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The care of the lung cancer patient in the 21st century: A new age
The Care of the Lung Cancer Patient in the 21st Century: A New Age Wade Smith and Fadlo R. Khuri Lung cancer is by far the leading cause of cancer-related death within the United States and throughout the world, with a global incidence estimating 1,240,000 in 2001. While median survival has improved from 7 months in 1960 to 16.8 months in 2001 for all patients diagnosed with lung cancer, much of this progress relates to improved surgical techniques, combined modality therapy for locally advanced disease, improved symptom palliation, and moderate but real improvements in survival of stage IV disease. However, much work remains to be done in a field in which only 15% to 17% of patients live 5 years. The role of chemotherapy in the last decade has expanded substantially, with evidence for extension of median survival in stage IV from 4 months to 8 to 10 months, improvements in symptom control, as well as 1-year survival almost tripling from 11% to 14% to 32% to 37% with modern chemotherapy regimens. Furthermore, progress has also been seen in the use of concomitant chemoradiotherapy, which has become the mainstream approach for treating patients with locally advanced non–small cell lung cancer. Finally, trials with cisplatin-based chemotherapy suggest that for resectable non–small cell lung cancer, improvement in disease-free and overall survival at 5 years is in the range of 4% to 5%. With the development of multiple small molecules and monoclonal antibodies targeting important growth factor receptors, oncogenes and tumor-suppressor genes known to be aberrant in lung cancer, there is hope for further incremental improvements in the treatment of this deadly disease. Semin Oncol 31 (suppl 4):11-15. © 2004 Elsevier Inc. All rights reserved.
W
ITHIN THE United States, approximately 170,000 people will be diagnosed with lung cancer in 2003.1 Worldwide, 901,746 new cases in men and 337,115 cases in women were reported in 2001.2 Histologic breakdown of these tumors is such that 75% to 80% of all lung cancers are non–small cell lung cancers (NSCLCs), accounting largely for the three subtypes of adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, while only 18% to 20% are small cell carcinoma histologically.2,3 Worldwide, there are substantial differences in the incidence and survival from this disease, with 5-year survival in the United States at 16.8%, while it is only 7% in Great Britain.2 Part of this difference is caused by slower adoption of chemotherapy, either alone or in combination with radiation therapy as a principal therapeutic tool in the British Isles compared Seminars in Oncology, Vol 31, No 2, Suppl 4 (April), 2004: pp 11-15
with the United States.2,3 A far greater dimension to this grim outcome is that 70% to 80% of patients with lung cancer present with evidence of either locally advanced or metastatic disease on diagnosis. While four third-generation cytotoxic regimens were approved for the treatment of metastatic NSCLC in the 1990s, much work remains to be carried out for a disease in which 83% to 85% of patients are dead 5 years after initial diagnosis.1-3 The last 15 years have seen a lifting of the veil of therapeutic nihilism that has long accompanied by nonsurgical treatment in lung cancer.4 With the development of novel agents and small molecules designed to curtail the aggressive aspects of this disease, some progress has been realized. However, much more effort and insight will be required for additional real gains to be made. A ROLE FOR CHEMOTHERAPY IN SMALL CELL AND NON–SMALL CELL LUNG CANCER?
