- Email: [email protected]
Radiosensitization by cytotoxic drugs. The EORTC experience by the Radiotherapy and Lung Cancer Cooperative Groups
Lung Cancer 10 Suppl. l(1994) S263S270
IRELAND
Radiosensitization by cytotoxic drugs. The EORTC experience by the Radiotherapy and Lung Cancer Cooperative Groups C. Schaake-Koning* a, W. van den Bogaert’t, 0. Dalesio”, J. Festenc, J. Hoogenhoutc, P. van Houtted, A. Kirkpatrick”, M. Koolenf, B. Maat g, A. Nijsg, A. Renaudh, P. Rodrigusb$, L. Schuster-Uitterhoevef, J. Sculierd, N. van Zandwijk”, H. Bartelink” “Netherlands Cancer Institute, Plesmanlaan 121, 1066 CXAmsterdam, Netherlands bMiddelheim Ziekenhuis, Antwerp, Belgium ‘St. Radboud Hospital, Nijmegen, Netherlands dInstitute Jules Bordet, Brussels, Belgium ‘EORTC Data Center, Brussels, Belgium fAcademisch Medisch Centrum, Vniwrsity of Amsterdam, Amsterdam, Netherlands “Dr. Bernard Verbeeten Institute, Tilburg, Netherlands “Centre Hospitalier Vniwrsitaire de Ticioli, La Loutiere, Belgium
Abstract
A three-arm randomized trial was performed to assess the acute and late toxicity and the impact on survival of the combination high-dose, split-course radiotherapy with 30 mg/m’ cisplatin (cDDP) weekly, with 6 mg/m* cisplatin daily compared to radiotherapy alone in patients with non-small cell lung cancer (NSCLC). The study started in May 1984 and was closed in May 1989 after 331 patients were randomised. The analysis was performed after a minimum follow-up period of 22 months. Radiotherapy (RT) consisted of 30 Gy, 10 fractions, five fractions a week; then a 3-week split followed by 25 Gy in 10 fractions.
*Corresponding
author.
t Present address: Dr. Bernard Verbeeten Institute, Tilburg, Netherlands $ Present address: U.S. St. Rafael, Leuven, Belgium. 0169~5002/94/$07.00
0 1994 Elsevier Science Ireland Ltd. AI1 rights resewed.
SSDI 0169-5002(93)00288-K
S264
C. Schaake-Koninget al. /Lung Cancer 10 Suppl. I (1994) S263-S270
Nausea and vomiting were increased for a majority of the patients in the combined treatment arms during treatment. There was no addition of bone marrow suppression, renal dysfunction or esophagitis. Increase of late radiation damage was not observed. Local control ( = absence of local progression) was improved for patients treated according to the daily cisplatin arm. This has lead to an improvement in overall survival. There was no effect in time to distant metastasis due to the combined modality. The treatment influence was confirmed in the multivariate analysis. Conclusion: local control and survival can be improved by combining radiotherapy with daily low-dose cisplatin in patients with inoperable NSCLC. Key words: High-dose, split-course radiotherapy; Low-dose cisplatin; Inoperable NSCLC
1. Introduction The EORTC experience of radiotherapy combined with low-dose cisplatin for patients with inoperable, non-metastasised NSCLC started in May 1984. The EORTC Radiotherapy and Lung Cancer Cooperative Groups embarked then on a randomized three arm Phase II study which could lead to a Phase III study. The design was based on two dose finding studies: one of Pinedo et al. [9] reporting that 6 mg/m’ cisplatin daily could be combined safely with radiotherapy and one of Schaake-Koning et al. [ll] who observed that 30 mg/m’ cisplatin once a week was feasible when given in combination with fractionated high-dose, split-course radiotherapy for patients with inoperable NSCLC. The Phase I, II and III studies were supported by radiobiological data that cisplatin could possibly act as a selectively tumoricidal agent when combined with radiotherapy. Although not all mechanisms were understood in detail and with still many questions to solve, Phase I studies were started for a variety of tumor types applying very different radiation schemes and doses of cisplatin in the early eighties. Data about clinical benefit were still lacking [1,4,6]. The EORTC Phase II study was meant to assess the acute and late toxicities of both combined treatment arms carefully as compared to radiotherapy alone. The Phase III study had survival as the most important endpoint. 2. Materials and methods Patients were treated according to one of three arms of the randomized trial, as seen in Table 1. Treatment of arm I consisted of 10 x 3 Gy, five fractions/week, 3 weeks split, 10 X 2.5 Gy; arm II: radiotherapy as arm I combined with 30 mg/m* cisplatin on each first day of a series of five fractions; arm III: radiotherapy as arm I combined with 6 mg/m* cisplatin daily before each fraction of radiation. For the first part of the radiotherapy two opposing anterior-posterior fields were used. The dose was specified at the mid depth of the central axes. After a 3-week rest the second part was given as a 2-3 oblique field treatment, using computer planning.
