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Chemoradiation for inoperable non small cell lung cancer
Lung Cancer 23 (1999) 233 – 240
Chemoradiation for inoperable non small cell lung cancer A phase II study using a regimen with acceptable toxicity Bryan H. Burmeister a,*, N. Kumar Gogna a, Guy P. Bryant a, John Armstrong b, Wayne Kelly b, John Mackintosh c, Euan Walpole b, Karen Morton a a
Queensland Radium Institute, Raymond Terrace, South Brisbane, QLD 4101 Queensland, Australia b Princess Alexandra Hospital, Woolloongabba, Queensland, Australia c Mater Hospital, Raymond Terrace, South Brisbane, Queensland, Australia
Received 7 September 1998; received in revised form 18 January 1999; accepted 22 January 1999
Abstract Over the past few years there have been numerous schedules of combined modality therapy proposed as being useful in the management of inoperable non-small cell lung cancer (NSCLC). These have generally involved the use of high dose radiation therapy to doses of the order of 60 Gy combined with chemotherapy given prior to or concurrently with the radiation. Concurrent chemotherapy has been given with the intention of being both active in NSCLC and with the role of being a possible radiosensitiser. The most commonly employed drugs have been cisplatin, etoposide, 5-fluorouracil, vindesine and mitomycin. Although response rates of the primary tumour to the combined therapy have been optimistic, there has not been a great survival benefit with the median survival in most series remaining at just over 12 months. In this study we have prospectively treated a group of patients with non-metastatic inoperable NSCLC with a regimen of known acceptable toxicity. These patients were inoperable because they were unfit for surgery or had locally advanced disease. The local radiological response rate was 86% and the median survival for the whole group was 13 months. Adenocarcinomas appeared to do significantly worse than squamous cell carcinomas. Toxicity was acceptable and lower than reported in other similar series. There was one treatment related death. We feel that this combination of radiation therapy and chemotherapy is a reasonable compromise for a disease which still has a very poor outlook. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non small cell lung cancer; Combined modality therapy; Concurrent chemoradiation
* Corresponding author. Fax: +61-7-38403399. 0169-5002/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 9 9 ) 0 0 0 1 0 - 0
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B.H. Burmeister et al. / Lung Cancer 23 (1999) 233–240
1. Introduction Lung cancer remains a leading cause of death in the western world. Non-small cell lung cancer (NSCLC) constitutes 75 – 80% of all lung cancers and has a cure rate of only 13% at 5 years [1]. Approximately 40–50% of patients present with localised non-metastatic NSCLC, half of whom are generally not suitable for surgical resection as a result of co morbidity and/or local extension within the thorax [2]. Inoperable NSCLC thus represents a spectrum of disease ranging from medically unfit patients with T1 N0 disease to patients with technically inoperable T1 – 3 N1 – 2 disease. Radiation therapy can successfully be used for inoperable NSCLC but its success appears confined mostly to patients with early tumours (usually less than 3 cm in size) [3]. In this setting, local control can from 50 – 75% [4]. Larger tumours have local control rates which are considerably less (only up to 40%) [5]. Poor local control in turn translates into decreased overall survival. Attempts have been made to improve the results of radiation therapy with the use of altered fractionation schemes [6] or by the use of concurrent chemotherapy [7–11]. While altered fractionation schedules do show some promise, the logistics involved are significant. Sequential chemotherapy and radiation therapy has been shown to be advantageous in two clinical trials although there has been no significant impact on local control [12 – 17]. Concurrent chemoradiation has become accepted routine therapy for anal carcinoma and non-resectable oesophageal carcinoma. A variety of agents have been used in combination with radiation, the most commonly used being cisplatin and 5-fluorouracil. Since 1984, a three armed phase II study utilising moderate dose cisplatin and 5-fluorouracil with radiation therapy has been piloted in Australasia for oesophageal cancer [18]. The cisplatin is administered as a single dose on day 1 which is followed by a 96 h infusion of 5-fluorouracil. The cycle is then repeated 3 weeks later. This regimen has produced both high response rates and low toxicity when compared with other concurrent chemoradiation schedules for the same disease [19].
For the patient with inoperable NSCLC, the important questions are: Can one really justify giving chemotherapy in addition to radiation therapy when there is only a small improvement in survival with considerable added toxicity? Is it possible to minimise the toxicity of combined therapy and still achieve the good local responses and a similar median survival? In this study we set out to answer these questions by employing high dose conventional radiation therapy with a schedule of chemotherapy which is known to be well tolerated. The investigators of this study decided to try the same moderate dose chemotherapy schedule being used for oesophageal cancer with apparent low toxicity, for the management of locally advanced NSCLC in a prospective phase II study. It was hoped that equivalent or improved results compared to other such studies could be obtained with acceptable toxicity.
