- Email: [email protected]
A phase II trial of induction chemotherapy followed by continuous hyperfractionated accelerated radiotherapy in locally advanced non-small-cell lung cancer
Radiotherapy and Oncology 93 (2009) 396–401
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Phase II trial
A phase II trial of induction chemotherapy followed by continuous hyperfractionated accelerated radiotherapy in locally advanced non-small-cell lung cancer Peter Jenkins *, Susan Anderson, Susan Wronski, Anita Ashton Gloucestershire Oncology Centre, Cheltenham General Hospital, Cheltenham, UK
a r t i c l e
i n f o
Article history: Received 19 December 2008 Received in revised form 4 April 2009 Accepted 6 April 2009 Available online 10 May 2009 Keywords: Lung cancer CHART Chemoradiation Accelerated radiotherapy
a b s t r a c t Background and purpose: We conducted a phase II study combining induction chemotherapy with continuous hyperfractionated accelerated radiotherapy (CHART) in locally advanced non-small-cell lung cancer (NSCLC). Materials and methods: A total of 40 patients with stage III NSCLC were enrolled. All patients received 3 cycles of chemotherapy followed by CHART (56 Gy in 36 fractions over 12 days). The primary outcome measure was radiation toxicity. Secondary endpoints were response rate, overall survival, disease-free survival and loco-regional progression-free survival. Results: Acute radiation toxicity was minimal and there were no significant late toxicities. The response rate after completion of chemoradiation was 65%. The median and 2-year overall survival, progressionfree survival and loco-regional progression-free survivals were 15.7 months, 28%; 12.1 months, 23%; and 26.4 months, 51%, respectively. Conclusions: Induction chemotherapy can be safely combined with CHART. The survival results are consistent with previous studies of chemotherapy followed by accelerated radiotherapy. This approach should be compared with synchronous chemoradiation to determine if it represents a less toxic alternative. Ó 2009 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 93 (2009) 396–401
Chemoradiotherapy represents the current treatment standard for locally advanced non-small-cell lung cancer (NSCLC). Historically patients with stage III disease have been treated with radiation therapy alone but results were disappointing with median survivals of only 10 months. A series of clinical trials conducted in the 1980s confirmed that the addition of sequential platinumbased chemotherapy improved outcomes compared with radiotherapy alone, extending the median survival to 13 months [1–3]. Concomitant chemoradiation has also shown to be superior to single modality radiotherapy [4]. More recently sequential and concomitant chemoradiation have been directly compared in four trials [5–8]. They indicate a superiority for the concomitant approach, albeit at the cost of increased acute toxicity. However the optimal chemoradiation strategy remains the subject of debate since all of these studies are open to criticism. For example, patients in the concomitant arm often received additional cycles of chemotherapy whilst not all patients randomised to the sequential treatment arm actually went on to receive the radiotherapy. Furthermore the negative impact of chemotherapy-induced anae* Corresponding author. Address: Gloucestershire Oncology Centre, Cheltenham General Hospital, Sandford Road, Cheltenham GL53 7AN, United Kingdom. E-mail address: [email protected] (P. Jenkins). 0167-8140/$ - see front matter Ó 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2009.04.002
mia on radiosensitivity was not adequately addressed. Thus there remains significant interest in the sequential chemoradiation approach not least because it is less toxic, allows full dose chemotherapy to be given and is more readily integrated with doseescalated radiotherapy protocols. Overall treatment time (OTT) is being increasingly recognised as an important factor in the treatment of lung tumours with combined modality approaches [9,10]. Once cytotoxic therapies such as chemotherapy and radiotherapy are started, accelerated repopulation of surviving tumour cells may reduce the effectiveness of later cycles or fractions of treatment [11,12]. Induction chemotherapy when added to radiation therapy inevitably prolongs the OTT, which is likely to be deleterious to outcome. This phenomenon may explain the failure of induction chemotherapy to significantly improve local control despite producing significant disease shrinkage [1,2]. The increased proliferation of surviving tumour cells after chemotherapy could be partly addressed by using accelerated radiation regimens such as continuous hyperfractionated accelerated radiotherapy (CHART). In contrast to conventionally fractionated radiotherapy which takes approximately 45 days to deliver, CHART is completed in just 12 days. The pivotal phase III trial showed a 9% improvement in 2-year survival with CHART when compared with a higher dose delivered by conventional
P. Jenkins et al. / Radiotherapy and Oncology 93 (2009) 396–401
fractionation [13]. Therefore it seemed logical to combine induction chemotherapy with CHART in an attempt to improve the proven survival benefits of both these approaches. As far as we are aware, this is the first study to formally test the feasibility of this strategy. We have previously reported on the impact that tumour shrinkage with chemotherapy had on radiation treatment planning for patients entered in this study [14]. Herein we report the mature, outcome results of the trial. Materials and methods Forty patients were enrolled in a prospective phase II study evaluating the use of induction chemotherapy followed by CHART. Eligibility criteria comprised: histologically confirmed stage III NSCLC (no pleural effusion or supraclavicular lymph node disease), World Health Organisation performance status 0–1, weight loss < 5% within the preceding 3 months, satisfactory lung function (forced expiratory volume in 1 s >1.5 l) and suitability for treatment with chemotherapy. The protocol was approved by the Gloucestershire Research and Ethics Committee. Pre-treatment evaluation included history, physical examination, chest radiograph, fibre-optic bronchoscopy and contrast enhanced computed tomography (CT) scan of the chest and upper abdomen. In addition 2 patients had staging positron emission tomography (PET) scans and 6 had previous exploratory surgery. Further investigations to exclude metastases were performed if clinically indicated. Patient demographics, tumour characteristics and treatment parameters are shown in Table 1. Treatment comprised 3 cycles of induction chemotherapy using mitomycin-C 8 mg/m2, vinblastine 6 mg/m2 (maximum 10 mg) and carboplatin. Mitomycin-C was omitted from the third cycle of treatment. Carboplatin was dosed using the Calvert equation, at an area under the concentration curve of 5. Glomerular filtration rate was determined using radiolabelled ethylenediamine tetraacetic acid (EDTA) clearance. Chemotherapy was delivered on a 3 weekly schedule. Treatment was delayed if the neutrophil count on the planned day of delivery was <1.5 109/l or if the platelet count was <100 109/l. Prophylactic antibiotics were used to minimise the risk of febrile neutropaenia. The protocol recommended Table 1 Demographics, tumour characteristics and treatment parameters. V20, the fractional volume of the lung receiving >20 Gy. MLD, mean lung dose. Age Gender
Median 66 (range 47–79) Male 25, female 15
Stage IIIA IIIB
9 (22.5%) 31 (77.5%)
Histology Squamous cell Adenocarcinoma Unspecified Pre-chemotherapy tumour volumea Pre-chemotherapy RECIST measurementa
23 (57.5%) 7 (17.5%) 10 (25%) Median 125 cc (range 36–679) Median 65 mm (range 23–137)
Tumour location (lobe)b Right upper Right middle Right lower Left upper Left lower
14 (35%) 5 (12.5%) 4 (10%) 9 (22.5%) 7 (17.5%)
Tumour positionb Central Peripheral
32 (80%) 7 (17.5%)
Radiotherapy parameters V20 MLD
Median 23% (range 4–41%) Median 12.3 Gy (range 5.2–18.4)
a b
Pretreatment tumour volume measurement in 36 assessable patients. In one patient the site of the primary could not be defined.