S265
C. Schaake-Koning et al. / Lung Cancer 10 Suppl. 1 (1994) S263-S270
Table 1 Treatment scheme Days
1 8
Arm I
xxxxxxxxxx
xxxxxxxxxx
1ox3cy
10 x 2.5 Gy
RT Arm II RT as under I + 30 mg/m2 cDDP once a week Arm III RT as under I + 6 mg/m* cDDP daily
t
TTTTT
15
(3-4 weeks rest)
t
TTTTT
1 8
t
TTTTT
15
1
TTTTT
x = daily fraction. T = application of cDDP.
The maximum total dose to the spinal cord was 40 Gy. The dose was specified at the intersection of the beam axes. The target volume of the first radiotherapy course included the primary tumor, ipsilateral hilar and mediastinal lymph nodes from the thoracic inlet to 5 cm below the carina. A 2-cm tumor free margin was obligatory. The full inferior mediastinum had to be included in case of lower lobe lesions; the supraclavicular areas for the upper lobe tumor or when the mediastinum superior was involved. For the second part the original tumor positive areas had to be encompassed by the 90% isodose with a maximum tumor free margin of 2 cm. Patients entering arm 2 received 30 mg/m2 cisplatin once a week. The cisplatin was intravenously (i.v.) given after a parenteral prehydration of 1 litre of glucose 2.5% in NaCl 0.45% and was followed by posthydration of 2 litres. The patients had to be hospitalized for at least l-2 days. Patients in arm 3 were treated daily with 6 mg/m2 cisplatin, i.v. given. If the patients could not reach an oral fluid intake of 2 litres, hospitalization was necessary to guarantee a good fluid balance. Eligibility criteria for entering the study were: inoperable non-small cell lung cancer, no suspicion of distant metastases by clinical examination and/or by biochemical parameters; histology; younger than 70 years of age; performance status 2 2 according to ECOG grading system; good renal function (creatinine clearance 2 70 ml/min); and informed consent. A CT-scan of the chest was required. Acute and late toxicity and responses were assessed according to the WHO scales [14]. A bronchoscopy with biopsies was required to confirm radiologic complete response. Patients were seen after 6-week intervals during the first year; thereafter every 3 months. Late damage was scored as Grade I with faint shadowing on the chest radiograph, as Grade 2 with moderate shadowing both without distortion of anatomy. Grade 3 was applied for faint and Grade 4 for moderate and dense shadowing with distortion of anatomy.
