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Induction Chemotherapy and Continuous Hyperfractionated Accelerated Radiotherapy (CHART) for Patients With Locally Advanced Inoperable Non–Small-Cell Lung Cancer: The MRC INCH Randomized Trial
Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 3, pp. 712–718, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2010.06.053
CLINICAL INVESTIGATION
Lung
INDUCTION CHEMOTHERAPY AND CONTINUOUS HYPERFRACTIONATED ACCELERATED RADIOTHERAPY (CHART) FOR PATIENTS WITH LOCALLY ADVANCED INOPERABLE NON–SMALL-CELL LUNG CANCER: THE MRC INCH RANDOMIZED TRIAL MATTHEW HATTON, F.R.C.R.,* MATTHEW NANKIVELL, M.SC.,y ETHAN LYN, M.B.B.CHIR.,z STEPHEN FALK, M.D.,x CHERYL PUGH, B.SC.,y NEAL NAVANI, M.D.,y RICHARD STEPHENS,y y AND MAHESH PARMAR, D.PHIL. From the *Weston Park Hospital, Sheffield, UK; yMRC Clinical Trials Unit, London, UK; zMount Vernon Hospital, London, UK; and x Bristol Oncology and Haematology Centre, Bristol, UK Purpose: Recent clinical trials and meta-analyses have shown that both CHART (continuous hyperfractionated accelerated radiation therapy) and induction chemotherapy offer a survival advantage over conventional radical radiotherapy for patients with inoperable non–small cell-lung cancer (NSCLC). This multicenter randomized controlled trial (INCH) was set up to assess the value of giving induction chemotherapy before CHART. Methods and Materials: Patients with histologically confirmed, inoperable, Stage I–III NSCLC were randomized to induction chemotherapy (ICT) (three cycles of cisplatin-based chemotherapy followed by CHART) or CHART alone. Results: Forty-six patients were randomized (23 in each treatment arm) from 9 UK centers. As a result of poor accrual, the trial was closed in December 2007. Twenty-eight patients were male, 28 had squamous cell histology, 34 were Stage IIIA or IIIB, and all baseline characteristics were well balanced between the two treatment arms. Seventeen (74%) of the 23 ICT patients completed the three cycles of chemotherapy. All 42 (22 CHART + 20 ICT) patients who received CHART completed the prescribed treatment. Median survival was 17 months in the CHART arm and 25 months in the ICT arm (hazard ratio of 0.60 [95% CI 0.31–1.16], p = 0.127). Grade 3 or 4 adverse events (mainly fatigue, dysphagia, breathlessness, and anorexia) were reported for 13 (57%) CHART and 13 (65%) ICT patients. Conclusions: This small randomized trial indicates that ICT followed by CHART is feasible and well tolerated. Despite closing early because of poor accrual, and so failing to show clear evidence of a survival benefit for the additional chemotherapy, the results suggest that CHART, and ICT before CHART, remain important options for the treatment of inoperable NSCLC and deserve further study. Ó 2011 Elsevier Inc. Non–small-cell lung cancer, Inoperable, Radiotherapy, CHART, Induction chemotherapy.
During a conventional (once a day, 5 days a week) course of radiotherapy, proliferation of the surviving cells may lead to repopulation of the tumor and local failure. Theoretically this may be combated by reducing the overall duration of the course and by delivering several fractions per day in an accelerated schedule that continues treatment over the weekend. This was the rationale behind the development of CHART in the 1980s in the United Kingdom, which delivered a total dose of 54 Gy in 36 fractions (three times per day) over 12 consecutive days including the weekend (4). A randomized trial of 563 patients compared CHART with conventional radical radiotherapy (60 Gy/30 f) given over
INTRODUCTION Patients with locally advanced or medically inoperable non–small-cell lung cancer (NSCLC) may be suitable for radical radiotherapy, but the 5-year survival rate after conventional radiotherapy (with a total dose of around 60 Gy given in 2 Gy daily fractions) is only 5–10% (1–3). Several clinical trials have looked at various options for improving patient outcomes. Two modifications that seemed to offer increased survival were continuous hyperfractionated accelerated radiation therapy (CHART), and the addition of chemotherapy to conventional radical radiotherapy.
tional educational meetings. R.S. has received honoraria from Pierre Fabre Oncology for giving talks. Received Feb 16, 2010, and in revised form June 14, 2010. Accepted for publication June 18, 2010.
Reprint requests to: Matthew Nankivell, MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK. Tel: 020 7670 4717; Fax: 020 7670 4818; E-mail: [email protected] Funded by Medical Research Council and Cancer Research UK. Pierre Fabre provided funds and support for the running of promo712
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6 weeks and suggested that CHART offered a 9% improvement in 2-year survival (5). The addition of chemotherapy prior to (or concurrently with) conventional radical radiotherapy, has been explored in meta-analyses that suggested that this offered a 4–7% improvement in 2-year survival (3, 6). The obvious question raised by these results was whether the survival improvements seen with CHART and chemotherapy separately were additive. Initially a dose escalation study (7) was set up for patients to receive two cycles of carboplatin and vinorelbine before CHART. However, the study was closed when 2 of the first 3 patients developed respiratory failure from widespread pulmonary fibrosis and died, although in both of the patients who died at postmortem there was evidence of preexisting pulmonary fibrosis in addition to more acute changes related to treatment. Nevertheless, the concern was that CHART was given too soon after chemotherapy and there should be a gap of at least 4 weeks between treatments. This was confirmed by Bell et al. (8), who treated 29 patients with platinum/vinorelbine chemotherapy followed by CHART with a median time from the first day of the last chemotherapy cycle to the start of radiotherapy of 41 days (range, 18–64). The only patient who had a treatment-related death (bronchopneumonia 13 days after completing radiotherapy) started CHART 24 days after chemotherapy. A multicenter randomized controlled trial (INCH) was therefore set up to assess the value of adding chemotherapy to CHART, randomizing patients to CHART alone or induction chemotherapy followed by CHART.
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Data were collected at each cycle of chemotherapy and immediately postradiotherapy. Patients were assessed for response on completion of chemotherapy and 6–8 weeks after completion of CHART. Follow-up assessments were scheduled to take place every month posttreatment until 6 months after randomization, then every 3 months up to 2 years, every 6 months to 3 years, and annually thereafter, with patients being followed until death. At each assessment, clinicians provided information on performance status, disease progression (assessed by chest x-ray at each visit, with subsequent computed tomography (CT) confirmation), additional anticancer treatment, adverse events, toxicity, and nights in hospital. Patients were asked to complete quality of life forms before randomization and at each subsequent assessment using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire (9), LC14 lung cancer–specific module (10), and the EQ5D questionnaire (11).
Radiotherapy quality assurance Radiotherapy quality assurance (QA) was a requirement for all participating centers, and was administered by a central QA group. Before randomization, centers had to complete a questionnaire covering immobilization and planning imaging, planning parameters, commissioning the treatment planning system, and treatment delivery facilities. Each clinician had to submit a patient plan (of a previous patient who would have been eligible for the INCH trial) and accreditation was only granted after the QA group had approved the plan. Subsequently each local radiotherapy team had to complete a delineation exercise based on three example patient cases within 3 months of randomizing their first patient, and each center was visited in order to perform dosimetric and portal imaging QA using phantoms. Detailed results of the quality assurance program will be presented in a separate publication.
