SEARCH

SEARCH BY CITATION

Keywords:

  • lung cancer;
  • chemoradiation;
  • dose escalation;
  • intensity-modulated radiotherapy;
  • image-guided radiotherapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

The objective of the current study was to evaluate the feasibility and toxicity of radiation dose escalation with concurrent chemotherapy using helical tomotherapy (HT) in patients with inoperable, locally advanced, stage III nonsmall cell lung cancer (LANSCLC) (grading determined according to the American Joint Committee on Cancer 6th edition grading system).

METHODS:

This phase 1/2 study was designed to determine the maximum tolerated dose (MTD) of radiotherapy in patients with LANSCLC administered concurrently with docetaxel and cisplatin. Radiotherapy was delivered using HT. A dose per fraction escalation was applied starting at 2 grays (Gy), with an increase of 6% per dose cohort (DC). The Radiation Therapy Oncology Group acute radiation morbidity score was used to monitor pulmonary, esophageal, and cardiac toxicity.

RESULTS:

Dose escalation was performed in 34 patients over 5 DCs to a dose per fraction of 2.48 Gy. No differences were observed in acute toxicity between the different DCs. However, a significant increase in late lung toxicity in DC IV, which received a fraction size of 2.36 Gy, necessitated a halt in further dose escalation with the MTD defined as 2.24 Gy per fraction. The overall incidence of acute grade ≥3 esophageal and pulmonary toxicity was 24% and 3%, respectively (grading determined according to the Radiation Therapy Oncology Group-European Organisation for Research and Treatment of Cancer toxicity scoring system). The overall incidence of late lung toxicity was 21%, but the incidence was an acceptable 13% in DCs I, II, and III. The local response rate was 61% on computed tomography images.

CONCLUSIONS:

The use of HT to 67.2 Gy with concurrent cisplatin/docetaxel was feasible and resulted in acceptable toxicity. A full phase 2 study has been initiated to establish the true local response rate at the MTD of 2.24 Gy per fraction. Cancer 2010. © 2010 American Cancer Society.

Curative treatment for inoperable, locally advanced, stage III nonsmall cell lung cancer (LANSCLC) remains a challenge. The survival rate at 5 years is dismal, and the low local control rate is a challenge for modern radiotherapy. It has been demonstrated that improving local control has an impact on survival.1 Many factors have contributed to improving the local control rate, including an increase in the nominal dose,2 an increase in the biologically equivalent dose (BED),3 the use of technical innovation in radiation delivery,4 and the addition of concurrent chemotherapy.5

In this prospective study, we incorporated several of these approaches. The increased BED was conceived as an increase in the nominal dose while maintaining a fixed overall treatment time (OTT), a so-called dose-per-fraction escalation.6 Often in dose escalation trials, the OTT is prolonged with increasing dose steps, but it has become evident that there is an adverse effect on outcome with the prolongation of treatment.7 Finally, because of its known radiosensitizing effect8 and the need for a platinum-containing doublet as effective systemic treatment, we adopted the cisplatin/docetaxel combination.9, 10

To adequately achieve dose escalation in patients who, on average, had large, bulky disease, we wanted to validate and justify the use of a rotational intensity-modulated radiotherapy technique (IMRT), called helical tomotherapy (HT). Compared with IMRT, the HT optimization procedure and dose delivery is much more refined and can lead to dose distributions that are even more conformal while limiting the dose to the surrounding normal tissues (conformal avoidance).11 The downside of this technique could be the low-dose spread in healthy lung tissue, a subject that had not yet been examined in a clinical setting at the start of the study.

Because of the increase in BED and the possible influence of low-dose spread, the primary endpoint of the current study was monitoring of toxicity. Secondary endpoints were to evaluate efficacy parameters in terms of overall response rate and survival, to monitor quality of life (QOL), and to examine changes in tumor volume during therapy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Patient Eligibility

Candidates for inclusion in the current study were patients who had a cytologic or histologic diagnosis of a stage III, inoperable LANSCLC with a life expectancy of at least 12 weeks, a Karnofsky performance status (KPS) ≥80, and a maximum weight loss of 10% within the last 3 months (grading determined according to the American Joint Committee on Cancer 6th edition grading system). Initial workup consisted of bronchoscopy, pulmonary function tests (PFTs), computed tomography (CT) of the thorax, positron emission tomography (PET) using the radio-labeled glucose analogue F18-fluorodeoxyglucose (FDG-PET), magnetic resonance imaging (MRI) of the brain, and additional imaging studies as indicated. Patients were eligible to enter the study when they were deemed fit for a combined-modality approach after multidisciplinary review. Patients had to sign an informed consent before entering the study protocol. The treatment protocol was reviewed and approved by the competent authorities and the institutional ethics committee and was registered (National Clinical Trial no. NCT00379717 and European Union Drug Regulating Authorities Clinical Trial no. EUDRACT2006-003708-21).