S266
C. Schaake-Koning et al. /Lung
Cancer 10 Suppl. I (1994) S263-S270
At first one hundred patients were randomized. We then analyzed the acute and late toxicity (Phase II study). The acute and late toxicities did not differ between the two combined treatment arms. The response rate did not favour one of the RT-cDDP modalities. It was decided to continue the study as a randomized Phase III trial. A total of 331 patients entered the study between May 1984 and May 1989. All patients were considered in all survival analyses, including the 22 patients who appeared to be ineligible. Reasons for ineligibility were: distant metastases at the time of randomization (10 patients (pts)), performance score ECOG 3 (4 pts), incomplete examination prior to randomization (2 pts>, excessively extensive lesions (2 pts), malignant pericardial infusion (1 pt), N3 disease (1 pt), soft tissue sarcoma (1 pt> and renal dysfunction (1 pt). Forty-five patients were not evaluable for toxicity testing. Not evaluable for response were 63 patients, mainly because of distant tumor progression during treatment time (21 pts> and treatment refusal (10 pts) [131. It was planned to enter 100 patients in each arm and follow them until death to allow an 80% power to detect a true increase of 50% in the median survival. Survival curves were calculated according to Kaplan-Meier. Comparisons were performed by the log-rank test. A Cox’s proportional hazards model was used to analyse treatment benefit taking into account possible prognostic factors. 3. Results The results were based on data collected after a minimum follow-up period of 22 months. Patient characteristics were equally balanced among the three treatment arms with a slight preference of Tl tumor stage in the radiotherapy only arm (Table 2). 3. I. Toxicity Esophagitis was not scored more frequently in the combined treatment arms. Due to a general effect of cDDP, nausea and vomiting were observed in 86% of the patients treated with weekly cisplatin and in 78% in the patients with daily cisplatin; in about one-third of them to WHO level grade 3 or 4 in both combined treatment arms. Hematological changes were seldom clinically relevant. Only one patient was observed with renal toxicity. Respiratory complaints due to radiation pneumonitis and fibrosis, as seen on chest radiographs, was not increased in the treatment arms with cisplatin (Table 3). 3.2. Suruiml Survival was found to be improved by adding 6 mg/m* cisplatin daily to the radiotherapy schedule used, when comparing the overall survival with radiotherapy only versus radiotherapy and daily cisplatin (P = 0.009). The weekly arm did not yield significant differences compared to radiotherapy alone (P = 0.36) (Fig.1). Time to local progression was significantly longer for patients treated daily with cisplatin (P = 0.003) (Fig. 2). Distant metastases were found in 53 patients of arm 1,40 patients of arm 2 and 52 of arm 3. The survival curves of the patients without
C. Schaake-Koning et al. /Lung
S261
Cancer 10 Suppl. 1 (1!#4) S263-S270
Table 2 Patient characteristics RT
Ineligible Eligible but lost to any follow-up With* and without** entry data Male Female
6 1* 100 8
RT + weekly cDDP 11
RT + daily cDDP 5
1** 90 8
92 10
Age-range Medium age
40-71 59
38-71 61
40-70 61
Squamous cell carcinoma Adenocarcinoma Large cell carcinoma Adeno-squamous carcinoma
12 19 15 2
IO 17 9 2
14 18 9 1
T,a
13 52 43
5 53 40
5 56 40 1
NX
13 10 83 2
12 6 77 3
11 11 71 3
Performance status 0 Performance status 1 Performance status 2
37 66 5
30 61 7
40 51 5
Upper lobe Other
71 37
59 39
60 42
No weight loss Any weight loss Unknown
61 46 1
59 38 1
63 39
7-2 T3 TX
No N, N2
aUICC system 1978.
distant metastases did not differ significantly among each other (P = 0.37 overall). Favorable prognostic factors were lack of weight loss (P = < O.OOl), and performance status (P < 0.001). In the multivariate analvsis the treatment maintained its significant influence on survival (P = 0.017). * 4. Discussion Survival was improved by adding 6 mg/m* cisplatin daily to a high-dose, split-course radiotherapy scheme in patients suffering from inoperable, non-
S268
C. Schaake-Koninget
al./Lung
Cancer 10 Suppl. 1 (1994) S263-S270
Table 3 Acute and late toxicities I. Acute
A. Hematological Nadir WBC Platelets B. Non hematolqggical Esophagitis Nausea Tiredness II. Late
RT damage on Chest X-ray Cough Dyspnea Tiredness
RT 94 pts
RT f weekly cDDP 83 pts
RT + daily cDDP 87 pts
11 2
22( 1) 3
48( 3) 6
58 ( 8)
41( 1) 71(21) 58( 7)
43 ( 4) 68 (24) 59( 8)
RT 84 pts
RT + weekly cDDP 74 pts
RT + daily cDDP 77 pts
70 (30) 66 (20) 61 (12) 61 (14)
50 (23) 60 (11) 57 (18) 55 (16)
65 (34) 65 (12) 52 (12) 57 (10)
a WHO grade 3 or 4.
survival
treatment
.~~+CDDPwaakly ::i! . . . . . . . . . . .. Rt +CDDP daily 107
number of patients at risk: 13 2
Fig. 1.