2. Materials and methods From January 1992 until December 1995, 45 patients were registered on study. All patients were diagnosed as having biopsy proven inoperable NSCLC. Six patients had early stage disease and were medically unfit for for surgery. The other 39 patients had locally advanced disease. Routine blood tests, bone scan, computerised tomography of the chest and abdomen as well as CT of the brain were performed to exclude distant metastases. Only patients of good performance status (ECOG 0–1) were eligible. Patients who had suffered more than 10% weight loss in the previous 3 months were not considered eligible. The patients were also required to have normal blood counts, a serum creatinine 5 0.13 mmol/l and no hearing deficit. Patients having an FEV1 of less than 1200 ml were regarded as being ineligible. Of the patients registered there were 30 males and 15 females. Details of clinical stage, histological subtypes, performance status and weight loss are summarised in Table 1. All patients received radical radiation therapy using a linear accelerator. The recommended dose schedule was 60 Gy to the isocentre in 30 fractions over 6 weeks. Where treatment extended
B.H. Burmeister et al. / Lung Cancer 23 (1999) 233–240
over three or more public holidays or required more than 3 days of unscheduled breaks, the dose was increased to 62 Gy in 31 fractions. Planning was performed using a simulator with CT interfacing to allow tissue inhomogeneity correction. The target volume included the primary tumour as well as all obviously involved nodal disease. Radiation was directed to a volume including the visible disease and a 2 cm margin laterally and a 3 cm margin superiorly and inferiorly. In most instances a three or four field technique was used to limit the spinal cord dose to 45 Gy. This technique also allowed the radiation dose to the contralateral lung to be kept as low as possible. Chemotherapy was administered concurrently with fractions 1–5 and 16 – 20. On days 1 and 22 (coinciding with fractions 1 and 16), patients were initially given radiation and the chemotherapy was commenced. Most patients were able to be given chemotherapy as an outpatient by being attached to a portable infusion pump via a central venous line. Cisplatin 80 mg/m2 was given as a slow infusion over 20 – 30 min following adequate prehydration. This was then followed by 5fluorouracil 800 mg/m2/day given over 96 hours as a continuous infusion. Suitable antiemetics were given when required. In three patients, the second course of chemotherapy was omitted as a result of toxicity. In two patients, a delay of one week occurred before the second course until blood counts had improved. Endpoints studied included local response, sites of relapse, toxicity of treatment, progression-free survival and overall survival. Survival and progression-free survival times were calculated from
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the first day of treatment. Following treatment a chest X-ray was performed every 3 months and a CT scan of the chest at 3 months and then every 6 months. Radiological investigations to detect distant metastases such as CT of the brain and radionuclide bone scans were performed only if symptoms justified the investigation. Particular attention was paid to the occurrence of oesophageal toxicity both during and following therapy. Effects of radiation therapy on lung tissue were monitored closely with regular spirometry at each follow up visit as well as noting changes on chest X-ray. Routine follow up bronchoscopy was not performed unless symptoms suggested recurrent endobronchial tumour. Assessment of response was thus primarily based on radiological assessment with CT scan. Given the slow response seen in some tumour it was felt that the optimum time for assessment for response would be based on a CT of the chest at 3 months. The tumour response was then recorded. If a partial response was noted, the CT was repeated at six months and if a complete response had then occurred, the maximum response was then recorded. Assessment of toxicity was performed according to the WHO and RTOG criteria. The worst grade of toxicity experienced was documented. An analysis was performed late in 1997 following 18 months of followup of the last patient entered on study. The Kaplan–Meier method was used to generate survival and progression free survival curves. Differences between the curves were analysed using the the log-rank test. A Pvalue of B 0.05 was regarded as significant.
Table 1 Patient details Clinical stage
No. of patients (%)
Histology
No. of patients (%)
1B 2 3A 3B ECOG 0 ECOG 1
4 (9%) 2 (4%) 31 (69%) 8 (18%) 14 (31%) 31 (69%)
SCC Adenocarcinoma large cell Other Mininal weight loss (B5%) Weight loss 5–10%
18 (40%) 18 (40%) 1 (2%) 8 (18%) 29 (64%) 16 (36%)
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Fig. 1. NSCLC study.
3. Results The median age for the group of patients was 57 years with a range of 31 – 76 years. At the time of response assessment (3 – 6 months after commencement of treatment), 36 patients (80%) had achieved a radiological complete response and five patients (11%) a partial response. Two patients had progressive or stable disease. Two patients were not evaluable (death before 3 months). Of the patients who had a complete response, 16 subsequently relapsed within the treated volume. This represents a 43% relapse rate among the apparent complete responders. In the whole group, 23 patients ultimately failed locally. Of these, only eight were associated with systemic relapse. The other sites of failure were brain (27%), nodes (16%), bone (14%), lung (11%), liver (9%), skin (7%), and pleura (5%). Of the adenocarcinomas, 33% developed cerebral metastases. The mean follow up for survivors was 36 months with a median survival of 13 months. The 95% confidence interval for the median survival for the whole group of patients was 37 – 63%. At the time
of writing three patients were alive and diseasefree. The overall survival curve showing the 95% confidence interval for the whole group is shown in Fig. 1. The progression-free survival curves for the two major histological groups (squamous cell carcinoma and adenocarcinoma) are shown in Fig. 2. At 3 years there was a significant difference in progression-free survival between these two subgroups (P B 0.025). It was felt that this difference was related to the high rate of cerebral relapse in adenocarcinomas. There was no difference in the rate of local relapse. In general the therapy was extremely well tolerated. The most significant side effect was oesophagitis which occurred in most patients. However Grade 3 or 4 oesophagitis was noted in only four patients who required admission for nasogastric feeding at the end of therapy. There was one treatment related death. This has occurred in a patient who had developed peritonitis following rupture of a large bowel diverticulum. Unfortunately the patient was at the end of the therapy schedule and was neutropenic at the time. Other acute side effects were generally minor.
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Fig. 2. NSCLC study — histology.
These are summarised in Table 2. The incidence of radiation pneumonitis was assessed according to changes on chest X-ray as well as follow-up spirometry. The incidence of late changes on chest X-ray are summarised in Table 3. There were no cases of cardiac toxicity or long term oesophageal stricture. No patients showed any evidence of spinal cord damage.