Treatment Protocol

This study was designed to determine the maximum tolerated dose (MTD) of radiotherapy in a concurrent setting with fixed-dose chemotherapy plus docetaxel and cisplatin at a dose of 20 mg/m2 each administered weekly and starting on Day 1 of radiotherapy for 6 cycles. Radiotherapy was delivered in 30 daily fractions. The OTT was set between 40 days and 44 days. This upfront chemoradiation was followed by 2 cycles of consolidation chemotherapy with docetaxel 75 mg/m2 and cisplatin at 75 mg/m2 administered up to 4 weeks after the completion of radiation with a 3-week interval.

The radiotherapy fraction size was escalated when the cumulative acute grade 3 dose-limiting toxicity (DLT) incidence was <50% for at least 3 patients who had a minimum follow-up of 3 months after the start of radiotherapy. To allow for a full 3-month assessment of at least 3 patients per cohort, inclusion in that same dose-escalation cohort was continued as long as required with a minimum of 5 patients. Grade 5 toxicity would result in an immediate halt of the study and acceptance of the previous cohort's dose as the MTD.

Dose specifications are summarized in Table 1. A protocol amendment was issued in February 2008 that omitted the consolidation chemotherapy after an interim toxicity analysis and based on literature data indicating that there was no benefit from consolidation chemotherapy.12

Table 1. Dose Parameters per Dose Cohort (Total Dose, Dose per Fraction, and Biologically Equivalent Dose) and the Dose/Volume Constraints for Plan Acceptance
Dose Parameter, GyDose Cohort, Gy
IIIIIIIVV
  • TD indicates total dose; Gy, grays; FD, dose per fraction; BED, biologically equivalent dose; nMLD, normalized mean lung dose; PTV, planning target volume.

  • a

    Volume is expressed as the lung volume in cc (V) that received x Gy (Vx) of radiation.

  • b

    The nMLD is a recalculated value that takes into account the FD.

  • c

    Minor violation.

TD6063.667.270.874.4
FD2.002.122.242.362.48
BED64.869.975.180.385.7
OrganDose Constraint, GyVolume Constraint, %a
Minimum/maximumnMLDbV20V40V66
PTV95%/107% of TD 
 Lung<17 (20)c<30 (35)c
 Esophagus<50<30
 Heart—/66<50
 Spinal cord—/53

Radiotherapy Technique

Patients were referred for a planning CT and FDG-PET in the treatment position on a dedicated PET-CT scanner (GeminiTF64; Philips Healthcare, Best, the Netherlands). Delineation was performed of the macroscopic (gross) tumor volume (GTV); the clinical target volume and planning target volume (CTV/PTV) for involved lymph nodes and the primary tumor separately; and the lungs, esophagus, spinal cord, thyroid gland, kidneys, heart, liver, and stomach. The CTV for the lymph nodes consisted of the entire FDG-PET-involved lymph node region13, 14 with an isotropic 3-mm expansion for the PTV. The primary CTV was a 5-mm margin around the GTV in the lungs or airway without bone, vessel, or other mediastinal organs unless there was proven invasion by the tumor. The PTV for the primary tumor was the isotropic expansion of 5 mm or 8 mm around the CTV in case of upper/middle or lower lobe locations, respectively. Protocol dose constraints are listed in Table 1.

Treatment delivery was performed on the TomoTherapy HiArt II system (TomoTherapy Inc., Madison, Wis), which is a linear accelerator that combines 6-megavolt (MV) IMRT with megavoltage CT imaging (MVCT) before treatment.15, 16 The gantry rotates continuously while the patient is translated through the bore, resulting in a helical treatment. Instead of choosing a fixed-beam setup, tomotherapy patients are treated with 51 equispaced beam directions per gantry rotation, which allows a much greater degree of freedom in the modulation because of the significant increase in the number of beamlets.17, 18

The tumor region was scanned on a daily basis, and positioning was done using the integrated registration with the planning CT.19-21 Although a difference in resolution exists between kilovolt and MVCT images, the quality of MV imaging is sufficient for patient positioning.22 Positioning was done both on bony and soft tissue anatomy and incorporated respiratory motion, because the MVCT procedure can be considered a “slow” CT. Daily MVCT allows the clinician to take into account any changes in internal anatomy that affect positioning based on tumor response during treatment.