Ftt Rt+ COOP weekly Rt +CDDP daily
C. Schaake-Koning et al. /Lung
S269
Cancer 10 Suppl. 1 (1994) S263-S270
time to local progression treatment ZZx E+CDDP weekly ::“o . . . . . . . . . . . . f?t+CDDP daily 107
1 0
1
I
I
1
2
3
4 years
9 10 14
:
Rt+CDDPweekly Rt+CDDPdaily
number of patients at risk: 114 110 107
26 26 36
Rt 8
Fig. 2.
NSCLC. The improvement in survival was related with an improvement in local control (= freedom from local progression). The price for this improvement was nausea and vomiting during the treatment with cisplatin in about 25% of all patients in arms 2 and 3 to a severe extent [12,13]. Favorable prognostic factors were lack of weight loss and a very good performance status D31. At first the trial results should be reconfirmed. If our data can be reproduced, these observations can be combined with other attempts of improving the poor prognosis of inoperable NSCLC patients. Examples of these are the use of higher daily doses of cisplatin, treatment with hyperfractionated radiotherapy [2,10] and/or chemotherapy [5,7]. As the observed toxic side effects are due to a general effect of cisplatin, these new combinations seem feasible, but this has to be proven before starting Phase III studies. Nausea and vomiting are likely to be treated more successfully nowadays by new 5-HT, receptor antagonists than during the trial period [3,8]. Some tumor cell types do not show any enhancement when treated by cisplatin and radiotherapy [1,4]. The reasons behind this difference of reaction are still unknown and deserve further research. Antibodies against cisplatin-DNA adducts exist. With the help of these one can detect cisplatin adducts in the DNA of human biopsy material to predict the possible cisplatin sensitivity at the clinical metastasized
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level. Other methods of refinement and improvement of the combined treatment might be found in methods increasing the cisplatin concentration in the tumor [l]. 5. Conclusion This study is rather the end of a beginning than the beginning of an end. Many new ways may be explored in more detail to examine the benefit of low-dose cisplatin added to radiotherapy in patients with NSCLC. 6. References 1 Begg AC, Stewart FA, Dewit L, Bartelink H. Interactions 2
3 4 5
6 7 8
9
10 11
12
13 14
between cisplatin and radiation in experimental rodent tumors and normal tissues. In: Hill B, Bellamy A, editors. Antitumor drug-radiation interactions.Boca Ratan, Florida: CRC Press Inc., 1989; 9: 154-70. Cox JD, Azamia N, Byhardt RW et al. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with 2 69.6 Gy in favorable patients with radiation therapy oncology group stage III non-small cell lung carcinoma: report of Radiation Therapy Oncology Group 73-11. J Clin Oncol 1990; 8: 1543-19554. Cubeddin LX, Hoffmann IS, Fuermayor NT, Finn AL. Efficacy of ondansetron (GR38032F) and the role of serotonin in cisplatin induced nausea and vomiting. N Engl J Med 1990; 332: 810-16. Dewit L. Combined treatment of radiation and cis-diammine dichloroplatinum (II): a review of experimental and clinical data. Int J Radiat OncoI Biol Phys 1987; 13: 403-26. 