Statistical analysis METHODS AND MATERIALS Patients and study design Patients had to have histologically or cytologically confirmed, inoperable, Stage I-III NSCLC. They had to be previously untreated with chemotherapy or radiotherapy, have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, have a life expectancy of at least 3 months, be free of any malignancy likely to interfere with protocol treatment or comparisons, have adequate respiratory function (forced expiratory volume in 1 second or transfer factor of greater than 50% predicted), and be considered suitable for both chemotherapy and CHART. Before randomization, patients had an up to date clinical assessment of eligibility, which included repeat pulmonary function tests, biochemistry tests, and bone/brain scans if required. Patient characteristics were collected, and then participating centers telephoned the MRC Clinical Trials Unit, who randomly allocated patients to one of the treatment arms using a minimization method, with stratification for TNM status, ECOG performance status, histology, smoking status, and whether the patient had had a positron emission tomography scan. Patients randomized to the induction chemotherapy (ICT) arm received three three-weekly cycles of cisplatin (80 mg/m2 on day 1) and vinorelbine (25 mg/m2 on days 1 and 8). CHART (54 Gy given over 12 consecutive days, with three 1.5 Gy fractions being given each day) was started after a 4–6 week gap from the start of the last chemotherapy cycle. Patients in the CHART arm received the same radiotherapy, starting as soon as possible after randomization.
The primary outcome measure was overall survival. Secondary outcome measures were progression-free survival, toxicity, response, and quality of life. The trial was designed to detect a 10% absolute improvement in 3-year survival, from 10% with CHART alone to 20% with induction chemotherapy and CHART. To obtain 5% significance and 95% power, 500 patients needed to be accrued and 410 events seen. Data were analyzed on an intention-to-treat basis. Overall survival was defined from the date of randomization until the date of death from any cause, with surviving patients censored at the date of their last assessment.
Trial governance The trial was approved by the Northern and Yorkshire Medical Research Ethics Council, and all patients provided written informed consent. An independent data monitoring committee was set up to review interim data, with a planned safety analysis after 80 patients had been randomized. The overall conduct of the trial was overseen by an independent trial steering committee.
RESULTS Between August 2005 and September 2007, 46 patients were enrolled (23 in each treatment arm) from 9 UK centers. As a result of poor accrual, the trial was closed in December 2007. Because of the early termination of the trial, there were too few patients and events to conclusively answer all the
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Table 1. Baseline characteristics CHART alone Total patients Median age (years [range]) Males Smoking history Never smoked Smoked previously Current smoker Histology Squamous Adenocarcinoma Large cell Unclassified Stage IA IB IIA IIB IIIA IIIB Missing ECOG performance status 0 1 Received PET scan Yes No
23 65 [43–75]
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Table 2. Grade 3/4 symptoms at baseline Induction CT + CHART 23 60 [41–77]
CHART alone
Induction CT + CHART
23 8 (35%) 3 (13%) 4 (17%) 1 (4%) 1 (4%) 0 (0%) 1 (4%) (hypertension)
23 7 (30%) 2 (9%) 5 (22%) 0 (0%) 0 (0%) 1 (4%) 2 (9%) (osteoarthritis, shoulder pain)
12 (52%)
16 (70%)
0 (0%) 18 (78%) 5 (22%)
1 (4%) 15 (65%) 7 (30%)
Patients with data Any Grade 3/4 symptom Cough Breathlessness Chest pain Anorexia Fatigue Other
13 (57%) 3 (13%) 2 (9%) 5 (22%)
15 (65%) 4 (17%) 2 (9%) 2 (9%)
Abbreviations: CHART = continuous hyperfractionated accelerated radiation therapy; CT = chemotherapy.
0 (0%) 0 (0%) 1 (5%) 3 (14%) 7 (33%) 10 (48%) 2
1 (5%) 0 (0%) 1 (5%) 3 (14%) 11 (50%) 6 (27%) 1
13 (57%) 10 (43%)
13 (57%) 10 (43%)
17 (74%) 6 (26%)
18 (78%) 5 (22%)
Abbreviations: CHART = continuous hyperfractionated accelerated radiation therapy; CT = chemotherapy; ECOG = eastern cooperative oncology group; PET = positron emission tomography.
hypotheses, and all analyses are underpowered. Therefore, the results presented here must be seen as hypothesis generating. Baseline characteristics Of the 46 patients, 28 (61%) were male, the median age was 64 years, 12 (26%) were current smokers, 28 (61%) had squamous cell histology, 34 (79%) were Stage IIIA or IIIB, and 26 (57%) were ECOG performance status 0. Baseline characteristics (Table 1) were well balanced between the treatment arms. The 9 patients who were Stage I or II were deemed to be inoperable based on a combination of clinical factors, as assessed by a lung cancer multi-discipinary team (MDT), and patient preference. Approximately one third of patients (15 [33%]) had Common Terminology Criteria for Adverse Events (CTCAE) (12) Grade 3 or 4 symptoms at presentation. The most common symptoms were breathlessness and cough, observed respectively in 9 (20%) and 5 (11%) patients. Baseline symptoms are summarized in Table 2. At baseline, 37 (80%) patients completed quality of life questionnaires. Levels of baseline quality of life seemed similar in the two arms. Most patients reported some coughing, although very few reported coughing up mucus or blood, or having any nausea or vomiting. Approximately one third of patients reported having moderate or severe worry, tension, or trouble sleeping; one quarter indicated a moderate or severe level of tiredness and problems experienced with physical activity.
Chemotherapy Of the 23 patients randomized to receive ICT, 17 (74%) received all three cycles, 3 (13%) received two cycles, and 3 (13%) received one cycle. Of the 6 patients who failed to complete three cycles of chemotherapy, 4 terminated treatment early because of excessive toxicity, 1 patient died after receiving one cycle, and 1 patient experienced disease progression after cycle two. Of the 17 patients who received three cycles, 11 received the full dose of each drug at each cycle, 4 received a full dose of cisplatin but omitted the day 8 dose of vinorelbine, and 2 received a reduced dose of cisplatin in their third cycle. The median time from randomization to the start of the first cycle was 14 days (range, 4–25). Chemotherapy toxicities were as expected with one half (11 patients) reporting Grade 3 or 4 toxicity during chemotherapy. Four patients had a drug dose reduced or a drug omitted because of toxicity, and 8 patients had a cycle delayed for toxicity. Radiotherapy Of the 23 ICT patients, 20 went on to receive CHART. The reasons for not being given radiotherapy were disease progression (1 patient), high toxicity coupled with patient request (1 patient), and 1 patient dying before completing chemotherapy. Twenty-two of the patients randomized to the CHART alone arm received radiotherapy, the remaining patient having disease progression. All 42 patients who received radiotherapy completed the full course of 54 Gy in 36 fractions. The median time from randomization to the start of radiotherapy was 18 days (range, 6–49) in the CHART arm, and 91 days (range, 56–174) in the ICT arm, with the median time from the first day of the last cycle of chemotherapy to the first day of radiotherapy being 33 days (range, 20–91). Response Response was assessed after radiotherapy in the CHART alone arm, post-chemotherapy in the ICT arm, and 6 months post-randomization in all patients. Only 13 of the 23 ICT patients had an assessment after chemotherapy, and of these 7 (54%) patients had a partial response, 4 (31%) stable disease, and 2 (15%) progressive
CHART in inoperable NSCLC d M. HATTON et al.
