- Email: [email protected]
The Role of Radiotherapy in Non-Small Cell Lung Cancer
The Role of Radiotherapy in Non-Small Cell Lung Cancer* William T. Sause, MD, FCCP
Most patients who receive a diagnosis of non-small cell lung cancer (NSCLC) have advanced disease and are not curable with surgery. Developments in the technology of radiation therapy (RT) have contributed to the broad utility of this treatment modality in both a curative and palliative capacity. Many patients at all stages, including those who are medically inoperable, may benefit from RT. Locally advanced NSCLC is treated commonly with combined modality therapy. Novel RT administration schedules and chemotherapy regimens for combined modality therapy are essential for improving the management of NSCLC. Additional benefits can be foreseen as new strategies for patient selection emerge. (CHEST 1999; 116:504S–508S) Abbreviations: CALGB 5 Cancer and Leukemia Group B; CMT 5 chemotherapy; HFX 5 hyperfractionated; KPS 5 Karnofsky performance status; NSCLC 5 non-small cell lung cancer; RT 5 radiation therapy; RTOG 5 Radiation Therapy Oncology Group
therapy (RT) is an effective method of local R adiation disease control for non-small cell lung cancer (NSCLC) and can be used for definitive management in selected patients. In patients with medically inoperable disease, RT also is valuable for symptom palliation. In the management of locally advanced (stage III) NSCLC, RT as a single modality has been superseded by combined chemotherapy (CMT) and RT as standard initial therapy.1 The optimal combination and sequence of these modalities are areas of current investigation.
RT in the Management of Inoperable NSCLC Both surgery and RT have been used as single modalities in NSCLC to achieve local control of the primary tumor and regional lymph nodes.1 In the only randomized trial comparing surgery with radiation for stage I and II NSCLC in 1963,2 the Medical Research Council found that 1-year survival rates were 43% for surgical patients and 64% for patients treated with RT; however, as follow-up continued, results of surgical resection clearly were better than those of RT, with 4-year survival rates of 23% vs 7%, respectively. In patients who are medically unfit for surgery, RT may be a reasonable alternative treatment, particularly in patients with small tumors.3– 8 In four studies involving . 200 patients (most with T1–2 disease) who were *From the LDS Hospital, Radiation Center, Salt Lake City, UT. Correspondence to: William T. Sause, MD, FCCP, President, Radiation Therapy, LDS Hospital, Radiation Center, 400 C St, Salt Lake City, UT 84143; e-mail: [email protected] 504S
medically inoperable or refused surgical resection, RT at doses of 50 to 60 Gy resulted in 5-year survival rates of 16 to 32%.5– 8 Because many patients with medically inoperable NSCLC are in need of immediate local palliation,9 the relief of symptoms is an important treatment goal.1 The palliative benefit of RT has been documented in a number of randomized trials.10 –12 The symptoms palliated by RT include hemoptysis, cough, shortness of breath, pain, anxiety, fatigue, and sleeping difficulty.
RT in Locally Advanced, Unresectable NSCLC The treatment of regionally advanced NSCLC with RT has been investigated in a large number of trials. Singlemodality external beam RT fails to eradicate disease in most patients with locally advanced, unresectable NSCLC.13 Therefore, therapeutic strategies that have evolved over the past 2 decades reflect an increasingly aggressive approach, incorporating combined modalities or nonstandard approaches to RT scheduling.13,14 Technologic advances have influenced many aspects of RT for NSCLC, from the development of computerized treatment planning and innovative methods of administration to the integration of other treatment modalities with RT.1,15 The optimization of RT administration has involved considerable manipulation of the dose, fractionation, and volume of radiation administered. Studies of the Radiation Therapy Oncology Group (RTOG; eg, RTOG 73– 01) have demonstrated the need to deliver sufficiently high doses of radiation to an adequate area to ensure tumor regression with decreased recurrence and improved survival.16 Prognostic Factors: Proper patient selection is critical to maximize the benefits of treatment for NSCLC patients. The RTOG observed in early analyses that patients with minimal weight loss (, 5%) and good Karnofsky performance status (KPS; $ 90%) demonstrated prolonged survival.17 In a more recent recursive partitioning analysis, data were examined from