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Addition of chemotherapy to radiation therapy alters failure patterns by cell type within non-small cell carcinoma of lung (NSCCL): analysis of radiation therapy oncology group (RTOG) trials
Int. J. Radiation Oncology Biol. Phys., Vol. 43, No. 3, pp. 505–509, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter
PII S0360-3016(98)00429-5
CLINICAL INVESTIGATION
Thorax
ADDITION OF CHEMOTHERAPY TO RADIATION THERAPY ALTERS FAILURE PATTERNS BY CELL TYPE WITHIN NON-SMALL CELL CARCINOMA OF LUNG (NSCCL): ANALYSIS OF RADIATION THERAPY ONCOLOGY GROUP (RTOG) TRIALS JAMES D. COX, M.D.*, CHARLES B. SCOTT, PH.D.,† ROGER W. BYHARDT, M.D.,‡ BAHMAN EMAMI, M.D.,§ ANTHONY H. RUSSELL, M.D.,\ KAREN K. FU, M.D.,¶ MATTHEW B. PARLIAMENT, M.D.,# RITSUKO KOMAKI, M.D.,* AND LAURIE E. W. GASPAR, M.D.* *The University of Texas M. D. Anderson Cancer Center, Houston, TX; †Statistical Center, RTOG, Philadelphia, PA; ‡Medical College of Wisconsin, Milwaukee, WI; §Washington University School of Medicine, St. Louis, MO; \Radiation Oncology Associates, Sacramento, CA; ¶University of California-San Francisco, CA; #University of Alberta, Edmonton, Alberta, Canada; and * Wayne State School of Medicine, Detroit, MI Purpose: To evaluate the influence of cell type within non-small cell carcinoma of lung (NSCCL) on failure patterns when chemotherapy (CT) is combined with radiation therapy (RT). Methods and Materials: Data from 4 RTOG studies including 1415 patients treated with RT alone, and 5 RTOG studies including 350 patients also treated with chemotherapy (RT 1 CT) were analyzed. Patterns of progression were evaluated for squamous cell carcinoma (SQ) (n 5 946), adenocarcinoma (AD) (n 5 532) and large cell carcinoma (LC) (n 5 287). Results: When treated with RT alone, SQ was more likely to progress at the primary site than LC (26% vs. 20%, p 5 0.05). AD and LC were more likely to progress in the brain than SQ (20% and 18% vs. 11%, p 5 0.0001 and 0.011, respectively). No differences were found in intrathoracic and distant metastasis by cell type. When treated with RT 1 CT, AD was less likely to progress at the primary than either SQ or LC (23% vs. 34% and 40%, respectively; p 5 0.057 and 0.035). AD was more likely than SQ to metastasize to the brain (16% vs. 8%, p 5 0.03), and other distant sites (26% vs. 14%, p 5 0.019). No differences were found in intrathoracic metastasis. LC progressed at the primary site more often with RT 1 CT than with RT alone (40% vs. 20%, p 5 0.036). Death with no clinical progression was more likely with SQ than AD or LC for RT alone and RT 1 CT (p < 0.01). Brain metastasis was altered little by the addition of CT, but other distant metastases were significantly decreased (p < 0.001) in all cell types by the addition of CT. Conclusion: CT, although effective in reducing distant metastasis in all types of NSCCL, has different effects on the primary tumor by cell type, and has no effect on brain metastasis or death with no progression. Different treatment strategies should be considered for the different cell types to advance progress with RT 1 CT in NSCCL. © 1999 Elsevier Science Inc. Lung, Neoplasms, Radiation therapy, Chemotherapy, Squamous cell carcinoma, Adenocarcinoma.
Cancer of the lung continues to be the most frequent cause of death from neoplastic diseases in the United States and many urbanized countries. Although modest improvements in outcome have been reported from many clinical trials employing combinations of treatment modalities, there has been little overall effect as reflected in national data (1). Constant search for more promising treatment strategies is warranted. Analyses of patterns of failure after cancer treatment can
suggest both reasons for the results obtained and strategies for future investigations (2). A recent failure pattern study from the Radiation Therapy Oncology Group (RTOG) for non-small cell carcinoma of the lung (NSCLC) suggested the possibility of important differences by histopathologic type within the NSCLC grouping (3). A more complete study of failure patterns by cell type based on data from several RTOG trials was undertaken (a) to identify whether there is a need to subdivide NSCLC in reporting results; and (b) to examine the influence of combination chemotherapy on outcomes.
Reprint requests to: James D. Cox, M.D., Department of Radiation Oncology, Box 97, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: [email protected]. Presented in part at the 8th World Conference on Lung Cancer,
Dublin, Ireland, August 10 –15, 1997. Supported by Grants CA 21661 and CA 32115 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Accepted for publication 29 September 1998.
