In! J Radrnrmn 0nmk1~1~ Btol Ph.n VoI 24. pp I I - I5 Printed in the U S.A. All nghts reserved.
0360.3016192 $5.00 t .M) C’opyght 1’ 1992 Pergamon Press Ltd.
0 Clinical Original Contribution RADIOTHERAPY VERSUS RADIOTHERAPY ENHANCED BY CISPLATIN IN STAGE III NON-SMALL CELL LUNG CANCER MAURO MARIA
G.
G. TROVE, BOCCIERI,
GIANBEPPI
CARLO
PIZZI,
GOBITTI,
M.D.,’
M.D.,*
M.D.,’ M.D.,’
EMILIO MINATEL,
OTTORINO
ALESSANDRO
M.D.,’
NASCIMBEN,
TORRETTA,
DALI J. ZANELLI,
PH.D.’
M.D.,3
M.D.,6
Oncologico
FRANCHIN,
GIANPAOLO
ANDREA
(C.R.O.) Aviano,
Operation Pordenone,
M.D.,’
BOLZICCO,
VERONESI,
AND SILVIO MONFARDINI,
North-Eastern Italian Oncology Group (G.O.C.C.N.E.), Centro di Riferimento
GIOVANNI
M.D.,4
M.D.,7 M.D.9
Office, Italy
Between January 1987 and June 1991, 173 patients with inoperable non-small cell lung cancer, Stage III, were entered into a randomized trial comparing radiotherapy only (RT) (45 Gy/15 fractions/3 weeks) (arm A) versus RT and a daily low dose of cDDP (6 mg/m’) (arm B). An overall response rate of 58.9% was observed in arm A and 50.6% in arm B, respectively. No differences in the pattern of relapse were noted between the two treatment groups. Median time to progression was 10.6 months for arm A and 14.2 months for arm B. Median survivals were 10.3 months and 9.97 months, respectively. Toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant advantage of the combined treatment over radiation therapy only was found. The encouraging results achieved in some trials together with the intractability of the disease suggest that further efforts should be made to optimize clinical trial protocols, perhaps by reviewing the radiobiological and pharmacological basis of the combined treatment. Non-small cell lung cancer, cDDP, Radiotherapy, Radiosensitizer. INTRODUCTION
(6, 1.5, 2 1, 22) using different dosages and schedules. From such non-randomized trials it is not possible to assess the resulting therapeutic gain. Recently, two randomized studies have been published and both have reported some favorable results. In one study, either daily low doses or weekly doses of cDDP plus RT (22) were used and in another study the cDDP was given weekly during the RT course (24). In both studies, the combined modality treatment was compared with RT only in patients with inoperable non-metastatic NSCLC. Experimental data (4, 16) suggest that a daily low dose of cDDP during fractionated RT might lead to higher therapeutic gains. Pinedo et al. (2 1) demonstrated the effectiveness of cDDP as radiosensitizer when administered at daily 8 mg/ m2 doses, but recorded that this was accompanied, 3 to 5 months from the beginning of treatment, by increased hemathologic toxicity. On the other hand, Keizer et al. tumors
The treatment of patients with primary unresectable bronchogenic carcinoma still remains a serious clinical challenge to oncologists involved in the care of these patients. The task of the medical community therefore is to continue to explore new modalities of therapy to improve the present survival rates. A recently developed strategy for the treatment of nonsmall cell lung cancer (NSCLC) consists of a combination of radiotherapy (RT) and radiosensitizer drugs, such as Cisplatin (cDDP). The interaction of cDDP and RT has been investigated mainly in vitro and the probably mechanisms of enhancement are hypoxic cell radiosensitization and inhibition of cellular repair mechanisms (7, 9, 11). In the literature, favorable results are reported in Phase I-II studies involving RT and cDDP in locally advanced
’ Scientific Director, Centro di Riferimento Oncologico (C.R.O.), Aviano (PN), Italy. Reprint requests to: Dr. Mauro G. Trov6, Radiotherapy Division, Centro di Riferimento Oncologico, 3308 1 Aviano (PN), Italy. Acknowledgements-The authors thank Mrs. Michilin Daniela for secretarial assistance and help in the preparation of the manuscript. Accepted for publication 5 March 1992.