4. Discussion The management of inoperable early stage or locally advanced NSCLC has until recently been with high dose radiation therapy. Several studies have indicated the necessity for a high radiation dose in order to optimise local control [20] although there is limited evidence for a dose response above 69.6 Gy [21]. Over the past few years attention has focused on the use of concomitant chemotherapy in order to optimise local control and possibly influence the rate of systemic relapse. Four randomised trials set out to answer the question of whether the radiosensitising properties of cisplatin do convey a benefit in combina-
tion with radiation therapy [7–10]. The administration of the drug during radiation varied from small daily doses of 6 mg/m2 to three weekly doses of 80–100 mg/m2. Of these, in only two cases was a survival benefit noted [7,9]. Other chemotherapeutic agents which have been used in combination with cisplatin are etoposide and vindesine. Further trials using the newer agents which are active in non-small cell cancer in combination with radiation are currently being investigated. These drugs include vinorelbine, the taxanes and gemcitabine either as sole agents or in Table 2 Acute toxicity Toxicity
Grade 1–2 No. of patients (%)
Grade 3–4 No. of patients (%)
Nausea/vomiting Oesophagitis Neutropenia Thrombocytopenia Skin reaction
20 (44%) 39 (87%) 7 (16%) 3 (7%) 24 (53%)
0 4 2 0 0
(0%) (9%) (4%) (0%) (0%)
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Table 3 Late pulmonary toxicity Toxicity grade
No. of patients (%)
Not assessable Grade 1 — faint shadows Grade 2 — moderate shadows Grade 3 — faint shadows, distorted anatomy
14 (31%) 21 (47%) 2 (4%) 3 (7%)
combination with platinum-containing agents and radiation therapy. The radiosensitising properties of these agents are uncertain but they are active in metastatic disease. It therefore may well be that their inclusion was to influence patterns of metastases rather than sensitise the tumour to radiation. Although 5-fluorouracil has been used as a radiosensitiser ar other sites e.g. oesophagus, there has been very little literature regarding its use in lung cancer. A study in palliative patients performed at the Peter MacCallum Cancer Institute showed some benefit in terms of responses noted in patients who received both palliative radiation therapy with concomitant 5-fluorouracil [22]. There was also a trend towards improved progression-free survival. Given the excellent results seen with the combination of radiation, cisplatin and 5-fluorouracil with both squamous cell and adenocarcinoma of the oesophagus, it is not unreasonable that the same combination be trialed in non-small cell lung cancer. As the tumour site is very similar, some information on toxicity is available from oesophageal cancer studies. We decided to implement in inoperable non-small cell lung cancer an identical regimen to that used in a large multicentre oesophageal study performed in Australia [18]. The regimen is a combination of known radiosensitisers with some probable effect on metastatic disease. It utilises moderate doses of cisplatin and 5-fluorouracil with very acceptable toxicity. Nevertheless, it appears no less effective than other high dose schedules for oesophageal cancer which have been trialed in the USA and are perhaps more toxic. There is however no randomised clinical trial in NSCLC comparing this regimen with radiation therapy alone. There have been several
randomised studies comparing radiation alone with other regimens containing concurrent cisplatin and radiation. Two meta-analyses have been performed to assess the benefit of adding chemotherapy to patients having radical radiation therapy. The meta-analysis by Pritchard of 1280 patients involved showed an improvement in median survival but also increased toxicity [23]. A second meta-analysis performed by the Non Small Cell Lung Cancer Collaborative Group involved more than 3000 patients from 22 randomised trials [24]. This showed a survival benefit for combined therapy of 2% at 5 years. There is also a suggestion that concurrent therapy is preferable to sequential neoadjuvant therapy [25]. What is clear from this and other numerous phase II studies is that combined therapy produces higher response rates than with radiation alone. The American Society of Clinical Oncology has recommended that combined therapy be considered in patients of good performance status with locally advanced NSCLC [26]. The treatment should include both high dose radiation therapy to a dose equivalent of 60 Gy over 6 weeks with platinum-based chemotherapy. We were disappointed in the local failure rate of 51%, especially as 15 patients developed isolated local recurrence in the absence of distant metastases. Could they have been salvaged by follow up surgery? Preliminary studies looking at neoadjuvant combined therapy followed by surgery have shown early promise [27]. Although it is not known what the ultimate chest recurrence rate will be, most of our patients who developed in-field recurrences did so after being in a period of apparent complete remission. It would thus be difficult to justify aggressive thoracic surgery involving nodal dissection of the mediastinum under these circumstances where a radical dose of radiation has been given. Because of the rate of local and distant failure, median survival of locally advanced NSCLC remains low and in the region of 12–14 months. Attempts at accelerating the radiation with multiple daily fractions also appears to result in good local control but a survival improvement was only noted in squamous cell carcinomas [6]. What is urgently required is a large multicentre study in-
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volving combined therapy with or without adjuvant chemotherapy. The meta-analysis of the Non Small Cell Lung Cancer Collaborative Group has certainly opened the door for a large randomised trial to address the value of adding chemotherapy to surgery, radiation therapy or symptomatic treatment [24]. The British Thoracic Society ‘Big Lung Trial’ is attempting to answer this question for each of these subgroups but have excluded patients having combined chemoradiation therapy. We were impressed with the good responses and low toxicity of our regime and have adopted it as the standard practice for the management of locally advanced disease. Unfortunately systemic relapse remains a problem. A high rate of relapse in the brain was noted in patients with adenocarcinomas. This would suggest a possible role for prophylactic whole brain irradiation in patients with adenocarcinoma, providing a complete local response had occurred. This approach may warrant further investigation.