Toxicity Monitoring

Acute DLTs were defined as esophageal, pulmonary and, cardiac toxicities and were scored according to a modified Radiation Therapy Oncology Group (RTOG)-European Organization for Research and Treatment of Cancer (EORTC) acute toxicity scoring table. All other toxicities were graded according to version 3.0 of the National Cancer Institute Common Toxicity Criteria for Adverse Events. Toxicity was monitored at least once weekly by the treating medical and radiation oncologist in patients who received ambulatory treatment and daily when patients were hospitalized because of excessive toxicity. During follow-up, patients were seen every 3 months during the first 2 years and every 4 months to 6 months thereafter. For late toxicity, the RTOG late morbidity scoring for esophagus, heart, and lungs was used together with the Subjective, Objective, Management, and Analytic/Late Effects in Normal Tissues (SOMA-LENT) scoring system for the lungs and esophagus.23 PFTs were repeated at every visit. The impact of the treatment schedule on QOL was assessed, using standardized questionnaires (the Functional Assessment of Cancer Therapy-Lung and the EORTC QLQ C30) at the beginning and at the end of treatment.

Response Assessment

Tumor size and metabolism were assessed before treatment and 3 months after the start of chemoradiation (and at least 2 weeks after the last consolidation chemotherapy) using PET-CT. Response Evaluation Criteria in Solid Tumors were used to evaluate treatment response based on CT studies. For FDG-PET, the standardized uptake value (SUV) (SUV = [decay-corrected activity per mL tissue]/[injected activity]*[body mass]) was calculated. The SUV was acquired by manually positioning a 3-dimensional, ellipsoidal region of interest that covered the target. To minimize partial volume effect, the pixel with the maximum SUV value (SUVmax) within the volume of interest was identified. SUV values were normalized further to the circulating serum glucose level (SUVmax.glu = SUVmax × serum glucose [mg percentage]/100). In addition, a metabolic volume was calculated by adding all pixels with an SUV ≥2.5 within the region of interest. Patients were considered complete metabolic responders when the metabolic volume became zero.24 In further follow-up, a scheduled CT scan of the thorax was obtained at least every 3 months, and an FDG-PET study was obtained yearly.

Statistical Analysis

Analyses of variance and Student t tests were performed using Statview software (version 5.0.1; SAS Institute Inc., Cary, NC). P values were considered significant at <.05, in which case, the 95% confidence interval (95% CI) also was calculated. Kaplan-Meier analysis was used for actuarial analysis with CIs using the “Greenwood method,” and overall survival was calculated from initial diagnosis. Simple regression analysis was used to identify the correlation between dose-volumetric characteristics and the degree of late lung DLT.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Treatment Feasibility

Between October 2006 and August 2008, 34 patients were included in the current study. Their baseline characteristics are summarized in Table 2. All patients received the prescribed radiotherapy dose with a mean treatment time of 42 days; the only exception was 1 patient who died because of early progressive disease. The dose intensity of concurrent cisplatin and docetaxel was 94% for each. Dose reductions and/or the omission of concurrent chemotherapy were mainly because of esophageal toxicity (n = 4) or hematologic toxicity (n = 3). In the consolidation phase (n = 23), dose intensity in Dose Cohort (DC) I was 94% but dropped to 64% in DC II and to 59% in DC III. Consolidation chemotherapy could not be administered to 6 patients (2 patients died, and 4 patients had progressive disease) and was given only for 1 cycle in 2 patients because of recall esophageal toxicity. In 15 patients who received 2 cycles of consolidation chemotherapy, the dose intensity was 98% with minor reductions because of persistent esophageal toxicity or infection. The mean OTT for patients who received any consolidation chemotherapy was 86 days.

Table 2. Baseline Patient and Tumor Characteristics
CharacteristicNo. of Patients%
  • Gy indicates grays.

  • a

    Grading determined according to the American Joint Committee on Cancer 6th edition grading system.

Age, y  
 Mean66 
 Range45-75 
Sex  
 Men2574
 Women926
Cohort  
 I (60.0 Gy)515
 II (63.6 Gy)721
 III (67.2 Gy)1132
 IV (70.8 Gy)1029
 V (74.4 Gy)13
Type of carcinoma  
 Adenocarcinoma926
 Spinocellular carcinoma1853
 Large cell carcinoma412
 Unspecified39
Staginga  
 Tumor classification  
  T139
  T21235
  T300
  T41956
 Lymph node status  
  N0618
  N113
  N21853
  N3926
 Disease stage  
  IIIA1029
  IIIB2471
No. of involved lymph nodes  
 0618
 1823
 2721
 326
 4618
 ≥5514

