Auswlas Radio1 199 1; 35: 66-67
Concurrent Radiotherapy and Carboplatin in Non Small-Cell Lung Cancer: A Pilot Study Using Conventional and Accelerated Fractionation DAVID BALL, JAMES BISHOP, ELIZABETH CRE” AND IAN OLVER Peter MacCallwn Cancer Institute 481 Little Lonsdale Street, Melbourne, Victoria 3000 Australia.
ABSTRACT
Thirteen patients with unresectable non small cell lung cancer were treated with radical radiotherapy and carboplatin administered concurrently. The first 6 patients were treated to a total dose of 60 Gy in 30 fractions in 6 weeks, with carboplatin 70 m&m2 /day on days 1 to 5 during weeks 1 and 5 of radiotherapy. The remaining 7 patients were given 60 Gy in 30 fractions in 3 weeks, treating twice a day (accelerated fractionation). Carboplatin was given as above but only during week 1 of radiotherapy. Twelve patients completed radiotherapy without intermption but 2 patients developed WHO grade 3 neutropenia. Major toxicity was oesophagitis, one patient requiring nasogastric feeding. Average duration of dysphagia (any grade) in the accelerated fractionation group was 2lweeks. Four patients achieved good partial responses even though intial tumour volume was large. We conclude that this treatment is associated with increased but acceptable early mucosal toxicity. INTRODUCTION Inability to control locoregional disease remains a major cause of treatment failure in patients receiving conventionally fractionated radical radiotherapy for non small cell lung cancer (NSCLC) (Perez et al 1987). Potential avenues for improving local control by radiotherapy include the use of radiosensitising platinum complexes (Korbelik and Skov 1989) and multiple fractions per day (Saunders and Dische 1986). Since carboplatin has a mild radiosensitising effect on RIF 1 cells in vitro and is a powerful inhibitor of repair of sublethal damage (Begg et al 1987), we have performed a pilot study to measure the toxicity of concurrent carboplatin and radical radiotherapy (both conventional and accelerated fractionation) in patients with unresectable NSCLC before proceeding to a phase III trial. MATERIALS AND METHODS Thirteen patients with unresectable biopsy proven NSCLC confined to primary site and mediastinum and maximum performance status of 1 (ECOG scale) were entered on the study. The f i t group of 6 patients who were treated between March 1987 and June 1987 were studied to determine the maximum tolerated dose of carboplatin that could be administered concurrently with conventionally fractionated radiotherapy. Radiotherapy was given as 60 Gy in 30 fractions over 6 weeks to the primary lesion and adjacent hilum and mediastinum. The fmt phase of treatment (40Gy) was given as anterior and
A d d m s for conospondeoce: Dr.D. Ball Peter h4acCallum Cancer Institute 481 Little Lonsdale Stmet Melboumc Victoria MOO Australia
66
posterior fields and the second phase (20 Gy) was given via oblique fields angled so as to avoid spinal cord, the dose to which did not exceed 45 Gy. Carboplatin was given as 70 m&m’ for 5 days (350 mdm’ /course) as an intravenous infusion over one hour and followed by radiotherapy 30 - 60 minutes later during thefirst and fifth weeks of radiotherapy. This dose of carboplatin was chosen based on our previous experience with this drug in patients with small cell lung cancer (Bishop et aZl987). The second group of 7 patients were given radiotherapy between May and October 1988; treatment was given twice a day so that 60 Gy was administered in 30 fractions over 3 weeks. A minimum of 4 hours gap was specified between treatments, but in practice was more often 6 - 8 hours. Carboplatin 70 mdmz was given daily as above on the first 5 days of radiotherapy only before the f i s t treatment of the day. Tumour response rates and treatment toxicity were documented according to the WHO criteria (Miller et a1 1981). Since there are no WHO criteria for oesophagitis we have modified the WHO scale for stomatitis as in Table I. All patients gave informed consent prior to entry on the study in accordance with the guidelines of the National Health and Medical Research Council of Australia, and the protocol was approved by the Ethics Committee of the Peter MacCallum Cancer Institute. TABLE 1