four RTOG trials (RTOG 83–11, 83–21, 84 – 03, and 84 – 07) including 1,592 patients.18 Among the factors suggested to be of prognostic importance based on univariate analysis were KPS, # 70% vs 80 to 100%; pleural effusion; weight loss, # 5% vs 5%; age, $ 60 years vs , 60 years; tumor stage, T1/T2 vs T3/T4; and nodal stage, N 2 vs N 1. Analyses such as this ultimately may permit discrimination between the efficacy of therapy and the natural history of disease in subsets of patients, thereby improving study design and patient selection.1,18 Altered Fractionation: In hyperfractionated (HFX) RT, 1.1 to 1.2 Gy are typically administered bid instead of the usual once-daily dose of 1.8 to 2.0 Gy.15 Although this approach may intensify adverse effects on oral and esophageal mucosa, it also may permit an overall dose increase with less effect on late-reacting normal tissues.15,19 Following a pilot study suggesting that doses of up to 69.6 Gy Multimodality Therapy of Chest Malignancies–Update ‘98
Table 1—Improved Survival With Chemoradiation in Unresectable NSCLC* RTOG Trial
RT Type
CMT Sequencing
Median Survival, mo
2-yr Survival Rate, %
88-08 88-0813 88-04, 92-0428,29 90-15, 91-06, 92-0428,30,31
Std RT Std RT Std RT HFX RT
None Induction Induction/Concurrent Concurrent
11.4 13.8 13.9 to 15.5 12.2 to 18.9
19 32 NR 28 to 36
13
*Std RT 5 external beam radiotherapy; NR 5 not reported.
could be administered in 1.2-Gy fractions bid,20 a significant (p 5 0.02) dose-survival relationship was observed in an RTOG trial (RTOG 83–11) of patients with favorable prognostic factors who received a total dose of 69.6 Gy compared to those who received lower doses (60 Gy or 64.8 Gy).21 In another trial, 509 patients from 11 centers in the United Kingdom were randomized to treatment with either 17 Gy in 2 fractions 1 week apart or 39 Gy in 13 fractions 5 days per week.22 Survival was lengthened in patients receiving more fractions, although palliation of symptoms was not as rapid. The median survival in patients receiving 2 fractions of RT was 7 months, compared to 9 months in patients receiving 13 fractions. Survival rates at 1 year and 2 years were 31% and 9%, respectively, in the 2-fraction group, compared to 36% and 12%, respectively, in the 13-fraction group. A condensed regimen, continuous HFX-accelerated radiotherapy, has been used to shorten the treatment period from 42 to 12 days by administering RT on consecutive days through weekends. A trial evaluated a total of 36 1.5-Gy fractions administered tid for a total dose of 5,400 Gy.23 This regime has been tested in a phase III trial, and superiority over standard RT has been confirmed,23,24 with a 9% improvement in survival at 2 years. Combined CMT and RT: Several phase III trials and a meta-analysis demonstrated the superiority of combined modality treatment of locally advanced, unresect-
able NSCLC over RT alone.25–27 In a meta-analysis including data from 2,589 patients with locally advanced, unresectable NSCLC, the addition of CMT to RT extended median survival from 10.3 to 12.0 months.27 However, increased biological activity and altering the natural history of disease are accompanied by increased toxicity. Future work should include optimization of delivery of CMT/RT and careful quantitation of the benefit of this type of treatment, which may be modest. The experience of the RTOG includes trials using no CMT or induction CMT (RTOG 88 – 08); induction and concurrent CMT/RT (RTOG 88 – 04, 92– 04); and concurrent CMT/RT alone (RTOG 90 –15, 91– 06, and 92– 04). When patients with favorable performance status were considered, this progression in design, together with altered RT fractionation, resulted in substantial gains in survival (Table 1). Sequential CMT/RT: When RT follows induction CMT, increased drug delivery is possible with less overall toxicity, and the effects of CMT may permit delivery of RT to a reduced tumor volume. However, toxicity may prevent administration of RT, cell resistance can decrease the efficacy of RT, and the overall duration of treatment may be lengthy. Several trials demonstrated benefits for treatment with induction CMT followed by RT (Table 2). The Cancer and Leukemia Group B (CALGB)25 and Intergroup studies enrolled only those patients with low weight loss, favorable KPS, and, in the CALGB trial, no palpable
Table 2—Trials of Induction CMT Followed by RT*
Trial
CMT
Supportive of combined therapy VP CALGB25 French26 VCPC USA Intergroup13,32 VP Unsupportive of combined therapy SWOG† FOMI/CAP FLCSG33 CAP NCCTG34
MACC
2-Year Survival Rate, %
Median Survival, mo