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PATIENTS AND METHODS The RTOG NSCLC database for this analysis consists of entries from 4 prospective clinical trials which used radiation therapy alone and 5 trials which employed combination chemotherapy in conjunction with radiation therapy. All patients had histologically or cytologically confirmed inoperable or unresectable Stage II, IIIA, or IIIB by the American Joint Committee on Cancer (AJCC) (4), Karnofsky performance status (KPS) (5) 50 or higher, and no definitive surgical resection, radiation therapy, or chemotherapy for NSCLC. The radiation therapy alone studies were RTOG 83-11 (6), 83-21 (7), 84-03 (8), and 84-07 (9). The trials which included both combination chemotherapy and radiation therapy were 88-04 (10), 88-08 (11), 90-15 (12), 91-06 (13), and 92-04 (14). All combination chemotherapy regimens were based upon the use of cisplatin. Protocol 88-08 required induction chemotherapy consisting of cisplatin (100 mg/m2) on days 1 and 29, and 5 mg/m2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation starting day 50. Protocol 88-04 used the same induction regimen as protocol 88-08, but added cisplatin (75 mg/m2) concurrent with standard radiation therapy on days 50, 71, and 92. Protocol 90-15 combined cisplatin (75 mg/m2) days 1, 29, and 50, and 5 mg/m2 vinblastine weekly for 5 weeks concurrent with hyperfractionated radiation therapy (69.6 Gy administered as 1.2 Gy twice daily, 5 days per week for 6 weeks). Protocol 91-06 combined cisplatin (50 mg/m2 days 1 and 8) and oral etoposide (100 mg/day in 2 divided doses, days 1–14) concurrent with the same hyperfractionated radiation therapy regimen as in 90-15); cisplatin and etoposide were repeated beginning day 29. Protocol 92-04 was a randomized Phase II comparison of the regimens piloted in protocols 88-04 and 91-06. Central pathology review was required in protocol 83-11. Observer variability between pathologists in originating institutions and RTOG central reviewers was determined to be sufficiently low (15) that central review was not required for subsequent studies. All studies required pretreatment computed tomography (CT) of the chest and upper abdomen in addition to posterior-anterior (PA) and lateral chest roentgenograms. Patients were followed after completion of treatment at 2-month intervals for 6 months, then every 3 months for 2 years, then every 6 months. Follow-up evaluations included PA and lateral chest roentgenograms, CT of the chest, liver function studies, and complete blood cell counts. Stable findings on chest films and CT scans were considered criteria for local control; progressive increases in size of abnormal masses were considered local failure. Local progression was evaluated by bronchoscopy and biopsy at the discretion of the physicians caring for the patients. Additional evaluations for metastasis were performed as indicated by patients’ signs and symptoms. Failure sites were separated into five categories which were not mutually exclusive. The first site of failure in the
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primary meant that the patient progressed within the irradiated volume. First failure in the thorax meant progression within the lung outside the irradiated volume or in the pleural cavity. First failure in the brain was considered separately from other distant metastases. Dead no progression was used if the patient died, but there was no evidence of progression in any of the other four categories.
STATISTICAL METHODS The data for this analysis were updated as of November 1996. The potential follow-up ranged from 2 to 13 years. Only 3% of all patients were censored (alive) at the time of analysis. Patterns of first failure were determined by finding the first occurrence, in time from date of treatment, of primary, thorax, brain, or other distant metastasis. Multiple events may be diagnosed simultaneously (e.g., primary and thoracic progression may have the same progression date): such events are recorded as a component of first failure. Because events are not independent, patterns of first failure do not sum, nor do the percentages sum to 100%. Differences between two groups for a component of first failure were computed using the Fisher’s exact test (16). There were no adjustments for multiple comparisons: all p-values are 2-sided. All survival-based distributions were estimated using the product-limit method (17). Differences in survival-based distributions were examined using the log-rank statistic (18). Each component of the patterns of first failure was used as an endpoint in logistic regression analyses. Karnofsky performance status, N-Stage, histology, and whether chemotherapy was given were factors examined for their prognostic importance. These factors were examined in each model. Odds ratios were based upon the coefficients of statistically significant prognostic factors for a given endpoint. Odds ratios significantly different from 1.0 indicate that one component of a factor has a greater or worse chance of the endpoint occurring, depending upon whether the radio is larger or smaller than 1.0, respectively.