397
that haemoglobin levels be maintained above 11 g/dl before starting radiation therapy. CT scans for radiotherapy planning were performed before starting and 2 weeks after completion of chemotherapy. These were subsequently spatially coregistered using XiO software (Computerized Medical systems, St. Louis, MO). CHART was commenced 3.5–4 weeks after the completion of chemotherapy. Our radiotherapy protocol has previously been described in detail [14]. Briefly, all patients were treated with 3-dimensional conformal radiation therapy. The primary and involved lymph nodes were included in a single phase of treatment. Pre-chemotherapy tumour dimensions were used to form the target volume. Most patients were treated with three coplanar beams designed such that the spinal cord did not received >40 Gy and that the fractional volume of lung receiving >20 Gy (V20) did not exceed 35%. Radiotherapy planning was performed with the XiO treatment planning system and its forerunners. All patients received CHART (54 Gy prescribed to the isocentre in 36 fractions over 12 days, treating three times a day with an interfraction interval of 6 h). The median OTT from the start of chemotherapy to finishing radiation therapy was 82 days (range 72–114). Patients were monitored weekly during and following the completion of radiotherapy, either for a minimum of 6 weeks or until resolution of acute radiation toxicity. Subsequent follow-up visits were at 3 monthly intervals for life. A CXR was performed at 4 weeks and at every subsequent visit. Post-therapy CT scans were performed routinely at 3 months and 12 months after the end of treatment, then yearly. Acute toxicity to chemotherapy was recorded using the National Cancer Institute common toxicity criteria (version 2) and acute and late toxicity to radiotherapy using Radiation Therapy Oncology Group criteria. The primary outcome measure was radiation toxicity. The secondary endpoints were response rate at 3 months, overall survival (OS), progression-free survival (PFS) and loco-regional progression-free survival (LR-PFS). The Response Evaluation Criteria in Solid Tumours (RECIST) measurement were used to determine response rates [15]. Survival was defined as the time from entry into the study to the event and was calculated using the Kaplan– Meier method. Patients who remained alive were censored as of May 2008. Treatment on progression comprised second line chemotherapy (gemcitabine or docetaxel based) in 14 and tyrosine kinase inhibitors (gefitinib or erlotinib) in 4. The rate of tumour growth after relapse was measured on serial diagnostic scans. Tumour volumes were estimated using the formula 4/3p(Dl–r/2 Da–p/2 Dc–c/2) where Dl–r is the maximum diameter in the left to right direction, Da–p is the maximum diameter in the anterior to posterior direction and Dc–c is the maximum diameter in the cranio-caudal direction. The tumour volume doubling time (Vd) was calculated using the standard volumetric formula Vd = (tln 2)/[ln Vf/Vi] where t is the time in days between the two CT scans, Vf is the volume measured on the final CT scan and Vi is the volume measured on the initial CT scan. Statistical analyses were performed using SPSS (SPSS Inc, Chicago, IL). Pearson’s correlation coefficient Student’s t-test, paired sample t-tests and chi-squared tests were used as appropriate.
Results Chemotherapy was well tolerated and all patients completed 3 cycles of treatment as planned. Ten patients experienced a grade 3 or above chemotherapy toxicity, mostly myelosuppression (Table 2). All toxicities were transient and resolved spontaneously. The most common acute radiation complication was oesophagitis which occurred in 38 (95%) patients (Table 2). In only 1 patient was this Pgrade 3 (weight loss > 15% and/or requiring opiate analgesics/feeding support) and in all cases oesophagitis resolved with
398
Induction chemotherapy and CHART
Table 2 Recorded maximum treatment-related toxicities.
Chemotherapy toxicity Haematological Anaemia Neutropaenia Thrombocytopaenia Febrile neutropaenia
Grade 1
Grade 2
Grade 3
13 (32.5%)
13 (32.5%)
2 (5%)
2 (5%)
3 2 1 4
Non-haematological Mucositis Nausea/vomiting Diarrhoea/constipation Pulmonary Peripheral neuropathy Anorexia Infection Fatigue
19 (47.5%) 7 (17.5%) 16 (16%) 1 (2.5%) 2 (5%) 7 (17.5%) 1 (2.5%) 18 (45%)
Radiation toxicity Oesophagitis Pneumonitis
25 (62.5%) 1 (2.5%)
(7.5%) (5%) (2.5%) (10%)
4 (10%) 2 (10%)
2 (5%) 2 (5%) 7 (17.5%) 12 (30%)
1 (2.5%) 4 (10%)
a supportive outpatient care in 3–6 weeks. Grade 3 (requiring corticosteroids) radiation pneumonitis occurred in 4 (10%) patients. There were no symptomatic late complications noted. Using the RECIST criteria, we evaluated the extent of the response to chemotherapy and radiotherapy. Fourteen patients had a partial response, 22 had stable disease and 1 had progressive disease following chemotherapy. In 3 patients it was not possible to measure tumour size accurately as a consequence of associated collapse or consolidation. The mean reduction in the RECIST measurement was 26%. The response to radiation in the 39 patients with non-progressive disease after chemotherapy was also assessed. Two patients had a complete response, 15 had a partial response and 18 had stable disease. Three patients had progressive disease (all distant metastatic relapse) and in 1 patient it was not possible to assess the local response due to peri-tumoural fibrosis post therapy. The mean reduction in the RECIST measurement following radiotherapy was 29%. The overall response rate following completion of all treatment was 65%. In 33 patients it was possible to measure both the response to radiation and the response to chemotherapy. As shown in Fig. 1 these were poorly correlated (r = 0.09, p = 0.61). Furthermore the extent of tumour shrinkage with neither chemotherapy (n = 36) or radiotherapy (n = 35) were not individually correlated with
Fig. 1. Shrinkage in the RECIST measurement in response to chemotherapy and radiotherapy for 33 assessable patients. Horizontal and vertical lines represent the cut point between stable disease (SD) and partial response (PR).
survival (r = 0.15, p = 0.37 and r = 0.29, p = 0.1, respectively). However the extent of disease shrinkage after completion of all therapy did correlated weakly with survival (r = 0.35, p = 0.05). Thirty four patients have died. With a minimum follow-up of 25 months for surviving patients the median (+95% confidence intervals) OS, PFS and LR-PFS were 15.7 (11.9–19.5), 12.1 (9.9–14.3) and 26.4 (10.0–42.8) months, respectively. OS, PFS and LR-PFS at 1 year and 2 years were 78% and 28%; 53% and 23%; 86% and 51% (Fig. 2). Seventeen patients had a prolongation in OTT beyond the planned 82 days, due to either a delay in their chemotherapy programme or logistic problems relating to the availability of CHART treatment. Fig. 3 illustrates the deleterious effect that prolonging OTT has on survival. At the time of analysis 37 patients had either relapsed or died. The site of first failure was categorised as locoregional alone in 11 (7 of these judged to be at the primary site), distant metastatic disease alone in 17 (7 developed brain metastases), locoregional as well as distant failure in 6 and intercurrent disease in the absence of documented relapse in 3. The primary intrathoracic tumour was judged to be controlled at the time of death in 61% patients. We also noted that in patients where the disease did relapse locally at the primary site, the rate of tumour growth was slow (Fig. 4). In 5 patients with predominantly in field relapse, serial scans were available prior to the commencement of second-line treatment, which was generally reserved for symptomatic progression. The median tumour volume doubling time for this group was 21 weeks (range 7–31 weeks). Due to concern about the possible negative impact of chemotherapy-related anaemia on the effectiveness of radiotherapy, the study protocol recommended that blood transfusions be used to maintain haemoglobin levels above 11 g/dl. In total, 24 patients received transfusions during chemotherapy to maintain their haemoglobin levels (2 units in 10, 3 units in 9, 4 units in 2, 6 units in 2 and 7 units in 1). On an average 1.9 units of blood were transfused per patient. Despite this active transfusion policy mean haemoglobin levels fell from 12.7 g/dl pre-chemotherapy to 11.3 g/dl post-chemotherapy, p < 0.001 (Fig. 5).
