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Unresectable Squamous Cell Carcinoma of the Lung: An Outcomes Study
Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 2, pp. 370–376, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.08.019
CLINICAL INVESTIGATION
Lung
UNRESECTABLE SQUAMOUS CELL CARCINOMA OF THE LUNG: AN OUTCOMES STUDY HEATHER E. NEWLIN, M.D., MEERA IYENGAR, CHRISTOPHER G. MORRIS, M.S., AND KENNETH OLIVIER, M.D. From the Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL Purpose: To report survival and control rates in patients with inoperable squamous cell carcinoma (SCC). Methods and Materials: Two hundred seventy-five patients with inoperable squamous cell carcinoma of the lung (Stages I–IIIB) who received radiotherapy alone or combined with chemotherapy given with curative intent at the University of Florida between 1963 and 2006 were retrospectively analyzed. Results: Overall survival (OS) at 5 years for Stages I, II, and III was 10%, 14%, and 7% (p = 0.0034); local-regional control at 5 years was 51%, 38%, and 29% (p = 0.0003); and freedom from metastases at 5 years was 81%, 60%, and 65% (p = 0.0689), respectively. Patients who received doses $ 65 Gy had improved cause-specific survival (CSS), OS, and metastasis-free survival at 5 years compared with those who received doses < 65 Gy. Five-year regional control was significantly improved with twice-daily vs. once-daily treatment (37% vs. 14%, p = 0.02). Chemotherapy significantly improved 5-year regional control (36% for patients who received chemotherapy vs. 13% for those who did not; p = 0.01). Conclusions: Dose escalation, accelerated fractionation, and combined modality therapies improve outcomes in SCC of the lung. Our review of the literature highlights the different natural history for SCC vs. other non–small cell lung cancers and emphasizes the importance of tailoring treatment strategies to individual patients. At the University of Florida, we have begun treating unresectable Stage III patients with SCC of the lung using 69.6 Gy twice daily with concurrent chemotherapy. Ó 2009 Elsevier Inc. Radiation therapy, Outcomes, Lung cancer, Dose, Fractionation, Chemotherapy.
INTRODUCTION
ure, whereas patients with adenocarcinoma were more likely to relapse with distant metastases (p = 0.005) (8). With respect to treatment outcomes, after correlating dose with histology (SCC vs. adenocarcinoma), patients with SCC showed a more clear dose–response effect for local control of the irradiated volume and intrathoracic site (p = 0.017) (8). Efforts to increase the dose to the intrathoracic tumor are indicated to improve local control and survival, so studies of combined modality therapies and hyperfractionation were performed to this end. An intriguing outcome in studies of hyperfractionation (HFx) is a greater numerical advantage in local control and survival for SCC tumors than other NSCLCs (7, 15, 16). Unfortunately, high rates of progression and early deaths due to cancer and intercurrent disease maintain 5-year survival rates at between 5% and 15% for patients with unresectable disease (5–7). Technological advances in treatment planning are being made to overcome faulty tumor localization and treatment precision. The most influential have been in the
Lung cancer remains the leading cause of cancer-related death worldwide, and 214,000 new diagnoses were expected to be made in 2007 (1). Approximately 30% of these are squamous cell carcinomas (SCC), and only 25%–40% will be amenable to a potentially curative resection (2–4). Although considerable attention has been directed toward improving treatment outcomes in unresectable patients, survival rates at 5 years remain in the range of 5%–15% (5–7). Histologies included under the umbrella of non–small cell lung cancers (NSCLC) are SCC, adenocarcinoma, and largecell carcinoma. Randomized and retrospective studies alike have noted differences in patterns of failure and treatment outcomes for SCC vs. other NSCLC histologies (3, 8–14) An in-depth discussion of SCC vs. other NSCLC appears in reports by Perez et al. for Radiation Therapy Oncology Group (RTOG) 7301 and 7302 (3, 8). Patients with SCC were more likely to have local recurrence as a site of first fail-
Conflict of interest: none. Received April 22, 2008, and in revised form July 21, 2008. Accepted for publication Aug 20, 2008.
Reprint requests to: Kenneth Olivier, M.D., Department of Radiation Oncology, University of Florida Health Science Center, 2000 SW Archer Rd., P.O. Box 100385, Gainesville, FL 32610-0385. Tel: (352) 265-0287; Fax: (352) 265-0759.; E-mail: kolivier@ufl. edu 370
Dose and fractionation on SCC of the lung d H. E. NEWLIN et al.
Table 1. Patient characteristics (N = 275) Age, years Median Range Race African American Caucasian Unknown Overall Stage I II III RT alone CT + RT BID treatment QD treatment Dose, Gy Median Range
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Table 2. Five-year outcomes according to tumor stage 64 33–87 29 244 2 73 (27%) 52 (18%) 150 (55%) 224 51 26 249 65 43–75
Abbreviations: BID = once daily; CT = chemotherapy; QD = twice daily; RT = radiotherapy.
areas of four-dimensional computed tomography (4D-CT) simulation, three-dimensional conformal radiotherapy (3DCRT) treatment planning, stereotactic radiotherapy (SRT) treatments, and intensity-modulated radiotherapy (IMRT). These technological advances allow us to optimize the biological effects of dose-escalated RT, altered fractionation, and combined modality therapies. Recommendations for optimal treatment protocols are still under discussion for patients who present with unresectable disease. The purpose of this article is to report survival and control rates as a baseline for comparing patients at the University of Florida with inoperable SCC as we move into an era that favors concurrent chemotherapy and offers increased radiation dose with HFx, IMRT, 3D-CRT, and SRT.