Acute Toxicity

Episodes of acute pulmonary and esophageal toxicity are summarized in Table 3. The cumulative incidence of grade ≥3 DLT was 27% and consisted mainly of esophageal toxicity (24%) and 1 patient who experienced acute lung toxicity (cough). The cumulative incidence of grade ≥3 esophageal toxicity was 36% (95% CI, 16-56%) and 0% for DCs I, II, and III versus DCs IV and V, respectively (P = .01). Peak incidence of grade ≥3 esophageal toxicity in DCs I, II, and III was 26% at Week 6 of concurrent chemoradiation. Serious, non-DLT adverse events (grade ≥3) that were observed included a 25% incidence of infection and a 14% hematologic complication rate (mainly lymphopenia and 1 patient with grade 4 pancytopenia). Grade 1 through 3 fatigue was observed in 46% of patients. The grade 1 and 2 gastrointestinal toxicity rate was 41% (nausea and constipation). In 14 patients, we recorded 1 or more episodes of hospitalization for an average of 16 days (range, 2-37 days) with a peak incidence at Week 6 of chemoradiation. The most frequent reasons for hospitalization were esophageal toxicity (41%) and infection (27%). The QOL assessment revealed a decrease in several functioning parameters with an increase in most symptom scores after treatment. The global health status diminished from a mean score of 59 at the start of treatment to 51 at the end of treatment (P < .001). By the end of concurrent chemoradiation, we observed an average weight loss of 4.1% (range, from −17% to +6%) and a drop in the median KPS from 100 to 80, whereas 24% of patients experienced a drop in KPS ≥30.

Table 3. Incidence (%) of Acute Toxicity During Chemoradiation and Consolidation Chemotherapy in Dose Cohorts I, II, and III (n = 23) and Dose Cohorts IV and V (n = 11)
Grade of ToxicityaIncidence, %
C1C2C3C4C5C6P1P2
  • C1-C6 indicate chemoradiation Courses 1-6; P1-P2, consolidation chemotherapy Courses 1 and 2; DC, dose cohort.

  • a

    Grading determined according to the Radiation Therapy Oncology Group-European Organisation for Research and Treatment of Cancer toxicity scoring system.

 Lung
DC I-III        
 07465614852394874
 12230303522302613
 24491726302613
 300000000
DC IV-V        
 0555555736473
 145363618279
 2099999
 3000009
 Esophagus
DC I-III        
 09691703930263961
 144263943352622
 20441717132213
 30004926134
DC IV-V        
 0100732791827
 102764824536
 200993636
 3000000

Late Toxicity

The incidence of late esophageal and pulmonary toxicity is summarized in Table 4. One patient developed esophageal stenosis, which necessitated a stent. Other episodes of late gastrointestinal toxicity consisted mainly of persistent weight loss, which occurred in 80% of episodes with a simultaneous diagnosis of progressive disease and subsequent second-line therapy. Cumulative late lung toxicity grade ≥3 was 21% and 29% according to the RTOG and SOMA-LENT scores, respectively. Grade ≥3 SOMA-LENT lung toxicity was scored as such because of dyspnea (4 patients), cough (1 patient), radiologic changes (6 patients), and decreased lung function (3 patients). These subjective and objective symptoms resulted in the management of grade ≥3 cough, dyspnea, and chest pain in 4 patients, 6 patients, and 1 patient, respectively.

Table 4. Incidence (%) of Late Toxicity Scored at 3 Months, at 6 Months, and at 1 Year of Follow-Up After the Start of Treatment
GradeIncidence, %
FU1FU2FU3
  1. FU1 indicates follow-up 3 months after starting treatment; FU2, follow-up 6 months after starting treatment; FU3, follow-up 1 year after starting treatment; RTOG, Radiation Therapy Oncology Group; SOMA-LENT, Subjective, Objective, Management, and Analytic/Late Effects in Normal Tissues.

RTOG   
 Lung   
  0222415
  1472440
  2253230
  331210
  4045
  5340
 Esophagus   
  0787680
  1191615
  2380
  3005
SOMA-LENT scale   
 Lung   
  0340
  1342840
  2504035
  362020
  4685
 Esophagus   
  0414835
  1311635
  2223220
  3345
  4305