Discussion Induction chemotherapy when combined with radical radiotherapy improves the survival of patients with stage III NSCLC [1–3]. However the results of sequential treatment are generally
Fig. 2. Kaplan–Meier curves for overall survival (OS), progression-free survival (PFS) and loco-regional progression-free survival (LR-PFS).
P. Jenkins et al. / Radiotherapy and Oncology 93 (2009) 396–401
Fig. 3. Correlation between overall treatment time and overall survival (r = 0.34, p = 0.03). Patients who were still alive at the time of analysis are represented by open circles.
considered to be inferior to synchronous chemoradiation [5–8]. Similar findings have been reported for other tumour sites treated with combined modality therapy [16]. In part this may reflect the prolongation of OTT which is an inevitable consequence of sequential chemoradiation [17]. There is now randomised trial evidence confirming that shorter radiotherapy schedules improve outcome in NSCLC [13] and small-cell lung cancer [18]. The combination of chemotherapy with CHART was therefore attractive, not only to combine the proven survival benefits of each of these treatments but also to minimise the negative effect of accelerated repopulation following induction chemotherapy. Three previous studies have attempted to combine chemotherapy with CHART. Oral et al. reported on the use of concomitant paclitaxel and CHART in 20 patients with NSCLC [19]. In this study acute toxicity was unacceptable with 70% of patients experiencing grade 2–3 oesophagitis and 50% experiencing grade 3 or greater pulmonary toxicity. Oner Dincbas et al. conducted a study of
399
induction, synchronous and consolidation vinorelbine based chemotherapy with CHART [20]. The median survival for the 22 patients enrolled was 12 months. Grade 3 oesophagitis was seen in 9% and 23% patients developed clinical pneumonitis. Finally, Kirkbride et al. reported a trial of induction chemotherapy using vinorelbine and cisplatin prior to CHART [21]. Their study was closed prematurely following 2 treatment-related deaths in the first 3 patients enrolled. Thus the toxicity of this approach seems considerable, particularly when chemotherapy is used synchronously or shortly before CHART. In contrast to these studies our trial mandated a 3.5–4 week interval between the completion of chemotherapy and the start of radiation therapy. Probably because of this interval, the acute radiation toxicity that we observed was low. There was only 1 (3%) case of grade 3 oesophagitis, 4 cases (10%) of grade 3 pneumonitis and no symptomatic late radiation toxicity. This toxicity profile compares very favourably with synchronous chemoradiation protocols which are associated with grade 3 oesophagitis in 20–30% of patients treated [6–8]. Studies of concomitant chemoradiation in NSCLC generally report median survivals of 16–17 months and 2-year OS of 34–39%. In contrast, sequential chemoradiation produces median survivals of 13–15 months and 2-year OS of 14–27% [5–8]. However when accelerated radiation fractionation is used, the results of sequential chemoradiation may be improved (Table 3). In this study we saw survival rates that are similar to synchronous chemoradiation, in a population that was staged prior to the widespread application of PET imaging. In several tumour sites including lung cancer the response to induction chemotherapy or chemoradiation has been advocated as a means of selecting patients for subsequent radiotherapy or surgery [22]. The rationale for this approach is the belief that if the tumour is responsive to chemotherapy it will also be sensitive to radiation. We found no evidence of an association between the response to chemotherapy and radiation to support this hypothesis in our study. Thus 48% of patients who fail to respond to chemotherapy still manifested significant disease shrinkage following radiotherapy (9 partial and 1 complete responses). Similarly 50% of the patients who initially responded to chemotherapy had only stable disease following radiation. Therefore we do not think that
Fig. 4. Serial CT scans for 2 patients illustrating the indolent nature of local relapses following chemoradiation. Both patients were observed until they became symptomatic. Patient A relapsed having achieved a complete response post therapy. Patient B had a residual mass post therapy (arrowed) that slowly progressed. Timings are months post radiotherapy.
400
Induction chemotherapy and CHART
Fig. 5. Fall in haemoglobin with chemotherapy. Despite an active transfusion policy, there was a significant fall in mean haemoglobin levels with chemotherapy (12.7–11.3 g/dl, p < 0.001).
initial chemotherapy response should be used to select patients as being any more or less suitable for subsequent radiotherapy. Despite the high frequency of distant metastases, loco-regional control rates for lung cancer remain poor and contribute to the lethality of this disease. Over 75% of patients with stage III NSCLC die with uncontrolled tumour in the chest. Strategies that improve loco-regional control would be expected to lead to better survival and are a prerequisite for cure. Indeed the benefit of synchronous chemoradiation is thought to accrue predominantly due to an improvement in local control [23]. In the light of these observations one of the most pleasing aspects of our results is the excellent local control rate. Only 7 (18%) patients relapsed ‘in field’ as a site of first failure and primary tumour control was achieved in 62% patients at the time of death. We hypothesise that this promising result most likely derives from the ability of CHART to minimise the impact of accelerated repopulation following chemotherapy. We note that recent overviews of chemoradiation in small-cell and non-small-cell lung cancer have found that OTT to be highly predictive of survival [9,10]. Fig. 3 illustrates the fact that even with CHART, it is important not to unduly protract the treatment course. Indeed further shortening the OTT, for example by delivering only 2 cycles of induction chemotherapy, may paradoxically improve the efficacy of combined modality treatment for lung tumours.