METHODS AND MATERIALS Two hundred seventy-five consecutive patients with inoperable SCC of the lung (Stages I–IIIB) who received RT alone or combined with adjuvant chemotherapy at the University of Florida between
Fig. 1. Overall survival for patients with Stages I–III tumors.
Stage
Overall survival
Local-regional control
Freedom from metastasis
I II III p value
10% 14% 7% 0.0068
51% 38% 29% 0.0004
81% 60% 65% 0.811
1963 and 2006 were retrospectively analyzed. All patients were treated with curative intent. Medical records were retrospectively reviewed in a comprehensive fashion in accordance with an institutional review board (IRB) protocol and Health Insurance Portability and Accountability Act regulations. Pathology reports were reviewed to confirm SCC histology. The determination of local control, regional control, distant metastases, and cause of death were made on the basis of the medical record and consisted of both radiographic reports and clinical notes. SAS and JMP software provided all statistical computations (SAS Institute, Cary, NC). The Kaplan-Meier product limit method allowed estimates of overall (OS) and cause-specific survival (CSS) and freedom from distant metastases (17). The log-rank test statistic indicated any statistically significant differences in these endpoints as stratified by dose and fractionation.
RESULTS Patient characteristics are shown in Table 1. The median age was 64 years (range, 33–87 years). Patients were deemed inoperable on the basis of tumor stage or medical comorbidity. Twenty-seven percent of patients had Stage I disease, 18% had Stage II disease, and 55% had Stage III disease. The median dose of radiation delivered was 65 Gy (range, 43–75 Gy). The median biological equivalent dose (BED) was 77 Gy (range, 51–105 Gy). Two hundred forty-nine patients received once-daily treatment, and 26 patients were treated twice daily. Patients treated twice daily were more likely to have Stage III or higher disease compared with those treated once daily (77% vs. 53%). Fifty-one patients (19%) received chemotherapy, with the majority (90%) receiving concurrent chemotherapy. Overall survival rates at 5 years were 10%, 14%, and 7% for Stages I, II, and III, respectively (p = 0.0034) (Fig. 1). Local-regional control rates at 5 years were 51%, 38%, and 29% for Stages I, II, and III, respectively (p = 0.0004). Freedom from metastases rates at 5 years were 81%, 60%, and 65% for Stages I, II, and III, respectively (p = 0.0811; Table 2). Patients who received $ 65 Gy had significantly improved CSS and OS at 5 years compared with those who received < 65 Gy (CSS 23% vs. 19%, p = 0.0258 and OS 10% vs. 7%, p = 0.0415) (Fig. 2). Total dose ($ 65 Gy vs. < 65 Gy) did not affect median survival (17 vs. 14 months) or local control (43% vs. 41%); however, 5-year freedom from metastasis was significantly improved with values of 73% for $ 65 Gy and 60% for < 65 Gy (p = 0.0119). Outcomes comparing patients who received once-daily vs. twice-daily treatment are shown in Fig. 3. Five-year regional control was significantly improved with twice-daily vs.
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Fig. 2. (a) Local control, (b) local-regional control, (c) cause-specific survival (CSS), and (d) overall survival (OS) comparing patients treated greater or less than the median dose (65 Gy). Those patients who received > 65 Gy had superior outcome in CSS, OS, and metastasis-free interval compared with those who received less than 65 Gy. Our OS at 5 years of 7%–10% compares with that seen elsewhere in both retrospective and prospective data.
once-daily treatment protocols (86% vs. 63%, p = 0.02). Five-year OS and CSS rates were 19% vs. 8% and 38% vs. 21% for twice-daily and once-daily, respectively. Although twice-daily dosing for inoperable SCC displayed a strong trend toward being more effective than once-daily dosing for OS and CSS, this trend was not statistically significant (p = 0.35 for OS and p = 0.43 for CSS). Outcomes comparing patients who received chemotherapy vs. those who did not are shown in Fig. 4. OS showed a trend toward improvement with the addition of chemotherapy. OS at 2 and 5 years for patients treated with chemotherapy was 34% and 16%, compared with 33% and 8% 2- and 5-year OS for patients not treated with chemotherapy (p = 0.6411). Local control trended toward improvement at 5 years. Local control was 58% for those patients treated with chemotherapy and 39% for patients who did not receive chemotherapy (p = 0.583). Chemotherapy significantly improved regional control (p = 0.01). On multivariate analysis, improved OS and CSS were seen in patients who received greater than the median dose and patients who were Stages I and II. The only factor on multivariate analysis that was significant for regional control is stage. In fact, stage was a significant factor in all categories of multivariate analysis (Table 3).