Local Failure Rate, %
RT Dose, Gy
CMT and RT
RT Alone
CMT and RT
RT Alone
CMT and RT
RT Alone
60 65 60 to 69.6
26 21 NR
13 14 NR
13.7 12 13.8
9.6 10 11.4
NR 83 NR
NR 85 NR
50 55.0, split course 60
NR 19
NR 17
9.1 10.2
9.2 10.9
NR 43
NR 60
21
16
10.4
10.3
50‡
47
*VP 5 vinblastine and cisplatin; VCPC 5 vindesine, lomustine, cisplatin, and cyclophosphamide; SWOG 5 Southwest Oncology Group; FOMI/CAP 5 fluorouracil, vincristine, mitomycin, cyclophosphamide, doxorubicin, and cisplatin; CAP 5 cyclophosphamide, doxorubicin, and cisplatin; FLCSG 5 Finnish Lung Cancer Study Group; MACC 5 methotrexate; NCCTG 5 North Central Cancer Study Group; see Table 1 for other abbreviation. †Unpublished data. ‡First site of progression. CHEST / 116 / 6 / DECEMBER, 1999 SUPPLEMENT
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Table 3—Trials of Concurent CMT/RT With Platinum-Containing CMT Regimens* Trial Supportive of combined therapy EORTC37
Jeremic et al38
Unsupportive of combined therapy GOCCNE39
Treatment Regimen
Patients, No.
Response Rate, %
1-yr Survival Rate, %
Cisplatin 30 mg/m2/wk plus 55 Gy RT or Cisplatin 6 mg/m2/d plus 55 Gy RT or 55 Gy RT CBDCA 50 mg/d plus VP-16 50 mg/d plus 69.6 Gy HFX RT or 69.6 Gy HFX RT
98
60
44
102
66
54
108 65
57 92
46 74
66
85
68
85
51
NR†
88
59
NR‡
Cisplatin 6 mg/m2/d plus 45 Gy RT or 45 Gy RT
*EORTC 5 European Organization for Research in the Treatment of Cancer; CBDCA 5 carboplatin; VP-16 5 etoposide; GOCCNE 5 NorthEastern Italian Oncology Group; see Table 1 for other abbreviation. †Median survival 5 10.0 mo. ‡Median survival 5 10.3 mo.
supraclavicular lymph nodes.13 Improved survival was observed in both of these trials, with median survival times of 13.7 months and 9.6 months reported by the CALGB for patients receiving CMT/RT or RT alone, respectively, and 13.8 months and 11.4 months reported by the RTOG for these patient groups, respectively.13 Concurrent CMT/RT: Concurrent CMT/RT presents an opportunity to benefit from synergy between modalities and a method for the potential control of micrometastatic disease.35 Concurrent treatments may be shorter in duration, but toxicity is enhanced and possible reductions in dose intensity may be necessary.35 Recent studies evaluating platinum-containing CMT demonstrated improved survival rates in patients with advanced NSCLC (Table 3).36 In a study conducted by the European Organization for Research and Treatment of Cancer, patients were randomized to treatment with RT, 10 fractions of 3 Gy, alone or in combination with weekly cisplatin, 30 mg/m2, or daily cisplatin, 6 mg/m2. Survival rates were significantly improved in the daily cisplatin/RT group compared to the group treated with RT alone (p 5 0.009), whereas survival rates with weekly cisplatin/RT were not significantly different from RT alone (p 5 0.36).37 Patients who received cisplatin experienced significantly longer times to local disease recurrence (p 5 0.015), particularly with daily cisplatin (p 5 0.003). Carboplatin in combination with RT also shows considerable promise for the treatment of locally advanced NSCLC and may have a role in combination CMT administered concurrently with RT. Concurrent and sequential regimens are being compared in current trials. In a phase III study, 320 patients with stage IIIA and IIIB NSCLC were randomized to treatment with cisplatin, 80 mg/m2, and mitomycin, 8 mg/m2, on days 1 and 29 plus vindesine, 3 mg/m2, on days 1, 8, 29, and 36 (MVP) and 56 Gy of concurrent or sequential RT.40 Preliminary analysis demonstrated signif506S
icantly better response and survival (p # 0.05) with concurrent treatment. Hybrid combined modality strategies, which maximize the advantages and minimize the disadvantages of sequential and concurrent CMT/RT, may be among the most promising approaches yet to treatment of unresectable stage IIIA and IIIB NSCLC and should continue to be an area of development.15
Conclusion Most patients have metastatic NSCLC at the time of diagnosis; only approximately one third of patients with NSCLC are treated surgically, due to nodal status or other factors.1 RT is an effective method of local disease control and is valuable for symptom palliation. In patients with locally advanced NSCLC, the combination of RT and CMT improves survival compared with RT alone. However, the optimal method and sequence of RT administration with other treatment modalities has not yet been determined. Methodologic refinements in RT administration and improved identification of prognostic factors and patient selection are likely to contribute to better responses with RT.