[6]
[7]
[8]
[9]
[10]
[11]
Acknowledgements The authors gratefully acknowledge all the staff of the Queensland Radium Institute and the Respiratory Unit at Princess Alexandra Hospital, Brisbane, Australia, for their assistance in conducting this Phase II study and compiling this report.
[12]
References
[14]
[1] Nesbitt JC, Putman JB, Walsh GL, et al. Survival in early-stage non small cell lung cancer. Ann Thoracic Surg 1995;60:466 – 72. [2] Payne DG. Non-small cell lung cancer: should unresectable stage 3 patients routinely receive high dose radiation therapy? J Clin Oncol 1988;6:552–8. [3] Gauden S, Ramsay J, Tripcony L. The curative treatment by radiation therapy alone of stage 1 non-small cell lung cancer. Chest 1995;108:1278–82. [4] Kaskowitz L, Graham MV, Emami B, Halverson KJ, Rush C. Radiation therapy alone for stage 1 non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1993;27:517 – 23. [5] Sandler HM, Curran WJ, Turrisi AT. The influence of tumor size and pre-treatment staging on outcome follow-
[13]
[15]
[16]
[17]
239
ing radiation therapy alone for stage 1 non-small cell lung cancer. Int J Radiat Biol Phys 1990;19:9 – 13. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: a randomised multicentre trial. Lancet 1997;350:161 – 5. Schaake-Koning C, Van den Bogaert W, Dalesio O, et al. The effects of concommitant cisplatin and radiation therapy on inoperable non-small cell lung cancer. N Engl J Med 1992;326:524 – 30. Trovo MG, Minotel E, Fravelun G, et al. Radiotherapy versus radiotherapy enhanced by cisplatin in stage 111 non-small cell lung cancer. Int J Radiat Biol Phys 1992;24:11 – 6. Soresi E., Clerici M., Grilli R. et al. A randomized clinical trial comparing radiation therapy versus radiation therapy plus cis-dichlorodiammine platinum in the treatment of locally advanced non-small cell lung cancer. Sem. Oncol. 1988; 15 (Suppl. 7): 20 – 25. Blanke C, Ansari R, Mantravadi R, et al. Phase III study of thoracic irradiation with or without cisplatin in locally advanced unresectable non-small-cell lung cancer; a Hoosier Oncology Group study. J Clin Oncol 1995;13:1425 – 9. Jeremic B, Shibamoto Y, Acimovic L, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III nonsmall cell lung cancer: a randomized study. J Clin Oncol 1996;14:1065 – 70. Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high dose radiation versus radiation alone in stage III non-small cell lung cancer. N Engl J Med 1990;323:940 – 5. 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 of regionally advanced, unresectable nonsmall cell lung cancer. J Natl Cancer Inst 1995;87:198 – 205. LeChevalier T, Arriagade R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in non-resectable non-small cell lung cancer: first analysis of a randomized trial of 353 patients. J Natl Cancer Inst 1991;83:417 – 22. Morton RF, Jett JR, McGinnis WL, et al. Thoracic radiation therapy alon compared with chemoradiotherapy for locally unresectable non-small cell lung cancer. Ann Intern Med 1991;115:681 – 6. Wolf M., Hans K., Becker H. et al. Radiotherapy alone versus chemotherapy with ifosfamide/vindesine followed by radiotherapy in unresectable locally advanced nonsmall cell lung cancer. Semin. Oncol. 1994; 21 (suppl 4): 42 – 7. Mattson K, Holsti LR, Holsti P, et al. Inoperable nonsmall cell lung cancer: Radiation with or without chemotherapy. Eur J Cancer Clin Oncol 1988;24:477 – 82.
240
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[18] Denham JW, Burmeister BH, Lamb DS, et al. Factors influencing outcome following radio-chemotherapy for oesophageal cancer. Radiother Oncol 1996;40:31–43. [19] Mackean J, Burmeister BH, Lamb DS, Denham JW. Concurrent chemoradiation for oesophageal cancer-factors influencing myelotoxicity. Austral Rad 1996;40:42–9. [20] Perez CA, Stanley K, Rubin P, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 1980;45:2744 – 53. [21] Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60 Gy to 79.2 Gy. Possible survival benefit with \ 69.6 Gy in favorable patients with RTOG stage III non-small cell carcinoma of the lung. Report of the Radiation Therapy Oncology Group 83–11. J Clin Oncol 1990;8:1543 – 55. [22] Ball D, Smith J, Bishop J, et al. A phase III study of radiation therapy with or without continuous infusion fluorouracil as palliation for non-small cell lung cancer. Br J Cancer 1997;75:690–7.
.
[23] Pritchard R, Anthony S. Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable non-small cell lung cancer: a meta-analysis. Ann Intern Med 1996;125:723 – 9. [24] Non Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a metaanalysis using updated data on individual patients from 52 randomised clinical trials. Br. Med. J. 1995;311:899 – 909. [25] Takada Y., Furuse K., Fukuoka M. et al. A randomized phase III study of concurrent versus sequential thoracic radiotherapy (TRT) in combination with mitomycin (M), vindesine (V) and cisplatin (P) in unresectable stage III non-small cell lung cancer (NSCLC): Preliminary analysis. Lung Cancer 1997;18(suppl 1):76. Abstract. [26] American Society of Clinical Oncology. Clinical practice guidelines for the treatment of unresectable non-small cell lung cancer. J. Clin. Oncol. 1997;15:2996 – 3018. [27] Choi N., Mathisen D., Carey R. et al. Preoperative accelerated radiotherapy (RT) and concurrent chemotherapy (CT) for stage IIIA (N2) non-small cell lung cancer (NSCLC): improved survival by enhanced local tumor control. Int. J. Radia. Biol. Phys. 1995;32(Suppl 1)198.
