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73.6 Gy and Beyond: Hyperfractionated, Accelerated Radiotherapy for Non–Small-Cell Lung Cancer

From the Department of Radiation Oncology and Cancer Center Biostatistics, Duke University Medical Center, Durham, NC.

Address reprint requests to Lawrence B. Marks, MD, Department of Radiation Oncology, Box 3085, Duke University Medical Center, Durham, NC 27710; email: marks{at}radonc.duke.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To assess results with twice-daily high-dose radiotherapy (RT) for non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Between 1991 and 1998, 94 patients with unresectable NSCLC were prescribed 73.6 Gy via accelerated fractionation. Fifty were on a phase II protocol (P group); 44 were similarly treated off-protocol (NP group). The clinical target volume received 45 Gy at 1.25 Gy bid (6-hour interval). The gross target volume received 1.6 Gy bid to 73.6 to 80 Gy over 4.5 to 5 weeks using a concurrent boost technique. Overall survival (OS) and local progression-free survival (LPFS) were calculated by the Kaplan-Meier method. Median follow-up durations for surviving P and NP patients were 67 and 16 months, respectively.

RESULTS: Total doses received were 72 Gy in 97% of patients. The median OS by stage was 34, 13, and 12 months for stages I/II, IIIa, and IIIb, respectively. LPFS was significantly longer for patients with T1 lesions (median, 43 months) versus T2-4 (median, 7 to 10 months; P = .01). Results were similar in the P and NP groups. Acute grade 3 toxicity included esophagus (14 patients; 15%), lung (three patients; 3% [one grade 5]), and skin (four patients; 4%). Grade 3 late toxicity in 86 assessable patients included esophagus (three patients; 3%), lung (15 patients; 17% [three grade 5]), skin (five patients; 6%), heart (two patients; 2%), and nerve (one patient; 1%).

CONCLUSION: This regimen yielded favorable survival results, particularly for T1 lesions. Acute grade 3 toxicity seems greater than for conventional RT, though most patients recovered. Late grade 3 pulmonary toxicity occurred in 17%. Because of continued locoregional recurrences, we are currently using doses 86 Gy.

	INTRODUCTION

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RADIOTHERAPY (RT) remains the locoregional treatment modality for patients with non–small-cell lung cancer (NSCLC) who have either medically inoperable or locally advanced, surgically unresectable disease. Conventionally fractionated RT alone to 60 Gy yields median overall survival (OS) of only 9 months.¹ Phase III trials of induction chemotherapy for well-selected patients with unresectable disease have revealed an improvement in median OS to approximately 14 months, with 5-year OS ranging from 6% to 17%.^2-5 Nevertheless, many patients continue to experience treatment failure with locoregional recurrence of disease, with estimates as high as 80% depending on the extent of follow-up and restaging.

Attempts to decrease the rate of intrathoracic disease recurrence in this setting have centered on altered RT fractionation schemes. Pure hyperfractionation, multiple daily fractions to achieve a higher dose over the same time as a conventional course, has yielded a dose-response relationship within the 60 to 70 Gy range.¹ Accelerated hyperfractionation, multiple daily fractions over a shorter time period than conventional RT, has also yielded slight improvements in OS, presumably via gains in locoregional disease control (LC).^6,7

In 1996, we reported a phase II trial of high-dose, hyperfractionated, accelerated RT using a concurrent boost technique for patients with either early, medically inoperable, or locally advanced, surgically unresectable NSCLC.⁸ Since that report, the 73.6 Gy regimen has been used as the standard fractionation scheme at Duke University Medical Center (DUMC). Since 1999, we have had an ongoing phase I dose-escalation study based on this initial experience in which patients have received more than 73.6 Gy. Herein, we report the updated and expanded experience prescribing 73.6 to 80 Gy, uncorrected for tissue inhomogeneity, for NSCLC.