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. 5th ed. Philadelphia, PA: Lippincott, 1997; 858 –911 2 Morrison R, Deeley TJ, Cleland WP. The treatment of carcinoma of the bronchus: a clinical trial to compare surgery and supervoltage radiotherapy. Lancet 1963; 1:683– 684 3 Dosoretz DE, Katin MJ, Blitzer PH, et al. Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 1992; 24:3–9 4 Kaskowitz L, Graham MV, Emami B, et al. Radiation therapy alone for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1993; 27:517–523 Multimodality Therapy of Chest Malignancies–Update ‘98
5 Noordijk EM, v d Poest Clement E, Hermans J, et al. Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol 1988; 13:83– 89 6 Smart J. Can lung cancer be cured by irradiation alone? JAMA 1966; 195:1034 –1035 7 Talton BM, Constable WC, Kersh CR. Curative radiotherapy in non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1990; 19:15–21 8 Zhang HX, Yin WB, Zhang LJ, et al. Curative radiotherapy of early operable non-small cell lung cancer. Radiother Oncol 1989; 14:89 –94 9 Carroll M, Morgan SA, Yarnold JR, et al. Prospective evaluation of a watch policy in patients with inoperable non-small cell lung cancer. Eur J Cancer Clin Oncol 1986; 22:1353– 1356 10 Bleehan NM, Girling DJ, Fayers PM, et al. Inoperable non-small-cell lung cancer (NSCLC): a Medical Research Council randomised trial of palliative radiotherapy with two fractions or ten fractions; report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer 1991; 63:265–270 11 Simpson JR, Francis ME, Perez-Tamayo R, et al. Palliative radiotherapy for inoperable carcinoma of the lung: final report of a RTOG multi-institutional trial. Int J Radiat Oncol Biol Phys 1985; 11:751–758 12 Teo P, Tai TH, Choy D, et al. A randomized study on palliative radiation therapy for inoperable non small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1988; 14:867– 871 13 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– small-cell lung cancer. J Natl Cancer Inst 1995; 87:198 – 205 14 Sause W, Scott C, Byhardt R, et al. Recursive partitioning analysis of 1,592 patients on four RTOG studies in non-small cell lung cancer [abstract 1123]. Proc Am Soc Clin Oncol 1993; 12:336 15 Wagner H Jr. Radiation therapy in the management of patients with unresectable stage IIIA and IIIB non-small cell lung cancer. Semin Oncol 1997; 24:423– 428 16 Perez CA, Stanley K, Grundy G, et al. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung: report by the Radiation Therapy Oncology Group. Cancer 1982; 50:1091–1099 17 Bauer M, Birch R, Pajak RT. Prognostic factors in cancer of the lung. In: Cox JD, ed. Syllabus: a categorical course in radiation therapy; lung cancer. Oak Brook, IL: Radiological Society of North America (RSNA) Publications, 1985; 116 – 117 18 Scott C, Sause WT, Byhardt R, et al. Recursive partitioning analysis of 1592 patients on four Radiation Therapy Oncology Group studies in inoperable non-small cell lung cancer. Lung Cancer 1997; 17(suppl 1):S59 –S74 19 Withers MR, Thomas MD, Peters LJ. Differences in the fractionation response of acutely and late responding tissues. In: Kaercher KM, Kogelnik D, Reinartz G, eds. Progress in radio-oncology. New York, NY: Raven, 1982; 287 20 Seydel HG, Diener-West M, Urtasun R, et al. Hyperfractionation in the radiation therapy of unresectable non-oat cell carcinoma of the lung: preliminary report of a RTOG pilot study. Int J Radiat Oncol Biol Phys 1985; 11:1841– 1847 21 Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial of hyperfractionated radiation therapy with total
22
23
24
25
26
27
28
29
30
31
32 33 34
35 36