OESOPHAGITIS GRADE No pain on swallowing Mild pain, normal diet, no medication 2 Pain, requires medication to eat solids 3 Pain such that liquid diet only is possible 4 Severe pain - alimentation not possible 0 1
RESULTS The study population consisted of 8 males and 5 females with a median age of 65 years (range 45 - 75). Nine patients had squamous cell carcinoma, two adenocarcinoma and two large cell anaplastic carcinoma. Ten of the 13 patients completed treatment as planned. In the conventionally fractionated group two patients did not receive the second cycle of carboplatin because of grade 3 neutropenia (0.5 to 0.99 x lo9 /I) persisting at week 5 of radiotherapy. In the accelerated radiation group one patient received only 54 Gy in 27 fractions because she was neutropenic and febrile at the time her last 3 fractions of radiotherapy were scheduled. Gastrointestinal
Submined for publication on: 1 lth July, 1990 Accepted for publication on: 12th October, 1990 Australasian Radiology, Vol.X X W , No.1, February, 1991
RADIOTHERAPY AND CARBOPLATIN IN NON SMALL-CELL LUNG CANCER toxicity (nausea and vomiting) was generally mild with only one patient experiencing grade 3 symptoms. In patients receiving conventional fractionation, the worst oesophageal toxicity (grade 2) occurred in only one patient. In the accelerated fractionation group all patients developed at least grade 2 oesophagitis, with two patients experiencing grade 3 symptoms and one patient required nasogastric feeding for two weeks (grade 4). In Figure 1 the duration of oesophagitis in the accelerated group has been plotted according to grade including maximum, minimum and average grade experienced at any time; the average duration of symptomatic oesophagitis was 2 1 weeks. Another patient who had resumed a normal diet and was free of dysphagia developed acute oesophageal obstruction at 23 weeks requiring dilatation but his swallowing has returned to normal and no other cases of oesophageal stricture have been observed, with minimum follow up 14 months. OESOPHAGITIS FOLLOWING ACCELERATED FRACTIONATION
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REFERENCES
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DISCUSSION This pilot study has established that carboplatin given as a total dose of 350 mg/m2 during week one of radical radiotherapy for NSCLC produced a degree of neutropenia in 2 of 6 patients such that a planned second course of carboplatin could not be given and so no attempt was made to escalate the dose further. No enhancement of oesophageal or pulmonary toxicity was seen as a result of concurrent carboplatin/radiotherapy, but one patient developed L‘Hermittes sign. Whilst this complication may be seen in patients treated with radiotherapy it was thought prudent to exclude the spinal cord from the irradiated volume in the second group of patients when cart>oplatin was administered in case the combination increased the risk of late neurologic toxicity. In the group of patients treated with concurrent c d w platin and accelerated radiotherapy the major toxicity was oesophagitis and although severe in some patients and protracted in most, no permanent long term sequelae have been observed and swallowing eventually returned to normal in all patients. In view of the increased but acceptable toxicity and high objective response rate seen in the pilot study, we are currently conducting a randomised trial in which accelerated fractionation and concurrent carboplatin are being compared with conventional radical radiotherapy in patients with unresectable NSCLC.
4
22
FIGURE 1 - Grade of oesophagitis according to duration in patients receiving combined carboplatidaccelerated radiotherapy.
No cases of radiation pneumonitis were observed but one patient in the conventionally fractionated group developed L’Hermittes sign which persisted for 3 weeks five months after radiotherapy. There were no treatment related deaths. Although the primary purpose of this study was to ascertain the toxicity of concurrent carboplatin/radiotherapy, response rates were measured for all patients. No patient achieved a complete response, but 4 of 6 patients in the conventionally fractionated group achieved a partial response (PR) and in the accelerated fractionation group, 4 of 7 patients achieved PR, including 3 patients with initially large tumour diameters (greater than 6 cm), i.e. a total PR rate of 8/13 (62%).