DISCUSSION This study reaffirms the results seen in other randomized and retrospective series showing that patients with SCC treated primarily with RT are more frequently affected by local-regional recurrence than distant metastases (3, 8, 10). Optimizing the methods used to improve local control in these patients can lead to improved survival. In our series, Stage I or II disease, twice-daily treatment, and chemotherapy significantly improved regional control, whereas increased dose improved OS, CSS, and freedom from metastatic disease. Overall, our results are congruent with those seen in historical series with a median survival range of 15–17 months and an overall survival rate of 8%–19% at 5 years. This series, like others before it, shows a survival benefit with dose escalation (18, 19). There was a statistically significant improvement in CSS, OS, and metastasis-free interval with doses > 65 Gy. Conventional RT with 2 Gy per fraction to a total dose of 60 Gy is limited in its ability to provide long-term local control. Two-year survival is < 20% in prospective studies (3, 8, 20). Dose escalation is limited by acute and late toxicity to normal tissues; however, trials of dose escalation use conformal treatment plans and eliminate treatment to elective nodal structures (18, 19,
Dose and fractionation on SCC of the lung d H. E. NEWLIN et al.
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Fig. 3. (a) Local control, (b) local-regional control, (c) cause-specific survival (CSS), and (d) overall survival (OS) comparing patients treated once daily (QD) vs. twice daily (BID). BID dosing for inoperable squamous cell carcinoma was superior to QD dosing for OS and CSS; however, this was not significant. Of note, 26 patients were treated BID, and 77% of these patients were Stage III.
21). These trials have shown the feasibility of delivering doses up to 74–78 Gy (18, 22–24) . Other studies are ongoing to enhance the delivery of concurrent chemotherapy and dose-escalated RT (15, 21). Our analysis reveals an intriguing trend in favor of twicedaily RT for inoperable SCC. RTOG 8808, the CHART trial, and RTOG 9410 have suggested that SCC responds more favorably when treated with Hfx or accelerated RT (7, 15, 16). Saunders et al. (16) compared CHART with conventional RT in NSCLC. Those in the CHART arm received 36 fractions of 1.5 Gy three times daily to a total dose of 54 Gy in 12 consecutive days. Eighty-two percent of the patients in this trial had SCC. In this subgroup, there was a 25% reduction in the risk ratios of local and distant progression (p = 0.025). No chemotherapy was given in this trial, which supports the belief that improvements in local control alone can improve survival. Similar results were seen in RTOG 9410, a trial of concurrent daily RT with chemotherapy vs. concurrent twice-daily RT with chemotherapy. Twice-daily RT for SCC of the lung significantly lengthened the time to infield failure and trended toward improvements in CSS and OS (7, 15, 16). In our study, there is a numeric trend toward improved overall survival (19% vs. 8%), but the limited number of patients treated
with twice-daily (26 twice-daily patients vs. 249 once-daily patients) hampers the statistical significance of the data. Another finding that can help explain why the difference in OS was not significantly better for twice-daily treatments includes bias associated with patient selection. Notably, 77% of the 26 patients in the twice-daily group (vs. 53% in the once-daily group) had Stage III disease and thus would not be expected to fare as well. Because analyses from retrospective studies cannot account for all potential biases, these data need to be queried and confirmed in randomized clinical trials. Two prospective, randomized Phase III trials established concurrent chemoradiotherapy as the standard of care for patients with unresectable NSCLC (6, 15). Concurrent chemoradiotherapy resulted in a median survival of 17 months in these studies. Our analysis demonstrates a median survival of 16 months for the patients given chemotherapy, although a range of chemotherapeutic doses, duration, and schedules were delivered. A median survival of 17 months was nevertheless achieved for patients who received greater than the median dose of radiation or twice-daily treatment. Interestingly, a subset analysis in studies of induction chemotherapy reveals that it offers the greatest benefit to patients with
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Fig. 4. (a) Local control, (b) local-regional control, (c) cause-specific survival (CSS), and (d) overall survival (OS) comparing patients who received chemotherapy vs. those who did not receive chemotherapy.
adenocarcinoma or large-cell carcinoma (7, 10). The treatment philosophy underlying this approach is that full systemic doses of induction chemotherapy improve the overall survival for these patients by reducing distant metastases.
One may conclude that induction chemotherapy may not be as important for patients with SCC in whom metastasis is considered a late event. Patients with SCC may be adversely affected by any regimen that would delay or prolong
Table 3. Univariate and Multivariate Analyses by Variable Variables Univariate analysis Fractionation (BID vs. QD) BED ($ and < median BED, 77 Gy) Dose ($ and < than median dose, 65 Gy) Duration of treatment Chemotherapy (with vs without) Stage (I-II vs. III) Treatment Era (<1985 VS. >=1985) Multivariate analysis Fractionation (BID vs. QD) BED ($ and < median BED, 77 Gy) Dose ($ and < than median dose, 65 Gy) Duration of treatment Chemotherapy (with vs without) Stage (I–II vs. III) Treatment era (< 1985 vs. >=1985)
Local Control
Regional Control
Metastasis-Free Survival
Overall Survival
Cause-Specific Survival
0.9312 0.4316 0.8550
0.0208 0.6364 0.6323
0.9804 0.0337 0.0119
0.3691 0.0362 0.0415
0.4304 0.0112 0.0258
0.1270 0.0583 0.0052 0.5400
0.5899 0.0140 0.0250 0.0381
0.4743 0.2659 0.0689 0.1500
0.9176 0.6411 0.0034 0.7888
0.2976 0.6422 <.0001 0.2537
0.1052 0.9031 0.3450
0.6014 0.7427 0.3863
0.8110 0.6544 0.0047
0.5098 0.5427 0.0046
0.9913 0.4705 0.0001
0.1449 0.0150 0.0011 0.8514
0.6388 0.3249 0.0318 0.0775
0.4846 0.1213 0.0258 0.2152
0.2454 0.9642 0.0005 0.7442
0.0241 0.7874 <0.0001 0.3986
Abbreviations: BED = bioequivalent dose; BID = twice daily; QD = once daily.