As opposed to small cell lung cancer, where early studies indicated that the disease was generally chemoresponsive, improving median survival in extensive disease from a median of 5 to 12 weeks up to a median of 8 to 10 months and improving 2-year survival from 0% to between 10% and 20%, there was much more therapeutic conservatism pervading the treatment of NSCLC.4,5 In the late 1980s, a series of clinical trials indicated that randomizing patients to cisplatin-based chemotherapy versus best supportive care afforded an improvement in median survival from 4 months to approximately 6.5 months, as
From the Winship Cancer Institute, Emory University, Atlanta, GA. Dr Khuri has received research grant support from Schering Plough Research Institute, Aventis Oncology, Amgen Pharmaceuticals, and AstraZeneca. He has served as a consultant to Aventis Oncology. Address reprint requests to Fadlo R. Khuri, MD, Winship Cancer Institute, Emory University, 1365 Clifton Rd, Bldg C, Room 3094, Atlanta, GA 30322. © 2004 Elsevier Inc. All rights reserved. 0093-7754/04/3102-0403$30.00/0 doi:10.1053/j.seminoncol.2004.02.012 11
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SMITH AND KHURI
Table 1. Comparison Between Supportive Care Versus Cisplatin-Based Chemotherapy
Study Rapp et al5 Woods et al6 Quoix et al7 Ganz et al8 Cartei et al9 Cellerino et al10 Cullen et al11 Helsing et al12
1-Year Survival
Median Survival (wk)
Chemo
No. of Patients
Chemo Arm
SC
Chemo v SC
CAP VP VP VP VP MCP CEP/MEC MIP VpCarbo
NR 137 188 46 48 102 115 359 48
24.7 32.6 27 28 20.4 36.6 34.3 29.7 29
NR 17 17 10 13.6 17.2 21.1 18.6 11
21% v 14% 26% v 14% 24% v 17% 24% v 11% 19% v 12% 38% v 12% 30% v 20% 28% v 18% 28% v 8%
Abbreviations: CAP, cyclophosphamide, adriamycin, and cisplatin; VP, vindesine and cisplatin; MCP, mitomycin, cyclophosphamide, and cisplatin; CEP/MEC, cyclophosphamide, epirubicin, cisplatin alternating with methotrexate, etoposide, and lomustine; MIP, mitomycin, ifosfamide, and cisplatin; VpCarbo, vindesine, cisplatin, and carboplatin.
well as improving 1-year survival from 11% to 17% up to 21% to 38% (see Table 1).5-12 The fact that this progress was seen only with the introduction of cisplatin was of substantial importance. Meanwhile, in extensive-stage small cell lung cancer, progress has continued. A recent trial by Noda et al10 randomized patients to treatment with a combination of cisplatin and irinotecan, with cisplatin given at a dose of 60 mg/m2 on day 1 and irinotecan (60 mg/m2) given on days 1, 8, and 15 versus cisplatin and etoposide at 80 mg/m2 day 1 and 100 mg/m2 days 1 to 3, respectively. Seventy-seven patients were randomized on each arm, with the irinotecan/cisplatin arm proving superior in terms of median and 2-year survival. A trial including stage IIIB and stage IV NSCLC conducted by the Eastern Cooperative Oncology Group randomized patients to four platinum-based chemotherapy regimens plus novel agents; the control arm being cisplatin plus paclitaxel. None of the other three arms of docetaxel plus cisplatin, carboplatin plus paclitaxel, or gemcitabine plus cisplatin were superior in terms of median, 1-year, or 2-year survival.11 A recent study (Fossella et al12) indicated that cisplatin and docetaxel appeared marginally superior to cisplatin and vinorelbine, although carboplatin and docetaxel were equivalent to cisplatin and vinorelbine in terms of median and overall 2-year survival. Both docetaxel-containing regimens led to improvements in quality of life and pain control,
as well as requirements for narcotic analgesics as compared with the cisplatin/vinorelbine arm with the median survivals in this trial improved by 10 to 11 months. Thus, over the last decade, we have seen improvements in survival in stage IIIB with pleural effusion or metastatic disease for NSCLC from 4 months with best supportive care in the mid to late 1980s to 8 to 10 months with platinum-containing chemotherapy. Similarly, 1-year survival has improved from 11% to 17% to 32% to 37%, with 2-year survival increasing from less than 5% to 10% to 15%. CHANGES IN THE STANDARDS FOR LOCALLY ADVANCED LUNG CANCER
During the last decade, progress has also been made in disease control and overall survival for limited-stage small cell lung cancer and locally advanced NSCLC. Recent data from Turissi et al,13 in a randomized intergroup trial, indicated that concurrent hyperfractionated chemoradiation therapy was superior to single-fraction radiotherapy delivered with chemotherapy in terms of improving overall survival (2-year survival, 47%; 5-year survival, 26%) and disease-free survival (2year survival, 29%) in limited-stage small cell lung cancer (Fig 1).13 In locally advanced NSCLC, chemotherapy followed by radiation was superior to radiotherapy alone in terms of overall and disease-free survival.14 A series of trials showed that in good performance status patients with locally
THE LUNG CANCER PATIENT IN THE 21ST CENTURY
Table 2. Comparing Survival Between Concurrent and Sequential Chemoradiotherapy RTOG 9410 Sequential Concurrent
MS
1 yr
2 yr
P Value
14.6 mo 17 mo
57% 63%
16% 35%
.038
West Japan
MS
3 yr
5 yr
Sequential Concurrent Historical Control
13 mo 16.5 mo XRT alone
14.7% 22.3%
8.8% 15.8% 10-11
.04 13-15%
Abbreviation: MS, median survival.