’Radiotherapy Div., Centro di Riferimento Oncologico (C.R.O.), Aviano (PN, Italy). * Pneumology Div., General Hospital, Pordenone, Italy. 3 Radiotherapy Div., General Hospital, Mestre (Ve), Italy. 4 Radiotherapy Div., General Hospital, Vicenza, Italy. 5 Radiotherapy Div., General Hospital, Udine, Italy. ’ Radiotherapy Div., General Hospital, Trieste, Italy. ’ Medical Oncology Div., General Hospital, Gorizia, Italy. * Radiochemistry Div., Clinical Research Centre, Harrow, UK. II
12
1. J. Radiation Oncology 0 Biology 0 Physics
( 15) have reported no severe hemathologic toxicity when cDDP at daily low doses of 6 mg/m* were combined with fractionated RT. In light of these data, a pilot study undertaken from January 1984 to December 1986 was carried out at our institute to assess the effectiveness of the combination of cDDP at daily low doses (6 mg/m*) and short-course RT (45 Gy/l5 fractions/3 weeks) in patients with Stage III inoperable NSCLC (Trove et al. in press). After the encouraging results of our pilot study in which 90 evaluable patients were assessed for tolerance and efficacy ( 15 complete remissions and 34 partial remissions) a randomized cooperative trial was started comparing RT only versus daily low-dose cDDP (6 mg/m*) and RT. The study was designed to assess the superiority of the combined treatment over RT only. METHODS
AND MATERIALS
From January 1987 until June 199 1, 173 patients with inoperable NSCLC Stage III were entered into the present randomized trial. Five institutes participated in the trial. Patients were considered eligible for entry provided the following criteria were met: Diagnosis of NSCLC established by bronchial biopsy and/or transparietal biopsy, limited unresectable disease (Stage III, according to the TNM classification) ( 13) or ipsilateral supraclavicular nodal metastasis without pleural effusion, Karnofsky score greater than 50, age less than 70 years, creatinine < 1.5 mg/ 100 mL, absence of superior vena cava obstructions, absence of life-threatening haemoptysis. Pre-treatment evaluation included clinical examination, chest x-ray, tracheobronchoscopy, routine blood analysis, renal and respiratory function tests, bone scintiscan, brain and chest CT scan, liver ultrasound, or abdominal CT scan. After staging, the patients were randomized to RT only or cDDP and RT. Informed oral consent was obtained from all patients. About 1 hour before each RT fraction, 6 mg/m* cDDP was administered by i.v. injection. No special pre-hydration was used unless patients were unable to have an oral intake of 1.5-2 liters of fluids daily. Antiemetics were not routinely used for vomiting and nausea control. cDDP was discontinued during RT if serum creatinine, measured weekly, was greater than 1.5 mg/ 100 mL. RT was delivered with high energy photon beams either from Cobalt 60 units or from 6 MeV linear accelerators. The total dose delivered was 45 Gy in 15 daily fractions, 5 fractions per week. The target volume included the primary tumor, with 2 cm margins, ipsilateral hilum and mediastinum from the sternal notch to 5 cm below the carina. Inferior mediastinal nodes were included in cases of lower lobe tumors and the supraclavicular nodes were included when the upper lobe bronchus was involved by the primary tumor or when the supraclavicular nodes were involved. The patients were treated using antero-posterior
Volume 24. Number I. 1992
fields during the first 10 fractions and subsequently with two to three computer planned fields. Supraclavicular nodes were treated with an anterior port using an 8 MeV electron beam. The maximum permissible dose to the spinal cord was 36 Gy. Dose distributions were plotted using a linear program. Response and toxicity were evaluated according to the WHO criteria ( 18) during followup. In case of bidimensional unmeasurable lesions, the criteria outlined by Eagan et al. ( 12) were employed. Chest x-rays and CT scans were used for the assessment of response. Histologic and cytologic confirmation were not mandatory for the definition of complete response. After treatment, patients were clinically examined at 2-month intervals during the first year and at 3-month intervals thereafter. The minimum follow-up period at the time of analysis for evaluable patients was 6 months. Progression free interval (from start of treatment to detection of first failure) and survival (from start of treatment to death) were analyzed using the actuarial life-table method. For the comparison of the two survival curves, the log-rank test was used.
RESULTS Out of the 173 randomized patients with unresectable Stage III NSCLC, four patients (three in the RT group and one in the combined treatment group) were subsequently found to be ineligible for the following reasons: metastatic disease at the time of randomization (two patients), small-cell histology (one patient), previous treatment (one patient). Twenty-one patients were not evaluable for response and toxicity (10 in the RT group and 11 in the combined treatment group) and two patients
Table I. Patient characteristics
Total number of patients M/F ratio Median age (range) Median P.S. Histology Squamous Adeno Large cell Weight loss > 10% Patients not eligible Patients not evaluable Patients not yet evaluable Patients evaluable Recruitment distribution per year 1987 1988 1989 1990 1991
RT
RT + cDDP
88 81/7 61 (43-70) 80
85 7411 I 62 (36-69) 80
62 16
62
11 3 10 2 73
13 11 73
35 22 10 19 2
29 26 12 16 2
15
RT vs. RT plus cDDP in Stage III NSCLC 0
Table 2. Response
to treatment
Complete remission Partial remission Stable disease Progression Total
;;I
(146 evaluable
TROVO
13
et al.
patients)
RT
RT + cDDP
(58.9%)
;!$ (50.6%)
24J 6 73
G.