The mean changes in PFTs were +1% (standard deviation [SD], 22%) and −14% (SD, 23%) for 1-second forced expiratory volume (FEV1) and carbon monoxide diffusion capacity (DLCO), respectively. In 41% of patients, a grade 2 decline in PFT was registered during follow-up. The incidence of grade ≥3 RTOG late lung toxicity in DCs I, II, and III was 14% (95% CI, 0%-28%) versus 44% (95% CI, 7%-82%) in DC IV (P = .06). Two patients in DC IV died of radiopneumonitis at 4 months and 5 months after the start of radiotherapy, respectively; in those patients, the relative lung volumes (V) that received 20 grays (Gy) (V20) were 24% and 23%, and the a normalized mean lung dose (nMLD) was 13.6 Gy and 8.3 Gy, respectively. The low-dose distribution (<20 Gy) for these 2 patients is illustrated in Figure 1 compared with the entire study population. No medication that had a known possible interaction with radiation was identified. The respective PFTs for both patients before treatment were 88% and 87% for FEV1 and 77% and 84% for DLCO.

thumbnail image

Figure 1. Low dose distribution (<20 grays [Gy]) in the lungs is illustrated by solid lines for patients who had grade 5 late lung toxicity and by dashed lines for all other patients. The dotted line indicates the average distribution.

Download figure to PowerPoint

The first patient died before PFTs were repeated, and the other patient had decreases of 18% and 46% in FEV1 and DLCO, respectively. Figure 2 illustrates the dose distribution of the latter patient with the PET-CT at the time of active radiopneumonitis.

thumbnail image

Figure 2. Dose distribution on (A) the planning computed tomography (CT) scan (blue line, 20 grays [Gy]; green line, 30 Gy; red line, 50 Gy; yellow line, 95% of the prescribed target dose) from a patient who died of a radiopneumonitis observed on (B) the CT scan 3 months after treatment with an increased metabolism (C) in the high-dose region on the corresponding F18-fluorodeoxyglucose-positron emission tomography image.

Download figure to PowerPoint

Response Evaluation

With a median follow-up at the time of analysis of 17 month in 17 surviving patients, we calculated a median survival of 17.9 months (95% CI, 12 months to not reached). Actuarial survival is illustrated in Figure 3. Response evaluation is summarized in Table 5. One patient died before any re-evaluation could be performed, and 2 additional patients died without control PET-CT images but with evidence of brain metastases on MRIs. Therefore, overall and local treatment responses were assessed in 33 patients and 31 patients, respectively. All patients who had progressive disease at 3 months failed in the brain (3 patients) or bone (3 patients).

thumbnail image

Figure 3. This graph illustrates a Kaplan-Meier of overall survival plot with the 95% confidence interval (in grays).

Download figure to PowerPoint

Table 5. Treatment Response Evaluation 3 Months After the Start of Treatment
Treatment Response: CT ScanNo. of Patients (%)
  1. CT indicates computed tomography; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; FDG-PET, F18 fluorodeoxyglucose-positron emission tomography; SD, standard deviation; SUVmax.ghu, maximum standardized uptake value further normalized to the circulating serum glucose level; CMR, complete metabolic response.

Overall response, n = 33 
 CR0 (0)
 PR17 (52)
 SD10 (30)
 PD6 (18)
Target lesion/s, n = 31 
 CR0 (0)
 PR19 (61)
 SD12 (39)
 PD0 (0)
Treatment Response: FDG-PET (n = 31)Mean ± SD Decrease, %
SUVmax.glu54 ± 37
Metabolic volume, cc78 ± 45
CMR, no. (%)17 (55)
Non-CMR, no. (%)14 (45)

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

To our knowledge, the current study is the first report on the use of HT and concurrent chemotherapy for LANSCLC. The treatment approach was feasible and had an acceptable dose intensity of radiation and chemotherapy in the concurrent phase. Radiotherapy could be given within the restricted delivery time in all patients. All radiation plans met the given dose constraints while maintaining sufficient PTV coverage even in this unbalanced patient population, in which the majority had stage IIIB disease. This suggested the usefulness of HT as a widely applicable technique for dose delivery in LANSCLC, even when doses were extended above the benchmark of 60 Gy.1 In previous hypofractionated dose-escalation trials, escalation was performed using 3-dimensional conformal radiotherapy (CRT).25-27 The use of CRT can be insufficient for large and/or centrally located lesions or for patients who have widespread lymph node involvement and can lead to increased toxicity rates and the inability to reach an appropriate dose.28-30 Liu et al demonstrated that IMRT could reduce the irradiated volumes of normal lung tissue and other critical structures significantly while maintaining an adequate dose to the target volume.31 When the complexity of target volumes increases, the difference between CRT and IMRT becomes even more significant in favor of IMRT. Therefore, the current results are in line with previous retrospective reports on static-beam IMRT in chemoradiation and dose-escalated conformal chemoradiation.32, 33 Compared with static IMRT, plan optimization possibilities with HT are more flexible and slightly better because of its rotational nature, resulting in the kind of dose delivery illustrated in Figure 2.11 The dose to the nearby spinal cord could be limited to 50 Gy while expelling the 20-Gy isodose from the contralateral lung and maintaining the adequate coverage (>95% of prescribed dose) of the target. However, this study was not comparative, so we cannot exclude the possibility that other IMRT techniques may achieve comparable results as long as the same dose constraints can be met.