advanced NSCLC, concurrent chemoradiotherapy was superior to radiotherapy alone. The most obvious results of the latter data are seen within the West Japan Lung Cancer Study and the Radiation Therapy Oncology Group Study 9410 (RTOG 9410).15,16 Both trials showed that concurrent chemoradiotherapy was superior to sequential chemotherapy followed by radiation. The mature 5-year data in the West Japan Lung Study favor concurrent therapy with 5-year survival of 15.8% versus 8.8% for sequential chemotherapy and radiation for stage IIIA, IIIB NSCLC (see Table 2).15 The similar RTOG 9410 study showed that concurrent chemoradiotherapy offered a 2-year survival of 35% versus 16% for sequential chemoradiation (P ⫽ 0.038).16 Recent data has been obtained regarding the sequencing of chemoradiotherapy in NSCLC. Of note, in a phase II trial by Gandara et al17 of patients with documented stage IIIB NSCLC who were treated with cisplatin and etoposide with concurrent thoracic radiation followed by up to 3 cycles of docetaxel, median survival was 27 months and 3-year survival was 37%, the best reported in the literature for patients with locally advanced, NSCLC without evidence for malignant pleural effusion.17 The success of this combination has led to the development of a randomized trial through the Southwestern Oncology Group in which all patients receive concurrent chemoradiotherapy with cisplatin, etoposide, and radiotherapy to 60 to 63 Gy. This is followed by three cycles of docetaxel, followed by subsequent randomization to gefitinib, 250 mg/day for 1 year
13
versus observation (Gandara DR et al, SWOG study 0023, personal communication). PROGRESS IN ADJUVANT CHEMOTHERAPY FOR NON–SMALL CELL LUNG CANCER
After almost two decades of dispute and debate regarding the relative value of adjuvant chemotherapy for resectable NSCLC, the International Adjuvant Lung Trial randomized 1,867 patients to either cisplatin-based adjuvant chemotherapy or no treatment. At 5 years, the arm that received cisplatin-based chemotherapy showed a survival advantage of 4.1% compared with the observation arm.18 In combination with the recently positive adjuvant trial of UFT (tegafur/uracil) in stage Ib NSCLC,19 there is an increasing likelihood of adjuvant cisplatin-based therapy becoming standard adjuvant treatment for patients with NSCLC. The choice of the second agent with cisplatin remains open to debate, and less evidence exists to date supporting carboplatin-based adjuvant therapy than cisplatin-based adjuvant therapy. NOVEL AGENTS IN DEVELOPMENT FOR NON–SMALL CELL LUNG CANCER: A DECADE OF PROMISE, BUT LITTLE PROOF
Over the past few years, several agents have been investigated for use in the treatment of NSCLC with limited success. The first new small molecule to be approved for third-line NSCLC, with a narrow indication for patients who have failed both cisplatin-based front-line therapy and second-line therapy with docetaxel, is gefitinib, which has been tested in a randomized trial by Kris et al.20 This phase IIB study randomized over 200 patients to receive either 250 mg/day versus 500 mg/day of gefitinib, based on some encouraging phase I results.21 However, despite the initial promise with gefitinib, and the subsequent randomized trial which, though not controlled with a placebo arm, suggested that some 35% to 43% of patients had evidence of clinical benefit from this agent,20 two randomized trials of gefitinib combined with platinum-based chemotherapy failed to show any advantage of this agent to standard chemotherapy.22 Two subsequent trials with erlotinib in combination with chemotherapy were also negative despite promising initial data from PerezSoler et al,23 showing a 14% response rate in
14
SMITH AND KHURI
Fig 1. Intergroup trial of concurrent chemoradiotherapy versus hyperfractionated chemotherapy in limited-stage small cell lung cancer. (Reprinted with permission from Turissi et al.13)
second-and third-line treatment of patients with NSCLC receiving this drug at 150 mg/day. This negative data cast some doubt on the future development of epidermal growth factor receptor inhibitors for front-line treatment of NSCLC, and have restricted them to a relatively limited role. Other agents in development for the treatment of NSCLC include the farnesyl transferase inhibitor, lonafarnib, as well as bexarotene.24-26 Both of these agents, which have very limited single-agent response rates and completely different functions (lonafarnib is a farnesyl transferase inhibitor targeting activated ras, among other prenylated proteins; bexarotene is a retinoid X receptor-specific agonist that may enhance PPAR-␥ function as well as cisplatin-based cytotoxicity), are showing some promise in phase II trials and are currently in phase III registration trials of combination chemotherapy compared with the same chemotherapy alone. However, at this point, including a recent negative trial of the antisense construct protein kinase C-␣ isomer, much caution must be observed before assuming any of these agents will play a major role in the treatment of NSCLC.27 CONCLUSION