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: 940-45. Douple EB. Keynote address: Platinum-radiation interactions. NC1 monographs 1988; 6: 315-19. Le Chevalier T, Arriagada R et al. Significant effect of adjuvant chemotherapy on survival in locally advanced non-small cell lung cancer. J Nat1 Cancer Inst 1992; 84: 58. Marty M, Pouillart P, Scholl S et al. Comparison of the 5 hydroxytryptamine, (serotonin) antagonist ondansetron (GR 38022F) with high dose metoclopramide in the control of cisplatin induced emesis. N Engl J Med 1990; 332: 816-21. Pinedo HM, Karim ABMF, van VIiet WH, Snow JB, Vermorken JB. Daily cisdichloridediammine platinum (II) as a radio enhancer: a preliminary toxicity report. J Cancer Res Clin Oncol 1983; 105: 79-82. accelerated radiotherapy (CHART) in Saunders MI, Dische S. Continuous hyperfractionated non-small cell carcinoma of the bronchus, 1990. Int J Radiat Oncol Biol Phys 1990; 19: 1211-15. L, Van Zandwijk N. Schaake-Koning C, Bartelink H, Hora Adema B, Schuster-Uitterhoeve Radiotherapy and cis-diamminedichloroplatinum (II) as a combined treatment modality for inoperable non-small cell lung cancer: a dose finding study. Int J Radiat Oncol Biol Phys 1986; 12: 379-83. Schaake-Koning C, Maat B, Van Houtte P et al. Radiotherapy combined with low = dose ck-diammine dichloroplatinum II (cDDP) in inoperable non-small cell lung cancer (NSCLO: a randomized three arm phase II study of the EORTC Lung Cancer and Radiotherapy Cooperative Groups. Int J Radiat Oncol Biol Phys 1990; 19: 967-72. Schaake-Koning C, van den Bogaert W, Dalesio 0, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992; 326: 524-530. WHO Handbook for reporting results of cancer treatment. Neoplasm 1980; 27: 5: 615-19.
IRELAND
Radiosensitization by cytotoxic drugs. The EORTC experience by the Radiotherapy and Lung Cancer Cooperative Groups C. Schaake-Koning* a, W. van den Bogaert’t, 0. Dalesio”, J. Festenc, J. Hoogenhoutc, P. van Houtted, A. Kirkpatrick”, M. Koolenf, B. Maat g, A. Nijsg, A. Renaudh, P. Rodrigusb$, L. Schuster-Uitterhoevef, J. Sculierd, N. van Zandwijk”, H. Bartelink” “Netherlands Cancer Institute, Plesmanlaan 121, 1066 CXAmsterdam, Netherlands bMiddelheim Ziekenhuis, Antwerp, Belgium ‘St. Radboud Hospital, Nijmegen, Netherlands dInstitute Jules Bordet, Brussels, Belgium ‘EORTC Data Center, Brussels, Belgium fAcademisch Medisch Centrum, Vniwrsity of Amsterdam, Amsterdam, Netherlands “Dr. Bernard Verbeeten Institute, Tilburg, Netherlands “Centre Hospitalier Vniwrsitaire de Ticioli, La Loutiere, Belgium
Abstract
A three-arm randomized trial was performed to assess the acute and late toxicity and the impact on survival of the combination high-dose, split-course radiotherapy with 30 mg/m’ cisplatin (cDDP) weekly, with 6 mg/m* cisplatin daily compared to radiotherapy alone in patients with non-small cell lung cancer (NSCLC). The study started in May 1984 and was closed in May 1989 after 331 patients were randomised. The analysis was performed after a minimum follow-up period of 22 months. Radiotherapy (RT) consisted of 30 Gy, 10 fractions, five fractions a week; then a 3-week split followed by 25 Gy in 10 fractions.
*Corresponding
author.
t Present address: Dr. Bernard Verbeeten Institute, Tilburg, Netherlands $ Present address: U.S. St. Rafael, Leuven, Belgium. 0169~5002/94/$07.00
0 1994 Elsevier Science Ireland Ltd. AI1 rights resewed.