The extent of the fall in haemoglobin levels following induction chemotherapy came as a surprise. Anaemia is thought to reduce oxygen delivery to the tumour, thereby increasing hypoxia and radioresistance. An analysis of pooled trials has shown that low pre-treatment haemoglobin level is predictive of poorer outcome following radiotherapy [24]. However, as yet, correction of haemoglobin by transfusion has not been shown to compensate for this deleterious effect. In our study 12 patients (30%) had a haemoglobin <12 g/dl pre-chemotherapy, whilst 31 patients (78%) had a haemoglobin <12 g/dl post-chemotherapy despite the active transfusion policy that we deployed. It may be that failure to fully compensate for falls in haemoglobin levels could confound the comparison between induction and concurrent chemotherapy. In addition small reductions in haemoglobin which are insufficient to be scored as grade 1 (<10 g/dl) may still have a profound impact on radiosensitivity. Close attention should be paid to haemoglobin levels pre-radiotherapy to ensure that the effectiveness of sequential chemoradiation is not potentially compromised. We also noted that in patients who subsequently develop local recurrence at the primary site, the rate of growth on recurrence is extremely slow (Fig. 4). The Vd in this group of patients was 5 months and their median survival from the time of relapse was 27 months. In comparison the Vd in untreated NSCLC is approximately 3 months, whilst for patients relapsing after chemotherapy, Vd is only 1 month [17]. This interesting observation may result from an effect of radiotherapy on the tumour vasculature resulting in reduced perfusion. Alternatively it may be an effect of CHART on tumour clonogens triggered into accelerated repopulation by chemotherapy. This population of rapidly cycling cells may be preferentially killed by CHART leaving only slowly proliferating tumour cells that are more able to repair sublethal radiation damage. Ultimately the latter population of slowly cycling cells expands leading to the indolent growth pattern seen. Several limitations of our study should be acknowledged. The chemotherapy regimen chosen would no longer be considered optimal by modern standards. In addition the early timing of the re-evaluation scans may underestimate the true response rate to chemotherapy. However for the first time we have shown that induction chemotherapy can be safely combined with CHART. The side effects of the combination used in this study are minimal and survival rates are comparable with those reported with concurrent chemoradiation. Interestingly we note that the only randomised trial which compared sequential with concurrent chemotherapy using an accelerated radiotherapy scheme, found no difference in survival between the arms [25]. Furthermore, the best results reported in a phase III study of chemoradiation in locally advanced NSCLC have come from the combination of 2 cycles of carboplatin-paclitaxel followed by hyperfractionated accelerated radiation therapy (HART) [26]. We think that this approach warrants further investigation.
Table 3 Published combinations of induction chemotherapy and radical radiotherapy using accelerated fractionation protocols (>2 Gy per day) for NSCLC. Abbreviations: PC, paclitaxel and carboplatin; VC, vinorelbine and cisplatin; GC, gemcitabine and cisplatin; MVP, mitomycin-C; vinblastine and cisplatin; MVC, mitomycin-C, vinblastine and carboplatin. First author
Study (phase)
Number (% stage III)
Total dose (Gy)/fraction size (Gy)/number of fractions/overall time (days)
Chemotherapy
Median survival (months)
2-Year survival
Belani [26] Belderbos [25] Bonomi [27] Ishikura [28] This study Chen [29] Rojas [30]
III III II II II II II
58 78 44 30 40 73 42
57.6/1.5–1.8 tid/36/18 66/2.75/24/32 <60/1.5 tid/<40/18 57.6/1.5–1.8 tid/36/18 54/1.5 tid/36/12 66/<1.5 bid/50/33 60/1.5 tid/40/<19
PC 2 GC 2 Various 3 VC 2 MVC 3 MVP 2 PC 3
20 16 20a 24 16 13 33
44% 34% 42%a 50% 26% 10% 57%
a
Read from graph.
(100%) (92%) (100%) (100%) (100%) (100%) (52%)
P. Jenkins et al. / Radiotherapy and Oncology 93 (2009) 396–401
Acknowledgements The authors acknowledge the assistance of Dr. S Elyan and Dr. D Farrugia in the completion of this study. References [1] Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III nonsmall-cell lung cancer. N Engl J Med 1990;323:940–5. [2] Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 1991;83:417–23. [3] Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88–08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 1995;87:198–205. [4] Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992;326:524–30. [5] Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17:2692–9. [6] Curran WJ, Scott CB, Langer CJ, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 2003;22:2499. [7] Zatloukal P, Petruzelka L, Zemanova M, et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced nonsmall cell lung cancer: a randomized study. Lung Cancer 2004;46:87–98. [8] 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;23:5910–7. [9] 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;63:667–71. [10] De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 2006;24:1057–63. [11] Davis AJ, Tannock JF. Repopulation of tumour cells between cycles of chemotherapy: a neglected factor. Lancet Oncol 2000;1:86–93. [12] Bentzen SM. Repopulation in radiation oncology: perspectives of clinical research. Int J Radiat Biol 2003;79:581–5. [13] Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol 1999;52:137–48. [14] Jenkins P, Milliner R, Latimer P. Shrinkage of locally advanced non-smallcell lung cancers in response to induction chemotherapy: implications for radiotherapy treatment planning. Int J Radiat Oncol Biol Phys 2007;69:993–1000.
401
[15] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16. [16] Bartelink H, Schellens JH, Verheij M. The combined use of radiotherapy and chemotherapy in the treatment of solid tumours. Eur J Cancer 2002;38:216–22. [17] El Sharouni SY, Kal HB, Battermann JJ. Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy. Br J Cancer 2003;89:2184–9. [18] Turrisi 3rd AT, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265–71. [19] Oral EN, Bavbek S, Kizir A, et al. Preliminary analysis of a phase II study of paclitaxel and CHART in locally advanced non-small cell lung cancer. Lung Cancer 1999;25:191–8. [20] Oner Dincbas F, Koca S, Altinel A, et al. Continuous accelerated hyperfractionated radiotherapy (CHART) plus chemotherapy (CT) with vinorelbine (VB) and cisplatinum (CDDP) in locally advanced NSCLC (TOG011 study). Eur J Cancer 2001;37:S53. [21] Kirkbride P, Hatton M, Lorigan P, Joyce P, Fisher P. Fatal pulmonary fibrosis associated with induction chemotherapy with carboplatin and vinorelbine followed by CHART radiotherapy for locally advanced non-small cell lung cancer. Clin Oncol (R Coll Radiol) 2002;14:361–6. [22] Albain KS, Swann RS, Rusch V, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol 2005;23:7014. [23] Auperin A, Rolland E, Curran W, et al. Concomitant radio-chemotherapy (RTCT) versus sequential RT-CT in locally advanced non-small cell lung cancer: a meta-analysis using individual patient data from randomised clinical trials. J Thoracic Oncol 2007;2:S310. [24] Werner-Wasik M, Scott C, Cox JD, et al. Recursive partitioning analysis of 1999 Radiation Therapy Oncology Group (RTOG) patients with locally-advanced non-small-cell lung cancer (LA-NSCLC): identification of five groups with different survival. Int J Radiat Oncol Biol Phys 2000;48:1475–82. [25] Belderbos J, Uitterhoeve L, van Zandwijk N, et al. Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972–22973). Eur J Cancer 2007;43:114–21. [26] Belani CP, Wang W, Johnson DH, 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;23:3760–7. [27] Bonomi M, Blanco-Savorio A, Cerchietti L, et al. Continuous hyperfractionated accelerated radiation therapy week-end less in combination with neoadjuvant chemotherapy for the treatment of stage III non-small-cell lung cancer. Lung Cancer 2008;60:75–82. [28] Ishikura S, Ohe Y, Nihei K, et al. A phase II study of hyperfractionated accelerated radiotherapy (HART) after induction cisplatin (CDDP) and vinorelbine (VNR) for stage III non-small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 2005;61:1117–22. [29] Chen GY, Jiang GL, Qian H, et al. Escalated hyperfractionated accelerated radiation therapy for locally advanced non-small cell lung cancer: a clinical phase II trial. Radiother Oncol 2004;71:157–62. [30] Rojas AM, Lyn BE, Wilson EM, et al. Toxicity and outcome of a phase II trial of taxane-based neoadjuvant chemotherapy and 3-dimensional, conformal, accelerated radiotherapy in locally advanced nonsmall cell lung cancer. Cancer 2006;107:1321–30.