disease. The main reason for not having an assessment of response was administrative errors (8 of the 10 patients with no assessment), with a combination of CT scans not being booked, scans not being performed prior to the start of radiotherapy, and patients missing appointments. Additionally, 1 patient died before the end of chemotherapy, and 1 refused to undergo a CT scan. Patients in the ICT arm were not reassessed for response immediately after radiotherapy. In the CHART arm, response was assessed after radiotherapy, and 10 (48%) patients were reported as having a partial response, 10 (48%) stable disease, and 1 (5%) progressive disease. Response could not be assessed in the remaining 2 patients. Both groups were assessed again 6 months after randomization. Of the 37 patients assessed (18 CHART, 19 ICT), complete or partial response was seen in 11 and 13 patients (61 vs 68%), and stable disease in 6 and 5 (33 vs 26%) patients in the CHART and ICT arms, respectively, with progressive disease observed in 1 patient in each arm. Over the course of the trial, 32 patients (16 in each arm) were assessed as having progressive disease. The site of first progression was recorded as being local in 16 patients (7 CHART, 9 ICT), brain in 5 patients (2 CHART, 3 ICT), and other distant metastases in 11 patients (7 CHART, 4 ICT). Toxicity and serious adverse events During and after the protocol treatment, data were recorded on toxicity and adverse events for all but 3 patients (all on the ICT arm), using the Common Terminology Criteria for Adverse Events version 3.0 (12). Grade 3 or 4 adverse events (Table 3) were reported for 13 (57%) CHART and 13 (65%) ICT patients. Extra anticancer treatment Two of the patients (1 CHART, 1 ICT) who did not receive CHART received radical thoracic radiotherapy using a daily fractionation regimen and 3 (13%) CHART and 5 (22%) ICT patients received additional palliative radiotherapy, for brain or bone metastases. Six (26%) CHART patients subsequently received chemotherapy and 4 (17%) ICT patients had further chemotherapy on relapse (9, 11, 17, and 27 months from completing CHART). Survival At the time of analysis, 36 patients have died (21 CHART, 15 ICT). The overall median survival (Figure 1) was 24 months (17 vs 25 months for CHART and ICT, respectively), corresponding to a hazard ratio of 0.60 (95% CI 0.31–1.16, p = 0.127). The median survival for the 34 Stage III patients was 21 months. The median length of follow-up of the 10 surviving patients is 33 months (IQR 26–40 months). All but 3 of the deaths were disease related. Two patients’ deaths may have been related to treatment: in an ICT patient with a background of alcohol-related cirrhosis, chemotherapy may have triggered liver failure, and a patient in the CHART alone arm had progressive lung fibrosis. The remaining ICT patient died
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Table 3. Grade 3/4 toxicities
Patients with data Any Grade 3/4 symptom Cough Breathlessness Chest pain Dysphagia Anorexia Nausea Fatigue Paresthesiae Hematological toxicity Neurological toxicity Other toxicities
CHART alone
Induction CT + CHART
23 13 (57%) 1 (4%) 4 (17%) 0 (0%) 3 (13%) 4 (17%) 0 (0%) 3 (13%) 0 (0%) 1 (4%) 0 (0%) 5 (22%) (chest infection; esophagitis; back pain; spine pain; muscular pain)
20 13 (50%) 4 (20%) 7 (35%) 1 (5%) 3 (15%) 2 (10%) 1 (5%) 5 (25%) 1 (5%) 1 (5%) 2 (10%) 5 (25%) (odynophagia; back pain; pleural effusion; hip pain; chest pain and dysphasia)
Abbreviations: CHART = continuous hyperfractionated accelerated Radiation Therapy; CT = chemotherapy. Other toxicities and adverse events asked about but not experienced: vomiting, abdominal pain, constipation, alopecia, phlebitis, rash, hemoptysis, renal toxicity, hepatic toxicity.
from myocardial infarction 11 days after starting his first cycle of chemotherapy. Quality of life Unfortunately, insufficient numbers of patients completed quality of life questionnaires to make any analysis meaningful. DISCUSSION The theoretical biological benefits of CHART have been translated into improved patient survival. Between 1990 and 1995, a total of 563 patients with Stage I–III NSCLC were entered into a multicenter randomized controlled trial comparing CHART with conventional (60 Gy/30 f) radiotherapy (5). The 2-year survival rate was improved from 20% with conventional radiotherapy to 29% with CHART. In addition, there was no evidence of a difference in morbidity and quality of life (13). The success of this trial led to the incorporation of CHART into Department of Health guidelines for lung cancer and subsequently the National Institute of Clinical Excellence guidance published in 2005 (14). Although CHART has been used in routine clinical practice for a decade, there had been sparse information on its performance until recently. Ghosh et al. (15) reported on 19 elderly (>70 years) patients with Stage I NSCLC who were given CHART. The median survival of 49 months suggested that CHART was a reasonable treatment for those patients deemed unsuitable for surgery. Din et al. (16) reported a series of 583 patients and confirmed that the survival reported in the original CHART paper seemed to be reproducible in day-to-day clinical practice with a 2-year survival of 33.6% and median survival of 16.2 months.
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Fig. Kaplan-Meier plot showing overall survival for patients receiving Continuous Hyperfractionated Accelerated Radiation Therapy (CHART) alone, compared with those receiving induction chemotherapy followed by CHART, along with the hazard ratio and corresponding 95% confidence interval for the difference between the two groups.
