Biol Phys 1990; 19:1211–1215 Sause WT, Scott C, Taylor S, et al. RTOG 88 – 08, ECOG 4588, Preliminary analysis of a phase III trial in regionally advanced unresectable non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 1994; 13:325 Jeremic B, Shibamoto Y, Acimovic L, et al. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. J Clin Oncol 1995; 13:452– 458 Saunders MI, Dische S, Barrett A, et al. Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small-cell lung cancer: an interim report. Br J Cancer 1996; 73:1455–1462 Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee Lancet 1997; 350:161–165

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35 Souquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993; 342:19 –21 36 Grilli R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol 1993; 11:1866 –1872 37 Chiappori A, DeVore RF, Johnson DH. New agents in the management of non-small cell lung cancer. Cancer Control 1997; 4:219 –227 38 Bonomi P, Kim K, Chang A, et al. Phase III trial comparing etoposide (E) cisplatin (C) versus taxol (T) with cisplatin-GCSF (G) versus taxol-cisplatin in advanced non-small cell lung cancer: an Eastern Cooperative Group (ECOG) trial [abstract 1145]. Proc Am Soc Clin Oncol 1996; 15:382 39 LeChevalier T, Brisgand D, Douillard JY, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 1994; 12:360 –367 40 Jeremic B, Shibamoto Y, Acimovic L, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. J Clin Oncol 1996; 14:1065–1070

Multimodality Approach to Lung Cancer