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Phase II trial
A phase II trial of induction chemotherapy followed by continuous hyperfractionated accelerated radiotherapy in locally advanced non-small-cell lung cancer Peter Jenkins *, Susan Anderson, Susan Wronski, Anita Ashton Gloucestershire Oncology Centre, Cheltenham General Hospital, Cheltenham, UK
a r t i c l e
i n f o
Article history: Received 19 December 2008 Received in revised form 4 April 2009 Accepted 6 April 2009 Available online 10 May 2009 Keywords: Lung cancer CHART Chemoradiation Accelerated radiotherapy
a b s t r a c t Background and purpose: We conducted a phase II study combining induction chemotherapy with continuous hyperfractionated accelerated radiotherapy (CHART) in locally advanced non-small-cell lung cancer (NSCLC). Materials and methods: A total of 40 patients with stage III NSCLC were enrolled. All patients received 3 cycles of chemotherapy followed by CHART (56 Gy in 36 fractions over 12 days). The primary outcome measure was radiation toxicity. Secondary endpoints were response rate, overall survival, disease-free survival and loco-regional progression-free survival. Results: Acute radiation toxicity was minimal and there were no significant late toxicities. The response rate after completion of chemoradiation was 65%. The median and 2-year overall survival, progressionfree survival and loco-regional progression-free survivals were 15.7 months, 28%; 12.1 months, 23%; and 26.4 months, 51%, respectively. Conclusions: Induction chemotherapy can be safely combined with CHART. The survival results are consistent with previous studies of chemotherapy followed by accelerated radiotherapy. This approach should be compared with synchronous chemoradiation to determine if it represents a less toxic alternative. Ó 2009 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 93 (2009) 396–401
Chemoradiotherapy represents the current treatment standard for locally advanced non-small-cell lung cancer (NSCLC). Historically patients with stage III disease have been treated with radiation therapy alone but results were disappointing with median survivals of only 10 months. A series of clinical trials conducted in the 1980s confirmed that the addition of sequential platinumbased chemotherapy improved outcomes compared with radiotherapy alone, extending the median survival to 13 months [1–3]. Concomitant chemoradiation has also shown to be superior to single modality radiotherapy [4]. More recently sequential and concomitant chemoradiation have been directly compared in four trials [5–8]. They indicate a superiority for the concomitant approach, albeit at the cost of increased acute toxicity. However the optimal chemoradiation strategy remains the subject of debate since all of these studies are open to criticism. For example, patients in the concomitant arm often received additional cycles of chemotherapy whilst not all patients randomised to the sequential treatment arm actually went on to receive the radiotherapy. Furthermore the negative impact of chemotherapy-induced anae* Corresponding author. Address: Gloucestershire Oncology Centre, Cheltenham General Hospital, Sandford Road, Cheltenham GL53 7AN, United Kingdom. E-mail address: [email protected] (P. Jenkins). 0167-8140/$ - see front matter Ó 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2009.04.002
mia on radiosensitivity was not adequately addressed. Thus there remains significant interest in the sequential chemoradiation approach not least because it is less toxic, allows full dose chemotherapy to be given and is more readily integrated with doseescalated radiotherapy protocols. Overall treatment time (OTT) is being increasingly recognised as an important factor in the treatment of lung tumours with combined modality approaches [9,10]. Once cytotoxic therapies such as chemotherapy and radiotherapy are started, accelerated repopulation of surviving tumour cells may reduce the effectiveness of later cycles or fractions of treatment [11,12]. Induction chemotherapy when added to radiation therapy inevitably prolongs the OTT, which is likely to be deleterious to outcome. This phenomenon may explain the failure of induction chemotherapy to significantly improve local control despite producing significant disease shrinkage [1,2]. The increased proliferation of surviving tumour cells after chemotherapy could be partly addressed by using accelerated radiation regimens such as continuous hyperfractionated accelerated radiotherapy (CHART). In contrast to conventionally fractionated radiotherapy which takes approximately 45 days to deliver, CHART is completed in just 12 days. The pivotal phase III trial showed a 9% improvement in 2-year survival with CHART when compared with a higher dose delivered by conventional
P. Jenkins et al. / Radiotherapy and Oncology 93 (2009) 396–401
fractionation [13]. Therefore it seemed logical to combine induction chemotherapy with CHART in an attempt to improve the proven survival benefits of both these approaches. As far as we are aware, this is the first study to formally test the feasibility of this strategy. We have previously reported on the impact that tumour shrinkage with chemotherapy had on radiation treatment planning for patients entered in this study [14]. Herein we report the mature, outcome results of the trial. Materials and methods Forty patients were enrolled in a prospective phase II study evaluating the use of induction chemotherapy followed by CHART. Eligibility criteria comprised: histologically confirmed stage III NSCLC (no pleural effusion or supraclavicular lymph node disease), World Health Organisation performance status 0–1, weight loss < 5% within the preceding 3 months, satisfactory lung function (forced expiratory volume in 1 s >1.5 l) and suitability for treatment with chemotherapy. The protocol was approved by the Gloucestershire Research and Ethics Committee. Pre-treatment evaluation included history, physical examination, chest radiograph, fibre-optic bronchoscopy and contrast enhanced computed tomography (CT) scan of the chest and upper abdomen. In addition 2 patients had staging positron emission tomography (PET) scans and 6 had previous exploratory surgery. Further investigations to exclude metastases were performed if clinically indicated. Patient demographics, tumour characteristics and treatment parameters are shown in Table 1. Treatment comprised 3 cycles of induction chemotherapy using mitomycin-C 8 mg/m2, vinblastine 6 mg/m2 (maximum 10 mg) and carboplatin. Mitomycin-C was omitted from the third cycle of treatment. Carboplatin was dosed using the Calvert equation, at an area under the concentration curve of 5. Glomerular filtration rate was determined using radiolabelled ethylenediamine tetraacetic acid (EDTA) clearance. Chemotherapy was delivered on a 3 weekly schedule. Treatment was delayed if the neutrophil count on the planned day of delivery was <1.5 109/l or if the platelet count was <100 109/l. Prophylactic antibiotics were used to minimise the risk of febrile neutropaenia. The protocol recommended Table 1 Demographics, tumour characteristics and treatment parameters. V20, the fractional volume of the lung receiving >20 Gy. MLD, mean lung dose. Age Gender
Median 66 (range 47–79) Male 25, female 15
Stage IIIA IIIB
9 (22.5%) 31 (77.5%)
Histology Squamous cell Adenocarcinoma Unspecified Pre-chemotherapy tumour volumea Pre-chemotherapy RECIST measurementa
23 (57.5%) 7 (17.5%) 10 (25%) Median 125 cc (range 36–679) Median 65 mm (range 23–137)
Tumour location (lobe)b Right upper Right middle Right lower Left upper Left lower
14 (35%) 5 (12.5%) 4 (10%) 9 (22.5%) 7 (17.5%)
Tumour positionb Central Peripheral
32 (80%) 7 (17.5%)
Radiotherapy parameters V20 MLD
Median 23% (range 4–41%) Median 12.3 Gy (range 5.2–18.4)
a b
Pretreatment tumour volume measurement in 36 assessable patients. In one patient the site of the primary could not be defined.