Chemoradiation for inoperable non small cell lung cancer A phase II study using a regimen with acceptable toxicity Bryan H. Burmeister a,*, N. Kumar Gogna a, Guy P. Bryant a, John Armstrong b, Wayne Kelly b, John Mackintosh c, Euan Walpole b, Karen Morton a a
Queensland Radium Institute, Raymond Terrace, South Brisbane, QLD 4101 Queensland, Australia b Princess Alexandra Hospital, Woolloongabba, Queensland, Australia c Mater Hospital, Raymond Terrace, South Brisbane, Queensland, Australia
Received 7 September 1998; received in revised form 18 January 1999; accepted 22 January 1999
Abstract Over the past few years there have been numerous schedules of combined modality therapy proposed as being useful in the management of inoperable non-small cell lung cancer (NSCLC). These have generally involved the use of high dose radiation therapy to doses of the order of 60 Gy combined with chemotherapy given prior to or concurrently with the radiation. Concurrent chemotherapy has been given with the intention of being both active in NSCLC and with the role of being a possible radiosensitiser. The most commonly employed drugs have been cisplatin, etoposide, 5-fluorouracil, vindesine and mitomycin. Although response rates of the primary tumour to the combined therapy have been optimistic, there has not been a great survival benefit with the median survival in most series remaining at just over 12 months. In this study we have prospectively treated a group of patients with non-metastatic inoperable NSCLC with a regimen of known acceptable toxicity. These patients were inoperable because they were unfit for surgery or had locally advanced disease. The local radiological response rate was 86% and the median survival for the whole group was 13 months. Adenocarcinomas appeared to do significantly worse than squamous cell carcinomas. Toxicity was acceptable and lower than reported in other similar series. There was one treatment related death. We feel that this combination of radiation therapy and chemotherapy is a reasonable compromise for a disease which still has a very poor outlook. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non small cell lung cancer; Combined modality therapy; Concurrent chemoradiation
* Corresponding author. Fax: +61-7-38403399. 0169-5002/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 9 9 ) 0 0 0 1 0 - 0
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1. Introduction Lung cancer remains a leading cause of death in the western world. Non-small cell lung cancer (NSCLC) constitutes 75 – 80% of all lung cancers and has a cure rate of only 13% at 5 years [1]. Approximately 40–50% of patients present with localised non-metastatic NSCLC, half of whom are generally not suitable for surgical resection as a result of co morbidity and/or local extension within the thorax [2]. Inoperable NSCLC thus represents a spectrum of disease ranging from medically unfit patients with T1 N0 disease to patients with technically inoperable T1 – 3 N1 – 2 disease. Radiation therapy can successfully be used for inoperable NSCLC but its success appears confined mostly to patients with early tumours (usually less than 3 cm in size) [3]. In this setting, local control can from 50 – 75% [4]. Larger tumours have local control rates which are considerably less (only up to 40%) [5]. Poor local control in turn translates into decreased overall survival. Attempts have been made to improve the results of radiation therapy with the use of altered fractionation schemes [6] or by the use of concurrent chemotherapy [7–11]. While altered fractionation schedules do show some promise, the logistics involved are significant. Sequential chemotherapy and radiation therapy has been shown to be advantageous in two clinical trials although there has been no significant impact on local control [12 – 17]. Concurrent chemoradiation has become accepted routine therapy for anal carcinoma and non-resectable oesophageal carcinoma. A variety of agents have been used in combination with radiation, the most commonly used being cisplatin and 5-fluorouracil. Since 1984, a three armed phase II study utilising moderate dose cisplatin and 5-fluorouracil with radiation therapy has been piloted in Australasia for oesophageal cancer [18]. The cisplatin is administered as a single dose on day 1 which is followed by a 96 h infusion of 5-fluorouracil. The cycle is then repeated 3 weeks later. This regimen has produced both high response rates and low toxicity when compared with other concurrent chemoradiation schedules for the same disease [19].
For the patient with inoperable NSCLC, the important questions are: Can one really justify giving chemotherapy in addition to radiation therapy when there is only a small improvement in survival with considerable added toxicity? Is it possible to minimise the toxicity of combined therapy and still achieve the good local responses and a similar median survival? In this study we set out to answer these questions by employing high dose conventional radiation therapy with a schedule of chemotherapy which is known to be well tolerated. The investigators of this study decided to try the same moderate dose chemotherapy schedule being used for oesophageal cancer with apparent low toxicity, for the management of locally advanced NSCLC in a prospective phase II study. It was hoped that equivalent or improved results compared to other such studies could be obtained with acceptable toxicity.