RESULTS Data were available from 1765 patients, 1415 treated with radiation therapy alone and 350 patients treated with chemotherapy and radiation therapy. Patterns of first failure for squamous cell carcinoma (778 patients, 55%), adenocarcinoma (395 patients, 28%), and large cell carcinoma (242 patients, 17%) are shown in Table 1 for patients treated with radiation therapy alone. Pair-wise comparisons show a marginally significant lower first failure at the primary for large cell carcinoma (20%) than squamous cell carcinoma (26%) (p 5 0.050). There are no significant differences for progression within the thorax. Adenocarcinoma (20%) and
Failure patterns by cell types
Table 1. Patterns of first failure by histology: patients treated on RT alone
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Table 3. Patterns of first failure by histology: patients treated with RT 1 CT
Histology Failure site Squamous Adenocarcinoma Large cell No. (%) No. (%) No. (%) Primary Thorax Brain Other distant metastases Dead–no progression No. Patients w/events
203 (26) 279 (36) 88 (11) 253 (33) 270 (35) 778
92 (23) 156 (39) 79 (20) 188 (48) 88 (22) 395
48 (20) 81 (33) 43 (18) 101 (42) 58 (24) 242
large cell carcinoma (18%) have significantly more frequent failure in the brain than squamous cell carcinoma (11%) (p 5 0.0001 and 0.011, respectively). Adenocarcinoma (48%) and large cell carcinoma (42%) are more likely to spread to other distant sites than squamous cell carcinoma (33%) (p 5 0.001 and 0.01, respectively). Death with no evidence of progression was significantly more likely to occur with squamous cell carcinoma (35%) than either adenocarcinoma (22%) or large cell carcinoma (24%) (p , 0.0001 and p 5 0.0035, respectively). In all of the comparisons, there were no significant differences between adenocarcinoma and large cell carcinoma. Table 2 shows patterns of first failure for 924 patients with the somewhat more favorable prognostic factors required for entry on more recent trials of the RTOG. The proportions are slightly different, but the findings are similar to the larger group of patients shown in Table 1. Patterns of first failure after chemotherapy plus radiation therapy studies are shown in Table 3: 168 patients (48%) had squamous cell carcinoma, 137 (39%) had adenocarcinoma, and 45 (13%) had large cell carcinoma. There were no significant differences by cell type for progression at the primary or thorax. Adenocarcinoma (16%) was more likely to fail in the brain than squamous cell carcinoma (8%) (p 5 0.030); large cell carcinoma also failed in the brain in 16% of patients, but the differences were not statistically significant. Metastases to other distant sites were more likely with adenocarcinoma (26%) than squamous cell carcinoma (14%) (p 5 0.019). Squamous cell carcinoma (30%) was more strongly associated with death with no clinical Table 2. Patterns of first failure by histology—patients with KPS 70 –100 and weight loss 0 –5% only: patients on RT alone Histology Failure site Primary Thorax Brain Other distant metastases Dead–no progression No. patients w/events
Squamous Adenocarcinoma Large cell No. (%) No. (%) No. (%) 132 (27) 177 (36) 68 (14) 171 (35) 159 (32) 493
67 (25) 105 (40) 55 (21) 130 (49) 54 (20) 264
39 (23) 56 (34) 30 (18) 75 (45) 38 (23) 167
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Squamous Adenocarcinoma Large cell No. (%) No. (%) No. (%)
Primary 57 (34) Thorax 43 (26) Brain metastases 13 (8) Other distant metastases 24 (14) Dead–no progression 50 (30) Total 168
32 (23) 38 (28) 22 (16) 35 (26) 20 (15) 137
18 (40) 10 (22) 7 (16) 7 (16) 6 (14) 45
evidence of progression than either adenocarcinoma (15%) or large cell carcinoma (14%) (p 5 0.0016 and 0.0233, respectively). Large cell carcinoma had a lower frequency of failure following radiation therapy alone (RT) (20%) than radiation therapy plus chemotherapy (RT 1 CT) (40%) (p 5 0.036); there were no differences with the other cell types. Progression in the thorax beyond the primary was less frequent with RT 1 CT than RT for squamous cell carcinoma (26% vs. 36%, p 5 0.018) and for adenocarcinoma (28% vs. 39%, p 5 0.021); the difference for large cell carcinoma was not statistically significant. There was a slightly lower rate of brain metastasis with RT 1 CT for squamous cell carcinoma (p 5 0.041), but no significant reduction for the other cell types. However, the reductions in distant metastasis other than brain with RT 1 CT compared with RT alone were highly significant (p , 0.001 for each histopathologic type). There were no significant differences with respect to death with no progression. In the multivariate model, the logistic regression for primary progression showed only RT alone to be significant (p 5 0.005; odds ratio 5 0.69); KPS, N-stage, and histology had no demonstrable effect. For thoracic progression, the converse obtained: the odds ratio for RT was 1.49 (p 5 0.012); cell type had no effect, nor did N-stage or KPS. Table 4 shows the logistic regression for brain metastases; the inverse relationship with KPS suggests that longer survival is associated with an increased risk. The odds ratios are much lower for squamous cell carcinoma than either adenocarcinoma or large cell carcinoma (p , 0.0001). RT alone is also associated with a higher risk of brain metastasis compared with RT 1 CT (p 5 0.02). Table 4. Logistic regression for brain metastases Covariate KPS (, 70 vs. 70) (, 70 vs. 80) (, 70 vs. 90) (, 70 vs. 100) N-Stage Histology (S vs. A) (S vs. L) Radiotherapy
Coefficient
p-value
Odds ratio
20.337 20.56 20.939 20.788 N.S.