However Din et al. (16) also documented a creeping practice of giving chemotherapy before CHART in almost a quarter of those treated in routine practice, probably as a result of extrapolating from trials that reported survival benefits for the addition of chemotherapy to conventional radiotherapy (3). This automatic addition of chemotherapy to CHART should be questioned, because Din et al. (16) reported a lower 2-year survival for those treated with chemotherapy and CHART compared with CHART alone. This confirms the importance of trials such as INCH to inform evidence-based practice. The current trial was designed to detect a 10% improvement in 3-year survival with the addition of induction chemotherapy to CHART, which required 500 patients. Only 46 patients were randomized in 2 years, and the limited number of patients makes interpretation of the data difficult. The median survival with CHART alone of 17 months was similar to that observed in previous studies. An improvement in median survival to 25 months in the ICT arm resulted in a hazard ratio of 0.6. However, this figure is unreliable, does not reach statistical significance, and cannot be used to fully address the survival concern raised by Din et al. (16). Reasons for the poor accrual into the current trial need exploring. Despite NICE guidelines, CHART has not been widely implemented, and is currently only available in 12 of the 54 UK radiotherapy centers. At the start of the trial, this number of centers was considered adequate to accrue the required number of patients. There were no competing trials, no significant design problems, the consensus was that the scientific case for the trial remained valid, and much had been done to promote the trial. There may be generic problems, as poor recruitment has been documented in the majority of recent radical radiotherapy trials in NSCLC (17–20), which may relate to a multitude of generic contributory factors, including increasing regulatory hurdles, and insufficient radiotherapy infrastructure from physics support for the QA program through to actual delivery of treatment. More specifically, CHART requires
radiotherapy for 12 consecutive days, which causes organizational issues in providing a weekend radiotherapy service, and a further consequence of this is that a course of CHART will only be offered every 4 weeks in most centers. This raises anxieties among clinicians that some patients will require a significant waiting period before treatment starts, with the possibility that the disease may progress in this interim (21). Another reason for the poor uptake of CHART and poor accrual to INCH may relate to improvements in conventional radiotherapy, especially the advent of conformal radiotherapy permitting increases in the total dose delivered. Kong et al. (22) demonstrated an association between higher total doses (up to 74–103 Gy) and improved survival using once per day, three-dimensional conformal radiotherapy. McGibney et al. (23) indicated that a combination of threedimensional conformal radiotherapy and omission of elective nodal irradiation, could allow escalation of an accelerated nonconventionally fractionated radiotherapy schedule, which would overcome the problem of accelerated tumor clonogen proliferation with dose-escalated conventional fractionation. Therefore dose escalation of the CHART schedule should be explored. An alternative to CHART is to develop accelerated, hyperfractionated radiotherapy schedules that avoid treatment over the weekend. The ECOG 2597 trial (17) gave two cycles of induction chemotherapy as standard and then randomized between hyperfractionated accelerated radiotherapy (57.6 Gy in 1.5 Gy three times daily for 2.5 weeks) and conventional radiotherapy (64 Gy in 32 daily fractions). The trial was closed early because of slow accrual, but results were encouraging and showed a 15% improvement in favor of hyperfractionated accelerated radiotherapy in 2- and 3-year survival, although this was not statistically significant. A trial comparing a similar European regimen, CHARTWEL (CHART WeekEnd Less 60 Gy in 40 fractions over 2.5 weeks using 1.5 Gy per fraction) to conventional
CHART in inoperable NSCLC d M. HATTON et al.
fractionation of 66 Gy in 33 fractions did complete its planned recruitment but has shown no evidence of a difference in survival (17). The addition of chemotherapy to conventional radical radiotherapy has advanced to the point where it is now accepted and recommended as the standard treatment for locally advanced and inoperable NSCLC, although it has never been shown to be feasible in combination with CHART. Trials of sequential chemoradiotherapy for Stage III NSCLC have show median survivals of approximately 14 months, and concurrent chemoradiotherapy regimens report median survivals of around 17 months (24). Hanna and colleagues (25) have reported an impressive median survival of 23.2 months for a concurrent cisplatin/etoposide and conventionally fractionated regimen. As a result concurrent chemoradiotherapy treatments are becoming accepted as a standard of treatment, despite reports of toxic death rates being up to 10% (26). The emergence of these data may have hindered recruitment to INCH because of reluctance to treat patients with radical radiotherapy without the addition of chemotherapy. Nevertheless CHART remains an important radiotherapy schedule, but moving forward from it poses major challenges, not the least in running large randomized trials. However, several strengths of the current trial must also be recognized: CHART was performed in a uniform and standardized manner in all nine contributing centers. Induction chemotherapy followed by CHART was feasible, well tolerated, and the median survival of 25 months suggests that the hypothesis that accelerated hyperfractionated radiotherapy has a role in the treatment of inoperable NSCLC deserves further study. Trial management group M. Hatton (chair), C. Barron, D Boyle, M. Cheung, J. Gardiner, N. Gower, N. Groom, A. Hughes, P. Jenkins, E. Lyn, F. Maclean, J. Millett, B. Moore, S. Morgan, M. Nankivell, C. Pugh, M. Sculpher, R. Stephens, A. Webster, J. Williams
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Trial steering committee H. Kitchener (chair), T. Maughan, M. Seymour Independent data monitoring committee C. Williams (chair), R. Rampling, J. Scholefield, R. Swindell MRC clinical trials unit staff A. Hodson, T. Hussain, S. Beall, K. Sanders, N. Tappenden, C. Courtney, C. Chung Participating centers 1. Bristol Haematology and Oncology Centre (S. Falk, P. Wilson, S. Cowley, S. Yarrow, K. Wright, H. Appleby, F. Hester, M. Simmonds, K. Jones, R. Peglar, R. Macefield, A. Webster) 2. Churchill Hospital, Oxford (T. Foord, T. Green, S. Lawrey, N. Stoner, J. Rowntree, J. Boutflower, N. Haynes) 3. Mount Vernon Hospital (E. Lyn, J. Dickson, J. Williams, N. Groom, B. Boughen, S. Cope, J. Graham, B. Delooze, A. Downs, U. Patel, R. Davies) 4. Nottingham City Hospital (S. Morgan, J. Worville, E. Stones, S. Fleet, C. Gooch, R. Chauhan, S. Elliott, K. Knowles) 5. Royal Gwent Hospital (A. Brewster, A. Prosser, A. Holton, D. Knight-Davies, V. Green, C. Heymann, S. Slade, L. Penketh, P. Webb, I. Bowman) 6. University Hospital, North Durham (R. McMenamin, J. Dent, D. Turnball, C. Barron, Z. Razvi, J. Eliot) 7. Velindre Hospital, Cardiff (F. Macbeth, B. Moore, B. Dillon, E. Mair-Bowden, L. Penketh, C. Heymann, B. Tranter, K. Jones, C. Vitolo, A. Kelly) 8. Weston Park Hospital Sheffield (M. Hatton, P. Fisher, B. Foran, J. Mohanamurali, R. Clarke, J. Gibbins, H. Wood, S.-A. Bell, E. Hodgkinson, M. Hutchinson, P. Joyce, K. Shaw, J. Bliss, N. Huxham, L. Borrill, M. Trigg, G. Brown, A. Leesley) 9. Yeovil District Hospital (S. Bulley, N. Beacham, K. Rennie)
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10. Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: A modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 1994;30A:635–642. 11. Kind P. The Euro QOL instrument: An index of health-related quality of life. In: Spilker B, editor. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed; 1996. P. 191–202. 12. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, version 3.0. http://ctep.cancer. gov. 2006. 13. Bailey AJ, Parmar MK, Stephens RJ. Patient-reported shortterm and long-term physical and psychologic symptoms: results of the continuous hyperfractionated accelerated [correction of accelerated] radiotherapy (CHART) randomized trial in nonsmall-cell lung cancer. CHART Steering Committee. J Clin Oncol 1998;16:3082–3093. 14. NICE guidelines for lung cancer. Availableonline at: http:// www.nice.org.uk/nicemedia/pdf/cg024, 2004. 15. Ghosh S, Sujendran V, Alexiou C, Beggs L, Beggs D. Long term results of surgery versus continuous hyperfractionated accelerated radiotherapy (CHART) in patients aged >70 years with stage 1 non-small cell lung cancer. Eur J Cardiothorac Surg 2003;24:1002–1007. 16. Din OS, Lester J, Cameron A, Ironside J, Gee A, Falk S, et al. Routine use of continuous, hyperfractionated, accelerated radiotherapy for non-small-cell lung cancer: A five-center experience. Int J Radiat Oncol Biol Phys 2008;72:716–722. 17. Belani CP, Wang W, Johnson DH, Wagner H, Schiller J, Veeder M, et al. Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597): Induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non-small-cell lung cancer. J Clin Oncol 2005;23: 3760–3767. 18. Baumann M, Herrmann T, Matthiessen W, Koch R, Strelocke K, Paul U. [CHARTWEL-Bronchus (ARO 97-1): A randomized multicenter trial to compare conventional fractionated radiotherapy with CHARTWEL radiotherapy in inoperable non-small-call bronchial carcinoma]. Strahlenther Onkol 1997; 173:663–667.