Dose and fractionation on SCC of the lung d H. E. NEWLIN et al.
treatment directly to the tumor. Likewise, concurrent chemotherapy that causes treatment breaks because of toxicity might paradoxically worsen local control or survival (or both). Indeed, prolonged treatment time has been shown to significantly worsen local-regional control and survival (25–27). A retrospective review of three RTOG concurrent chemoradiotherapy trials demonstrated that prolonged treatment time was associated with poorer survival on multivariate analysis (28). The authors note that patients with modest treatment breaks should be encouraged to complete therapy. They conclude that concurrent chemoradiotherapy is safe and that most patients complete the treatment course as prescribed (28). Although treatment duration was not on found univariate analysis to have a significant impact on CSS, multivariate analysis suggests that it is indeed correlated with this endpoint. Closer examination of the other two variables that were significant on multivariate analysis—stage and dose— suggest an interaction between treatment duration and these other two prognostic factors with respect to CSS. Specifically, treatment duration has a significant effect on CSS when
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restricting the sample to Stage III patients receiving > 65 Gy (p = 0.0033). No other stratification of stage and dose yields a significant treatment duration effect for this endpoint. CONCLUSIONS This retrospective study confirms the ample data suggesting that dose escalation, accelerated fractionation, and combined modality therapies improve outcomes in SCC of the lung. Our review of the literature highlights the different natural history for SCC compared with other NSCLC and emphasizes the importance of tailoring treatment strategies to individual patients. Our outcomes are congruent with historical expectations for patients with unresectable NSCLC, and this will serve as a baseline to compare with our future studies. Additional prospective trials using altered fractionation and dose escalation with concurrent chemotherapy in SCC of the lung may reveal a more potent benefit for this patient population. At the University of Florida, we have begun treating unresectable Stage III patients with SCC of the lung using 69.6 Gy twice daily with concurrent low-dose chemotherapy.
REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics 2007. CA Cancer J Clin 2007;57:43–66. 2. Yang P, Allen MS, Aubry MC, et al. Clinical features of 5,628 primary lung cancer patients: Experience at Mayo Clinic from 1997 to 2003. Chest 2005;128:452–462. 3. Perez CA, Stanley K, Rubin P, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung: Preliminary report by the Radiation Therapy Oncology Group. Cancer 1980;45:2744–2753. 4. Jett JR. Current treatment of unresectable lung cancer. Mayo Clin Proc 1993;68:603–611. 5. Rosenthal SA, Curran WJ Jr., Herbert SH, et al. Clinical Stage II non–small cell lung cancer treated with radiation therapy alone. The significance of clinically staged ipsilateral hilar adenopathy (N1 disease). Cancer 1992;70:2410–2417. 6. 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 1999;17: 2692–2699. 7. Sause W, Kolesar P, Taylor S IV, et al. Final results of Phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 2000;117:358–364. 8. Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report by the Radiation Therapy Oncology Group. Cancer 1987;59:1874–1881. 9. Komaki R, Scott CB, Sause WT, et al. Induction cisplatin/vinblastine and irradiation vs. irradiation in unresectable squamous cell lung cancer: Failure patterns by cell type in RTOG 88-08/ ECOG 4588. Radiation Therapy Oncology Group. Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys 1997; 39:537–544. 10. Huang EH, Liao Z, Cox JD, et al. Comparison of outcomes for patients with unresectable, locally advanced non-small-cell
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lung cancer treated with induction chemotherapy followed by concurrent chemoradiation vs. concurrent chemoradiation alone. Int J Radiat Oncol Biol Phys 2007;68:779–785. Sibley GS. Radiotherapy for patients with medically inoperable Stage I nonsmall cell lung carcinoma smaller volumes and higher doses—a review. Cancer 1998;82:433–438. Libshitz HI, McKenna RJ Jr., Mountain CF. Patterns of mediastinal metastases in bronchogenic carcinoma. Chest 1986;90: 229–232. Line DH, Deeley TJ. The necropsy findings in carcinoma of the bronchus. Br J Dis Chest 1971;65:238–242. Komaki R, Swann S, Ettinger D, et al. Phase I dose-escalation study of thoracic irradiation with concurrent chemotherapy for patients with limited small cell lung cancer (LSCLC) [abstract]. Int J Radiat Oncol Biol Phys 2003;57. Curran W Jr., Scott C, Langer C, et al. Phase III comparison of sequential vs concurrent chemoradiation for pts with unresected Stage III NSCLC: Initial report of RTOG 9410 [abstract]. Proc Am Soc Clin Oncol 2000;19. Saunders M, Dische S, Barrett A, et al. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: Mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol 1999;52:137–148. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. Bradley J, Graham MV, Winter K, et al. Toxicity and outcome results of RTOG 9311: A Phase I–II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 2005;61:318–328. Socinski MA, Morris DE, Halle JS, et al. Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: A dose-escalation Phase I trial. J Clin Oncol 2004;22: 4341–4350. Perez CA, Bauer M, Edelstein S, et al. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 1986;12:539–547.