0.002
0.967 0.571 0.391 0.455
20.651 20.55 0.419
, 0.0001
0.265
0.02
0.522 0.577 1.52
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Analyses for other distant metastasis produced results similar to those with brain metastases, for example, lower odds ratios for lower KPS compared with higher values (p 5 0.002, odds ratios of 0.247 for KPS , 70 vs. 100). Squamous cell carcinoma was significantly less likely (p , 0.0001) to have distant metastasis than adenocarcinoma (odds ratio 0.53) or large cell carcinoma. (odds ratio 0.65). RT was significantly associated with distant metastases compared with RT 1 CT (odds ratio 2.64, p , 0.0001). Odds ratios for death without progression were much higher for low KPS: 2.20 for , 70 vs. 70 and 3.33 for , 70 vs. 90 or 100 (p , 0.0001). N-stage was associated with a higher risk (odds ratio 1.75 for N3 vs. N0, p 5 0.0178). Finally, squamous cell carcinoma carried a significantly greater risk (p , 0.0001) of death without progression than adenocarcinoma (odds ratio 1.85) or large cell carcinoma (odds ratio 1.66). DISCUSSION The findings that adenocarcinoma and large cell carcinoma of the lung spread more frequently beyond the thorax, to the brain, and other distant sites, confirms several previous studies. It is of considerable interest that chemotherapy combined with radiation therapy in several different ways (induction, concurrent and induction plus concurrent) unquestionably decreased the risk of distant metastasis, regardless of cell type. The phenomenon of greater risk of distant metastasis for adenocarcinoma compared with squamous cell carcinoma was not affected by chemotherapy. Another important phenomenon that was not altered by the addition of chemotherapy to radiation therapy was death without clinical progression. There has been considerable debate whether this type of failure results from progressive local disease or occult but nonetheless lethal distant metastasis. The strong relationship between death without progression and low KPS could be interpreted as due either to the local-regional tumor or to distant metastasis, although studies of the major symptoms contributing to KPS have suggested historically that most are consequences of the local-regional tumor (19). The findings in the present study suggest that death without clinical progression in prospective trials is more a failure to overcome the local-regional tumor than the result of distant metastasis. First, the fact that
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death without progression is strongly associated with squamous cell carcinoma which is less likely to spread beyond the thorax clinically, suggests the lethal events are occurring within the thorax. Second, the fact that chemotherapy has no effect on this phenomenon suggests it is not dominated by distant metastasis. The apparent adverse effect of chemotherapy on radiotherapeutic control of large cell carcinoma might better be understood by separating the different approaches to chemotherapy and radiation therapy (induction vs. concurrent). The existing data in this RTOG database were insufficient to evaluate the different chemotherapy approaches. Several tentative conclusions can be drawn from this RTOG database study which could influence strategies for clinical investigations for inoperable NSCCL. First, patients with low performance are at such high risk for death without progression that they either should be excluded from study altogether and offered short-term palliative treatment, or the study should concentrate on correcting the cardiopulmonary compromise that is leading to early death. Second, since radiation therapy is related to improved control at the primary site but not elsewhere in the thorax, combination chemotherapy for control of distant metastasis should be combined with further dose intensification by such means as accelerated fractionation (20) or high dose 3-dimensional conformal radiation therapy. Third, since there is major effect of chemotherapy on distant metastasis, but no effect on local tumor control, emphasis should be placed on ways of combining chemotherapy with radiation therapy that enhance local tumor control, such as concurrent chemoradiation. Finally, serious consideration needs to be given to separating squamous cell carcinoma from adenocarcinoma and from large cell carcinoma to pursue the most directed treatment strategies. Squamous cell carcinomas, because of the central location, may be amenable to external plus endobronchial irradiation (21) or gene therapy combined with radiation therapy (22). The significantly higher risk of brain metastasis with adenocarcinoma and large cell carcinoma justifies a new evaluation of prophylactic cranial irradiation in the context of effective combination chemotherapy which reduces other distant metastases. The higher risk of death without progression for squamous cell carcinoma, even when correcting for KPS, suggests that this cell type should be approached in a different manner than the others.
REFERENCES 1. Parker SL, Tong T, Bolden S, et al. Cancer statistics, 1997. CA: Cancer J Clin 1997;47:5–27. 2. Cox JD. Failure analysis in diagnostic and treatment strategies in cancer management. Cancer Treat Symp 1983;2:1–3. 3. Komaki R, Scott CB, Sause WT, et al. Induction cisplatin/ vinblastine and irradiation vs. irradiation in unresectable nonsmall cell lung cancer: Failure patterns by cell type in RTOG 88-08/ECOG 4588. Int J Radiat Oncol Biol Phys 1997;39: 527–544. 4. American Joint Committee on Cancer. Thorax. In: Beahrs OH,
Henson DE, Hutter RVP, et al. editors. Manual for staging of cancer. Philadelphia: JB Lippincott Company; 1992. p. 115– 122. 5. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: Macleod CM, editors. Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949. p. 191–205. 6. 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
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7. 8.
9.
10.
11.
12.
13.
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. Asbell SO, Pajak T, Seydel HG, et al. Phase III RTOG double blind lung cancer trial of XRT and subsequent thymosin or placebo. Proc Am Soc Clin Oncol 1990;8:242. Russell AH, Pajak TE, Selim HM, et al. Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: Results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1991;21:637– 643. Byhardt RW, Pajak TF, Emami B, et al. A phase I/II study to evaluate accelerated fractionation via concomitant boost for squamous, adeno, and large cell carcinoma of the lung: Report of Radiation Therapy Oncology Group 84-07. Int J Radiat Oncol Biol Phys 1993;26:459 – 468. 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. Sause WT, Scott CB, Taylor SGI, et al. RTOG 88-08 and 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. Byhardt RW, Scott CB, Ettinger DS, et al. Concurrent hyperfractionated irradiation and chemotherapy for unresectable non-small cell lung cancer. Results of Radiation Therapy Oncology Group (RTOG) 90-15. Cancer 1995;75: 2337–2344. Lee JS, Scott C, Komaki R, et al. Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced
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14.
15.
16. 17. 18. 19. 20.
21.
22.
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inoperable non-small cell lung cancer: Radiation Therapy Oncology Group protocol 91-06. J Clin Oncol 1996;14:1055– 1064. 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) 9204. Int J Radiat Oncol Biol Phys 1997;38:149 –155. Yesner R, Seydel GH, Asbell SO, et al. Biopsies of non-small cell lung cancer: Central review in cooperative studies of the Radiation Therapy Oncology Group. Mod Pathol 1991;4:432– 435. Mehta C, Patel N. StatXact. Cambridge: CYTEL Software; 1992. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem Rep 1966; 50:163–170. Hyde L, Hyde CI. Clinical manifestations of lung cancer. Chest 1974;65:299 –306. 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. Komaki R, Morice RC, Walsh GL. High-dose-rate remote afterloading endobronchial brachytherapy. In: Roth JA, Cox JD, Hong WK, editors. Lung cancer. 2nd ed. Oxford: Blackwell Science; 1998. p. 163–179. Roth JA, Nguyen D, Lawrence DD, et al. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. Nature Med 1996;2:985–991.