397
that haemoglobin levels be maintained above 11 g/dl before starting radiation therapy. CT scans for radiotherapy planning were performed before starting and 2 weeks after completion of chemotherapy. These were subsequently spatially coregistered using XiO software (Computerized Medical systems, St. Louis, MO). CHART was commenced 3.5–4 weeks after the completion of chemotherapy. Our radiotherapy protocol has previously been described in detail [14]. Briefly, all patients were treated with 3-dimensional conformal radiation therapy. The primary and involved lymph nodes were included in a single phase of treatment. Pre-chemotherapy tumour dimensions were used to form the target volume. Most patients were treated with three coplanar beams designed such that the spinal cord did not received >40 Gy and that the fractional volume of lung receiving >20 Gy (V20) did not exceed 35%. Radiotherapy planning was performed with the XiO treatment planning system and its forerunners. All patients received CHART (54 Gy prescribed to the isocentre in 36 fractions over 12 days, treating three times a day with an interfraction interval of 6 h). The median OTT from the start of chemotherapy to finishing radiation therapy was 82 days (range 72–114). Patients were monitored weekly during and following the completion of radiotherapy, either for a minimum of 6 weeks or until resolution of acute radiation toxicity. Subsequent follow-up visits were at 3 monthly intervals for life. A CXR was performed at 4 weeks and at every subsequent visit. Post-therapy CT scans were performed routinely at 3 months and 12 months after the end of treatment, then yearly. Acute toxicity to chemotherapy was recorded using the National Cancer Institute common toxicity criteria (version 2) and acute and late toxicity to radiotherapy using Radiation Therapy Oncology Group criteria. The primary outcome measure was radiation toxicity. The secondary endpoints were response rate at 3 months, overall survival (OS), progression-free survival (PFS) and loco-regional progression-free survival (LR-PFS). The Response Evaluation Criteria in Solid Tumours (RECIST) measurement were used to determine response rates [15]. Survival was defined as the time from entry into the study to the event and was calculated using the Kaplan– Meier method. Patients who remained alive were censored as of May 2008. Treatment on progression comprised second line chemotherapy (gemcitabine or docetaxel based) in 14 and tyrosine kinase inhibitors (gefitinib or erlotinib) in 4. The rate of tumour growth after relapse was measured on serial diagnostic scans. Tumour volumes were estimated using the formula 4/3p(Dl–r/2 Da–p/2 Dc–c/2) where Dl–r is the maximum diameter in the left to right direction, Da–p is the maximum diameter in the anterior to posterior direction and Dc–c is the maximum diameter in the cranio-caudal direction. The tumour volume doubling time (Vd) was calculated using the standard volumetric formula Vd = (tln 2)/[ln Vf/Vi] where t is the time in days between the two CT scans, Vf is the volume measured on the final CT scan and Vi is the volume measured on the initial CT scan. Statistical analyses were performed using SPSS (SPSS Inc, Chicago, IL). Pearson’s correlation coefficient Student’s t-test, paired sample t-tests and chi-squared tests were used as appropriate.
Results Chemotherapy was well tolerated and all patients completed 3 cycles of treatment as planned. Ten patients experienced a grade 3 or above chemotherapy toxicity, mostly myelosuppression (Table 2). All toxicities were transient and resolved spontaneously. The most common acute radiation complication was oesophagitis which occurred in 38 (95%) patients (Table 2). In only 1 patient was this Pgrade 3 (weight loss > 15% and/or requiring opiate analgesics/feeding support) and in all cases oesophagitis resolved with
398
Induction chemotherapy and CHART
Table 2 Recorded maximum treatment-related toxicities.
Chemotherapy toxicity Haematological Anaemia Neutropaenia Thrombocytopaenia Febrile neutropaenia
Grade 1
Grade 2
Grade 3
13 (32.5%)
13 (32.5%)
2 (5%)
2 (5%)
3 2 1 4
Non-haematological Mucositis Nausea/vomiting Diarrhoea/constipation Pulmonary Peripheral neuropathy Anorexia Infection Fatigue
19 (47.5%) 7 (17.5%) 16 (16%) 1 (2.5%) 2 (5%) 7 (17.5%) 1 (2.5%) 18 (45%)
Radiation toxicity Oesophagitis Pneumonitis
25 (62.5%) 1 (2.5%)
(7.5%) (5%) (2.5%) (10%)
4 (10%) 2 (10%)
2 (5%) 2 (5%) 7 (17.5%) 12 (30%)
1 (2.5%) 4 (10%)
a supportive outpatient care in 3–6 weeks. Grade 3 (requiring corticosteroids) radiation pneumonitis occurred in 4 (10%) patients. There were no symptomatic late complications noted. Using the RECIST criteria, we evaluated the extent of the response to chemotherapy and radiotherapy. Fourteen patients had a partial response, 22 had stable disease and 1 had progressive disease following chemotherapy. In 3 patients it was not possible to measure tumour size accurately as a consequence of associated collapse or consolidation. The mean reduction in the RECIST measurement was 26%. The response to radiation in the 39 patients with non-progressive disease after chemotherapy was also assessed. Two patients had a complete response, 15 had a partial response and 18 had stable disease. Three patients had progressive disease (all distant metastatic relapse) and in 1 patient it was not possible to assess the local response due to peri-tumoural fibrosis post therapy. The mean reduction in the RECIST measurement following radiotherapy was 29%. The overall response rate following completion of all treatment was 65%. In 33 patients it was possible to measure both the response to radiation and the response to chemotherapy. As shown in Fig. 1 these were poorly correlated (r = 0.09, p = 0.61). Furthermore the extent of tumour shrinkage with neither chemotherapy (n = 36) or radiotherapy (n = 35) were not individually correlated with
Fig. 1. Shrinkage in the RECIST measurement in response to chemotherapy and radiotherapy for 33 assessable patients. Horizontal and vertical lines represent the cut point between stable disease (SD) and partial response (PR).
survival (r = 0.15, p = 0.37 and r = 0.29, p = 0.1, respectively). However the extent of disease shrinkage after completion of all therapy did correlated weakly with survival (r = 0.35, p = 0.05). Thirty four patients have died. With a minimum follow-up of 25 months for surviving patients the median (+95% confidence intervals) OS, PFS and LR-PFS were 15.7 (11.9–19.5), 12.1 (9.9–14.3) and 26.4 (10.0–42.8) months, respectively. OS, PFS and LR-PFS at 1 year and 2 years were 78% and 28%; 53% and 23%; 86% and 51% (Fig. 2). Seventeen patients had a prolongation in OTT beyond the planned 82 days, due to either a delay in their chemotherapy programme or logistic problems relating to the availability of CHART treatment. Fig. 3 illustrates the deleterious effect that prolonging OTT has on survival. At the time of analysis 37 patients had either relapsed or died. The site of first failure was categorised as locoregional alone in 11 (7 of these judged to be at the primary site), distant metastatic disease alone in 17 (7 developed brain metastases), locoregional as well as distant failure in 6 and intercurrent disease in the absence of documented relapse in 3. The primary intrathoracic tumour was judged to be controlled at the time of death in 61% patients. We also noted that in patients where the disease did relapse locally at the primary site, the rate of tumour growth was slow (Fig. 4). In 5 patients with predominantly in field relapse, serial scans were available prior to the commencement of second-line treatment, which was generally reserved for symptomatic progression. The median tumour volume doubling time for this group was 21 weeks (range 7–31 weeks). Due to concern about the possible negative impact of chemotherapy-related anaemia on the effectiveness of radiotherapy, the study protocol recommended that blood transfusions be used to maintain haemoglobin levels above 11 g/dl. In total, 24 patients received transfusions during chemotherapy to maintain their haemoglobin levels (2 units in 10, 3 units in 9, 4 units in 2, 6 units in 2 and 7 units in 1). On an average 1.9 units of blood were transfused per patient. Despite this active transfusion policy mean haemoglobin levels fell from 12.7 g/dl pre-chemotherapy to 11.3 g/dl post-chemotherapy, p < 0.001 (Fig. 5).