	PATIENTS AND METHODS

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Patients
Between 1991 and 1994, 50 patients with either medically inoperable or surgically unresectable NSCLC were treated on a phase II protocol (P group).⁸ This regimen (described below) was adopted as the standard RT regimen at DUMC, and 18 patients were treated accordingly between 1994 and 1998. Twenty-six additional patients were treated on a subsequent phase I dose-escalation study with prescribed doses of 73.6 to 80 Gy.⁹ Thus 44 patients (NP group) were treated after closure of the phase II trial, though with the same RT technique used in the protocol. A total of 94 patients at DUMC and affiliated hospitals were treated with this approach between 1991 and 1998. Ninety-two patients were treated for newly diagnosed disease, and two were treated for biopsy-proven recurrence after prior surgical resection. All patients had Karnofsky performance status 70.

Pretreatment evaluation included a thorough history and physical examination, complete blood cell count, hepatic and renal function testing, chest x-ray, and computed tomography (CT) of the chest and upper abdomen in all patients. Further staging studies for the two groups are listed in Table 1. Pretreatment patient and tumor characteristics are listed by group in Table 2. The P and NP groups are similar.

Elective irradiation of the ipsilateral hilar, bilateral mediastinal, and supraclavicular nodes was delivered at the discretion of the treating physician. Even when treatment of these nodal areas was not intended, they were often incidentally included based on their proximity to the GTV and the path of the treatment beams. In patients without nodal involvement (N0), the rates of elective/incidental irradiation of the hilar, mediastinal, ipsilateral supraclavicular, and contralateral supraclavicular nodes were 83%, 69%, 6%, and 6%, respectively. In patients with hilar disease (N1), the rates of irradiation of these same nodal sites were 100%, 83%, 17%, and 17%, respectively. For patients with ipsilateral mediastinal disease (N2), these rates were 100%, 100%, 17%, and 14%, respectively. In patients with contralateral mediastinal disease (N3), the rates were 100%, 100%, 40%, and 30%, respectively. Involved nodal sites were prescribed to receive full dose ( 73.6 Gy), and electively treated sites received a minimum of 45 Gy. When the mediastinum was to be treated, field borders were typically placed beyond the radiographically identifiable mediastinal structures (eg, aortic arch, descending aorta, great vessels). For supraclavicular treatment, areas superior to the clavicle and medial to the lateral aspect of the first rib were included. Conformal three-dimensional treatment planning was used for 65 patients (69%) using either GRATIS (Sherouse Systems Inc, 1991 to 1995) or PLUNC (Plan University of North Carolina Hospitals; 1996 to 1998).

Patients with stage III disease were offered induction chemotherapy after 1994. Twenty-five patients (27%) were treated with one to three cycles of one of the following three regimens: carboplatin/vinorelbine (n = 11), carboplatin/paclitaxel (n = 10), or cisplatin/vinorelbine (n = 4). No patient received chemotherapy concurrent with RT.

Follow-Up
Follow-up evaluation for all patients in P group included physical examination, chest x-ray, CT of the chest and upper abdomen, and pulmonary function test at 3 and 6 months after the completion of RT. Bronchoscopy was performed at 3 and 6 months post-RT in 18 patients (36%) in P group. Serial chest x-rays and CT scans were performed routinely at 3- to 6-month intervals thereafter. Follow-up evaluation of patients in the NP Group was at the discretion of the attending radiation oncologist, but typically included a clinical and radiologic evaluation (chest x-ray, CT, and/or positron-emission tomography) at 3- to 6-month intervals. Median follow-up was 67 months (range, 2 to 82 months) for nine surviving patients in P group and 16 months (range, 5 to 39 months) for 17 surviving patients in NP group.

Statistical Methods
OS and local progression-free survival (LPFS) were calculated from the date of completion of RT to the date of death from any cause, and the date of documented clinical or radiographic progression of disease either within or at the margin of the initial RT fields, respectively. All survival estimates were calculated using the Kaplan-Meier method.¹⁰ Cox proportional hazards model was used to assess the joint effect of various potential prognostic factors on OS. Radiation Therapy Oncology Group (RTOG) toxicity grading scale was used. Acute toxicity was defined as that which occurred within 90 days after the completion of RT. Late toxicity was defined as that which occurred more than 90 days after completion of RT, analyzed and reported for the 86 patients who survived beyond that point. Patients whose acute toxicity persisted beyond 90 days after completion of RT were also recorded as having late toxicity.