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ADDITION OF CHEMOTHERAPY TO RADIATION THERAPY ALTERS FAILURE PATTERNS BY CELL TYPE WITHIN NON-SMALL CELL CARCINOMA OF LUNG (NSCCL): ANALYSIS OF RADIATION THERAPY ONCOLOGY GROUP (RTOG) TRIALS JAMES D. COX, M.D.*, CHARLES B. SCOTT, PH.D.,† ROGER W. BYHARDT, M.D.,‡ BAHMAN EMAMI, M.D.,§ ANTHONY H. RUSSELL, M.D.,\ KAREN K. FU, M.D.,¶ MATTHEW B. PARLIAMENT, M.D.,# RITSUKO KOMAKI, M.D.,* AND LAURIE E. W. GASPAR, M.D.* *The University of Texas M. D. Anderson Cancer Center, Houston, TX; †Statistical Center, RTOG, Philadelphia, PA; ‡Medical College of Wisconsin, Milwaukee, WI; §Washington University School of Medicine, St. Louis, MO; \Radiation Oncology Associates, Sacramento, CA; ¶University of California-San Francisco, CA; #University of Alberta, Edmonton, Alberta, Canada; and * Wayne State School of Medicine, Detroit, MI Purpose: To evaluate the influence of cell type within non-small cell carcinoma of lung (NSCCL) on failure patterns when chemotherapy (CT) is combined with radiation therapy (RT). Methods and Materials: Data from 4 RTOG studies including 1415 patients treated with RT alone, and 5 RTOG studies including 350 patients also treated with chemotherapy (RT 1 CT) were analyzed. Patterns of progression were evaluated for squamous cell carcinoma (SQ) (n 5 946), adenocarcinoma (AD) (n 5 532) and large cell carcinoma (LC) (n 5 287). Results: When treated with RT alone, SQ was more likely to progress at the primary site than LC (26% vs. 20%, p 5 0.05). AD and LC were more likely to progress in the brain than SQ (20% and 18% vs. 11%, p 5 0.0001 and 0.011, respectively). No differences were found in intrathoracic and distant metastasis by cell type. When treated with RT 1 CT, AD was less likely to progress at the primary than either SQ or LC (23% vs. 34% and 40%, respectively; p 5 0.057 and 0.035). AD was more likely than SQ to metastasize to the brain (16% vs. 8%, p 5 0.03), and other distant sites (26% vs. 14%, p 5 0.019). No differences were found in intrathoracic metastasis. LC progressed at the primary site more often with RT 1 CT than with RT alone (40% vs. 20%, p 5 0.036). Death with no clinical progression was more likely with SQ than AD or LC for RT alone and RT 1 CT (p < 0.01). Brain metastasis was altered little by the addition of CT, but other distant metastases were significantly decreased (p < 0.001) in all cell types by the addition of CT. Conclusion: CT, although effective in reducing distant metastasis in all types of NSCCL, has different effects on the primary tumor by cell type, and has no effect on brain metastasis or death with no progression. Different treatment strategies should be considered for the different cell types to advance progress with RT 1 CT in NSCCL. © 1999 Elsevier Science Inc. Lung, Neoplasms, Radiation therapy, Chemotherapy, Squamous cell carcinoma, Adenocarcinoma.
Cancer of the lung continues to be the most frequent cause of death from neoplastic diseases in the United States and many urbanized countries. Although modest improvements in outcome have been reported from many clinical trials employing combinations of treatment modalities, there has been little overall effect as reflected in national data (1). Constant search for more promising treatment strategies is warranted. Analyses of patterns of failure after cancer treatment can
suggest both reasons for the results obtained and strategies for future investigations (2). A recent failure pattern study from the Radiation Therapy Oncology Group (RTOG) for non-small cell carcinoma of the lung (NSCLC) suggested the possibility of important differences by histopathologic type within the NSCLC grouping (3). A more complete study of failure patterns by cell type based on data from several RTOG trials was undertaken (a) to identify whether there is a need to subdivide NSCLC in reporting results; and (b) to examine the influence of combination chemotherapy on outcomes.
Reprint requests to: James D. Cox, M.D., Department of Radiation Oncology, Box 97, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: [email protected]. Presented in part at the 8th World Conference on Lung Cancer,
Dublin, Ireland, August 10 –15, 1997. Supported by Grants CA 21661 and CA 32115 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Accepted for publication 29 September 1998.