2. Materials and methods From January 1992 until December 1995, 45 patients were registered on study. All patients were diagnosed as having biopsy proven inoperable NSCLC. Six patients had early stage disease and were medically unfit for for surgery. The other 39 patients had locally advanced disease. Routine blood tests, bone scan, computerised tomography of the chest and abdomen as well as CT of the brain were performed to exclude distant metastases. Only patients of good performance status (ECOG 0–1) were eligible. Patients who had suffered more than 10% weight loss in the previous 3 months were not considered eligible. The patients were also required to have normal blood counts, a serum creatinine 5 0.13 mmol/l and no hearing deficit. Patients having an FEV1 of less than 1200 ml were regarded as being ineligible. Of the patients registered there were 30 males and 15 females. Details of clinical stage, histological subtypes, performance status and weight loss are summarised in Table 1. All patients received radical radiation therapy using a linear accelerator. The recommended dose schedule was 60 Gy to the isocentre in 30 fractions over 6 weeks. Where treatment extended
B.H. Burmeister et al. / Lung Cancer 23 (1999) 233–240
over three or more public holidays or required more than 3 days of unscheduled breaks, the dose was increased to 62 Gy in 31 fractions. Planning was performed using a simulator with CT interfacing to allow tissue inhomogeneity correction. The target volume included the primary tumour as well as all obviously involved nodal disease. Radiation was directed to a volume including the visible disease and a 2 cm margin laterally and a 3 cm margin superiorly and inferiorly. In most instances a three or four field technique was used to limit the spinal cord dose to 45 Gy. This technique also allowed the radiation dose to the contralateral lung to be kept as low as possible. Chemotherapy was administered concurrently with fractions 1–5 and 16 – 20. On days 1 and 22 (coinciding with fractions 1 and 16), patients were initially given radiation and the chemotherapy was commenced. Most patients were able to be given chemotherapy as an outpatient by being attached to a portable infusion pump via a central venous line. Cisplatin 80 mg/m2 was given as a slow infusion over 20 – 30 min following adequate prehydration. This was then followed by 5fluorouracil 800 mg/m2/day given over 96 hours as a continuous infusion. Suitable antiemetics were given when required. In three patients, the second course of chemotherapy was omitted as a result of toxicity. In two patients, a delay of one week occurred before the second course until blood counts had improved. Endpoints studied included local response, sites of relapse, toxicity of treatment, progression-free survival and overall survival. Survival and progression-free survival times were calculated from
235
the first day of treatment. Following treatment a chest X-ray was performed every 3 months and a CT scan of the chest at 3 months and then every 6 months. Radiological investigations to detect distant metastases such as CT of the brain and radionuclide bone scans were performed only if symptoms justified the investigation. Particular attention was paid to the occurrence of oesophageal toxicity both during and following therapy. Effects of radiation therapy on lung tissue were monitored closely with regular spirometry at each follow up visit as well as noting changes on chest X-ray. Routine follow up bronchoscopy was not performed unless symptoms suggested recurrent endobronchial tumour. Assessment of response was thus primarily based on radiological assessment with CT scan. Given the slow response seen in some tumour it was felt that the optimum time for assessment for response would be based on a CT of the chest at 3 months. The tumour response was then recorded. If a partial response was noted, the CT was repeated at six months and if a complete response had then occurred, the maximum response was then recorded. Assessment of toxicity was performed according to the WHO and RTOG criteria. The worst grade of toxicity experienced was documented. An analysis was performed late in 1997 following 18 months of followup of the last patient entered on study. The Kaplan–Meier method was used to generate survival and progression free survival curves. Differences between the curves were analysed using the the log-rank test. A Pvalue of B 0.05 was regarded as significant.
Table 1 Patient details Clinical stage
No. of patients (%)
Histology
No. of patients (%)
1B 2 3A 3B ECOG 0 ECOG 1
4 (9%) 2 (4%) 31 (69%) 8 (18%) 14 (31%) 31 (69%)
SCC Adenocarcinoma large cell Other Mininal weight loss (B5%) Weight loss 5–10%
18 (40%) 18 (40%) 1 (2%) 8 (18%) 29 (64%) 16 (36%)
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Fig. 1. NSCLC study.
3. Results The median age for the group of patients was 57 years with a range of 31 – 76 years. At the time of response assessment (3 – 6 months after commencement of treatment), 36 patients (80%) had achieved a radiological complete response and five patients (11%) a partial response. Two patients had progressive or stable disease. Two patients were not evaluable (death before 3 months). Of the patients who had a complete response, 16 subsequently relapsed within the treated volume. This represents a 43% relapse rate among the apparent complete responders. In the whole group, 23 patients ultimately failed locally. Of these, only eight were associated with systemic relapse. The other sites of failure were brain (27%), nodes (16%), bone (14%), lung (11%), liver (9%), skin (7%), and pleura (5%). Of the adenocarcinomas, 33% developed cerebral metastases. The mean follow up for survivors was 36 months with a median survival of 13 months. The 95% confidence interval for the median survival for the whole group of patients was 37 – 63%. At the time
of writing three patients were alive and diseasefree. The overall survival curve showing the 95% confidence interval for the whole group is shown in Fig. 1. The progression-free survival curves for the two major histological groups (squamous cell carcinoma and adenocarcinoma) are shown in Fig. 2. At 3 years there was a significant difference in progression-free survival between these two subgroups (P B 0.025). It was felt that this difference was related to the high rate of cerebral relapse in adenocarcinomas. There was no difference in the rate of local relapse. In general the therapy was extremely well tolerated. The most significant side effect was oesophagitis which occurred in most patients. However Grade 3 or 4 oesophagitis was noted in only four patients who required admission for nasogastric feeding at the end of therapy. There was one treatment related death. This has occurred in a patient who had developed peritonitis following rupture of a large bowel diverticulum. Unfortunately the patient was at the end of the therapy schedule and was neutropenic at the time. Other acute side effects were generally minor.
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Fig. 2. NSCLC study — histology.
These are summarised in Table 2. The incidence of radiation pneumonitis was assessed according to changes on chest X-ray as well as follow-up spirometry. The incidence of late changes on chest X-ray are summarised in Table 3. There were no cases of cardiac toxicity or long term oesophageal stricture. No patients showed any evidence of spinal cord damage.