An issue in the delivery of consolidation chemotherapy was encountered. Although part of it was because of progressive disease, omissions, reductions, and postponements of consolidation chemotherapy reduced overall dose intensity and prolonged OTT. An intercurrent publication indicated no survival benefit but increased toxicity for consolidation chemotherapy.12 In light of this finding, a protocol amendment was issued during the conduct of this study to allow further dose escalation without consolidation chemotherapy.

In their most recent meta-analysis, in which concurrent and sequential chemotherapy were compared, Auperin et al emphasized the 5.7-fold increase in the incidence of esophagitis to 18%34 also reported in published, individual phase 3 studies with statistically significant increases in the rate of grade ≥3 esophagitis from 4% to 18%35 and from 3% to 32%.36 We concluded that the acute toxicity rate in the current dose-escalation trial of 24% and 3% for esophagus and lung, respectively was within the expected range and, thus, was acceptable. Encouraging for the use of HT was the observation of a remarkable reduction in grade ≥3 esophagitis for the higher DCs, although no anatomic difference with respect to proximity between the esophagus and the PTV could be observed. We assumed that, because of the higher nominal dose in these higher DCs, the inverse planning system avoided the region of overlap between the esophagus and the PTV. Whether this reduced circumferential irradiation resulted in the lower toxicity rate is being investigated in a phase 2 study that incorporates more stringent dose constraints regarding the esophagus.

The study was halted in September 2008 because of 2 toxic deaths that were caused by late lung toxicity. In both patients, the pathology reports confirmed massive radiation-induced inflammation and fibrosis. The overall RTOG grade ≥3 late lung toxicity rate was 21%. This cumulative incidence of severe late lung toxicity seemed higher than the 9% to 15.6% that was reported in 3 other radiation dose-escalation trials. Only 1 patient with grade 5 toxicity was reported in those 3 studies combined.26, 27, 37 However, those trials reported on patients with stage I, II, and III NSCLC; only 16% received induction chemotherapy, and no concurrent chemotherapy was allowed. However, the reported RTOG grade ≥3 late lung toxicity rate of 14% in DCs I, II, and III appeared to be acceptable.

An analysis of known dose-volume and dose-distribution parameters (V20 and nMLD), as identified in these dose-escalation studies and in other reports on the prediction of late lung toxicity, did not reveal why these 2 patients developed lethal radiopneumonitis.38, 39 At the start of this study, the nMLD still was considered valid as a planning constraint because it was proposed and used in a synchronous dose-escalation study using HT in patients who had inoperable stage I, II, and III NSCLC.6, 40 There may be a concern that the late lung toxicity in the current study was caused by an increase in the lung volume that received low-dose irradiation (dose littering), which is more common in complex irradiation techniques, such as HT.41 However the low-dose region in the 2 patients who had grade 5 toxicity could not be singled out compared with all other study patients (Fig. 1). The relative lung volumes that received 5 Gy and 10 Gy (V5/V10) in the current series (Table 6) were comparable to the values reported in a clinical study using static-beam IMRT.32 Preliminary correlation analyses of dose volumetric parameters and the occurrence of overall and RTOG grade ≥3 late lung toxicity were performed. Even in this small series, those analyses revealed the larger impact of high-dose regions and primarily the tumor volume compared with low-dose spread (Table 6). Although further analysis in a larger population certainly is warranted, our results corroborate those of Willner et al, who reported that the reduction in the high-dose region was more important than the often counterbalanced increase in the low-dose region.42 Gopal et al demonstrated that local functional loss was nonexistent in lung subvolumes that received <10 Gy.43 Compared with dose-escalated concurrent chemoradiation, the overall RTOG grade ≥3 late lung toxicity was equal to the 25% reported using CRT.44 The reported 14% in DCs I, II, and III was in line with a retrospective analysis of IMRT for concurrent chemoradiation that even demonstrated an advantage over CRT.32 Therefore, we decided that the MTD should be set at 2.24 Gy per fraction.

Table 6. Tumor Volume and Planning Details (Lung Subvolumes Receiving x Grays) and the Normalized Mean Lung Dose
VariableMedian (Range)Pa
LLTGrade ≥3 LLT
  • LLT indicates late lung toxicity; nMLD, normalized mean lung dose; Gy, grays.

  • a

    P values reflect the strength of correlation with the occurrence of overall and grade ≥3 Radiation Therapy Oncology Group LLT.