Discussion Induction chemotherapy when combined with radical radiotherapy improves the survival of patients with stage III NSCLC [1–3]. However the results of sequential treatment are generally
Fig. 2. Kaplan–Meier curves for overall survival (OS), progression-free survival (PFS) and loco-regional progression-free survival (LR-PFS).
P. Jenkins et al. / Radiotherapy and Oncology 93 (2009) 396–401
Fig. 3. Correlation between overall treatment time and overall survival (r = 0.34, p = 0.03). Patients who were still alive at the time of analysis are represented by open circles.
considered to be inferior to synchronous chemoradiation [5–8]. Similar findings have been reported for other tumour sites treated with combined modality therapy [16]. In part this may reflect the prolongation of OTT which is an inevitable consequence of sequential chemoradiation [17]. There is now randomised trial evidence confirming that shorter radiotherapy schedules improve outcome in NSCLC [13] and small-cell lung cancer [18]. The combination of chemotherapy with CHART was therefore attractive, not only to combine the proven survival benefits of each of these treatments but also to minimise the negative effect of accelerated repopulation following induction chemotherapy. Three previous studies have attempted to combine chemotherapy with CHART. Oral et al. reported on the use of concomitant paclitaxel and CHART in 20 patients with NSCLC [19]. In this study acute toxicity was unacceptable with 70% of patients experiencing grade 2–3 oesophagitis and 50% experiencing grade 3 or greater pulmonary toxicity. Oner Dincbas et al. conducted a study of
399
induction, synchronous and consolidation vinorelbine based chemotherapy with CHART [20]. The median survival for the 22 patients enrolled was 12 months. Grade 3 oesophagitis was seen in 9% and 23% patients developed clinical pneumonitis. Finally, Kirkbride et al. reported a trial of induction chemotherapy using vinorelbine and cisplatin prior to CHART [21]. Their study was closed prematurely following 2 treatment-related deaths in the first 3 patients enrolled. Thus the toxicity of this approach seems considerable, particularly when chemotherapy is used synchronously or shortly before CHART. In contrast to these studies our trial mandated a 3.5–4 week interval between the completion of chemotherapy and the start of radiation therapy. Probably because of this interval, the acute radiation toxicity that we observed was low. There was only 1 (3%) case of grade 3 oesophagitis, 4 cases (10%) of grade 3 pneumonitis and no symptomatic late radiation toxicity. This toxicity profile compares very favourably with synchronous chemoradiation protocols which are associated with grade 3 oesophagitis in 20–30% of patients treated [6–8]. Studies of concomitant chemoradiation in NSCLC generally report median survivals of 16–17 months and 2-year OS of 34–39%. In contrast, sequential chemoradiation produces median survivals of 13–15 months and 2-year OS of 14–27% [5–8]. However when accelerated radiation fractionation is used, the results of sequential chemoradiation may be improved (Table 3). In this study we saw survival rates that are similar to synchronous chemoradiation, in a population that was staged prior to the widespread application of PET imaging. In several tumour sites including lung cancer the response to induction chemotherapy or chemoradiation has been advocated as a means of selecting patients for subsequent radiotherapy or surgery [22]. The rationale for this approach is the belief that if the tumour is responsive to chemotherapy it will also be sensitive to radiation. We found no evidence of an association between the response to chemotherapy and radiation to support this hypothesis in our study. Thus 48% of patients who fail to respond to chemotherapy still manifested significant disease shrinkage following radiotherapy (9 partial and 1 complete responses). Similarly 50% of the patients who initially responded to chemotherapy had only stable disease following radiation. Therefore we do not think that
Fig. 4. Serial CT scans for 2 patients illustrating the indolent nature of local relapses following chemoradiation. Both patients were observed until they became symptomatic. Patient A relapsed having achieved a complete response post therapy. Patient B had a residual mass post therapy (arrowed) that slowly progressed. Timings are months post radiotherapy.
400
Induction chemotherapy and CHART
Fig. 5. Fall in haemoglobin with chemotherapy. Despite an active transfusion policy, there was a significant fall in mean haemoglobin levels with chemotherapy (12.7–11.3 g/dl, p < 0.001).
initial chemotherapy response should be used to select patients as being any more or less suitable for subsequent radiotherapy. Despite the high frequency of distant metastases, loco-regional control rates for lung cancer remain poor and contribute to the lethality of this disease. Over 75% of patients with stage III NSCLC die with uncontrolled tumour in the chest. Strategies that improve loco-regional control would be expected to lead to better survival and are a prerequisite for cure. Indeed the benefit of synchronous chemoradiation is thought to accrue predominantly due to an improvement in local control [23]. In the light of these observations one of the most pleasing aspects of our results is the excellent local control rate. Only 7 (18%) patients relapsed ‘in field’ as a site of first failure and primary tumour control was achieved in 62% patients at the time of death. We hypothesise that this promising result most likely derives from the ability of CHART to minimise the impact of accelerated repopulation following chemotherapy. We note that recent overviews of chemoradiation in small-cell and non-small-cell lung cancer have found that OTT to be highly predictive of survival [9,10]. Fig. 3 illustrates the fact that even with CHART, it is important not to unduly protract the treatment course. Indeed further shortening the OTT, for example by delivering only 2 cycles of induction chemotherapy, may paradoxically improve the efficacy of combined modality treatment for lung tumours.