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PATIENTS AND METHODS The RTOG NSCLC database for this analysis consists of entries from 4 prospective clinical trials which used radiation therapy alone and 5 trials which employed combination chemotherapy in conjunction with radiation therapy. All patients had histologically or cytologically confirmed inoperable or unresectable Stage II, IIIA, or IIIB by the American Joint Committee on Cancer (AJCC) (4), Karnofsky performance status (KPS) (5) 50 or higher, and no definitive surgical resection, radiation therapy, or chemotherapy for NSCLC. The radiation therapy alone studies were RTOG 83-11 (6), 83-21 (7), 84-03 (8), and 84-07 (9). The trials which included both combination chemotherapy and radiation therapy were 88-04 (10), 88-08 (11), 90-15 (12), 91-06 (13), and 92-04 (14). All combination chemotherapy regimens were based upon the use of cisplatin. Protocol 88-08 required induction chemotherapy consisting of cisplatin (100 mg/m2) on days 1 and 29, and 5 mg/m2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation starting day 50. Protocol 88-04 used the same induction regimen as protocol 88-08, but added cisplatin (75 mg/m2) concurrent with standard radiation therapy on days 50, 71, and 92. Protocol 90-15 combined cisplatin (75 mg/m2) days 1, 29, and 50, and 5 mg/m2 vinblastine weekly for 5 weeks concurrent with hyperfractionated radiation therapy (69.6 Gy administered as 1.2 Gy twice daily, 5 days per week for 6 weeks). Protocol 91-06 combined cisplatin (50 mg/m2 days 1 and 8) and oral etoposide (100 mg/day in 2 divided doses, days 1–14) concurrent with the same hyperfractionated radiation therapy regimen as in 90-15); cisplatin and etoposide were repeated beginning day 29. Protocol 92-04 was a randomized Phase II comparison of the regimens piloted in protocols 88-04 and 91-06. Central pathology review was required in protocol 83-11. Observer variability between pathologists in originating institutions and RTOG central reviewers was determined to be sufficiently low (15) that central review was not required for subsequent studies. All studies required pretreatment computed tomography (CT) of the chest and upper abdomen in addition to posterior-anterior (PA) and lateral chest roentgenograms. Patients were followed after completion of treatment at 2-month intervals for 6 months, then every 3 months for 2 years, then every 6 months. Follow-up evaluations included PA and lateral chest roentgenograms, CT of the chest, liver function studies, and complete blood cell counts. Stable findings on chest films and CT scans were considered criteria for local control; progressive increases in size of abnormal masses were considered local failure. Local progression was evaluated by bronchoscopy and biopsy at the discretion of the physicians caring for the patients. Additional evaluations for metastasis were performed as indicated by patients’ signs and symptoms. Failure sites were separated into five categories which were not mutually exclusive. The first site of failure in the
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primary meant that the patient progressed within the irradiated volume. First failure in the thorax meant progression within the lung outside the irradiated volume or in the pleural cavity. First failure in the brain was considered separately from other distant metastases. Dead no progression was used if the patient died, but there was no evidence of progression in any of the other four categories.
STATISTICAL METHODS The data for this analysis were updated as of November 1996. The potential follow-up ranged from 2 to 13 years. Only 3% of all patients were censored (alive) at the time of analysis. Patterns of first failure were determined by finding the first occurrence, in time from date of treatment, of primary, thorax, brain, or other distant metastasis. Multiple events may be diagnosed simultaneously (e.g., primary and thoracic progression may have the same progression date): such events are recorded as a component of first failure. Because events are not independent, patterns of first failure do not sum, nor do the percentages sum to 100%. Differences between two groups for a component of first failure were computed using the Fisher’s exact test (16). There were no adjustments for multiple comparisons: all p-values are 2-sided. All survival-based distributions were estimated using the product-limit method (17). Differences in survival-based distributions were examined using the log-rank statistic (18). Each component of the patterns of first failure was used as an endpoint in logistic regression analyses. Karnofsky performance status, N-Stage, histology, and whether chemotherapy was given were factors examined for their prognostic importance. These factors were examined in each model. Odds ratios were based upon the coefficients of statistically significant prognostic factors for a given endpoint. Odds ratios significantly different from 1.0 indicate that one component of a factor has a greater or worse chance of the endpoint occurring, depending upon whether the radio is larger or smaller than 1.0, respectively.
RESULTS Data were available from 1765 patients, 1415 treated with radiation therapy alone and 350 patients treated with chemotherapy and radiation therapy. Patterns of first failure for squamous cell carcinoma (778 patients, 55%), adenocarcinoma (395 patients, 28%), and large cell carcinoma (242 patients, 17%) are shown in Table 1 for patients treated with radiation therapy alone. Pair-wise comparisons show a marginally significant lower first failure at the primary for large cell carcinoma (20%) than squamous cell carcinoma (26%) (p 5 0.050). There are no significant differences for progression within the thorax. Adenocarcinoma (20%) and
Failure patterns by cell types
Table 1. Patterns of first failure by histology: patients treated on RT alone
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Table 3. Patterns of first failure by histology: patients treated with RT 1 CT
Histology Failure site Squamous Adenocarcinoma Large cell No. (%) No. (%) No. (%) Primary Thorax Brain Other distant metastases Dead–no progression No. Patients w/events
203 (26) 279 (36) 88 (11) 253 (33) 270 (35) 778
92 (23) 156 (39) 79 (20) 188 (48) 88 (22) 395