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19. Price A, Dixon B, Erridge SC, Mohammed N. GRiN: A trial and tribulation in respiratory radiotherapy research. Clin Oncol (R Coll Radiol) 2005;17:328–331. 20. McGuire J. Arandomized phase III trial of sequential chemotherapy followed by radical radiotherapy versus concurrent chemo-radiotherapy followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer and good performance status ISCRTN 13746987. http://www. controlled-trials.com/, 2009. 21. O’Rourke N, Edwards R. Lung cancer treatment waiting times and tumour growth. Clin Oncol (R Coll Radiol) 2000;12:141– 144. 22. Kong FM, Ten Haken RK, Schipper MJ, Sullivan MA, Chen M, Lopez C, 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. 23. McGibney C, Holmberg O, McClean B, Williams C, McCrea P, Sutton P, et al. Dose escalation of chart in non-small cell lung cancer: Is three-dimensional conformal radiation therapy really necessary? Int J Radiat Oncol Biol Phys 1999;45:339–350. 24. Vokes EE, Herndon JE, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 2007;25:1698– 1704. 25. Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, 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. 26. Fournel P, Robinet G, Thomas P, Souquet PJ, Lena H, Vergnenegre A, 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.
doi:10.1016/j.ijrobp.2010.06.053
CLINICAL INVESTIGATION
Lung
INDUCTION CHEMOTHERAPY AND CONTINUOUS HYPERFRACTIONATED ACCELERATED RADIOTHERAPY (CHART) FOR PATIENTS WITH LOCALLY ADVANCED INOPERABLE NON–SMALL-CELL LUNG CANCER: THE MRC INCH RANDOMIZED TRIAL MATTHEW HATTON, F.R.C.R.,* MATTHEW NANKIVELL, M.SC.,y ETHAN LYN, M.B.B.CHIR.,z STEPHEN FALK, M.D.,x CHERYL PUGH, B.SC.,y NEAL NAVANI, M.D.,y RICHARD STEPHENS,y y AND MAHESH PARMAR, D.PHIL. From the *Weston Park Hospital, Sheffield, UK; yMRC Clinical Trials Unit, London, UK; zMount Vernon Hospital, London, UK; and x Bristol Oncology and Haematology Centre, Bristol, UK Purpose: Recent clinical trials and meta-analyses have shown that both CHART (continuous hyperfractionated accelerated radiation therapy) and induction chemotherapy offer a survival advantage over conventional radical radiotherapy for patients with inoperable non–small cell-lung cancer (NSCLC). This multicenter randomized controlled trial (INCH) was set up to assess the value of giving induction chemotherapy before CHART. Methods and Materials: Patients with histologically confirmed, inoperable, Stage I–III NSCLC were randomized to induction chemotherapy (ICT) (three cycles of cisplatin-based chemotherapy followed by CHART) or CHART alone. Results: Forty-six patients were randomized (23 in each treatment arm) from 9 UK centers. As a result of poor accrual, the trial was closed in December 2007. Twenty-eight patients were male, 28 had squamous cell histology, 34 were Stage IIIA or IIIB, and all baseline characteristics were well balanced between the two treatment arms. Seventeen (74%) of the 23 ICT patients completed the three cycles of chemotherapy. All 42 (22 CHART + 20 ICT) patients who received CHART completed the prescribed treatment. Median survival was 17 months in the CHART arm and 25 months in the ICT arm (hazard ratio of 0.60 [95% CI 0.31–1.16], p = 0.127). Grade 3 or 4 adverse events (mainly fatigue, dysphagia, breathlessness, and anorexia) were reported for 13 (57%) CHART and 13 (65%) ICT patients. Conclusions: This small randomized trial indicates that ICT followed by CHART is feasible and well tolerated. Despite closing early because of poor accrual, and so failing to show clear evidence of a survival benefit for the additional chemotherapy, the results suggest that CHART, and ICT before CHART, remain important options for the treatment of inoperable NSCLC and deserve further study. Ó 2011 Elsevier Inc. Non–small-cell lung cancer, Inoperable, Radiotherapy, CHART, Induction chemotherapy.
During a conventional (once a day, 5 days a week) course of radiotherapy, proliferation of the surviving cells may lead to repopulation of the tumor and local failure. Theoretically this may be combated by reducing the overall duration of the course and by delivering several fractions per day in an accelerated schedule that continues treatment over the weekend. This was the rationale behind the development of CHART in the 1980s in the United Kingdom, which delivered a total dose of 54 Gy in 36 fractions (three times per day) over 12 consecutive days including the weekend (4). A randomized trial of 563 patients compared CHART with conventional radical radiotherapy (60 Gy/30 f) given over
INTRODUCTION Patients with locally advanced or medically inoperable non–small-cell lung cancer (NSCLC) may be suitable for radical radiotherapy, but the 5-year survival rate after conventional radiotherapy (with a total dose of around 60 Gy given in 2 Gy daily fractions) is only 5–10% (1–3). Several clinical trials have looked at various options for improving patient outcomes. Two modifications that seemed to offer increased survival were continuous hyperfractionated accelerated radiation therapy (CHART), and the addition of chemotherapy to conventional radical radiotherapy.
tional educational meetings. R.S. has received honoraria from Pierre Fabre Oncology for giving talks. Received Feb 16, 2010, and in revised form June 14, 2010. Accepted for publication June 18, 2010.
Reprint requests to: Matthew Nankivell, MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK. Tel: 020 7670 4717; Fax: 020 7670 4818; E-mail: [email protected] Funded by Medical Research Council and Cancer Research UK. Pierre Fabre provided funds and support for the running of promo712
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6 weeks and suggested that CHART offered a 9% improvement in 2-year survival (5). The addition of chemotherapy prior to (or concurrently with) conventional radical radiotherapy, has been explored in meta-analyses that suggested that this offered a 4–7% improvement in 2-year survival (3, 6). The obvious question raised by these results was whether the survival improvements seen with CHART and chemotherapy separately were additive. Initially a dose escalation study (7) was set up for patients to receive two cycles of carboplatin and vinorelbine before CHART. However, the study was closed when 2 of the first 3 patients developed respiratory failure from widespread pulmonary fibrosis and died, although in both of the patients who died at postmortem there was evidence of preexisting pulmonary fibrosis in addition to more acute changes related to treatment. Nevertheless, the concern was that CHART was given too soon after chemotherapy and there should be a gap of at least 4 weeks between treatments. This was confirmed by Bell et al. (8), who treated 29 patients with platinum/vinorelbine chemotherapy followed by CHART with a median time from the first day of the last chemotherapy cycle to the start of radiotherapy of 41 days (range, 18–64). The only patient who had a treatment-related death (bronchopneumonia 13 days after completing radiotherapy) started CHART 24 days after chemotherapy. A multicenter randomized controlled trial (INCH) was therefore set up to assess the value of adding chemotherapy to CHART, randomizing patients to CHART alone or induction chemotherapy followed by CHART.