Over the last decade we have seen significant progress in the treatment of both small cell and NSCLC to the point where adjuvant chemotherapy for all operable lung cancer other than stage IA is increasingly used. In addition, chemotherapy
and radiation given concomitantly is now commonly used for locally advanced lung cancer. There are multiple effective regimens that can prolong life and improve quality of life in stage IIIB with pleural effusion or stage IV NSCLC. Similarly, considerable strides have been made in both limited-stage and extensive-stage small cell lung cancer. However, given the dismal 5-year survival statistics for all of these diseases, much progress remains to be made both in the clinic and in the laboratory to improve survival and quality of life in these dreaded diseases. REFERENCES 1. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5-26, 2003 2. Steward BW, Kleihues P: Lung cancer, in Stewart BW, Kleihues P (eds): World Cancer Report. Lyon, France, IARC Press, 2003, pp 182-187 3. Schottenfield D: Epidemiology of lung cancer, in Pass HI, Mitchell JB, Johnson DH (eds): Lung Cancer Principles and Practice. Philadelphia, PA, Lippincott-Raven, 1996, pp 305321 4. Khuri FR, Herbst RS, Fossella FV: Emerging therapies in non–small-cell lung cancer. Ann Oncol 12:739-744, 2001 5. Rapp E, Willan A, Cormies Y, et al: Chemotherapy can prolong survival in patients with advanced non–small-cell lung cancer–Report of a Canadian multi-center randomized trial. J Clin Oncol 6:633-641, 1988 6. Woods RL, Williams CJ, Levi J, et al: A randomized trial of cisplatin and vindesin versus supportive care only in advanced non–small-cell lung cancer. Br J Cancer 61:608-611, 1990 6. Quoix E, Dietemann A, Charbonneau J, et al: Is chemo-
THE LUNG CANCER PATIENT IN THE 21ST CENTURY
therapy with cisplatin useful in non small cell bronchial cancer at staging IV. Bull Cancer 78:341-346, 1991 8. Ganz PA, Figlin RA, Haskell CM, et al: Supportive care versus supportive care and combination chemotherapy in metastatic non–small-cell lung Cancer. Does chemotherapy make a difference? Cancer 63:1271-1278, 1989 9. Cartei G, Cartei F, Cantone A, et al: Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care vs. supportive care alone for treatment of metastatic non–small-cell lung cancer. J Natl Cancer Inst 85:794800, 1993 10. 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 9:1453-1461, 1991 11. Cullen MH, Joshi R, Chetiyawandana AD, et al: Mitomycin, ifosfamide, and cisplatin in non–small cell lung cancer: Treatment good enough to compare. Br J Cancer 58:359-361, 1988 12. Helsing M, Bergman B, Thaning L, et al: Quality of life and survival in patients with advanced non-small cell lung cancer receiving supportive care plus chemotherapy with carboplatin and etoposide or supportive care only. A multicenter randomized phase III trial. Joint Lung Cancer Study group. J Cancer 34:1036-1044, 1998 13. Noda K, Nishiwaki Y, Kawahara M, et al, Japan Clinical Oncology Group: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85-91, 2002 14. Schiller JH, Harrington D, Belani CP, et al, Eastern Cooperative Oncology Group: Comparison of four chemotherapy regimens for advanced non–small-cell lung cancer. N Engl J Med 346:92-98, 2002 15. Fossella F, Pereira JR, von Pawel J, et al: Randomized, multinational phase 3 study of docetaxel plus platinum combination vs. vinorelbine plus cisplatin for advanced non–smallcell lung cancer: The TAX 326 Study Group. J Clin Oncol 21:3016-3024, 2003 16. Turissi AT, Kim K, Blun R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265-271, 1999 17. 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 18. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non–small-cell lung cancer. J Clin Oncol 17: 2692-2699, 1999 19. Curran WJ Jr, Scott C, Bonomi P, et al: Initial report of locally advanced multimodality protocol (LAMP): ACR 427: A randomized 3-arm phase II study of Paclitaxel (T), Carbo-
15