SSDI 0169-5002(93)00288-K
S264
C. Schaake-Koninget al. /Lung Cancer 10 Suppl. I (1994) S263-S270
Nausea and vomiting were increased for a majority of the patients in the combined treatment arms during treatment. There was no addition of bone marrow suppression, renal dysfunction or esophagitis. Increase of late radiation damage was not observed. Local control ( = absence of local progression) was improved for patients treated according to the daily cisplatin arm. This has lead to an improvement in overall survival. There was no effect in time to distant metastasis due to the combined modality. The treatment influence was confirmed in the multivariate analysis. Conclusion: local control and survival can be improved by combining radiotherapy with daily low-dose cisplatin in patients with inoperable NSCLC. Key words: High-dose, split-course radiotherapy; Low-dose cisplatin; Inoperable NSCLC
1. Introduction The EORTC experience of radiotherapy combined with low-dose cisplatin for patients with inoperable, non-metastasised NSCLC started in May 1984. The EORTC Radiotherapy and Lung Cancer Cooperative Groups embarked then on a randomized three arm Phase II study which could lead to a Phase III study. The design was based on two dose finding studies: one of Pinedo et al. [9] reporting that 6 mg/m’ cisplatin daily could be combined safely with radiotherapy and one of Schaake-Koning et al. [ll] who observed that 30 mg/m’ cisplatin once a week was feasible when given in combination with fractionated high-dose, split-course radiotherapy for patients with inoperable NSCLC. The Phase I, II and III studies were supported by radiobiological data that cisplatin could possibly act as a selectively tumoricidal agent when combined with radiotherapy. Although not all mechanisms were understood in detail and with still many questions to solve, Phase I studies were started for a variety of tumor types applying very different radiation schemes and doses of cisplatin in the early eighties. Data about clinical benefit were still lacking [1,4,6]. The EORTC Phase II study was meant to assess the acute and late toxicities of both combined treatment arms carefully as compared to radiotherapy alone. The Phase III study had survival as the most important endpoint. 2. Materials and methods Patients were treated according to one of three arms of the randomized trial, as seen in Table 1. Treatment of arm I consisted of 10 x 3 Gy, five fractions/week, 3 weeks split, 10 X 2.5 Gy; arm II: radiotherapy as arm I combined with 30 mg/m* cisplatin on each first day of a series of five fractions; arm III: radiotherapy as arm I combined with 6 mg/m* cisplatin daily before each fraction of radiation. For the first part of the radiotherapy two opposing anterior-posterior fields were used. The dose was specified at the mid depth of the central axes. After a 3-week rest the second part was given as a 2-3 oblique field treatment, using computer planning.
S265
C. Schaake-Koning et al. / Lung Cancer 10 Suppl. 1 (1994) S263-S270
Table 1 Treatment scheme Days
1 8
Arm I
xxxxxxxxxx
xxxxxxxxxx
1ox3cy
10 x 2.5 Gy
RT Arm II RT as under I + 30 mg/m2 cDDP once a week Arm III RT as under I + 6 mg/m* cDDP daily
t
TTTTT
15
(3-4 weeks rest)
t
TTTTT
1 8
t
TTTTT
15
1
TTTTT
x = daily fraction. T = application of cDDP.
The maximum total dose to the spinal cord was 40 Gy. The dose was specified at the intersection of the beam axes. The target volume of the first radiotherapy course included the primary tumor, ipsilateral hilar and mediastinal lymph nodes from the thoracic inlet to 5 cm below the carina. A 2-cm tumor free margin was obligatory. The full inferior mediastinum had to be included in case of lower lobe lesions; the supraclavicular areas for the upper lobe tumor or when the mediastinum superior was involved. For the second part the original tumor positive areas had to be encompassed by the 90% isodose with a maximum tumor free margin of 2 cm. Patients entering arm 2 received 30 mg/m2 cisplatin once a week. The cisplatin was intravenously (i.v.) given after a parenteral prehydration of 1 litre of glucose 2.5% in NaCl 0.45% and was followed by posthydration of 2 litres. The patients had to be hospitalized for at least l-2 days. Patients in arm 3 were treated daily with 6 mg/m2 cisplatin, i.v. given. If the patients could not reach an oral fluid intake of 2 litres, hospitalization was necessary to guarantee a good fluid balance. Eligibility criteria for entering the study were: inoperable non-small cell lung cancer, no suspicion of distant metastases by clinical examination and/or by biochemical parameters; histology; younger than 70 years of age; performance status 2 2 according to ECOG grading system; good renal function (creatinine clearance 2 70 ml/min); and informed consent. A CT-scan of the chest was required. Acute and late toxicity and responses were assessed according to the WHO scales [14]. A bronchoscopy with biopsies was required to confirm radiologic complete response. Patients were seen after 6-week intervals during the first year; thereafter every 3 months. Late damage was scored as Grade I with faint shadowing on the chest radiograph, as Grade 2 with moderate shadowing both without distortion of anatomy. Grade 3 was applied for faint and Grade 4 for moderate and dense shadowing with distortion of anatomy.