doses of 60.0 Gy to 79.2 Gy: possible survival benefit with $ 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non–small-cell lung carcinoma; report of Radiation Therapy Oncology Group 83–11. J Clin Oncol 1990; 8:1543–1555 Macbeth FR, Bolger JJ, Hopwood P, et al. Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status: Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol) 1996; 8:167–175 Saunders MI, Lyn BE, Dische S. Continuous, hyperfractionated, accelerated radiotherapy (CHART) in non-small cell lung cancer. Lung Cancer 1993; 9:221–228 Saunders MJ, Barltrop MA, Rassa P, et al. The relationship between tumor response and survival following radiotherapy for carcinoma of the bronchus. Int J Radiat Oncol Biol Phys 1984; 10:503–508 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 Le Chevalier 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 Pritchard RS, Anthony SP. Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non–small-cell lung cancer: a metaanalysis. Ann Intern Med 1996; 125:723–729 Komaki R, Scott C, Ettinger D, et al. Randomized study of chemotherapy/radiation therapy combinations for favorable patients with locally advanced inoperable nonsmall cell lung cancer: Radiation Therapy Oncology Group (RTOG) 92– 04. Int J Radiat Oncol Biol Phys 1997; 398:149 –155 Sause WT, Scott C, Taylor S, et al. Phase II trial of combination chemotherapy and irradiation in non-small-cell lung cancer: Radiation Therapy Oncology Group 88 – 04. Am J Clin Oncol 1992; 15:163–167 Byhardt RW, Scott C, Ettinger DS, et al. Concurrent hyperfractionated irradiation and chemotherapy for unresectable nonsmall cell lung cancer. Cancer 1995; 75:2337–2344 Komaki R, Scott C, Lee JS, et al. Impact of adding concurrent chemotherapy to hyperfractionated radiotherapy for locally advanced non-small cell lung cancer (NSCLC): comparison of RTOG 83–11 and RTOG 91– 06. Am J Clin Oncol 1997; 20:435– 440 Ruckdeschel JC. Combined modality therapy of non-small cell lung cancer. Semin Oncol 1997; 24:429 – 439 Mattson K, Holsti LR, Holsti P, et al. Inoperable non-small cell lung cancer: radiation with or without chemotherapy. Eur J Cancer Clin Oncol 1988; 4:477– 482 Morton RF, Jett JR, Maher L, et al. Randomized trial of thoracic radiation therapy (TRT) with or without chemotherapy for treatment of locally unresectable non-small cell lung cancer (NSCLC) [abstract 772]. Proc Am Soc Clin Oncol 1988; 7:200 Belani CP. Multimodality management of regionally advanced non–small-cell lung cancer. Semin Oncol 1993; 20: 302–314 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 1988; 6:663– 641 CHEST / 116 / 6 / DECEMBER, 1999 SUPPLEMENT
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37 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 1992; 326:524 –530 38 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 39 Trovo´ MG, Minatel E, Franchin G, et al. Radiotherapy
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versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1992; 24:11–15 40 Takada Y, Furuse K, Fukuoka M, et al. A randomized phase III study of concurrent versus sequential thoracic radiotherapy (TRT) in combination with mitomycin (M), vindesine (V), and cisplatin (P) in unresectable stage III non-small cell lung cancer (NSCLC): preliminary analysis [abstract 294]. Lung Cancer 1997; 18(suppl 1):76 –77
Multimodality Therapy of Chest Malignancies–Update ‘98
Most patients who receive a diagnosis of non-small cell lung cancer (NSCLC) have advanced disease and are not curable with surgery. Developments in the technology of radiation therapy (RT) have contributed to the broad utility of this treatment modality in both a curative and palliative capacity. Many patients at all stages, including those who are medically inoperable, may benefit from RT. Locally advanced NSCLC is treated commonly with combined modality therapy. Novel RT administration schedules and chemotherapy regimens for combined modality therapy are essential for improving the management of NSCLC. Additional benefits can be foreseen as new strategies for patient selection emerge. (CHEST 1999; 116:504S–508S) Abbreviations: CALGB 5 Cancer and Leukemia Group B; CMT 5 chemotherapy; HFX 5 hyperfractionated; KPS 5 Karnofsky performance status; NSCLC 5 non-small cell lung cancer; RT 5 radiation therapy; RTOG 5 Radiation Therapy Oncology Group
therapy (RT) is an effective method of local R adiation disease control for non-small cell lung cancer (NSCLC) and can be used for definitive management in selected patients. In patients with medically inoperable disease, RT also is valuable for symptom palliation. In the management of locally advanced (stage III) NSCLC, RT as a single modality has been superseded by combined chemotherapy (CMT) and RT as standard initial therapy.1 The optimal combination and sequence of these modalities are areas of current investigation.