	RESULTS

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Actual Doses Received
Eighty-four percent of patients (79 of 94) received 73.6 Gy. Of the 15 who received lower doses, 12 received within 2% of a planned dose of 73.6 Gy (72.0 to 73.5 Gy). Most of these were due to minor adjustments to the delivered dose calculation during routine dosimetry quality assurance checks. Three patients intended to received 73.6 Gy were intentionally treated to lower doses (59 to 67 Gy) because of poor acute tolerance (esophagitis, fatigue, pain within irradiated volume). Seven patients received 1% greater than the planned dose of 73.6 (73.8 to 74.3), again because of minor dosimetric/technical issues. Eight patients received a planned dose of 80 Gy.

OS
Median OS was 13 months for P group and 12 months for NP group (P = .57). Median OS was 34 months for patients with stage I/II disease, 13 months for stage IIIa, and 10 months for stage IIIb disease, as shown in Fig 1. OS was longer for patients with T1 primary lesions (median, 35 months) than T2 (median, 13 months; P = .03), T3 (median, 11 months; P = .01), or T4 primaries (median, 10 months; P = .02).

View larger version (14K): [in this window] [in a new window]   Fig 1. Actuarial OS by stage.

View larger version (13K): [in this window] [in a new window]   Fig 2. Actuarial LPFS by stage.

View larger version (15K): [in this window] [in a new window]   Fig 3. Actuarial LPFS by primary tumor (T) stage.

View this table: [in this window] [in a new window]   Table 4. RTOG Toxicity Grade (G) 3

Late Toxicity
Twenty-three patients developed late grade 3 to 5 toxicity. Of three patients with late esophagitis, one had grade 4 toxicity requiring repeated dilatations. Heart toxicity consisted of two cases of constrictive pericarditis. One patient developed a vocal cord paralysis secondary to presumed RT-induced damage of the recurrent laryngeal nerve in the aorticopulmonary window. She had multiple examinations of the larynx that failed to reveal an intrinsic lesion over a 3-year interval.

Fifteen patients developed late pulmonary toxicity (includes two cases of acute toxicity that persisted > 90 days post-RT), three of which presumably contributed to the patients’ deaths. The first patient was 70 years of age and had stage T3N2 disease. He received no chemotherapy and his pre-RT FEV1 was 1 L. RT fields included the ipsilateral mediastinum, tight coverage of the contralateral mediastinum, without the supraclavicular area. He died of respiratory failure 10 months after receiving 73.3 Gy, without definite evidence of radiographic progression. A second patient was 74 years of age and had a T3N2 lesion. He received two cycles of carboplatin/vinorelbine followed by 73.6 Gy and died 5 months later. The RT fields included the mediastinum without the supraclavicular area, and pre-RT FEV1 and diffusion capacity of carbon monoxide were 87% and 71% of predicted, respectively. Chest CT scan before death revealed bilateral pulmonary nodules and ground glass opacities. No autopsy was performed. The third patient was a 56-year-old woman with T4N3 (supraclavicular) disease. She received two cycles of carboplatin/paclitaxel followed by 73.6 Gy. RT fields included the mediastinum and supraclavicular areas. She developed acute grade 4 esophagitis, followed by late bronchial stenosis. She died of massive hemoptysis from the left pulmonary artery at the time of bronchoscopy 16 months after completion of RT.

Neither elective nodal irradiation nor protocol versus nonprotocol group impacted significantly on the survival end points or the rate of grade 3 toxicities. However, the number of patients in the subgroups for these comparisons and the number of events are small. Of the four deaths that appear to have been related to RT, one late death occurred in the P group. The other three, one acute and two late, were in the NP group.