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Data were collected at each cycle of chemotherapy and immediately postradiotherapy. Patients were assessed for response on completion of chemotherapy and 6–8 weeks after completion of CHART. Follow-up assessments were scheduled to take place every month posttreatment until 6 months after randomization, then every 3 months up to 2 years, every 6 months to 3 years, and annually thereafter, with patients being followed until death. At each assessment, clinicians provided information on performance status, disease progression (assessed by chest x-ray at each visit, with subsequent computed tomography (CT) confirmation), additional anticancer treatment, adverse events, toxicity, and nights in hospital. Patients were asked to complete quality of life forms before randomization and at each subsequent assessment using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire (9), LC14 lung cancer–specific module (10), and the EQ5D questionnaire (11).
Radiotherapy quality assurance Radiotherapy quality assurance (QA) was a requirement for all participating centers, and was administered by a central QA group. Before randomization, centers had to complete a questionnaire covering immobilization and planning imaging, planning parameters, commissioning the treatment planning system, and treatment delivery facilities. Each clinician had to submit a patient plan (of a previous patient who would have been eligible for the INCH trial) and accreditation was only granted after the QA group had approved the plan. Subsequently each local radiotherapy team had to complete a delineation exercise based on three example patient cases within 3 months of randomizing their first patient, and each center was visited in order to perform dosimetric and portal imaging QA using phantoms. Detailed results of the quality assurance program will be presented in a separate publication.
Statistical analysis METHODS AND MATERIALS Patients and study design Patients had to have histologically or cytologically confirmed, inoperable, Stage I-III NSCLC. They had to be previously untreated with chemotherapy or radiotherapy, have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, have a life expectancy of at least 3 months, be free of any malignancy likely to interfere with protocol treatment or comparisons, have adequate respiratory function (forced expiratory volume in 1 second or transfer factor of greater than 50% predicted), and be considered suitable for both chemotherapy and CHART. Before randomization, patients had an up to date clinical assessment of eligibility, which included repeat pulmonary function tests, biochemistry tests, and bone/brain scans if required. Patient characteristics were collected, and then participating centers telephoned the MRC Clinical Trials Unit, who randomly allocated patients to one of the treatment arms using a minimization method, with stratification for TNM status, ECOG performance status, histology, smoking status, and whether the patient had had a positron emission tomography scan. Patients randomized to the induction chemotherapy (ICT) arm received three three-weekly cycles of cisplatin (80 mg/m2 on day 1) and vinorelbine (25 mg/m2 on days 1 and 8). CHART (54 Gy given over 12 consecutive days, with three 1.5 Gy fractions being given each day) was started after a 4–6 week gap from the start of the last chemotherapy cycle. Patients in the CHART arm received the same radiotherapy, starting as soon as possible after randomization.
The primary outcome measure was overall survival. Secondary outcome measures were progression-free survival, toxicity, response, and quality of life. The trial was designed to detect a 10% absolute improvement in 3-year survival, from 10% with CHART alone to 20% with induction chemotherapy and CHART. To obtain 5% significance and 95% power, 500 patients needed to be accrued and 410 events seen. Data were analyzed on an intention-to-treat basis. Overall survival was defined from the date of randomization until the date of death from any cause, with surviving patients censored at the date of their last assessment.
Trial governance The trial was approved by the Northern and Yorkshire Medical Research Ethics Council, and all patients provided written informed consent. An independent data monitoring committee was set up to review interim data, with a planned safety analysis after 80 patients had been randomized. The overall conduct of the trial was overseen by an independent trial steering committee.
RESULTS Between August 2005 and September 2007, 46 patients were enrolled (23 in each treatment arm) from 9 UK centers. As a result of poor accrual, the trial was closed in December 2007. Because of the early termination of the trial, there were too few patients and events to conclusively answer all the
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Table 1. Baseline characteristics CHART alone Total patients Median age (years [range]) Males Smoking history Never smoked Smoked previously Current smoker Histology Squamous Adenocarcinoma Large cell Unclassified Stage IA IB IIA IIB IIIA IIIB Missing ECOG performance status 0 1 Received PET scan Yes No
23 65 [43–75]
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Table 2. Grade 3/4 symptoms at baseline Induction CT + CHART 23 60 [41–77]
CHART alone
Induction CT + CHART
23 8 (35%) 3 (13%) 4 (17%) 1 (4%) 1 (4%) 0 (0%) 1 (4%) (hypertension)
23 7 (30%) 2 (9%) 5 (22%) 0 (0%) 0 (0%) 1 (4%) 2 (9%) (osteoarthritis, shoulder pain)
12 (52%)
16 (70%)
0 (0%) 18 (78%) 5 (22%)
1 (4%) 15 (65%) 7 (30%)
Patients with data Any Grade 3/4 symptom Cough Breathlessness Chest pain Anorexia Fatigue Other
13 (57%) 3 (13%) 2 (9%) 5 (22%)
15 (65%) 4 (17%) 2 (9%) 2 (9%)
Abbreviations: CHART = continuous hyperfractionated accelerated radiation therapy; CT = chemotherapy.
0 (0%) 0 (0%) 1 (5%) 3 (14%) 7 (33%) 10 (48%) 2
1 (5%) 0 (0%) 1 (5%) 3 (14%) 11 (50%) 6 (27%) 1
13 (57%) 10 (43%)
13 (57%) 10 (43%)
17 (74%) 6 (26%)
18 (78%) 5 (22%)
Abbreviations: CHART = continuous hyperfractionated accelerated radiation therapy; CT = chemotherapy; ECOG = eastern cooperative oncology group; PET = positron emission tomography.
hypotheses, and all analyses are underpowered. Therefore, the results presented here must be seen as hypothesis generating. Baseline characteristics Of the 46 patients, 28 (61%) were male, the median age was 64 years, 12 (26%) were current smokers, 28 (61%) had squamous cell histology, 34 (79%) were Stage IIIA or IIIB, and 26 (57%) were ECOG performance status 0. Baseline characteristics (Table 1) were well balanced between the treatment arms. The 9 patients who were Stage I or II were deemed to be inoperable based on a combination of clinical factors, as assessed by a lung cancer multi-discipinary team (MDT), and patient preference. Approximately one third of patients (15 [33%]) had Common Terminology Criteria for Adverse Events (CTCAE) (12) Grade 3 or 4 symptoms at presentation. The most common symptoms were breathlessness and cough, observed respectively in 9 (20%) and 5 (11%) patients. Baseline symptoms are summarized in Table 2. At baseline, 37 (80%) patients completed quality of life questionnaires. Levels of baseline quality of life seemed similar in the two arms. Most patients reported some coughing, although very few reported coughing up mucus or blood, or having any nausea or vomiting. Approximately one third of patients reported having moderate or severe worry, tension, or trouble sleeping; one quarter indicated a moderate or severe level of tiredness and problems experienced with physical activity.