S266
C. Schaake-Koning et al. /Lung
Cancer 10 Suppl. I (1994) S263-S270
At first one hundred patients were randomized. We then analyzed the acute and late toxicity (Phase II study). The acute and late toxicities did not differ between the two combined treatment arms. The response rate did not favour one of the RT-cDDP modalities. It was decided to continue the study as a randomized Phase III trial. A total of 331 patients entered the study between May 1984 and May 1989. All patients were considered in all survival analyses, including the 22 patients who appeared to be ineligible. Reasons for ineligibility were: distant metastases at the time of randomization (10 patients (pts)), performance score ECOG 3 (4 pts), incomplete examination prior to randomization (2 pts>, excessively extensive lesions (2 pts), malignant pericardial infusion (1 pt), N3 disease (1 pt), soft tissue sarcoma (1 pt> and renal dysfunction (1 pt). Forty-five patients were not evaluable for toxicity testing. Not evaluable for response were 63 patients, mainly because of distant tumor progression during treatment time (21 pts> and treatment refusal (10 pts) [131. It was planned to enter 100 patients in each arm and follow them until death to allow an 80% power to detect a true increase of 50% in the median survival. Survival curves were calculated according to Kaplan-Meier. Comparisons were performed by the log-rank test. A Cox’s proportional hazards model was used to analyse treatment benefit taking into account possible prognostic factors. 3. Results The results were based on data collected after a minimum follow-up period of 22 months. Patient characteristics were equally balanced among the three treatment arms with a slight preference of Tl tumor stage in the radiotherapy only arm (Table 2). 3. I. Toxicity Esophagitis was not scored more frequently in the combined treatment arms. Due to a general effect of cDDP, nausea and vomiting were observed in 86% of the patients treated with weekly cisplatin and in 78% in the patients with daily cisplatin; in about one-third of them to WHO level grade 3 or 4 in both combined treatment arms. Hematological changes were seldom clinically relevant. Only one patient was observed with renal toxicity. Respiratory complaints due to radiation pneumonitis and fibrosis, as seen on chest radiographs, was not increased in the treatment arms with cisplatin (Table 3). 3.2. Suruiml Survival was found to be improved by adding 6 mg/m* cisplatin daily to the radiotherapy schedule used, when comparing the overall survival with radiotherapy only versus radiotherapy and daily cisplatin (P = 0.009). The weekly arm did not yield significant differences compared to radiotherapy alone (P = 0.36) (Fig.1). Time to local progression was significantly longer for patients treated daily with cisplatin (P = 0.003) (Fig. 2). Distant metastases were found in 53 patients of arm 1,40 patients of arm 2 and 52 of arm 3. The survival curves of the patients without
C. Schaake-Koning et al. /Lung
S261
Cancer 10 Suppl. 1 (1!#4) S263-S270
Table 2 Patient characteristics RT
Ineligible Eligible but lost to any follow-up With* and without** entry data Male Female
6 1* 100 8
RT + weekly cDDP 11
RT + daily cDDP 5
1** 90 8
92 10
Age-range Medium age
40-71 59
38-71 61
40-70 61
Squamous cell carcinoma Adenocarcinoma Large cell carcinoma Adeno-squamous carcinoma
12 19 15 2
IO 17 9 2
14 18 9 1
T,a
13 52 43
5 53 40
5 56 40 1
NX
13 10 83 2
12 6 77 3
11 11 71 3
Performance status 0 Performance status 1 Performance status 2
37 66 5
30 61 7
40 51 5
Upper lobe Other
71 37
59 39
60 42
No weight loss Any weight loss Unknown
61 46 1
59 38 1
63 39
7-2 T3 TX
No N, N2
aUICC system 1978.