	DISCUSSION

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This high-dose, hyperfractionated, accelerated RT regimen resulted in a median OS of 34 months and LPFS of 23 months for patients with medically inoperable stage I/II disease. In particular, patients with T1 primary lesions had a median LPFS of 43 months. These figures differ from historical series. Standard doses of RT result in median OS ranging from 16 to 28 months for medically inoperable patients with T1/T2 primary lesions.^11-13 Thus this highly aggressive regimen may improve OS via increased LC for these patients. The comorbidities of medically inoperable, stage I/II patients make comparison with similarly staged, surgically resectable patients difficult. Nevertheless, because the cure rate for stage I/II NSCLC is approximately 50% with surgery alone, high-dose RT should yield improved LC and OS for similarly staged, medically inoperable patients. The hypothetical OS benefit of high-dose over standard-dose RT for these patients remains to be tested in a phase III trial.

Unfortunately, even with excellent LC, the development of distant metastases (DM) with resultant death looms evident for a large proportion of these patients. Several retrospective series of surgically resected stage I/II patients, including one from our own institution, have shown the utility of various molecular markers as possible predictors of DM.¹⁴ Theoretically, one might select a subset of these early-stage patients, including medically inoperable cases, who are at high risk for developing DM, to whom chemotherapy might be offered with a potential OS benefit.

The OS and LPFS results for stage IIIa/b patients in the current series seem similar to historical results with conventionally fractionated RT alone.¹ A comparison of our results with high-dose RT regimens from other institutions is listed in Table 5.^15-18 Our LPFS results are somewhat lower than other institutions, though this may reflect vigilant restaging, which often included bronchoscopy and, in recent years, positron-emission tomography with ¹⁸fluorodeoxyglucose. The generally poor OS observed in these series, despite the use of high-dose thoracic RT, is discouraging. We believe that a greater burden of disease within the chest may narrow the margin for improvement of the therapeutic ratio in at least two ways.

The combination of an aggressive RT regimen with concurrent chemotherapy should decrease the risk of both local recurrence and DM, thus improving OS. Jeremic et al¹⁹ reported a phase III trial of hyperfractionated RT to 69.6 Gy versus the same RT regimen delivered concurrently with carboplatin and etoposide, yielding median OS of 14 versus 22 months, respectively. The RTOG has conducted several trials testing similar regimens that also seem promising.^20,21We await reporting of the three-arm, phase III RTOG 94-10 trial, which pits the Cancer and Leukemia Group B 8433 regimen versus standard RT delivered concurrently with cisplatin/vinblastine versus the RTOG 91-06 regimen of hyperfractionated RT to 69 Gy concurrent with cisplatin/etoposide. The Cancer and Leukemia Group B 9431 trial, which used induction cisplatin coupled with one of three newer chemotherapeutic agents (vinorelbine, paclitaxel, or gemcitabine) followed by the same agents delivered concurrently with 66 Gy thoracic RT, revealed a median OS of 18 months on preliminary analysis.²² It remains to be seen whether high-dose, hyperfractionated RT delivered concurrently with any of these newer chemotherapeutic regimens will yield further improvement in OS.

The second reason for a narrower window of therapeutic gain in patients with stage III disease may relate to the numerator in the risk-benefit ratio. Extensive thoracic disease warrants an increased volume of normal tissue to be encompassed within the high-dose RT field, with an associated potential increased risk of acute and late toxicity. Nevertheless, despite our high-dose, aggressive regimen, both acute and late toxicity was usually moderate. There was an increased rate of grade 3 acute esophagitis relative to that reported with standard-dose RT. This result was expected, because the esophageal mucosa is a rapidly proliferating tissue. On the other hand, only one patient died from acute toxicity (pulmonary), and the majority recovered completely. An increased incidence of acute toxicity would be anticipated with subsequent trials of high-dose RT in combination with concurrent (rather than sequential) chemotherapy.

Three patients died because of presumed late lung toxicity. Interestingly, none of these three cases were preceded by acute pneumonitis. Only one of the three deaths was preceded by documented RT-induced late toxicity. Equivocal radiographic findings and lack of postmortem examination in the other two cases made distinction between toxicity and metastatic disease unclear. Nevertheless, this regimen seems to be more toxic than standard-dose RT, the latter of which rarely results in grade 5 pulmonary toxicity.