RT in the Management of Inoperable NSCLC Both surgery and RT have been used as single modalities in NSCLC to achieve local control of the primary tumor and regional lymph nodes.1 In the only randomized trial comparing surgery with radiation for stage I and II NSCLC in 1963,2 the Medical Research Council found that 1-year survival rates were 43% for surgical patients and 64% for patients treated with RT; however, as follow-up continued, results of surgical resection clearly were better than those of RT, with 4-year survival rates of 23% vs 7%, respectively. In patients who are medically unfit for surgery, RT may be a reasonable alternative treatment, particularly in patients with small tumors.3– 8 In four studies involving . 200 patients (most with T1–2 disease) who were *From the LDS Hospital, Radiation Center, Salt Lake City, UT. Correspondence to: William T. Sause, MD, FCCP, President, Radiation Therapy, LDS Hospital, Radiation Center, 400 C St, Salt Lake City, UT 84143; e-mail: [email protected] 504S
medically inoperable or refused surgical resection, RT at doses of 50 to 60 Gy resulted in 5-year survival rates of 16 to 32%.5– 8 Because many patients with medically inoperable NSCLC are in need of immediate local palliation,9 the relief of symptoms is an important treatment goal.1 The palliative benefit of RT has been documented in a number of randomized trials.10 –12 The symptoms palliated by RT include hemoptysis, cough, shortness of breath, pain, anxiety, fatigue, and sleeping difficulty.
RT in Locally Advanced, Unresectable NSCLC The treatment of regionally advanced NSCLC with RT has been investigated in a large number of trials. Singlemodality external beam RT fails to eradicate disease in most patients with locally advanced, unresectable NSCLC.13 Therefore, therapeutic strategies that have evolved over the past 2 decades reflect an increasingly aggressive approach, incorporating combined modalities or nonstandard approaches to RT scheduling.13,14 Technologic advances have influenced many aspects of RT for NSCLC, from the development of computerized treatment planning and innovative methods of administration to the integration of other treatment modalities with RT.1,15 The optimization of RT administration has involved considerable manipulation of the dose, fractionation, and volume of radiation administered. Studies of the Radiation Therapy Oncology Group (RTOG; eg, RTOG 73– 01) have demonstrated the need to deliver sufficiently high doses of radiation to an adequate area to ensure tumor regression with decreased recurrence and improved survival.16 Prognostic Factors: Proper patient selection is critical to maximize the benefits of treatment for NSCLC patients. The RTOG observed in early analyses that patients with minimal weight loss (, 5%) and good Karnofsky performance status (KPS; $ 90%) demonstrated prolonged survival.17 In a more recent recursive partitioning analysis, data were examined from four RTOG trials (RTOG 83–11, 83–21, 84 – 03, and 84 – 07) including 1,592 patients.18 Among the factors suggested to be of prognostic importance based on univariate analysis were KPS, # 70% vs 80 to 100%; pleural effusion; weight loss, # 5% vs 5%; age, $ 60 years vs , 60 years; tumor stage, T1/T2 vs T3/T4; and nodal stage, N 2 vs N 1. Analyses such as this ultimately may permit discrimination between the efficacy of therapy and the natural history of disease in subsets of patients, thereby improving study design and patient selection.1,18 Altered Fractionation: In hyperfractionated (HFX) RT, 1.1 to 1.2 Gy are typically administered bid instead of the usual once-daily dose of 1.8 to 2.0 Gy.15 Although this approach may intensify adverse effects on oral and esophageal mucosa, it also may permit an overall dose increase with less effect on late-reacting normal tissues.15,19 Following a pilot study suggesting that doses of up to 69.6 Gy Multimodality Therapy of Chest Malignancies–Update ‘98
Table 1—Improved Survival With Chemoradiation in Unresectable NSCLC* RTOG Trial
RT Type
CMT Sequencing
Median Survival, mo
2-yr Survival Rate, %
88-08 88-0813 88-04, 92-0428,29 90-15, 91-06, 92-0428,30,31
Std RT Std RT Std RT HFX RT
None Induction Induction/Concurrent Concurrent
11.4 13.8 13.9 to 15.5 12.2 to 18.9
19 32 NR 28 to 36
13
*Std RT 5 external beam radiotherapy; NR 5 not reported.