4. Discussion The management of inoperable early stage or locally advanced NSCLC has until recently been with high dose radiation therapy. Several studies have indicated the necessity for a high radiation dose in order to optimise local control [20] although there is limited evidence for a dose response above 69.6 Gy [21]. Over the past few years attention has focused on the use of concomitant chemotherapy in order to optimise local control and possibly influence the rate of systemic relapse. Four randomised trials set out to answer the question of whether the radiosensitising properties of cisplatin do convey a benefit in combina-
tion with radiation therapy [7–10]. The administration of the drug during radiation varied from small daily doses of 6 mg/m2 to three weekly doses of 80–100 mg/m2. Of these, in only two cases was a survival benefit noted [7,9]. Other chemotherapeutic agents which have been used in combination with cisplatin are etoposide and vindesine. Further trials using the newer agents which are active in non-small cell cancer in combination with radiation are currently being investigated. These drugs include vinorelbine, the taxanes and gemcitabine either as sole agents or in Table 2 Acute toxicity Toxicity
Grade 1–2 No. of patients (%)
Grade 3–4 No. of patients (%)
Nausea/vomiting Oesophagitis Neutropenia Thrombocytopenia Skin reaction
20 (44%) 39 (87%) 7 (16%) 3 (7%) 24 (53%)
0 4 2 0 0
(0%) (9%) (4%) (0%) (0%)
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Table 3 Late pulmonary toxicity Toxicity grade
No. of patients (%)
Not assessable Grade 1 — faint shadows Grade 2 — moderate shadows Grade 3 — faint shadows, distorted anatomy
14 (31%) 21 (47%) 2 (4%) 3 (7%)
combination with platinum-containing agents and radiation therapy. The radiosensitising properties of these agents are uncertain but they are active in metastatic disease. It therefore may well be that their inclusion was to influence patterns of metastases rather than sensitise the tumour to radiation. Although 5-fluorouracil has been used as a radiosensitiser ar other sites e.g. oesophagus, there has been very little literature regarding its use in lung cancer. A study in palliative patients performed at the Peter MacCallum Cancer Institute showed some benefit in terms of responses noted in patients who received both palliative radiation therapy with concomitant 5-fluorouracil [22]. There was also a trend towards improved progression-free survival. Given the excellent results seen with the combination of radiation, cisplatin and 5-fluorouracil with both squamous cell and adenocarcinoma of the oesophagus, it is not unreasonable that the same combination be trialed in non-small cell lung cancer. As the tumour site is very similar, some information on toxicity is available from oesophageal cancer studies. We decided to implement in inoperable non-small cell lung cancer an identical regimen to that used in a large multicentre oesophageal study performed in Australia [18]. The regimen is a combination of known radiosensitisers with some probable effect on metastatic disease. It utilises moderate doses of cisplatin and 5-fluorouracil with very acceptable toxicity. Nevertheless, it appears no less effective than other high dose schedules for oesophageal cancer which have been trialed in the USA and are perhaps more toxic. There is however no randomised clinical trial in NSCLC comparing this regimen with radiation therapy alone. There have been several
randomised studies comparing radiation alone with other regimens containing concurrent cisplatin and radiation. Two meta-analyses have been performed to assess the benefit of adding chemotherapy to patients having radical radiation therapy. The meta-analysis by Pritchard of 1280 patients involved showed an improvement in median survival but also increased toxicity [23]. A second meta-analysis performed by the Non Small Cell Lung Cancer Collaborative Group involved more than 3000 patients from 22 randomised trials [24]. This showed a survival benefit for combined therapy of 2% at 5 years. There is also a suggestion that concurrent therapy is preferable to sequential neoadjuvant therapy [25]. What is clear from this and other numerous phase II studies is that combined therapy produces higher response rates than with radiation alone. The American Society of Clinical Oncology has recommended that combined therapy be considered in patients of good performance status with locally advanced NSCLC [26]. The treatment should include both high dose radiation therapy to a dose equivalent of 60 Gy over 6 weeks with platinum-based chemotherapy. We were disappointed in the local failure rate of 51%, especially as 15 patients developed isolated local recurrence in the absence of distant metastases. Could they have been salvaged by follow up surgery? Preliminary studies looking at neoadjuvant combined therapy followed by surgery have shown early promise [27]. Although it is not known what the ultimate chest recurrence rate will be, most of our patients who developed in-field recurrences did so after being in a period of apparent complete remission. It would thus be difficult to justify aggressive thoracic surgery involving nodal dissection of the mediastinum under these circumstances where a radical dose of radiation has been given. Because of the rate of local and distant failure, median survival of locally advanced NSCLC remains low and in the region of 12–14 months. Attempts at accelerating the radiation with multiple daily fractions also appears to result in good local control but a survival improvement was only noted in squamous cell carcinomas [6]. What is urgently required is a large multicentre study in-
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volving combined therapy with or without adjuvant chemotherapy. The meta-analysis of the Non Small Cell Lung Cancer Collaborative Group has certainly opened the door for a large randomised trial to address the value of adding chemotherapy to surgery, radiation therapy or symptomatic treatment [24]. The British Thoracic Society ‘Big Lung Trial’ is attempting to answer this question for each of these subgroups but have excluded patients having combined chemoradiation therapy. We were impressed with the good responses and low toxicity of our regime and have adopted it as the standard practice for the management of locally advanced disease. Unfortunately systemic relapse remains a problem. A high rate of relapse in the brain was noted in patients with adenocarcinomas. This would suggest a possible role for prophylactic whole brain irradiation in patients with adenocarcinoma, providing a complete local response had occurred. This approach may warrant further investigation.
[6]
[7]
[8]
[9]
[10]
[11]
Acknowledgements The authors gratefully acknowledge all the staff of the Queensland Radium Institute and the Respiratory Unit at Princess Alexandra Hospital, Brisbane, Australia, for their assistance in conducting this Phase II study and compiling this report.