  • b

    Volume is expressed as the lung volume in cc (V) that received x Gy (Vx) of radiation.

Volume, ccb250 (23-1099).03.004
 V563 (29-99).79.63
 V1049 (16-91).49.31
 V2023 (11-35).16.33
 V3015 (6-27).07.10
 V4010 (4-22).06.08
 V507 (2-19).03.03
 nMLD, Gy13 (6-20).55.43

Although it was not a primary endpoint in the current study, response analysis revealed a complete metabolic response in 55% of patients. This appeared to be encouraging enough to continue the amended study as a full phase 2 study using a Bryant and Day design.45 Unacceptable cumulative esophageal and pulmonary ≥ grade 3 toxicity (T) was set at 30%, and an unacceptable local metabolic response rate (R) was set at ≤50% (the probability for accepting poor response [άR] or rejecting good response [β] was set at 15%; the probability of acceptance of a toxic treatment [άT] was kept at 5%).

In this phase 1/2 study, we assessed the possibility of radiation dose escalation with HT and concurrent cisplatin/docetaxel. The MTD for concurrent chemoradiation was set at 67.2 Gy in 30 fractions. This treatment schedule is feasible and has acceptable toxicity with a promising response rate. To confirm the treatment efficacy and toxicity at the MTD, this schedule currently us being investigated in a phase 2 study.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Supported in part by a grant of the “Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO),” by grants G.0486.06 and G.0412.08, and by a grant from “Wetenschappelijk fonds Willy Gepts.”