platin (C), and thoracic radiation (TRT) for patients with stage III non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 20:312(abstr 1244), 2001 20. Gandara DR, Chansky K, Albain KS, et al, Southwest Oncology Group: Consolidation docetaxel after noncurrent chemoradiotherapy in stage 3b non–small-cell lung cancer: Phase 2 Southwest Oncology Group Study S9504. J Clin Oncol 21:2004-2010, 2003 21. Le Chevalier T, for the IALT Investigators: Results of the randomized international adjuvant lung cancer trial (IALT): Cisplatin-based chemotherapy (ct) vs. no ct in 1867 patients with resected non–small cell lung cancer. Proc Am Soc Clin Oncol 22:2, 2003 (abstr 6) 22. Kato H, Tsuboi M, Ohta M, et al: A randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage 1 adenocarcinoma of the lung. Proc Am Soc Clin Oncol 22:621, 2003 (abstr 2498) 23. Kris MG, Natale RB, Herbst RS, et al: Efficiency of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non–small-cell lung cancer, a randomized trial. JAMA 290:2149-2158, 2003 24. Herbst RS, Maddox AM, Rothenberg MS, et al: Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZDD 1839 is generally well-tolerated and has activity in non–small-cell lung cancer and other solid tumors; Results of a phase 1 trial. J Clin Oncol 20:3815-3825, 2002 25. Giaccone G, Johnson D, Scagliotti GV, et al: Results of a multivariate analysis of prognostic factors of overall survival of patients with advanced non–small cell lung cancer (NSCLC) treated with gefitinib (ZD1839) in combination with platinum-based chemotherapy (CT) in two large phase III trials (INTACT 1 and 2). Proc Am Soc Clin Oncol 22:627, 2003 (abstr 2522) 26. Perez-Soler R, Burke TG, Liu X, et al: Pre-clinical pharmacology and development of liposomal formulations of the potent topoisomerase I inhibitor. Proc Am Soc Clin Oncol 21:118, 2002 (abstr 469) 27. Khuri FR, Glisson BS, Meyers ML, et al: Phase I study of farnesyl transferase inhibitors (FTI) SCH66336 with paclitaxel in solid tumors. Dose finding, pharmacokinetics, efficacy/safety. Lung Cancer 29:63, 2000 (abstr 205) 28. Khuri FR, Kim ES, Kies MS, et al: A phase I/II study of the farnesyl transferase inhibitor (FTI) SCH66336 (Ionafarnib) with paclitaxel in taxane-refractory/resistant patients with non–small cell lung cancer (NSCLC). Final report. Proc Am Assoc Cancer Res 43:550, 2002 (abstr 2735) 29. Khuri FR, Rigas JR, Figlin RA, et al: Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non–small-cell lung cancer. J Clin Oncol 19:2626-2637, 2001 30. Lynch TJ, Raju R, Lind M, et al: Randomized phase III trial of chemotherapy and antisense oligonucleotide LY900003 (ISIS 3521) in patients with advanced NSCLC: Initial report. Proc Am Soc Clin Oncol 22:623, 2003 (abstr 2504)
W
ITHIN THE United States, approximately 170,000 people will be diagnosed with lung cancer in 2003.1 Worldwide, 901,746 new cases in men and 337,115 cases in women were reported in 2001.2 Histologic breakdown of these tumors is such that 75% to 80% of all lung cancers are non–small cell lung cancers (NSCLCs), accounting largely for the three subtypes of adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, while only 18% to 20% are small cell carcinoma histologically.2,3 Worldwide, there are substantial differences in the incidence and survival from this disease, with 5-year survival in the United States at 16.8%, while it is only 7% in Great Britain.2 Part of this difference is caused by slower adoption of chemotherapy, either alone or in combination with radiation therapy as a principal therapeutic tool in the British Isles compared Seminars in Oncology, Vol 31, No 2, Suppl 4 (April), 2004: pp 11-15
with the United States.2,3 A far greater dimension to this grim outcome is that 70% to 80% of patients with lung cancer present with evidence of either locally advanced or metastatic disease on diagnosis. While four third-generation cytotoxic regimens were approved for the treatment of metastatic NSCLC in the 1990s, much work remains to be carried out for a disease in which 83% to 85% of patients are dead 5 years after initial diagnosis.1-3 The last 15 years have seen a lifting of the veil of therapeutic nihilism that has long accompanied by nonsurgical treatment in lung cancer.4 With the development of novel agents and small molecules designed to curtail the aggressive aspects of this disease, some progress has been realized. However, much more effort and insight will be required for additional real gains to be made. A ROLE FOR CHEMOTHERAPY IN SMALL CELL AND NON–SMALL CELL LUNG CANCER?