Encouraged by our early results from the initial phase II study,⁸ 73.6 Gy at 1.6 bid became the standard fractionation scheme used at Duke. The present analysis is somewhat confounded by the fusion of patients treated in a formal protocol and patients who received essentially identical RT per policy. This pooling of patients is reasonable, given the unique and uniform fractionation scheme used. There were no statistical differences in outcomes between the P and NP groups; however, the small number of patients in the subgroups limits the power of the comparison. One of the four deaths occurred in the P group. Of the three NP deaths, one had received prior RT, and a second had supraclavicular adenopathy. Based largely on the results of the present analysis and the toxic deaths that we have encountered, most patients treated to doses in the 73.6 Gy range are presently enrolled onto formal dose-escalation protocols.^9,23 The deaths may have occurred, in part, because of the application of this aggressive approach in patients who would not have been deemed appropriate had formal protocol guidelines been in place.

Full three-dimensional dosimetric information was not available in all of our patients. Our group has reported on potential dosimetric and clinical predictors of both esophageal and pulmonary late toxicity in patients treated with high-dose RT.^24-26 On further prospective testing, we expect that these tools will aid in limiting future long-term toxicity. Because of the relatively high rate of esophageal injury in this series and the results of our prior dosimetric analyses,²⁴ we presently limit the dose to any length of full organ circumference to 60 Gy. Prospective selection of the small subset of patients at risk for severe late pulmonary toxicity after high-dose RT remains a challenge. We continue to monitor plasma transforming growth factor beta1 levels in this regard, attempting to select patients at low risk for pulmonary toxicity for RT dose escalation.^9,26

In summary, our high-dose, hyperfractionated, accelerated RT regimen may yield favorable results for patients with stage I/II lesions. Acute and late toxicity was greater than for conventional RT, although the majority of patients recovered. We are currently treating to 80 to 86 Gy after induction chemotherapy in phase I/II trials.

	ACKNOWLEDGMENTS

 
We thank the University of North Carolina Hospitals for the use of PLUNC treatment planning software and Jane Hoppenworth for assistance with manuscript preparation.

	NOTES

 
Presented at the Forty-First Annual Meeting of the American Society of Therapeutic Radiology and Oncology, San Antonio, TX, October 30-November 4, 1999.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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14. D’Amico TA, Massey M, Herndon JE, et al: A biologic risk model for stage I lung cancer: Immunohistochemical analysis of 408 patients with the use of ten molecular markers. J Thorac Cardiovasc Surg 117: 736-743, 1999[Abstract/Free Full Text]

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16. Hazuka MB, Turrisi AT, Lutz ST, et al: Results of high-dose thoracic irradiation incorporating beam’s eye view display in non-small cell lung cancer: A retrospective multivariate analysis. Int J Radiat Oncol Biol Phys 27: 273-284, 1993[Medline]

17. Graham MV, Purdy JA, Emami B, et al: Preliminary results of a prospective trial using three dimensional radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 33: 993-1000, 1995[Medline]

18. Rosenzweig KE, Mychalczak B, Fuks Z, et al: Final report of the 70.2-Gy and 75.6-Gy dose levels of a phase I dose escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable non-small cell lung cancer. Cancer J 6: 82-87, 2000[Medline]

19. Jeremic B, Shibamoto Y, Acimovic L, et al: Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: A randomized study. J Clin Oncol 14: 1065-1070, 1996[Abstract/Free Full Text]

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23. Marks LB, Sibley GS, Socinski MA, et al: Carboplatin/Taxol (C/T) or carboplatin/Navelbine (C/N) followed by accelerated hyperfractionated conformal radiation therapy (RT) to >73: 6 Gy. A phase i-ii dose escalation study from the Carolina 3D Consortium. Proc Int Lung Cancer Meeting (in press) (abstr)

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Submitted February 23, 2000; accepted September 22, 2000.

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