A restricted grant for data management was provided by Sanofi-Aventis.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES
  • 1
    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.
  • 2
    Kong FM, Ten Haken RK, Schipper MJ, et al. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys. 2005; 63: 324-333.
  • 3
    Saunders M, Dische S, Barrett A, Harvey A, Gibson D, Parmar M. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet. 1997; 350: 161-165.
  • 4
    Fang LC, Komaki R, Allen P, Guerrero T, Mohan R, Cox JD. Comparison of outcomes for patients with medically inoperable stage I non-small-cell lung cancer treated with 2-dimensional versus 3-dimensional radiotherapy. Int J Radiat Oncol Biol Phys. 2006; 66: 108-116.
  • 5
    Auperin A, Le Pechoux C, Pignon JP, et al. Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol. 2006; 17: 473-483.
  • 6
    Mehta M, Scrimger R, Mackie R, Paliwal B, Chappell R, Fowler J. A new approach to dose escalation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2001; 49: 23-33.
  • 7
    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.
  • 8
    Mason KA, Kishi K, Hunter N, et al. Effect of docetaxel on the therapeutic ratio of fractionated radiotherapy in vivo. Clin Cancer Res. 1999; 5: 4191-4198.
  • 9
    [No authors listed] Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ. 1995; 311: 899-909.
  • 10
    D'Addario G, Pintilie M, Leighl NB, Feld R, Cerny T, Shepherd FA. Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol. 2005; 23: 2926-2936.
  • 11
    Kron T, Grigorov G, Yu E, et al. Planning evaluation of radiotherapy for complex lung cancer cases using helical tomotherapy. Phys Med Biol. 2004; 49: 3675-3690.
  • 12
    Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol. 2008; 26: 5755-5760.
  • 13
    De Ruysscher D, Wanders S, van Haren E, et al. Selective mediastinal node irradiation based on FDG-PET scan data in patients with non-small-cell lung cancer: a prospective clinical study. Int J Radiat Oncol Biol Phys. 2005; 62: 988-994.
  • 14
    Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest. 1997; 111: 1718-1723.
  • 15
    Mackie TR, Holmes T, Swerdloff S, et al. Tomotherapy: a new concept for the delivery of dynamic conformal radiotherapy. Med Phys. 1993; 20: 1709-1719.
  • 16
    Mackie TR. History of tomotherapy. Phys Med Biol. 2006; 51: R427-R453.
  • 17
    Scrimger RA, Tome WA, Olivera GH, Reckwerdt PJ, Mehta MP, Fowler JF. Reduction in radiation dose to lung and other normal tissues using helical tomotherapy to treat lung cancer, in comparison to conventional field arrangements. Am J Clin Oncol. 2003; 26: 70-78.
  • 18
    Beavis AW. Is tomotherapy the future of IMRT? Br J Radiol. 2004; 77: 285-295.
  • 19
    Boswell S, Tome W, Jeraj R, Jaradat H, Mackie TR. Automatic registration of megavoltage to kilovoltage CT images in helical tomotherapy: an evaluation of the setup verification process for the special case of a rigid head phantom. Med Phys. 2006; 33: 4395-4404.
  • 20
    Langen KM, Zhang Y, Andrews RD, et al. Initial experience with megavoltage (MV) CT guidance for daily prostate alignments. Int J Radiat Oncol Biol Phys. 2005; 62: 1517-1524.
  • 21
    Woodford C, Yartsev S, Van Dyk J. Optimization of megavoltage CT scan registration settings for thoracic cases on helical tomotherapy. Phys Med Biol. 2007; 52: N345-N354.
  • 22
    Ruchala KJ, Olivera GH, Schloesser EA, Mackie TR. Megavoltage CT on a tomotherapy system. Phys Med Biol. 1999; 44: 2597-2621.
  • 23
    [No authors listed] LENT SOMA tables. Radiother Oncol. 1995; 35: 17-60.
  • 24
    Decoster L, Schallier D, Everaert H, et al. Complete metabolic tumour response, assessed by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET), after induction chemotherapy predicts a favourable outcome in patients with locally advanced non-small cell lung cancer (NSCLC). Lung Cancer. 2008; 62: 55-61.
  • 25
    Belderbos JS, Heemsbergen WD, De JK, Baas P, Lebesque JV. Final results of a phase I/II dose escalation trial in non-small-cell lung cancer using 3-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2006; 66: 126-134.
  • 26
    Kong FM, Hayman JA, Griffith KA, et al. Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys. 2006; 65: 1075-1086.
  • 27
    Bradley J, Graham MV, Winter K, et al. Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using 3-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys. 2005; 61: 318-328.
  • 28
    Sura S, Gupta V, Yorke E, Jackson A, Amols H, Rosenzweig KE. Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol. 2008; 87: 17-23.
  • 29
    Murshed H, Liu HH, Liao Z, et al. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004; 58: 1258-1267.
  • 30
    Cattaneo GM, Dell'oca I, Broggi S, et al. Treatment planning comparison between conformal radiotherapy and helical tomotherapy in the case of locally advanced-stage NSCLC. Radiother Oncol. 2008; 88: 310-318.
  • 31
    Liu HH, Wang X, Dong L, et al. Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004; 58: 1268-1279.
  • 32
    Yom SS, Liao Z, Liu HH, et al. Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2007; 68: 94-102.
  • 33
    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.
  • 34
    Auperin A, Rolland E, Curran WJ, et al. Concomitant radio-chemotherapy (RT-CT) versus sequential RT-CT in locally advanced non-small cell lung cancer (NSCLC): a meta-analysis using individual patient data (IPD) from randomized clinical trials (RCTs). J Thorac Oncol. 2007; 2( 4 suppl): s310.
  • 35
    Zatloukal P, Petruzelka L, Zemanova M, et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer. 2004; 46: 87-98.
  • 36
    Fournel P, Robinet G, Thomas P, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Francais de Pneumo-Cancerologie NPC 95-01 Study. J Clin Oncol. 2005; 23: 5910-5917.
  • 37
    Rosenzweig KE, Fox JL, Yorke E, et al. Results of a phase I dose-escalation study using 3-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma. Cancer. 2005; 103: 2118-2127.
  • 38
    Graham MV, Purdy JA, Emami B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys. 1999; 45: 323-329.
  • 39
    Kwa SL, Lebesque JV, Theuws JC, et al. Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys. 1998; 42: 1-9.
  • 40
    Adkison JB, Khuntia D, Bentzen SM, et al. Dose escalated, hypofractionated radiotherapy using helical tomotherapy for inoperable non-small cell lung cancer: preliminary results of a risk-stratified phase I dose escalation study. Technol Cancer Res Treat. 2008; 7: 441-447.
  • 41
    Semenenko VA, Molthen RC, et al. Irradiation of varying volumes of rat lung to same mean lung dose: a little to a lot or a lot to a little? Int J Radiat Oncol Biol Phys. 2008; 71: 838-847.
  • 42
    Willner J, Jost A, Baier K, Flentje M. A little to a lot or a lot to a little? An analysis of pneumonitis risk from dose-volume histogram parameters of the lung in patients with lung cancer treated with 3-D conformal radiotherapy. Strahlenther Onkol. 2003; 179: 548-556.
  • 43
    Gopal R, Tucker SL, Komaki R, et al. The relationship between local dose and loss of function for irradiated lung. Int J Radiat Oncol Biol Phys. 2003; 56: 106-113.
  • 44
    Socinski MA, Blackstock AW, Bogart JA, et al. Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol. 2008; 26: 2457-2463.
  • 45
    Bryant J, Day R. Incorporating toxicity considerations into the design of two-stages phase II clinical trials. Biometrics. 1995; 51: 1372-1383.