As opposed to small cell lung cancer, where early studies indicated that the disease was generally chemoresponsive, improving median survival in extensive disease from a median of 5 to 12 weeks up to a median of 8 to 10 months and improving 2-year survival from 0% to between 10% and 20%, there was much more therapeutic conservatism pervading the treatment of NSCLC.4,5 In the late 1980s, a series of clinical trials indicated that randomizing patients to cisplatin-based chemotherapy versus best supportive care afforded an improvement in median survival from 4 months to approximately 6.5 months, as
From the Winship Cancer Institute, Emory University, Atlanta, GA. Dr Khuri has received research grant support from Schering Plough Research Institute, Aventis Oncology, Amgen Pharmaceuticals, and AstraZeneca. He has served as a consultant to Aventis Oncology. Address reprint requests to Fadlo R. Khuri, MD, Winship Cancer Institute, Emory University, 1365 Clifton Rd, Bldg C, Room 3094, Atlanta, GA 30322. © 2004 Elsevier Inc. All rights reserved. 0093-7754/04/3102-0403$30.00/0 doi:10.1053/j.seminoncol.2004.02.012 11
12
SMITH AND KHURI
Table 1. Comparison Between Supportive Care Versus Cisplatin-Based Chemotherapy
Study Rapp et al5 Woods et al6 Quoix et al7 Ganz et al8 Cartei et al9 Cellerino et al10 Cullen et al11 Helsing et al12
1-Year Survival
Median Survival (wk)
Chemo
No. of Patients
Chemo Arm
SC
Chemo v SC
CAP VP VP VP VP MCP CEP/MEC MIP VpCarbo
NR 137 188 46 48 102 115 359 48
24.7 32.6 27 28 20.4 36.6 34.3 29.7 29
NR 17 17 10 13.6 17.2 21.1 18.6 11
21% v 14% 26% v 14% 24% v 17% 24% v 11% 19% v 12% 38% v 12% 30% v 20% 28% v 18% 28% v 8%
Abbreviations: CAP, cyclophosphamide, adriamycin, and cisplatin; VP, vindesine and cisplatin; MCP, mitomycin, cyclophosphamide, and cisplatin; CEP/MEC, cyclophosphamide, epirubicin, cisplatin alternating with methotrexate, etoposide, and lomustine; MIP, mitomycin, ifosfamide, and cisplatin; VpCarbo, vindesine, cisplatin, and carboplatin.