The extent of the fall in haemoglobin levels following induction chemotherapy came as a surprise. Anaemia is thought to reduce oxygen delivery to the tumour, thereby increasing hypoxia and radioresistance. An analysis of pooled trials has shown that low pre-treatment haemoglobin level is predictive of poorer outcome following radiotherapy [24]. However, as yet, correction of haemoglobin by transfusion has not been shown to compensate for this deleterious effect. In our study 12 patients (30%) had a haemoglobin <12 g/dl pre-chemotherapy, whilst 31 patients (78%) had a haemoglobin <12 g/dl post-chemotherapy despite the active transfusion policy that we deployed. It may be that failure to fully compensate for falls in haemoglobin levels could confound the comparison between induction and concurrent chemotherapy. In addition small reductions in haemoglobin which are insufficient to be scored as grade 1 (<10 g/dl) may still have a profound impact on radiosensitivity. Close attention should be paid to haemoglobin levels pre-radiotherapy to ensure that the effectiveness of sequential chemoradiation is not potentially compromised. We also noted that in patients who subsequently develop local recurrence at the primary site, the rate of growth on recurrence is extremely slow (Fig. 4). The Vd in this group of patients was 5 months and their median survival from the time of relapse was 27 months. In comparison the Vd in untreated NSCLC is approximately 3 months, whilst for patients relapsing after chemotherapy, Vd is only 1 month [17]. This interesting observation may result from an effect of radiotherapy on the tumour vasculature resulting in reduced perfusion. Alternatively it may be an effect of CHART on tumour clonogens triggered into accelerated repopulation by chemotherapy. This population of rapidly cycling cells may be preferentially killed by CHART leaving only slowly proliferating tumour cells that are more able to repair sublethal radiation damage. Ultimately the latter population of slowly cycling cells expands leading to the indolent growth pattern seen. Several limitations of our study should be acknowledged. The chemotherapy regimen chosen would no longer be considered optimal by modern standards. In addition the early timing of the re-evaluation scans may underestimate the true response rate to chemotherapy. However for the first time we have shown that induction chemotherapy can be safely combined with CHART. The side effects of the combination used in this study are minimal and survival rates are comparable with those reported with concurrent chemoradiation. Interestingly we note that the only randomised trial which compared sequential with concurrent chemotherapy using an accelerated radiotherapy scheme, found no difference in survival between the arms [25]. Furthermore, the best results reported in a phase III study of chemoradiation in locally advanced NSCLC have come from the combination of 2 cycles of carboplatin-paclitaxel followed by hyperfractionated accelerated radiation therapy (HART) [26]. We think that this approach warrants further investigation.
Table 3 Published combinations of induction chemotherapy and radical radiotherapy using accelerated fractionation protocols (>2 Gy per day) for NSCLC. Abbreviations: PC, paclitaxel and carboplatin; VC, vinorelbine and cisplatin; GC, gemcitabine and cisplatin; MVP, mitomycin-C; vinblastine and cisplatin; MVC, mitomycin-C, vinblastine and carboplatin. First author
Study (phase)
Number (% stage III)
Total dose (Gy)/fraction size (Gy)/number of fractions/overall time (days)
Chemotherapy
Median survival (months)
2-Year survival
Belani [26] Belderbos [25] Bonomi [27] Ishikura [28] This study Chen [29] Rojas [30]
III III II II II II II
58 78 44 30 40 73 42
57.6/1.5–1.8 tid/36/18 66/2.75/24/32 <60/1.5 tid/<40/18 57.6/1.5–1.8 tid/36/18 54/1.5 tid/36/12 66/<1.5 bid/50/33 60/1.5 tid/40/<19
PC 2 GC 2 Various 3 VC 2 MVC 3 MVP 2 PC 3
20 16 20a 24 16 13 33
44% 34% 42%a 50% 26% 10% 57%
a
Read from graph.
(100%) (92%) (100%) (100%) (100%) (100%) (52%)
P. Jenkins et al. / Radiotherapy and Oncology 93 (2009) 396–401
Acknowledgements The authors acknowledge the assistance of Dr. S Elyan and Dr. D Farrugia in the completion of this study. References [1] Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III nonsmall-cell lung cancer. N Engl J Med 1990;323:940–5. [2] Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 1991;83:417–23. [3] Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88–08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 1995;87:198–205. [4] Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992;326:524–30. [5] Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17:2692–9. [6] Curran WJ, Scott CB, Langer CJ, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 2003;22:2499. [7] Zatloukal P, Petruzelka L, Zemanova M, et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced nonsmall cell lung cancer: a randomized study. Lung Cancer 2004;46:87–98. [8] 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;23:5910–7. [9] 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;63:667–71. [10] De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 2006;24:1057–63. [11] Davis AJ, Tannock JF. Repopulation of tumour cells between cycles of chemotherapy: a neglected factor. Lancet Oncol 2000;1:86–93. [12] Bentzen SM. Repopulation in radiation oncology: perspectives of clinical research. Int J Radiat Biol 2003;79:581–5. [13] Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol 1999;52:137–48. [14] Jenkins P, Milliner R, Latimer P. Shrinkage of locally advanced non-smallcell lung cancers in response to induction chemotherapy: implications for radiotherapy treatment planning. Int J Radiat Oncol Biol Phys 2007;69:993–1000.
401
[15] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16. [16] Bartelink H, Schellens JH, Verheij M. The combined use of radiotherapy and chemotherapy in the treatment of solid tumours. Eur J Cancer 2002;38:216–22. [17] El Sharouni SY, Kal HB, Battermann JJ. Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy. Br J Cancer 2003;89:2184–9. [18] Turrisi 3rd AT, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265–71. [19] Oral EN, Bavbek S, Kizir A, et al. Preliminary analysis of a phase II study of paclitaxel and CHART in locally advanced non-small cell lung cancer. Lung Cancer 1999;25:191–8. [20] Oner Dincbas F, Koca S, Altinel A, et al. Continuous accelerated hyperfractionated radiotherapy (CHART) plus chemotherapy (CT) with vinorelbine (VB) and cisplatinum (CDDP) in locally advanced NSCLC (TOG011 study). Eur J Cancer 2001;37:S53. [21] Kirkbride P, Hatton M, Lorigan P, Joyce P, Fisher P. Fatal pulmonary fibrosis associated with induction chemotherapy with carboplatin and vinorelbine followed by CHART radiotherapy for locally advanced non-small cell lung cancer. Clin Oncol (R Coll Radiol) 2002;14:361–6. [22] Albain KS, Swann RS, Rusch V, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol 2005;23:7014. [23] Auperin A, Rolland E, Curran W, et al. Concomitant radio-chemotherapy (RTCT) versus sequential RT-CT in locally advanced non-small cell lung cancer: a meta-analysis using individual patient data from randomised clinical trials. J Thoracic Oncol 2007;2:S310. [24] Werner-Wasik M, Scott C, Cox JD, et al. Recursive partitioning analysis of 1999 Radiation Therapy Oncology Group (RTOG) patients with locally-advanced non-small-cell lung cancer (LA-NSCLC): identification of five groups with different survival. Int J Radiat Oncol Biol Phys 2000;48:1475–82. [25] Belderbos J, Uitterhoeve L, van Zandwijk N, et al. Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972–22973). Eur J Cancer 2007;43:114–21. [26] Belani CP, Wang W, Johnson DH, 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;23:3760–7. [27] Bonomi M, Blanco-Savorio A, Cerchietti L, et al. Continuous hyperfractionated accelerated radiation therapy week-end less in combination with neoadjuvant chemotherapy for the treatment of stage III non-small-cell lung cancer. Lung Cancer 2008;60:75–82. [28] Ishikura S, Ohe Y, Nihei K, et al. A phase II study of hyperfractionated accelerated radiotherapy (HART) after induction cisplatin (CDDP) and vinorelbine (VNR) for stage III non-small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 2005;61:1117–22. [29] Chen GY, Jiang GL, Qian H, et al. Escalated hyperfractionated accelerated radiation therapy for locally advanced non-small cell lung cancer: a clinical phase II trial. Radiother Oncol 2004;71:157–62. [30] Rojas AM, Lyn BE, Wilson EM, et al. Toxicity and outcome of a phase II trial of taxane-based neoadjuvant chemotherapy and 3-dimensional, conformal, accelerated radiotherapy in locally advanced nonsmall cell lung cancer. Cancer 2006;107:1321–30.