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21. Bradley JD, Graham M, Suzanne S, et al. Phase I results of RTOG L-0117; a Phase I/II dose intensification study using 3DCRT and concurrent chemotherapy for patients with inoperable NSCLC [abstract]. J Clin Oncol 2005;23. 22. Martel MK, Strawderman M, Hazuka MB, et al. Volume and dose parameters for survival of non-small cell lung cancer patients. Radiother Oncol 1997;44:23–29. 23. Rosenman JG, Halle JS, Socinski MA, et al. High-dose conformal radiotherapy for treatment of Stage IIIA/IIIB non-small-cell lung cancer: Technical issues and results of a Phase I/II trial. Int J Radiat Oncol Biol Phys 2002;54:348–356. 24. Rengan R, Rosenzweig KE, Venkatraman E, et al. Improved local control with higher doses of radiation in large-volume Stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;60:741–747.
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25. Cox JD, Pajak TF, Asbell S, et al. Interruptions of high-dose radiation therapy decrease long-term survival of favorable patients with unresectable non-small cell carcinoma of the lung: Analysis of 1244 cases from 3 Radiation Therapy Oncology Group (RTOG) trials. Int J Radiat Oncol Biol Phys 1993;27: 493–498. 26. Chen M, Jiang GL, Fu XL, et al. The impact of overall treatment time on outcomes in radiation therapy for non–small cell lung cancer. Lung Cancer 2000;28:11–19. 27. Bengtsson A, Henriksson KG. [Causes of fibromyalgia are both peripheral and central]. Lakartidningen 1996;93:161–163. 28. Machtay M, Hsu C, Komaki R, et al. Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced non-small-cell lung carcinoma: Analysis of the Radiation Therapy Oncology Group (RTOG) experience. Int J Radiat Oncol Biol Phys 2005;63:667–671.
doi:10.1016/j.ijrobp.2008.08.019
CLINICAL INVESTIGATION
Lung
UNRESECTABLE SQUAMOUS CELL CARCINOMA OF THE LUNG: AN OUTCOMES STUDY HEATHER E. NEWLIN, M.D., MEERA IYENGAR, CHRISTOPHER G. MORRIS, M.S., AND KENNETH OLIVIER, M.D. From the Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL Purpose: To report survival and control rates in patients with inoperable squamous cell carcinoma (SCC). Methods and Materials: Two hundred seventy-five patients with inoperable squamous cell carcinoma of the lung (Stages I–IIIB) who received radiotherapy alone or combined with chemotherapy given with curative intent at the University of Florida between 1963 and 2006 were retrospectively analyzed. Results: Overall survival (OS) at 5 years for Stages I, II, and III was 10%, 14%, and 7% (p = 0.0034); local-regional control at 5 years was 51%, 38%, and 29% (p = 0.0003); and freedom from metastases at 5 years was 81%, 60%, and 65% (p = 0.0689), respectively. Patients who received doses $ 65 Gy had improved cause-specific survival (CSS), OS, and metastasis-free survival at 5 years compared with those who received doses < 65 Gy. Five-year regional control was significantly improved with twice-daily vs. once-daily treatment (37% vs. 14%, p = 0.02). Chemotherapy significantly improved 5-year regional control (36% for patients who received chemotherapy vs. 13% for those who did not; p = 0.01). Conclusions: Dose escalation, accelerated fractionation, and combined modality therapies improve outcomes in SCC of the lung. Our review of the literature highlights the different natural history for SCC vs. other non–small cell lung cancers and emphasizes the importance of tailoring treatment strategies to individual patients. At the University of Florida, we have begun treating unresectable Stage III patients with SCC of the lung using 69.6 Gy twice daily with concurrent chemotherapy. Ó 2009 Elsevier Inc. Radiation therapy, Outcomes, Lung cancer, Dose, Fractionation, Chemotherapy.