well as improving 1-year survival from 11% to 17% up to 21% to 38% (see Table 1).5-12 The fact that this progress was seen only with the introduction of cisplatin was of substantial importance. Meanwhile, in extensive-stage small cell lung cancer, progress has continued. A recent trial by Noda et al10 randomized patients to treatment with a combination of cisplatin and irinotecan, with cisplatin given at a dose of 60 mg/m2 on day 1 and irinotecan (60 mg/m2) given on days 1, 8, and 15 versus cisplatin and etoposide at 80 mg/m2 day 1 and 100 mg/m2 days 1 to 3, respectively. Seventy-seven patients were randomized on each arm, with the irinotecan/cisplatin arm proving superior in terms of median and 2-year survival. A trial including stage IIIB and stage IV NSCLC conducted by the Eastern Cooperative Oncology Group randomized patients to four platinum-based chemotherapy regimens plus novel agents; the control arm being cisplatin plus paclitaxel. None of the other three arms of docetaxel plus cisplatin, carboplatin plus paclitaxel, or gemcitabine plus cisplatin were superior in terms of median, 1-year, or 2-year survival.11 A recent study (Fossella et al12) indicated that cisplatin and docetaxel appeared marginally superior to cisplatin and vinorelbine, although carboplatin and docetaxel were equivalent to cisplatin and vinorelbine in terms of median and overall 2-year survival. Both docetaxel-containing regimens led to improvements in quality of life and pain control,
as well as requirements for narcotic analgesics as compared with the cisplatin/vinorelbine arm with the median survivals in this trial improved by 10 to 11 months. Thus, over the last decade, we have seen improvements in survival in stage IIIB with pleural effusion or metastatic disease for NSCLC from 4 months with best supportive care in the mid to late 1980s to 8 to 10 months with platinum-containing chemotherapy. Similarly, 1-year survival has improved from 11% to 17% to 32% to 37%, with 2-year survival increasing from less than 5% to 10% to 15%. CHANGES IN THE STANDARDS FOR LOCALLY ADVANCED LUNG CANCER
During the last decade, progress has also been made in disease control and overall survival for limited-stage small cell lung cancer and locally advanced NSCLC. Recent data from Turissi et al,13 in a randomized intergroup trial, indicated that concurrent hyperfractionated chemoradiation therapy was superior to single-fraction radiotherapy delivered with chemotherapy in terms of improving overall survival (2-year survival, 47%; 5-year survival, 26%) and disease-free survival (2year survival, 29%) in limited-stage small cell lung cancer (Fig 1).13 In locally advanced NSCLC, chemotherapy followed by radiation was superior to radiotherapy alone in terms of overall and disease-free survival.14 A series of trials showed that in good performance status patients with locally
THE LUNG CANCER PATIENT IN THE 21ST CENTURY
Table 2. Comparing Survival Between Concurrent and Sequential Chemoradiotherapy RTOG 9410 Sequential Concurrent
MS
1 yr
2 yr
P Value
14.6 mo 17 mo
57% 63%
16% 35%
.038
West Japan
MS
3 yr
5 yr
Sequential Concurrent Historical Control
13 mo 16.5 mo XRT alone
14.7% 22.3%
8.8% 15.8% 10-11
.04 13-15%
Abbreviation: MS, median survival.
advanced NSCLC, concurrent chemoradiotherapy was superior to radiotherapy alone. The most obvious results of the latter data are seen within the West Japan Lung Cancer Study and the Radiation Therapy Oncology Group Study 9410 (RTOG 9410).15,16 Both trials showed that concurrent chemoradiotherapy was superior to sequential chemotherapy followed by radiation. The mature 5-year data in the West Japan Lung Study favor concurrent therapy with 5-year survival of 15.8% versus 8.8% for sequential chemotherapy and radiation for stage IIIA, IIIB NSCLC (see Table 2).15 The similar RTOG 9410 study showed that concurrent chemoradiotherapy offered a 2-year survival of 35% versus 16% for sequential chemoradiation (P ⫽ 0.038).16 Recent data has been obtained regarding the sequencing of chemoradiotherapy in NSCLC. Of note, in a phase II trial by Gandara et al17 of patients with documented stage IIIB NSCLC who were treated with cisplatin and etoposide with concurrent thoracic radiation followed by up to 3 cycles of docetaxel, median survival was 27 months and 3-year survival was 37%, the best reported in the literature for patients with locally advanced, NSCLC without evidence for malignant pleural effusion.17 The success of this combination has led to the development of a randomized trial through the Southwestern Oncology Group in which all patients receive concurrent chemoradiotherapy with cisplatin, etoposide, and radiotherapy to 60 to 63 Gy. This is followed by three cycles of docetaxel, followed by subsequent randomization to gefitinib, 250 mg/day for 1 year
13
versus observation (Gandara DR et al, SWOG study 0023, personal communication). PROGRESS IN ADJUVANT CHEMOTHERAPY FOR NON–SMALL CELL LUNG CANCER