distant metastases did not differ significantly among each other (P = 0.37 overall). Favorable prognostic factors were lack of weight loss (P = < O.OOl), and performance status (P < 0.001). In the multivariate analvsis the treatment maintained its significant influence on survival (P = 0.017). * 4. Discussion Survival was improved by adding 6 mg/m* cisplatin daily to a high-dose, split-course radiotherapy scheme in patients suffering from inoperable, non-
S268
C. Schaake-Koninget
al./Lung
Cancer 10 Suppl. 1 (1994) S263-S270
Table 3 Acute and late toxicities I. Acute
A. Hematological Nadir WBC Platelets B. Non hematolqggical Esophagitis Nausea Tiredness II. Late
RT damage on Chest X-ray Cough Dyspnea Tiredness
RT 94 pts
RT f weekly cDDP 83 pts
RT + daily cDDP 87 pts
11 2
22( 1) 3
48( 3) 6
58 ( 8)
41( 1) 71(21) 58( 7)
43 ( 4) 68 (24) 59( 8)
RT 84 pts
RT + weekly cDDP 74 pts
RT + daily cDDP 77 pts
70 (30) 66 (20) 61 (12) 61 (14)
50 (23) 60 (11) 57 (18) 55 (16)
65 (34) 65 (12) 52 (12) 57 (10)
a WHO grade 3 or 4.
survival
treatment
.~~+CDDPwaakly ::i! . . . . . . . . . . .. Rt +CDDP daily 107
number of patients at risk: 13 2
Fig. 1.
Ftt Rt+ COOP weekly Rt +CDDP daily
C. Schaake-Koning et al. /Lung
S269
Cancer 10 Suppl. 1 (1994) S263-S270
time to local progression treatment ZZx E+CDDP weekly ::“o . . . . . . . . . . . . f?t+CDDP daily 107
1 0
1
I
I
1
2
3
4 years
9 10 14
:
Rt+CDDPweekly Rt+CDDPdaily
number of patients at risk: 114 110 107
26 26 36
Rt 8
Fig. 2.
NSCLC. The improvement in survival was related with an improvement in local control (= freedom from local progression). The price for this improvement was nausea and vomiting during the treatment with cisplatin in about 25% of all patients in arms 2 and 3 to a severe extent [12,13]. Favorable prognostic factors were lack of weight loss and a very good performance status D31. At first the trial results should be reconfirmed. If our data can be reproduced, these observations can be combined with other attempts of improving the poor prognosis of inoperable NSCLC patients. Examples of these are the use of higher daily doses of cisplatin, treatment with hyperfractionated radiotherapy [2,10] and/or chemotherapy [5,7]. As the observed toxic side effects are due to a general effect of cisplatin, these new combinations seem feasible, but this has to be proven before starting Phase III studies. Nausea and vomiting are likely to be treated more successfully nowadays by new 5-HT, receptor antagonists than during the trial period [3,8]. Some tumor cell types do not show any enhancement when treated by cisplatin and radiotherapy [1,4]. The reasons behind this difference of reaction are still unknown and deserve further research. Antibodies against cisplatin-DNA adducts exist. With the help of these one can detect cisplatin adducts in the DNA of human biopsy material to predict the possible cisplatin sensitivity at the clinical metastasized
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level. Other methods of refinement and improvement of the combined treatment might be found in methods increasing the cisplatin concentration in the tumor [l]. 5. Conclusion This study is rather the end of a beginning than the beginning of an end. Many new ways may be explored in more detail to examine the benefit of low-dose cisplatin added to radiotherapy in patients with NSCLC. 6. References 1 Begg AC, Stewart FA, Dewit L, Bartelink H. Interactions 2
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