INTRODUCTION
ure, whereas patients with adenocarcinoma were more likely to relapse with distant metastases (p = 0.005) (8). With respect to treatment outcomes, after correlating dose with histology (SCC vs. adenocarcinoma), patients with SCC showed a more clear dose–response effect for local control of the irradiated volume and intrathoracic site (p = 0.017) (8). Efforts to increase the dose to the intrathoracic tumor are indicated to improve local control and survival, so studies of combined modality therapies and hyperfractionation were performed to this end. An intriguing outcome in studies of hyperfractionation (HFx) is a greater numerical advantage in local control and survival for SCC tumors than other NSCLCs (7, 15, 16). Unfortunately, high rates of progression and early deaths due to cancer and intercurrent disease maintain 5-year survival rates at between 5% and 15% for patients with unresectable disease (5–7). Technological advances in treatment planning are being made to overcome faulty tumor localization and treatment precision. The most influential have been in the
Lung cancer remains the leading cause of cancer-related death worldwide, and 214,000 new diagnoses were expected to be made in 2007 (1). Approximately 30% of these are squamous cell carcinomas (SCC), and only 25%–40% will be amenable to a potentially curative resection (2–4). Although considerable attention has been directed toward improving treatment outcomes in unresectable patients, survival rates at 5 years remain in the range of 5%–15% (5–7). Histologies included under the umbrella of non–small cell lung cancers (NSCLC) are SCC, adenocarcinoma, and largecell carcinoma. Randomized and retrospective studies alike have noted differences in patterns of failure and treatment outcomes for SCC vs. other NSCLC histologies (3, 8–14) An in-depth discussion of SCC vs. other NSCLC appears in reports by Perez et al. for Radiation Therapy Oncology Group (RTOG) 7301 and 7302 (3, 8). Patients with SCC were more likely to have local recurrence as a site of first fail-
Conflict of interest: none. Received April 22, 2008, and in revised form July 21, 2008. Accepted for publication Aug 20, 2008.
Reprint requests to: Kenneth Olivier, M.D., Department of Radiation Oncology, University of Florida Health Science Center, 2000 SW Archer Rd., P.O. Box 100385, Gainesville, FL 32610-0385. Tel: (352) 265-0287; Fax: (352) 265-0759.; E-mail: kolivier@ufl. edu 370
Dose and fractionation on SCC of the lung d H. E. NEWLIN et al.
Table 1. Patient characteristics (N = 275) Age, years Median Range Race African American Caucasian Unknown Overall Stage I II III RT alone CT + RT BID treatment QD treatment Dose, Gy Median Range
371
Table 2. Five-year outcomes according to tumor stage 64 33–87 29 244 2 73 (27%) 52 (18%) 150 (55%) 224 51 26 249 65 43–75
Abbreviations: BID = once daily; CT = chemotherapy; QD = twice daily; RT = radiotherapy.
areas of four-dimensional computed tomography (4D-CT) simulation, three-dimensional conformal radiotherapy (3DCRT) treatment planning, stereotactic radiotherapy (SRT) treatments, and intensity-modulated radiotherapy (IMRT). These technological advances allow us to optimize the biological effects of dose-escalated RT, altered fractionation, and combined modality therapies. Recommendations for optimal treatment protocols are still under discussion for patients who present with unresectable disease. The purpose of this article is to report survival and control rates as a baseline for comparing patients at the University of Florida with inoperable SCC as we move into an era that favors concurrent chemotherapy and offers increased radiation dose with HFx, IMRT, 3D-CRT, and SRT.
METHODS AND MATERIALS Two hundred seventy-five consecutive patients with inoperable SCC of the lung (Stages I–IIIB) who received RT alone or combined with adjuvant chemotherapy at the University of Florida between
Fig. 1. Overall survival for patients with Stages I–III tumors.
Stage
Overall survival
Local-regional control
Freedom from metastasis
I II III p value
10% 14% 7% 0.0068
51% 38% 29% 0.0004
81% 60% 65% 0.811
1963 and 2006 were retrospectively analyzed. All patients were treated with curative intent. Medical records were retrospectively reviewed in a comprehensive fashion in accordance with an institutional review board (IRB) protocol and Health Insurance Portability and Accountability Act regulations. Pathology reports were reviewed to confirm SCC histology. The determination of local control, regional control, distant metastases, and cause of death were made on the basis of the medical record and consisted of both radiographic reports and clinical notes. SAS and JMP software provided all statistical computations (SAS Institute, Cary, NC). The Kaplan-Meier product limit method allowed estimates of overall (OS) and cause-specific survival (CSS) and freedom from distant metastases (17). The log-rank test statistic indicated any statistically significant differences in these endpoints as stratified by dose and fractionation.
RESULTS Patient characteristics are shown in Table 1. The median age was 64 years (range, 33–87 years). Patients were deemed inoperable on the basis of tumor stage or medical comorbidity. Twenty-seven percent of patients had Stage I disease, 18% had Stage II disease, and 55% had Stage III disease. The median dose of radiation delivered was 65 Gy (range, 43–75 Gy). The median biological equivalent dose (BED) was 77 Gy (range, 51–105 Gy). Two hundred forty-nine patients received once-daily treatment, and 26 patients were treated twice daily. Patients treated twice daily were more likely to have Stage III or higher disease compared with those treated once daily (77% vs. 53%). Fifty-one patients (19%) received chemotherapy, with the majority (90%) receiving concurrent chemotherapy. Overall survival rates at 5 years were 10%, 14%, and 7% for Stages I, II, and III, respectively (p = 0.0034) (Fig. 1). Local-regional control rates at 5 years were 51%, 38%, and 29% for Stages I, II, and III, respectively (p = 0.0004). Freedom from metastases rates at 5 years were 81%, 60%, and 65% for Stages I, II, and III, respectively (p = 0.0811; Table 2). Patients who received $ 65 Gy had significantly improved CSS and OS at 5 years compared with those who received < 65 Gy (CSS 23% vs. 19%, p = 0.0258 and OS 10% vs. 7%, p = 0.0415) (Fig. 2). Total dose ($ 65 Gy vs. < 65 Gy) did not affect median survival (17 vs. 14 months) or local control (43% vs. 41%); however, 5-year freedom from metastasis was significantly improved with values of 73% for $ 65 Gy and 60% for < 65 Gy (p = 0.0119). Outcomes comparing patients who received once-daily vs. twice-daily treatment are shown in Fig. 3. Five-year regional control was significantly improved with twice-daily vs.