After almost two decades of dispute and debate regarding the relative value of adjuvant chemotherapy for resectable NSCLC, the International Adjuvant Lung Trial randomized 1,867 patients to either cisplatin-based adjuvant chemotherapy or no treatment. At 5 years, the arm that received cisplatin-based chemotherapy showed a survival advantage of 4.1% compared with the observation arm.18 In combination with the recently positive adjuvant trial of UFT (tegafur/uracil) in stage Ib NSCLC,19 there is an increasing likelihood of adjuvant cisplatin-based therapy becoming standard adjuvant treatment for patients with NSCLC. The choice of the second agent with cisplatin remains open to debate, and less evidence exists to date supporting carboplatin-based adjuvant therapy than cisplatin-based adjuvant therapy. NOVEL AGENTS IN DEVELOPMENT FOR NON–SMALL CELL LUNG CANCER: A DECADE OF PROMISE, BUT LITTLE PROOF
Over the past few years, several agents have been investigated for use in the treatment of NSCLC with limited success. The first new small molecule to be approved for third-line NSCLC, with a narrow indication for patients who have failed both cisplatin-based front-line therapy and second-line therapy with docetaxel, is gefitinib, which has been tested in a randomized trial by Kris et al.20 This phase IIB study randomized over 200 patients to receive either 250 mg/day versus 500 mg/day of gefitinib, based on some encouraging phase I results.21 However, despite the initial promise with gefitinib, and the subsequent randomized trial which, though not controlled with a placebo arm, suggested that some 35% to 43% of patients had evidence of clinical benefit from this agent,20 two randomized trials of gefitinib combined with platinum-based chemotherapy failed to show any advantage of this agent to standard chemotherapy.22 Two subsequent trials with erlotinib in combination with chemotherapy were also negative despite promising initial data from PerezSoler et al,23 showing a 14% response rate in
14
SMITH AND KHURI
Fig 1. Intergroup trial of concurrent chemoradiotherapy versus hyperfractionated chemotherapy in limited-stage small cell lung cancer. (Reprinted with permission from Turissi et al.13)
second-and third-line treatment of patients with NSCLC receiving this drug at 150 mg/day. This negative data cast some doubt on the future development of epidermal growth factor receptor inhibitors for front-line treatment of NSCLC, and have restricted them to a relatively limited role. Other agents in development for the treatment of NSCLC include the farnesyl transferase inhibitor, lonafarnib, as well as bexarotene.24-26 Both of these agents, which have very limited single-agent response rates and completely different functions (lonafarnib is a farnesyl transferase inhibitor targeting activated ras, among other prenylated proteins; bexarotene is a retinoid X receptor-specific agonist that may enhance PPAR-␥ function as well as cisplatin-based cytotoxicity), are showing some promise in phase II trials and are currently in phase III registration trials of combination chemotherapy compared with the same chemotherapy alone. However, at this point, including a recent negative trial of the antisense construct protein kinase C-␣ isomer, much caution must be observed before assuming any of these agents will play a major role in the treatment of NSCLC.27 CONCLUSION
Over the last decade we have seen significant progress in the treatment of both small cell and NSCLC to the point where adjuvant chemotherapy for all operable lung cancer other than stage IA is increasingly used. In addition, chemotherapy
and radiation given concomitantly is now commonly used for locally advanced lung cancer. There are multiple effective regimens that can prolong life and improve quality of life in stage IIIB with pleural effusion or stage IV NSCLC. Similarly, considerable strides have been made in both limited-stage and extensive-stage small cell lung cancer. However, given the dismal 5-year survival statistics for all of these diseases, much progress remains to be made both in the clinic and in the laboratory to improve survival and quality of life in these dreaded diseases. REFERENCES 1. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5-26, 2003 2. Steward BW, Kleihues P: Lung cancer, in Stewart BW, Kleihues P (eds): World Cancer Report. Lyon, France, IARC Press, 2003, pp 182-187 3. Schottenfield D: Epidemiology of lung cancer, in Pass HI, Mitchell JB, Johnson DH (eds): Lung Cancer Principles and Practice. Philadelphia, PA, Lippincott-Raven, 1996, pp 305321 4. Khuri FR, Herbst RS, Fossella FV: Emerging therapies in non–small-cell lung cancer. Ann Oncol 12:739-744, 2001 5. Rapp E, Willan A, Cormies Y, et al: Chemotherapy can prolong survival in patients with advanced non–small-cell lung cancer–Report of a Canadian multi-center randomized trial. J Clin Oncol 6:633-641, 1988 6. Woods RL, Williams CJ, Levi J, et al: A randomized trial of cisplatin and vindesin versus supportive care only in advanced non–small-cell lung cancer. Br J Cancer 61:608-611, 1990 6. Quoix E, Dietemann A, Charbonneau J, et al: Is chemo-
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