Chemotherapy Of the 23 patients randomized to receive ICT, 17 (74%) received all three cycles, 3 (13%) received two cycles, and 3 (13%) received one cycle. Of the 6 patients who failed to complete three cycles of chemotherapy, 4 terminated treatment early because of excessive toxicity, 1 patient died after receiving one cycle, and 1 patient experienced disease progression after cycle two. Of the 17 patients who received three cycles, 11 received the full dose of each drug at each cycle, 4 received a full dose of cisplatin but omitted the day 8 dose of vinorelbine, and 2 received a reduced dose of cisplatin in their third cycle. The median time from randomization to the start of the first cycle was 14 days (range, 4–25). Chemotherapy toxicities were as expected with one half (11 patients) reporting Grade 3 or 4 toxicity during chemotherapy. Four patients had a drug dose reduced or a drug omitted because of toxicity, and 8 patients had a cycle delayed for toxicity. Radiotherapy Of the 23 ICT patients, 20 went on to receive CHART. The reasons for not being given radiotherapy were disease progression (1 patient), high toxicity coupled with patient request (1 patient), and 1 patient dying before completing chemotherapy. Twenty-two of the patients randomized to the CHART alone arm received radiotherapy, the remaining patient having disease progression. All 42 patients who received radiotherapy completed the full course of 54 Gy in 36 fractions. The median time from randomization to the start of radiotherapy was 18 days (range, 6–49) in the CHART arm, and 91 days (range, 56–174) in the ICT arm, with the median time from the first day of the last cycle of chemotherapy to the first day of radiotherapy being 33 days (range, 20–91). Response Response was assessed after radiotherapy in the CHART alone arm, post-chemotherapy in the ICT arm, and 6 months post-randomization in all patients. Only 13 of the 23 ICT patients had an assessment after chemotherapy, and of these 7 (54%) patients had a partial response, 4 (31%) stable disease, and 2 (15%) progressive
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disease. The main reason for not having an assessment of response was administrative errors (8 of the 10 patients with no assessment), with a combination of CT scans not being booked, scans not being performed prior to the start of radiotherapy, and patients missing appointments. Additionally, 1 patient died before the end of chemotherapy, and 1 refused to undergo a CT scan. Patients in the ICT arm were not reassessed for response immediately after radiotherapy. In the CHART arm, response was assessed after radiotherapy, and 10 (48%) patients were reported as having a partial response, 10 (48%) stable disease, and 1 (5%) progressive disease. Response could not be assessed in the remaining 2 patients. Both groups were assessed again 6 months after randomization. Of the 37 patients assessed (18 CHART, 19 ICT), complete or partial response was seen in 11 and 13 patients (61 vs 68%), and stable disease in 6 and 5 (33 vs 26%) patients in the CHART and ICT arms, respectively, with progressive disease observed in 1 patient in each arm. Over the course of the trial, 32 patients (16 in each arm) were assessed as having progressive disease. The site of first progression was recorded as being local in 16 patients (7 CHART, 9 ICT), brain in 5 patients (2 CHART, 3 ICT), and other distant metastases in 11 patients (7 CHART, 4 ICT). Toxicity and serious adverse events During and after the protocol treatment, data were recorded on toxicity and adverse events for all but 3 patients (all on the ICT arm), using the Common Terminology Criteria for Adverse Events version 3.0 (12). Grade 3 or 4 adverse events (Table 3) were reported for 13 (57%) CHART and 13 (65%) ICT patients. Extra anticancer treatment Two of the patients (1 CHART, 1 ICT) who did not receive CHART received radical thoracic radiotherapy using a daily fractionation regimen and 3 (13%) CHART and 5 (22%) ICT patients received additional palliative radiotherapy, for brain or bone metastases. Six (26%) CHART patients subsequently received chemotherapy and 4 (17%) ICT patients had further chemotherapy on relapse (9, 11, 17, and 27 months from completing CHART). Survival At the time of analysis, 36 patients have died (21 CHART, 15 ICT). The overall median survival (Figure 1) was 24 months (17 vs 25 months for CHART and ICT, respectively), corresponding to a hazard ratio of 0.60 (95% CI 0.31–1.16, p = 0.127). The median survival for the 34 Stage III patients was 21 months. The median length of follow-up of the 10 surviving patients is 33 months (IQR 26–40 months). All but 3 of the deaths were disease related. Two patients’ deaths may have been related to treatment: in an ICT patient with a background of alcohol-related cirrhosis, chemotherapy may have triggered liver failure, and a patient in the CHART alone arm had progressive lung fibrosis. The remaining ICT patient died
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Table 3. Grade 3/4 toxicities
Patients with data Any Grade 3/4 symptom Cough Breathlessness Chest pain Dysphagia Anorexia Nausea Fatigue Paresthesiae Hematological toxicity Neurological toxicity Other toxicities
CHART alone
Induction CT + CHART
23 13 (57%) 1 (4%) 4 (17%) 0 (0%) 3 (13%) 4 (17%) 0 (0%) 3 (13%) 0 (0%) 1 (4%) 0 (0%) 5 (22%) (chest infection; esophagitis; back pain; spine pain; muscular pain)
20 13 (50%) 4 (20%) 7 (35%) 1 (5%) 3 (15%) 2 (10%) 1 (5%) 5 (25%) 1 (5%) 1 (5%) 2 (10%) 5 (25%) (odynophagia; back pain; pleural effusion; hip pain; chest pain and dysphasia)
Abbreviations: CHART = continuous hyperfractionated accelerated Radiation Therapy; CT = chemotherapy. Other toxicities and adverse events asked about but not experienced: vomiting, abdominal pain, constipation, alopecia, phlebitis, rash, hemoptysis, renal toxicity, hepatic toxicity.
from myocardial infarction 11 days after starting his first cycle of chemotherapy. Quality of life Unfortunately, insufficient numbers of patients completed quality of life questionnaires to make any analysis meaningful. DISCUSSION The theoretical biological benefits of CHART have been translated into improved patient survival. Between 1990 and 1995, a total of 563 patients with Stage I–III NSCLC were entered into a multicenter randomized controlled trial comparing CHART with conventional (60 Gy/30 f) radiotherapy (5). The 2-year survival rate was improved from 20% with conventional radiotherapy to 29% with CHART. In addition, there was no evidence of a difference in morbidity and quality of life (13). The success of this trial led to the incorporation of CHART into Department of Health guidelines for lung cancer and subsequently the National Institute of Clinical Excellence guidance published in 2005 (14). Although CHART has been used in routine clinical practice for a decade, there had been sparse information on its performance until recently. Ghosh et al. (15) reported on 19 elderly (>70 years) patients with Stage I NSCLC who were given CHART. The median survival of 49 months suggested that CHART was a reasonable treatment for those patients deemed unsuitable for surgery. Din et al. (16) reported a series of 583 patients and confirmed that the survival reported in the original CHART paper seemed to be reproducible in day-to-day clinical practice with a 2-year survival of 33.6% and median survival of 16.2 months.
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Fig. Kaplan-Meier plot showing overall survival for patients receiving Continuous Hyperfractionated Accelerated Radiation Therapy (CHART) alone, compared with those receiving induction chemotherapy followed by CHART, along with the hazard ratio and corresponding 95% confidence interval for the difference between the two groups.