could be administered in 1.2-Gy fractions bid,20 a significant (p 5 0.02) dose-survival relationship was observed in an RTOG trial (RTOG 83–11) of patients with favorable prognostic factors who received a total dose of 69.6 Gy compared to those who received lower doses (60 Gy or 64.8 Gy).21 In another trial, 509 patients from 11 centers in the United Kingdom were randomized to treatment with either 17 Gy in 2 fractions 1 week apart or 39 Gy in 13 fractions 5 days per week.22 Survival was lengthened in patients receiving more fractions, although palliation of symptoms was not as rapid. The median survival in patients receiving 2 fractions of RT was 7 months, compared to 9 months in patients receiving 13 fractions. Survival rates at 1 year and 2 years were 31% and 9%, respectively, in the 2-fraction group, compared to 36% and 12%, respectively, in the 13-fraction group. A condensed regimen, continuous HFX-accelerated radiotherapy, has been used to shorten the treatment period from 42 to 12 days by administering RT on consecutive days through weekends. A trial evaluated a total of 36 1.5-Gy fractions administered tid for a total dose of 5,400 Gy.23 This regime has been tested in a phase III trial, and superiority over standard RT has been confirmed,23,24 with a 9% improvement in survival at 2 years. Combined CMT and RT: Several phase III trials and a meta-analysis demonstrated the superiority of combined modality treatment of locally advanced, unresect-
able NSCLC over RT alone.25–27 In a meta-analysis including data from 2,589 patients with locally advanced, unresectable NSCLC, the addition of CMT to RT extended median survival from 10.3 to 12.0 months.27 However, increased biological activity and altering the natural history of disease are accompanied by increased toxicity. Future work should include optimization of delivery of CMT/RT and careful quantitation of the benefit of this type of treatment, which may be modest. The experience of the RTOG includes trials using no CMT or induction CMT (RTOG 88 – 08); induction and concurrent CMT/RT (RTOG 88 – 04, 92– 04); and concurrent CMT/RT alone (RTOG 90 –15, 91– 06, and 92– 04). When patients with favorable performance status were considered, this progression in design, together with altered RT fractionation, resulted in substantial gains in survival (Table 1). Sequential CMT/RT: When RT follows induction CMT, increased drug delivery is possible with less overall toxicity, and the effects of CMT may permit delivery of RT to a reduced tumor volume. However, toxicity may prevent administration of RT, cell resistance can decrease the efficacy of RT, and the overall duration of treatment may be lengthy. Several trials demonstrated benefits for treatment with induction CMT followed by RT (Table 2). The Cancer and Leukemia Group B (CALGB)25 and Intergroup studies enrolled only those patients with low weight loss, favorable KPS, and, in the CALGB trial, no palpable
Table 2—Trials of Induction CMT Followed by RT*
Trial
CMT
Supportive of combined therapy VP CALGB25 French26 VCPC USA Intergroup13,32 VP Unsupportive of combined therapy SWOG† FOMI/CAP FLCSG33 CAP NCCTG34
MACC
2-Year Survival Rate, %
Median Survival, mo
Local Failure Rate, %
RT Dose, Gy
CMT and RT
RT Alone
CMT and RT
RT Alone
CMT and RT
RT Alone
60 65 60 to 69.6
26 21 NR
13 14 NR
13.7 12 13.8
9.6 10 11.4
NR 83 NR
NR 85 NR
50 55.0, split course 60
NR 19
NR 17
9.1 10.2
9.2 10.9
NR 43
NR 60
21
16
10.4
10.3
50‡
47
*VP 5 vinblastine and cisplatin; VCPC 5 vindesine, lomustine, cisplatin, and cyclophosphamide; SWOG 5 Southwest Oncology Group; FOMI/CAP 5 fluorouracil, vincristine, mitomycin, cyclophosphamide, doxorubicin, and cisplatin; CAP 5 cyclophosphamide, doxorubicin, and cisplatin; FLCSG 5 Finnish Lung Cancer Study Group; MACC 5 methotrexate; NCCTG 5 North Central Cancer Study Group; see Table 1 for other abbreviation. †Unpublished data. ‡First site of progression. CHEST / 116 / 6 / DECEMBER, 1999 SUPPLEMENT
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Table 3—Trials of Concurent CMT/RT With Platinum-Containing CMT Regimens* Trial Supportive of combined therapy EORTC37
Jeremic et al38
Unsupportive of combined therapy GOCCNE39
Treatment Regimen
Patients, No.