[12]
References
[14]
[1] Nesbitt JC, Putman JB, Walsh GL, et al. Survival in early-stage non small cell lung cancer. Ann Thoracic Surg 1995;60:466 – 72. [2] Payne DG. Non-small cell lung cancer: should unresectable stage 3 patients routinely receive high dose radiation therapy? J Clin Oncol 1988;6:552–8. [3] Gauden S, Ramsay J, Tripcony L. The curative treatment by radiation therapy alone of stage 1 non-small cell lung cancer. Chest 1995;108:1278–82. [4] Kaskowitz L, Graham MV, Emami B, Halverson KJ, Rush C. Radiation therapy alone for stage 1 non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1993;27:517 – 23. [5] Sandler HM, Curran WJ, Turrisi AT. The influence of tumor size and pre-treatment staging on outcome follow-
[13]
[15]
[16]
[17]
239
ing radiation therapy alone for stage 1 non-small cell lung cancer. Int J Radiat Biol Phys 1990;19:9 – 13. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: a randomised multicentre trial. Lancet 1997;350:161 – 5. Schaake-Koning C, Van den Bogaert W, Dalesio O, et al. The effects of concommitant cisplatin and radiation therapy on inoperable non-small cell lung cancer. N Engl J Med 1992;326:524 – 30. Trovo MG, Minotel E, Fravelun G, et al. Radiotherapy versus radiotherapy enhanced by cisplatin in stage 111 non-small cell lung cancer. Int J Radiat Biol Phys 1992;24:11 – 6. Soresi E., Clerici M., Grilli R. et al. A randomized clinical trial comparing radiation therapy versus radiation therapy plus cis-dichlorodiammine platinum in the treatment of locally advanced non-small cell lung cancer. Sem. Oncol. 1988; 15 (Suppl. 7): 20 – 25. Blanke C, Ansari R, Mantravadi R, et al. Phase III study of thoracic irradiation with or without cisplatin in locally advanced unresectable non-small-cell lung cancer; a Hoosier Oncology Group study. J Clin Oncol 1995;13:1425 – 9. Jeremic B, Shibamoto Y, Acimovic L, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III nonsmall cell lung cancer: a randomized study. J Clin Oncol 1996;14:1065 – 70. Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high dose radiation versus radiation alone in stage III non-small cell lung cancer. N Engl J Med 1990;323:940 – 5. 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 of regionally advanced, unresectable nonsmall cell lung cancer. J Natl Cancer Inst 1995;87:198 – 205. LeChevalier T, Arriagade R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in non-resectable non-small cell lung cancer: first analysis of a randomized trial of 353 patients. J Natl Cancer Inst 1991;83:417 – 22. Morton RF, Jett JR, McGinnis WL, et al. Thoracic radiation therapy alon compared with chemoradiotherapy for locally unresectable non-small cell lung cancer. Ann Intern Med 1991;115:681 – 6. Wolf M., Hans K., Becker H. et al. Radiotherapy alone versus chemotherapy with ifosfamide/vindesine followed by radiotherapy in unresectable locally advanced nonsmall cell lung cancer. Semin. Oncol. 1994; 21 (suppl 4): 42 – 7. Mattson K, Holsti LR, Holsti P, et al. Inoperable nonsmall cell lung cancer: Radiation with or without chemotherapy. Eur J Cancer Clin Oncol 1988;24:477 – 82.
240
B.H. Burmeister et al. / Lung Cancer 23 (1999) 233–240
[18] Denham JW, Burmeister BH, Lamb DS, et al. Factors influencing outcome following radio-chemotherapy for oesophageal cancer. Radiother Oncol 1996;40:31–43. [19] Mackean J, Burmeister BH, Lamb DS, Denham JW. Concurrent chemoradiation for oesophageal cancer-factors influencing myelotoxicity. Austral Rad 1996;40:42–9. [20] Perez CA, Stanley K, Rubin P, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 1980;45:2744 – 53. [21] Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60 Gy to 79.2 Gy. Possible survival benefit with \ 69.6 Gy in favorable patients with RTOG stage III non-small cell carcinoma of the lung. Report of the Radiation Therapy Oncology Group 83–11. J Clin Oncol 1990;8:1543 – 55. [22] Ball D, Smith J, Bishop J, et al. A phase III study of radiation therapy with or without continuous infusion fluorouracil as palliation for non-small cell lung cancer. Br J Cancer 1997;75:690–7.
.
[23] Pritchard R, Anthony S. Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable non-small cell lung cancer: a meta-analysis. Ann Intern Med 1996;125:723 – 9. [24] Non Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a metaanalysis using updated data on individual patients from 52 randomised clinical trials. Br. Med. J. 1995;311:899 – 909. [25] Takada Y., Furuse K., Fukuoka M. et al. A randomized phase III study of concurrent versus sequential thoracic radiotherapy (TRT) in combination with mitomycin (M), vindesine (V) and cisplatin (P) in unresectable stage III non-small cell lung cancer (NSCLC): Preliminary analysis. Lung Cancer 1997;18(suppl 1):76. Abstract. [26] American Society of Clinical Oncology. Clinical practice guidelines for the treatment of unresectable non-small cell lung cancer. J. Clin. Oncol. 1997;15:2996 – 3018. [27] Choi N., Mathisen D., Carey R. et al. Preoperative accelerated radiotherapy (RT) and concurrent chemotherapy (CT) for stage IIIA (N2) non-small cell lung cancer (NSCLC): improved survival by enhanced local tumor control. Int. J. Radia. Biol. Phys. 1995;32(Suppl 1)198.