48 (20) 81 (33) 43 (18) 101 (42) 58 (24) 242
large cell carcinoma (18%) have significantly more frequent failure in the brain than squamous cell carcinoma (11%) (p 5 0.0001 and 0.011, respectively). Adenocarcinoma (48%) and large cell carcinoma (42%) are more likely to spread to other distant sites than squamous cell carcinoma (33%) (p 5 0.001 and 0.01, respectively). Death with no evidence of progression was significantly more likely to occur with squamous cell carcinoma (35%) than either adenocarcinoma (22%) or large cell carcinoma (24%) (p , 0.0001 and p 5 0.0035, respectively). In all of the comparisons, there were no significant differences between adenocarcinoma and large cell carcinoma. Table 2 shows patterns of first failure for 924 patients with the somewhat more favorable prognostic factors required for entry on more recent trials of the RTOG. The proportions are slightly different, but the findings are similar to the larger group of patients shown in Table 1. Patterns of first failure after chemotherapy plus radiation therapy studies are shown in Table 3: 168 patients (48%) had squamous cell carcinoma, 137 (39%) had adenocarcinoma, and 45 (13%) had large cell carcinoma. There were no significant differences by cell type for progression at the primary or thorax. Adenocarcinoma (16%) was more likely to fail in the brain than squamous cell carcinoma (8%) (p 5 0.030); large cell carcinoma also failed in the brain in 16% of patients, but the differences were not statistically significant. Metastases to other distant sites were more likely with adenocarcinoma (26%) than squamous cell carcinoma (14%) (p 5 0.019). Squamous cell carcinoma (30%) was more strongly associated with death with no clinical Table 2. Patterns of first failure by histology—patients with KPS 70 –100 and weight loss 0 –5% only: patients on RT alone Histology Failure site Primary Thorax Brain Other distant metastases Dead–no progression No. patients w/events
Squamous Adenocarcinoma Large cell No. (%) No. (%) No. (%) 132 (27) 177 (36) 68 (14) 171 (35) 159 (32) 493
67 (25) 105 (40) 55 (21) 130 (49) 54 (20) 264
39 (23) 56 (34) 30 (18) 75 (45) 38 (23) 167
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Squamous Adenocarcinoma Large cell No. (%) No. (%) No. (%)
Primary 57 (34) Thorax 43 (26) Brain metastases 13 (8) Other distant metastases 24 (14) Dead–no progression 50 (30) Total 168
32 (23) 38 (28) 22 (16) 35 (26) 20 (15) 137
18 (40) 10 (22) 7 (16) 7 (16) 6 (14) 45
evidence of progression than either adenocarcinoma (15%) or large cell carcinoma (14%) (p 5 0.0016 and 0.0233, respectively). Large cell carcinoma had a lower frequency of failure following radiation therapy alone (RT) (20%) than radiation therapy plus chemotherapy (RT 1 CT) (40%) (p 5 0.036); there were no differences with the other cell types. Progression in the thorax beyond the primary was less frequent with RT 1 CT than RT for squamous cell carcinoma (26% vs. 36%, p 5 0.018) and for adenocarcinoma (28% vs. 39%, p 5 0.021); the difference for large cell carcinoma was not statistically significant. There was a slightly lower rate of brain metastasis with RT 1 CT for squamous cell carcinoma (p 5 0.041), but no significant reduction for the other cell types. However, the reductions in distant metastasis other than brain with RT 1 CT compared with RT alone were highly significant (p , 0.001 for each histopathologic type). There were no significant differences with respect to death with no progression. In the multivariate model, the logistic regression for primary progression showed only RT alone to be significant (p 5 0.005; odds ratio 5 0.69); KPS, N-stage, and histology had no demonstrable effect. For thoracic progression, the converse obtained: the odds ratio for RT was 1.49 (p 5 0.012); cell type had no effect, nor did N-stage or KPS. Table 4 shows the logistic regression for brain metastases; the inverse relationship with KPS suggests that longer survival is associated with an increased risk. The odds ratios are much lower for squamous cell carcinoma than either adenocarcinoma or large cell carcinoma (p , 0.0001). RT alone is also associated with a higher risk of brain metastasis compared with RT 1 CT (p 5 0.02). Table 4. Logistic regression for brain metastases Covariate KPS (, 70 vs. 70) (, 70 vs. 80) (, 70 vs. 90) (, 70 vs. 100) N-Stage Histology (S vs. A) (S vs. L) Radiotherapy
Coefficient
p-value
Odds ratio
20.337 20.56 20.939 20.788 N.S.
0.002
0.967 0.571 0.391 0.455
20.651 20.55 0.419
, 0.0001
0.265
0.02
0.522 0.577 1.52
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Analyses for other distant metastasis produced results similar to those with brain metastases, for example, lower odds ratios for lower KPS compared with higher values (p 5 0.002, odds ratios of 0.247 for KPS , 70 vs. 100). Squamous cell carcinoma was significantly less likely (p , 0.0001) to have distant metastasis than adenocarcinoma (odds ratio 0.53) or large cell carcinoma. (odds ratio 0.65). RT was significantly associated with distant metastases compared with RT 1 CT (odds ratio 2.64, p , 0.0001). Odds ratios for death without progression were much higher for low KPS: 2.20 for , 70 vs. 70 and 3.33 for , 70 vs. 90 or 100 (p , 0.0001). N-stage was associated with a higher risk (odds ratio 1.75 for N3 vs. N0, p 5 0.0178). Finally, squamous cell carcinoma carried a significantly greater risk (p , 0.0001) of death without progression than adenocarcinoma (odds ratio 1.85) or large cell carcinoma (odds ratio 1.66). DISCUSSION The findings that adenocarcinoma and large cell carcinoma of the lung spread more frequently beyond the thorax, to the brain, and other distant sites, confirms several previous studies. It is of considerable interest that chemotherapy combined with radiation therapy in several different ways (induction, concurrent and induction plus concurrent) unquestionably decreased the risk of distant metastasis, regardless of cell type. The phenomenon of greater risk of distant metastasis for adenocarcinoma compared with squamous cell carcinoma was not affected by chemotherapy. Another important phenomenon that was not altered by the addition of chemotherapy to radiation therapy was death without clinical progression. There has been considerable debate whether this type of failure results from progressive local disease or occult but nonetheless lethal distant metastasis. The strong relationship between death without progression and low KPS could be interpreted as due either to the local-regional tumor or to distant metastasis, although studies of the major symptoms contributing to KPS have suggested historically that most are consequences of the local-regional tumor (19). The findings in the present study suggest that death without clinical progression in prospective trials is more a failure to overcome the local-regional tumor than the result of distant metastasis. First, the fact that