Response Rate, %
1-yr Survival Rate, %
Cisplatin 30 mg/m2/wk plus 55 Gy RT or Cisplatin 6 mg/m2/d plus 55 Gy RT or 55 Gy RT CBDCA 50 mg/d plus VP-16 50 mg/d plus 69.6 Gy HFX RT or 69.6 Gy HFX RT
98
60
44
102
66
54
108 65
57 92
46 74
66
85
68
85
51
NR†
88
59
NR‡
Cisplatin 6 mg/m2/d plus 45 Gy RT or 45 Gy RT
*EORTC 5 European Organization for Research in the Treatment of Cancer; CBDCA 5 carboplatin; VP-16 5 etoposide; GOCCNE 5 NorthEastern Italian Oncology Group; see Table 1 for other abbreviation. †Median survival 5 10.0 mo. ‡Median survival 5 10.3 mo.
supraclavicular lymph nodes.13 Improved survival was observed in both of these trials, with median survival times of 13.7 months and 9.6 months reported by the CALGB for patients receiving CMT/RT or RT alone, respectively, and 13.8 months and 11.4 months reported by the RTOG for these patient groups, respectively.13 Concurrent CMT/RT: Concurrent CMT/RT presents an opportunity to benefit from synergy between modalities and a method for the potential control of micrometastatic disease.35 Concurrent treatments may be shorter in duration, but toxicity is enhanced and possible reductions in dose intensity may be necessary.35 Recent studies evaluating platinum-containing CMT demonstrated improved survival rates in patients with advanced NSCLC (Table 3).36 In a study conducted by the European Organization for Research and Treatment of Cancer, patients were randomized to treatment with RT, 10 fractions of 3 Gy, alone or in combination with weekly cisplatin, 30 mg/m2, or daily cisplatin, 6 mg/m2. Survival rates were significantly improved in the daily cisplatin/RT group compared to the group treated with RT alone (p 5 0.009), whereas survival rates with weekly cisplatin/RT were not significantly different from RT alone (p 5 0.36).37 Patients who received cisplatin experienced significantly longer times to local disease recurrence (p 5 0.015), particularly with daily cisplatin (p 5 0.003). Carboplatin in combination with RT also shows considerable promise for the treatment of locally advanced NSCLC and may have a role in combination CMT administered concurrently with RT. Concurrent and sequential regimens are being compared in current trials. In a phase III study, 320 patients with stage IIIA and IIIB NSCLC were randomized to treatment with cisplatin, 80 mg/m2, and mitomycin, 8 mg/m2, on days 1 and 29 plus vindesine, 3 mg/m2, on days 1, 8, 29, and 36 (MVP) and 56 Gy of concurrent or sequential RT.40 Preliminary analysis demonstrated signif506S
icantly better response and survival (p # 0.05) with concurrent treatment. Hybrid combined modality strategies, which maximize the advantages and minimize the disadvantages of sequential and concurrent CMT/RT, may be among the most promising approaches yet to treatment of unresectable stage IIIA and IIIB NSCLC and should continue to be an area of development.15
Conclusion Most patients have metastatic NSCLC at the time of diagnosis; only approximately one third of patients with NSCLC are treated surgically, due to nodal status or other factors.1 RT is an effective method of local disease control and is valuable for symptom palliation. In patients with locally advanced NSCLC, the combination of RT and CMT improves survival compared with RT alone. However, the optimal method and sequence of RT administration with other treatment modalities has not yet been determined. Methodologic refinements in RT administration and improved identification of prognostic factors and patient selection are likely to contribute to better responses with RT.
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