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Fig. 2. (a) Local control, (b) local-regional control, (c) cause-specific survival (CSS), and (d) overall survival (OS) comparing patients treated greater or less than the median dose (65 Gy). Those patients who received > 65 Gy had superior outcome in CSS, OS, and metastasis-free interval compared with those who received less than 65 Gy. Our OS at 5 years of 7%–10% compares with that seen elsewhere in both retrospective and prospective data.
once-daily treatment protocols (86% vs. 63%, p = 0.02). Five-year OS and CSS rates were 19% vs. 8% and 38% vs. 21% for twice-daily and once-daily, respectively. Although twice-daily dosing for inoperable SCC displayed a strong trend toward being more effective than once-daily dosing for OS and CSS, this trend was not statistically significant (p = 0.35 for OS and p = 0.43 for CSS). Outcomes comparing patients who received chemotherapy vs. those who did not are shown in Fig. 4. OS showed a trend toward improvement with the addition of chemotherapy. OS at 2 and 5 years for patients treated with chemotherapy was 34% and 16%, compared with 33% and 8% 2- and 5-year OS for patients not treated with chemotherapy (p = 0.6411). Local control trended toward improvement at 5 years. Local control was 58% for those patients treated with chemotherapy and 39% for patients who did not receive chemotherapy (p = 0.583). Chemotherapy significantly improved regional control (p = 0.01). On multivariate analysis, improved OS and CSS were seen in patients who received greater than the median dose and patients who were Stages I and II. The only factor on multivariate analysis that was significant for regional control is stage. In fact, stage was a significant factor in all categories of multivariate analysis (Table 3).
DISCUSSION This study reaffirms the results seen in other randomized and retrospective series showing that patients with SCC treated primarily with RT are more frequently affected by local-regional recurrence than distant metastases (3, 8, 10). Optimizing the methods used to improve local control in these patients can lead to improved survival. In our series, Stage I or II disease, twice-daily treatment, and chemotherapy significantly improved regional control, whereas increased dose improved OS, CSS, and freedom from metastatic disease. Overall, our results are congruent with those seen in historical series with a median survival range of 15–17 months and an overall survival rate of 8%–19% at 5 years. This series, like others before it, shows a survival benefit with dose escalation (18, 19). There was a statistically significant improvement in CSS, OS, and metastasis-free interval with doses > 65 Gy. Conventional RT with 2 Gy per fraction to a total dose of 60 Gy is limited in its ability to provide long-term local control. Two-year survival is < 20% in prospective studies (3, 8, 20). Dose escalation is limited by acute and late toxicity to normal tissues; however, trials of dose escalation use conformal treatment plans and eliminate treatment to elective nodal structures (18, 19,
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Fig. 3. (a) Local control, (b) local-regional control, (c) cause-specific survival (CSS), and (d) overall survival (OS) comparing patients treated once daily (QD) vs. twice daily (BID). BID dosing for inoperable squamous cell carcinoma was superior to QD dosing for OS and CSS; however, this was not significant. Of note, 26 patients were treated BID, and 77% of these patients were Stage III.
21). These trials have shown the feasibility of delivering doses up to 74–78 Gy (18, 22–24) . Other studies are ongoing to enhance the delivery of concurrent chemotherapy and dose-escalated RT (15, 21). Our analysis reveals an intriguing trend in favor of twicedaily RT for inoperable SCC. RTOG 8808, the CHART trial, and RTOG 9410 have suggested that SCC responds more favorably when treated with Hfx or accelerated RT (7, 15, 16). Saunders et al. (16) compared CHART with conventional RT in NSCLC. Those in the CHART arm received 36 fractions of 1.5 Gy three times daily to a total dose of 54 Gy in 12 consecutive days. Eighty-two percent of the patients in this trial had SCC. In this subgroup, there was a 25% reduction in the risk ratios of local and distant progression (p = 0.025). No chemotherapy was given in this trial, which supports the belief that improvements in local control alone can improve survival. Similar results were seen in RTOG 9410, a trial of concurrent daily RT with chemotherapy vs. concurrent twice-daily RT with chemotherapy. Twice-daily RT for SCC of the lung significantly lengthened the time to infield failure and trended toward improvements in CSS and OS (7, 15, 16). In our study, there is a numeric trend toward improved overall survival (19% vs. 8%), but the limited number of patients treated
with twice-daily (26 twice-daily patients vs. 249 once-daily patients) hampers the statistical significance of the data. Another finding that can help explain why the difference in OS was not significantly better for twice-daily treatments includes bias associated with patient selection. Notably, 77% of the 26 patients in the twice-daily group (vs. 53% in the once-daily group) had Stage III disease and thus would not be expected to fare as well. Because analyses from retrospective studies cannot account for all potential biases, these data need to be queried and confirmed in randomized clinical trials. Two prospective, randomized Phase III trials established concurrent chemoradiotherapy as the standard of care for patients with unresectable NSCLC (6, 15). Concurrent chemoradiotherapy resulted in a median survival of 17 months in these studies. Our analysis demonstrates a median survival of 16 months for the patients given chemotherapy, although a range of chemotherapeutic doses, duration, and schedules were delivered. A median survival of 17 months was nevertheless achieved for patients who received greater than the median dose of radiation or twice-daily treatment. Interestingly, a subset analysis in studies of induction chemotherapy reveals that it offers the greatest benefit to patients with
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Fig. 4. (a) Local control, (b) local-regional control, (c) cause-specific survival (CSS), and (d) overall survival (OS) comparing patients who received chemotherapy vs. those who did not receive chemotherapy.