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death without progression is strongly associated with squamous cell carcinoma which is less likely to spread beyond the thorax clinically, suggests the lethal events are occurring within the thorax. Second, the fact that chemotherapy has no effect on this phenomenon suggests it is not dominated by distant metastasis. The apparent adverse effect of chemotherapy on radiotherapeutic control of large cell carcinoma might better be understood by separating the different approaches to chemotherapy and radiation therapy (induction vs. concurrent). The existing data in this RTOG database were insufficient to evaluate the different chemotherapy approaches. Several tentative conclusions can be drawn from this RTOG database study which could influence strategies for clinical investigations for inoperable NSCCL. First, patients with low performance are at such high risk for death without progression that they either should be excluded from study altogether and offered short-term palliative treatment, or the study should concentrate on correcting the cardiopulmonary compromise that is leading to early death. Second, since radiation therapy is related to improved control at the primary site but not elsewhere in the thorax, combination chemotherapy for control of distant metastasis should be combined with further dose intensification by such means as accelerated fractionation (20) or high dose 3-dimensional conformal radiation therapy. Third, since there is major effect of chemotherapy on distant metastasis, but no effect on local tumor control, emphasis should be placed on ways of combining chemotherapy with radiation therapy that enhance local tumor control, such as concurrent chemoradiation. Finally, serious consideration needs to be given to separating squamous cell carcinoma from adenocarcinoma and from large cell carcinoma to pursue the most directed treatment strategies. Squamous cell carcinomas, because of the central location, may be amenable to external plus endobronchial irradiation (21) or gene therapy combined with radiation therapy (22). The significantly higher risk of brain metastasis with adenocarcinoma and large cell carcinoma justifies a new evaluation of prophylactic cranial irradiation in the context of effective combination chemotherapy which reduces other distant metastases. The higher risk of death without progression for squamous cell carcinoma, even when correcting for KPS, suggests that this cell type should be approached in a different manner than the others.
REFERENCES 1. Parker SL, Tong T, Bolden S, et al. Cancer statistics, 1997. CA: Cancer J Clin 1997;47:5–27. 2. Cox JD. Failure analysis in diagnostic and treatment strategies in cancer management. Cancer Treat Symp 1983;2:1–3. 3. Komaki R, Scott CB, Sause WT, et al. Induction cisplatin/ vinblastine and irradiation vs. irradiation in unresectable nonsmall cell lung cancer: Failure patterns by cell type in RTOG 88-08/ECOG 4588. Int J Radiat Oncol Biol Phys 1997;39: 527–544. 4. American Joint Committee on Cancer. Thorax. In: Beahrs OH,
Henson DE, Hutter RVP, et al. editors. Manual for staging of cancer. Philadelphia: JB Lippincott Company; 1992. p. 115– 122. 5. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: Macleod CM, editors. Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949. p. 191–205. 6. 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
Failure patterns by cell types
7. 8.
9.
10.
11.
12.
13.
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. Asbell SO, Pajak T, Seydel HG, et al. Phase III RTOG double blind lung cancer trial of XRT and subsequent thymosin or placebo. Proc Am Soc Clin Oncol 1990;8:242. Russell AH, Pajak TE, Selim HM, et al. Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: Results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1991;21:637– 643. Byhardt RW, Pajak TF, Emami B, et al. A phase I/II study to evaluate accelerated fractionation via concomitant boost for squamous, adeno, and large cell carcinoma of the lung: Report of Radiation Therapy Oncology Group 84-07. Int J Radiat Oncol Biol Phys 1993;26:459 – 468. 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. Sause WT, Scott CB, Taylor SGI, et al. RTOG 88-08 and 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. Byhardt RW, Scott CB, Ettinger DS, et al. Concurrent hyperfractionated irradiation and chemotherapy for unresectable non-small cell lung cancer. Results of Radiation Therapy Oncology Group (RTOG) 90-15. Cancer 1995;75: 2337–2344. Lee JS, Scott C, Komaki R, et al. Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced
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14.
15.
16. 17. 18. 19. 20.
21.
22.
J. D. COX et al.
509
inoperable non-small cell lung cancer: Radiation Therapy Oncology Group protocol 91-06. J Clin Oncol 1996;14:1055– 1064. 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) 9204. Int J Radiat Oncol Biol Phys 1997;38:149 –155. Yesner R, Seydel GH, Asbell SO, et al. Biopsies of non-small cell lung cancer: Central review in cooperative studies of the Radiation Therapy Oncology Group. Mod Pathol 1991;4:432– 435. Mehta C, Patel N. StatXact. Cambridge: CYTEL Software; 1992. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem Rep 1966; 50:163–170. Hyde L, Hyde CI. Clinical manifestations of lung cancer. Chest 1974;65:299 –306. 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. Komaki R, Morice RC, Walsh GL. High-dose-rate remote afterloading endobronchial brachytherapy. In: Roth JA, Cox JD, Hong WK, editors. Lung cancer. 2nd ed. Oxford: Blackwell Science; 1998. p. 163–179. Roth JA, Nguyen D, Lawrence DD, et al. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. Nature Med 1996;2:985–991.