Australasian Radiology, Vol. XXW, No. I . February, I991
Begg AC, Van der Kolk PI, Emondt J and Ba~teliinkH. Radiosensitisation in Vitro by Cis-Diammine (1. I-Cyclobutane Dicarboxylato) Platinum (11) (Carboplatin, J M 8) and EthylenediammineMaionatoplatinum (n) (JM40).Radiotherapy and Oncology 1987; 9 : 157-165. Bishop JF,Raghavan D, Stuart-HarrisR Morstyn G, Aromy R, Kefford R, Yuen K,Lee J, Gianoutsos P, Olver IN, Zalcberg J, Ball D, Bull C and Fox R. Carboplatin (DBDCA, JM-8) and VP-16-213 in Previously Untreated Patients with Small Cell Lung Cancer. J CIi Oncol 1987; 5 : 1574-1578. Korbelik M and Skov KA. Inactivation of Hypoxic Cells by Cisplatin and Radiation at Clinically Relevant Doses. Rad Res 1989; 119 : 145-156. Miller AB, Hmgsmten B. Staquet M and Winkler A. Reporting Results of Cancer Treatment. Cancer 1981; 47 : 207-214. Perez CA, Pajak TF,Rubin P, Simpson JR. Mohiuddin M, Brady LW, Perez-Tamayo R and Rotman M. Long-Tern Observations of the Patterns of Failure in Patients with Unresectable Non-Oat Cell Carcinoma of the Lung Treated with Definitive Radiotherapy. Cancer 1987; 59 : 1874-1881. Saunders MI and Discbe S. Radiotherapy Employing T h e Fwctions in Each Day Over a Continuous Period of 12 Days. British J Radio1 1986; 59 : 523-525.
67
Concurrent Radiotherapy and Carboplatin in Non Small-Cell Lung Cancer: A Pilot Study Using Conventional and Accelerated Fractionation DAVID BALL, JAMES BISHOP, ELIZABETH CRE” AND IAN OLVER Peter MacCallwn Cancer Institute 481 Little Lonsdale Street, Melbourne, Victoria 3000 Australia.
ABSTRACT
Thirteen patients with unresectable non small cell lung cancer were treated with radical radiotherapy and carboplatin administered concurrently. The first 6 patients were treated to a total dose of 60 Gy in 30 fractions in 6 weeks, with carboplatin 70 m&m2 /day on days 1 to 5 during weeks 1 and 5 of radiotherapy. The remaining 7 patients were given 60 Gy in 30 fractions in 3 weeks, treating twice a day (accelerated fractionation). Carboplatin was given as above but only during week 1 of radiotherapy. Twelve patients completed radiotherapy without intermption but 2 patients developed WHO grade 3 neutropenia. Major toxicity was oesophagitis, one patient requiring nasogastric feeding. Average duration of dysphagia (any grade) in the accelerated fractionation group was 2lweeks. Four patients achieved good partial responses even though intial tumour volume was large. We conclude that this treatment is associated with increased but acceptable early mucosal toxicity. INTRODUCTION Inability to control locoregional disease remains a major cause of treatment failure in patients receiving conventionally fractionated radical radiotherapy for non small cell lung cancer (NSCLC) (Perez et al 1987). Potential avenues for improving local control by radiotherapy include the use of radiosensitising platinum complexes (Korbelik and Skov 1989) and multiple fractions per day (Saunders and Dische 1986). Since carboplatin has a mild radiosensitising effect on RIF 1 cells in vitro and is a powerful inhibitor of repair of sublethal damage (Begg et al 1987), we have performed a pilot study to measure the toxicity of concurrent carboplatin and radical radiotherapy (both conventional and accelerated fractionation) in patients with unresectable NSCLC before proceeding to a phase III trial. MATERIALS AND METHODS Thirteen patients with unresectable biopsy proven NSCLC confined to primary site and mediastinum and maximum performance status of 1 (ECOG scale) were entered on the study. The f i t group of 6 patients who were treated between March 1987 and June 1987 were studied to determine the maximum tolerated dose of carboplatin that could be administered concurrently with conventionally fractionated radiotherapy. Radiotherapy was given as 60 Gy in 30 fractions over 6 weeks to the primary lesion and adjacent hilum and mediastinum. The fmt phase of treatment (40Gy) was given as anterior and