However Din et al. (16) also documented a creeping practice of giving chemotherapy before CHART in almost a quarter of those treated in routine practice, probably as a result of extrapolating from trials that reported survival benefits for the addition of chemotherapy to conventional radiotherapy (3). This automatic addition of chemotherapy to CHART should be questioned, because Din et al. (16) reported a lower 2-year survival for those treated with chemotherapy and CHART compared with CHART alone. This confirms the importance of trials such as INCH to inform evidence-based practice. The current trial was designed to detect a 10% improvement in 3-year survival with the addition of induction chemotherapy to CHART, which required 500 patients. Only 46 patients were randomized in 2 years, and the limited number of patients makes interpretation of the data difficult. The median survival with CHART alone of 17 months was similar to that observed in previous studies. An improvement in median survival to 25 months in the ICT arm resulted in a hazard ratio of 0.6. However, this figure is unreliable, does not reach statistical significance, and cannot be used to fully address the survival concern raised by Din et al. (16). Reasons for the poor accrual into the current trial need exploring. Despite NICE guidelines, CHART has not been widely implemented, and is currently only available in 12 of the 54 UK radiotherapy centers. At the start of the trial, this number of centers was considered adequate to accrue the required number of patients. There were no competing trials, no significant design problems, the consensus was that the scientific case for the trial remained valid, and much had been done to promote the trial. There may be generic problems, as poor recruitment has been documented in the majority of recent radical radiotherapy trials in NSCLC (17–20), which may relate to a multitude of generic contributory factors, including increasing regulatory hurdles, and insufficient radiotherapy infrastructure from physics support for the QA program through to actual delivery of treatment. More specifically, CHART requires
radiotherapy for 12 consecutive days, which causes organizational issues in providing a weekend radiotherapy service, and a further consequence of this is that a course of CHART will only be offered every 4 weeks in most centers. This raises anxieties among clinicians that some patients will require a significant waiting period before treatment starts, with the possibility that the disease may progress in this interim (21). Another reason for the poor uptake of CHART and poor accrual to INCH may relate to improvements in conventional radiotherapy, especially the advent of conformal radiotherapy permitting increases in the total dose delivered. Kong et al. (22) demonstrated an association between higher total doses (up to 74–103 Gy) and improved survival using once per day, three-dimensional conformal radiotherapy. McGibney et al. (23) indicated that a combination of threedimensional conformal radiotherapy and omission of elective nodal irradiation, could allow escalation of an accelerated nonconventionally fractionated radiotherapy schedule, which would overcome the problem of accelerated tumor clonogen proliferation with dose-escalated conventional fractionation. Therefore dose escalation of the CHART schedule should be explored. An alternative to CHART is to develop accelerated, hyperfractionated radiotherapy schedules that avoid treatment over the weekend. The ECOG 2597 trial (17) gave two cycles of induction chemotherapy as standard and then randomized between hyperfractionated accelerated radiotherapy (57.6 Gy in 1.5 Gy three times daily for 2.5 weeks) and conventional radiotherapy (64 Gy in 32 daily fractions). The trial was closed early because of slow accrual, but results were encouraging and showed a 15% improvement in favor of hyperfractionated accelerated radiotherapy in 2- and 3-year survival, although this was not statistically significant. A trial comparing a similar European regimen, CHARTWEL (CHART WeekEnd Less 60 Gy in 40 fractions over 2.5 weeks using 1.5 Gy per fraction) to conventional
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fractionation of 66 Gy in 33 fractions did complete its planned recruitment but has shown no evidence of a difference in survival (17). The addition of chemotherapy to conventional radical radiotherapy has advanced to the point where it is now accepted and recommended as the standard treatment for locally advanced and inoperable NSCLC, although it has never been shown to be feasible in combination with CHART. Trials of sequential chemoradiotherapy for Stage III NSCLC have show median survivals of approximately 14 months, and concurrent chemoradiotherapy regimens report median survivals of around 17 months (24). Hanna and colleagues (25) have reported an impressive median survival of 23.2 months for a concurrent cisplatin/etoposide and conventionally fractionated regimen. As a result concurrent chemoradiotherapy treatments are becoming accepted as a standard of treatment, despite reports of toxic death rates being up to 10% (26). The emergence of these data may have hindered recruitment to INCH because of reluctance to treat patients with radical radiotherapy without the addition of chemotherapy. Nevertheless CHART remains an important radiotherapy schedule, but moving forward from it poses major challenges, not the least in running large randomized trials. However, several strengths of the current trial must also be recognized: CHART was performed in a uniform and standardized manner in all nine contributing centers. Induction chemotherapy followed by CHART was feasible, well tolerated, and the median survival of 25 months suggests that the hypothesis that accelerated hyperfractionated radiotherapy has a role in the treatment of inoperable NSCLC deserves further study. Trial management group M. Hatton (chair), C. Barron, D Boyle, M. Cheung, J. Gardiner, N. Gower, N. Groom, A. Hughes, P. Jenkins, E. Lyn, F. Maclean, J. Millett, B. Moore, S. Morgan, M. Nankivell, C. Pugh, M. Sculpher, R. Stephens, A. Webster, J. Williams
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Trial steering committee H. Kitchener (chair), T. Maughan, M. Seymour Independent data monitoring committee C. Williams (chair), R. Rampling, J. Scholefield, R. Swindell MRC clinical trials unit staff A. Hodson, T. Hussain, S. Beall, K. Sanders, N. Tappenden, C. Courtney, C. Chung Participating centers 1. Bristol Haematology and Oncology Centre (S. Falk, P. Wilson, S. Cowley, S. Yarrow, K. Wright, H. Appleby, F. Hester, M. Simmonds, K. Jones, R. Peglar, R. Macefield, A. Webster) 2. Churchill Hospital, Oxford (T. Foord, T. Green, S. Lawrey, N. Stoner, J. Rowntree, J. Boutflower, N. Haynes) 3. Mount Vernon Hospital (E. Lyn, J. Dickson, J. Williams, N. Groom, B. Boughen, S. Cope, J. Graham, B. Delooze, A. Downs, U. Patel, R. Davies) 4. Nottingham City Hospital (S. Morgan, J. Worville, E. Stones, S. Fleet, C. Gooch, R. Chauhan, S. Elliott, K. Knowles) 5. Royal Gwent Hospital (A. Brewster, A. Prosser, A. Holton, D. Knight-Davies, V. Green, C. Heymann, S. Slade, L. Penketh, P. Webb, I. Bowman) 6. University Hospital, North Durham (R. McMenamin, J. Dent, D. Turnball, C. Barron, Z. Razvi, J. Eliot) 7. Velindre Hospital, Cardiff (F. Macbeth, B. Moore, B. Dillon, E. Mair-Bowden, L. Penketh, C. Heymann, B. Tranter, K. Jones, C. Vitolo, A. Kelly) 8. Weston Park Hospital Sheffield (M. Hatton, P. Fisher, B. Foran, J. Mohanamurali, R. Clarke, J. Gibbins, H. Wood, S.-A. Bell, E. Hodgkinson, M. Hutchinson, P. Joyce, K. Shaw, J. Bliss, N. Huxham, L. Borrill, M. Trigg, G. Brown, A. Leesley) 9. Yeovil District Hospital (S. Bulley, N. Beacham, K. Rennie)
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