adenocarcinoma or large-cell carcinoma (7, 10). The treatment philosophy underlying this approach is that full systemic doses of induction chemotherapy improve the overall survival for these patients by reducing distant metastases.
One may conclude that induction chemotherapy may not be as important for patients with SCC in whom metastasis is considered a late event. Patients with SCC may be adversely affected by any regimen that would delay or prolong
Table 3. Univariate and Multivariate Analyses by Variable Variables Univariate analysis Fractionation (BID vs. QD) BED ($ and < median BED, 77 Gy) Dose ($ and < than median dose, 65 Gy) Duration of treatment Chemotherapy (with vs without) Stage (I-II vs. III) Treatment Era (<1985 VS. >=1985) Multivariate analysis Fractionation (BID vs. QD) BED ($ and < median BED, 77 Gy) Dose ($ and < than median dose, 65 Gy) Duration of treatment Chemotherapy (with vs without) Stage (I–II vs. III) Treatment era (< 1985 vs. >=1985)
Local Control
Regional Control
Metastasis-Free Survival
Overall Survival
Cause-Specific Survival
0.9312 0.4316 0.8550
0.0208 0.6364 0.6323
0.9804 0.0337 0.0119
0.3691 0.0362 0.0415
0.4304 0.0112 0.0258
0.1270 0.0583 0.0052 0.5400
0.5899 0.0140 0.0250 0.0381
0.4743 0.2659 0.0689 0.1500
0.9176 0.6411 0.0034 0.7888
0.2976 0.6422 <.0001 0.2537
0.1052 0.9031 0.3450
0.6014 0.7427 0.3863
0.8110 0.6544 0.0047
0.5098 0.5427 0.0046
0.9913 0.4705 0.0001
0.1449 0.0150 0.0011 0.8514
0.6388 0.3249 0.0318 0.0775
0.4846 0.1213 0.0258 0.2152
0.2454 0.9642 0.0005 0.7442
0.0241 0.7874 <0.0001 0.3986
Abbreviations: BED = bioequivalent dose; BID = twice daily; QD = once daily.
Dose and fractionation on SCC of the lung d H. E. NEWLIN et al.
treatment directly to the tumor. Likewise, concurrent chemotherapy that causes treatment breaks because of toxicity might paradoxically worsen local control or survival (or both). Indeed, prolonged treatment time has been shown to significantly worsen local-regional control and survival (25–27). A retrospective review of three RTOG concurrent chemoradiotherapy trials demonstrated that prolonged treatment time was associated with poorer survival on multivariate analysis (28). The authors note that patients with modest treatment breaks should be encouraged to complete therapy. They conclude that concurrent chemoradiotherapy is safe and that most patients complete the treatment course as prescribed (28). Although treatment duration was not on found univariate analysis to have a significant impact on CSS, multivariate analysis suggests that it is indeed correlated with this endpoint. Closer examination of the other two variables that were significant on multivariate analysis—stage and dose— suggest an interaction between treatment duration and these other two prognostic factors with respect to CSS. Specifically, treatment duration has a significant effect on CSS when
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restricting the sample to Stage III patients receiving > 65 Gy (p = 0.0033). No other stratification of stage and dose yields a significant treatment duration effect for this endpoint. CONCLUSIONS This retrospective study confirms the ample data suggesting that dose escalation, accelerated fractionation, and combined modality therapies improve outcomes in SCC of the lung. Our review of the literature highlights the different natural history for SCC compared with other NSCLC and emphasizes the importance of tailoring treatment strategies to individual patients. Our outcomes are congruent with historical expectations for patients with unresectable NSCLC, and this will serve as a baseline to compare with our future studies. Additional prospective trials using altered fractionation and dose escalation with concurrent chemotherapy in SCC of the lung may reveal a more potent benefit for this patient population. At the University of Florida, we have begun treating unresectable Stage III patients with SCC of the lung using 69.6 Gy twice daily with concurrent low-dose chemotherapy.
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