A d d m s for conospondeoce: Dr.D. Ball Peter h4acCallum Cancer Institute 481 Little Lonsdale Stmet Melboumc Victoria MOO Australia
66
posterior fields and the second phase (20 Gy) was given via oblique fields angled so as to avoid spinal cord, the dose to which did not exceed 45 Gy. Carboplatin was given as 70 m&m’ for 5 days (350 mdm’ /course) as an intravenous infusion over one hour and followed by radiotherapy 30 - 60 minutes later during thefirst and fifth weeks of radiotherapy. This dose of carboplatin was chosen based on our previous experience with this drug in patients with small cell lung cancer (Bishop et aZl987). The second group of 7 patients were given radiotherapy between May and October 1988; treatment was given twice a day so that 60 Gy was administered in 30 fractions over 3 weeks. A minimum of 4 hours gap was specified between treatments, but in practice was more often 6 - 8 hours. Carboplatin 70 mdmz was given daily as above on the first 5 days of radiotherapy only before the f i s t treatment of the day. Tumour response rates and treatment toxicity were documented according to the WHO criteria (Miller et a1 1981). Since there are no WHO criteria for oesophagitis we have modified the WHO scale for stomatitis as in Table I. All patients gave informed consent prior to entry on the study in accordance with the guidelines of the National Health and Medical Research Council of Australia, and the protocol was approved by the Ethics Committee of the Peter MacCallum Cancer Institute. TABLE 1
OESOPHAGITIS GRADE No pain on swallowing Mild pain, normal diet, no medication 2 Pain, requires medication to eat solids 3 Pain such that liquid diet only is possible 4 Severe pain - alimentation not possible 0 1
RESULTS The study population consisted of 8 males and 5 females with a median age of 65 years (range 45 - 75). Nine patients had squamous cell carcinoma, two adenocarcinoma and two large cell anaplastic carcinoma. Ten of the 13 patients completed treatment as planned. In the conventionally fractionated group two patients did not receive the second cycle of carboplatin because of grade 3 neutropenia (0.5 to 0.99 x lo9 /I) persisting at week 5 of radiotherapy. In the accelerated radiation group one patient received only 54 Gy in 27 fractions because she was neutropenic and febrile at the time her last 3 fractions of radiotherapy were scheduled. Gastrointestinal
Submined for publication on: 1 lth July, 1990 Accepted for publication on: 12th October, 1990 Australasian Radiology, Vol.X X W , No.1, February, 1991
RADIOTHERAPY AND CARBOPLATIN IN NON SMALL-CELL LUNG CANCER toxicity (nausea and vomiting) was generally mild with only one patient experiencing grade 3 symptoms. In patients receiving conventional fractionation, the worst oesophageal toxicity (grade 2) occurred in only one patient. In the accelerated fractionation group all patients developed at least grade 2 oesophagitis, with two patients experiencing grade 3 symptoms and one patient required nasogastric feeding for two weeks (grade 4). In Figure 1 the duration of oesophagitis in the accelerated group has been plotted according to grade including maximum, minimum and average grade experienced at any time; the average duration of symptomatic oesophagitis was 2 1 weeks. Another patient who had resumed a normal diet and was free of dysphagia developed acute oesophageal obstruction at 23 weeks requiring dilatation but his swallowing has returned to normal and no other cases of oesophageal stricture have been observed, with minimum follow up 14 months. OESOPHAGITIS FOLLOWING ACCELERATED FRACTIONATION
. ...................
2//,f
:
:
:
r r
;
..........
REFERENCES
0 0
2
DISCUSSION This pilot study has established that carboplatin given as a total dose of 350 mg/m2 during week one of radical radiotherapy for NSCLC produced a degree of neutropenia in 2 of 6 patients such that a planned second course of carboplatin could not be given and so no attempt was made to escalate the dose further. No enhancement of oesophageal or pulmonary toxicity was seen as a result of concurrent carboplatin/radiotherapy, but one patient developed L‘Hermittes sign. Whilst this complication may be seen in patients treated with radiotherapy it was thought prudent to exclude the spinal cord from the irradiated volume in the second group of patients when cart>oplatin was administered in case the combination increased the risk of late neurologic toxicity. In the group of patients treated with concurrent c d w platin and accelerated radiotherapy the major toxicity was oesophagitis and although severe in some patients and protracted in most, no permanent long term sequelae have been observed and swallowing eventually returned to normal in all patients. In view of the increased but acceptable toxicity and high objective response rate seen in the pilot study, we are currently conducting a randomised trial in which accelerated fractionation and concurrent carboplatin are being compared with conventional radical radiotherapy in patients with unresectable NSCLC.
4
22
FIGURE 1 - Grade of oesophagitis according to duration in patients receiving combined carboplatidaccelerated radiotherapy.
No cases of radiation pneumonitis were observed but one patient in the conventionally fractionated group developed L’Hermittes sign which persisted for 3 weeks five months after radiotherapy. There were no treatment related deaths. Although the primary purpose of this study was to ascertain the toxicity of concurrent carboplatin/radiotherapy, response rates were measured for all patients. No patient achieved a complete response, but 4 of 6 patients in the conventionally fractionated group achieved a partial response (PR) and in the accelerated fractionation group, 4 of 7 patients achieved PR, including 3 patients with initially large tumour diameters (greater than 6 cm), i.e. a total PR rate of 8/13 (62%).
Australasian Radiology, Vol. XXW, No. I . February, I991
Begg AC, Van der Kolk PI, Emondt J and Ba~teliinkH. Radiosensitisation in Vitro by Cis-Diammine (1. I-Cyclobutane Dicarboxylato) Platinum (11) (Carboplatin, J M 8) and EthylenediammineMaionatoplatinum (n) (JM40).Radiotherapy and Oncology 1987; 9 : 157-165. Bishop JF,Raghavan D, Stuart-HarrisR Morstyn G, Aromy R, Kefford R, Yuen K,Lee J, Gianoutsos P, Olver IN, Zalcberg J, Ball D, Bull C and Fox R. Carboplatin (DBDCA, JM-8) and VP-16-213 in Previously Untreated Patients with Small Cell Lung Cancer. J CIi Oncol 1987; 5 : 1574-1578. Korbelik M and Skov KA. Inactivation of Hypoxic Cells by Cisplatin and Radiation at Clinically Relevant Doses. Rad Res 1989; 119 : 145-156. Miller AB, Hmgsmten B. Staquet M and Winkler A. Reporting Results of Cancer Treatment. Cancer 1981; 47 : 207-214. Perez CA, Pajak TF,Rubin P, Simpson JR. Mohiuddin M, Brady LW, Perez-Tamayo R and Rotman M. Long-Tern Observations of the Patterns of Failure in Patients with Unresectable Non-Oat Cell Carcinoma of the Lung Treated with Definitive Radiotherapy. Cancer 1987; 59 : 1874-1881. Saunders MI and Discbe S. Radiotherapy Employing T h e Fwctions in Each Day Over a Continuous Period of 12 Days. British J Radio1 1986; 59 : 523-525.
67