M.
33’ 3 73 .23?3
are not yet evaluable (Table 1). One hundred and fortysix patients (73 in each group) are evaluable for response and toxicity; 167 for survival. Patient characteristics are shown in Table 1. One hundred and fifty-five patients were males and 18 females with a median age of 6 1.5 years and a median performance status of 80. One hundred and twenty-four patients had squamous cell carcinoma, 3 1 adenocarcinoma, and 14 large cell carcinoma. All the 146 evaluable patients completed the planned treatment. The two groups of patients were homogeneous for age, sex, performance status, and weight loss during the previous 6 months. An overall response rate of 58.9% was observed in the RT only group and 50.6% in the combined treatment group, a difference which is not statistically significant. Patterns of response are shown in Table 2. The most frequent sites of distant metastases were recorded to be the following, respectively ,for the RT and RT -I- cDDP arm: bone (IO/l I), brain (7/ I l), lung (2/3), liver (2/2), supraclavicular lymphnodes (2/3). The sites of disease progression are shown in Table 3. No obvious difference in the pattern of relapse was noted in the two treatment groups. Time to local and distant progression curves (patients with no change and with progression included) for patients receiving RT only versus the cDDP and RT group are shown in Figure 1. There is no significant difference in median survival time for the two groups of patients (10.3 months for RT only and 9.97 for cDDP and RT) (Fig. 2). In both groups, 66% of patients developed esophagitis after RT. Severe reversible esophagitis (grade III) was observed in 8% with RT only and in 16% with cDDP and RT. Severe nausea and vomiting (grade III) was observed in one patient and renal toxicity (grade I) in three patients in the combined treatment group. The patterns of acute toxicity are shown in Table 4. No late renal toxicity was documented. Patients with longer survival showed signs of typical, asymptomatic radiation fibrosis on the chest radiograph.
QV 0
Y4
6lzia249JF,v248
Fig. 1. Time to local and distant progression change and with progression included).
m-e ms~
(patients
with no
DISCUSSION
In NSCLC, local control remains an important goal that has been shown to contribute to the improvement of the overall survival rates (20). Several trials in which chemotherapy was combined with standard RT have been conducted (1-3, 5, 8, 10, 14, 17, 19. 25) but no clear evidence in favor of this approach has emerged. Higher RT doses or their biological equivalent in combined modality therapy may be necessary to improve local control. However, the true efficacy of sensitizers in the treatment of lung cancer has not yet been assessed in patients. Dose limitations caused by the side effects of the chemotherapeutic agents preclude the use of optimum dose levels (23). An agent that deserves special attention as a radioenhancing drug is cDDP, but its real effectiveness on local control and the best timing of the combined treatment have yet to be assessed. In the randomized Phase II study by Shaake-Koning et al. (22) although the number of patients is too small to
SURVlVA4
kdlal
10.3 mm
83 uts
RT + DDP **.#“**l..*lcdlal
9.97 NJ%
e4 m.?
RT
_
I AlIve X2 1 - om
Table 3. Progression
Overall Local Local + distant Distant
sites (146 evaluable
P - 0.89
patients)
RT
RT + cDDP
46173 20146 3146 23146
43173 21143 5143 17143
0
6
12
16
24
30
36
42
Fig. 2. Overall survival time.
98
50
14
I. J. Radiation Oncology 0 Biology 0 Physics Table 4. Toxicity ( 146 evaluable
patients)
RT Esophagitis (Grade III) Nausea and vomiting (Grade III) Renal toxicity (Grade I) Hemoglobin (Grade I, II) Leukopenia
RT + cDDP
48 (6) U)
(;;) 21 (I)
(0) 3
(3) 4
2
3
allow conclusions to be drawn, complete responses were observed more frequently in the group of patients treated with RT and daily cDDP. Furthermore, local progression
was observed at a later time in patients treated with daily cDDP than in patients treated with either RT only or RT and weekly cDDP (p = 0.057). Soresi et al. (24) reported that although no statistically significant differences in median survival time and progression-free interval were seen when RT only and RT combined with weekly cDDP, a smaller number of intrathoracic relapses was observed in the combined treatment group. The forthcoming results of the E.O.R.T.C. Phase III study should either confirm or deny the hypothesis for a better tumor response, less recurrences, and improved survival in the daily cDDP arm. In our previous experience, we concluded that the combined treatment was well tolerated and yielded some encouraging results on response rate even though the real efficacy of the combined modality approach was not clearly ascertained. In this cooperative randomized study, the results of the combined treatment group confirm those obtained in the previous pilot study as regards both response rate and survival, but without showing any statistically significant differences for the two treatment modalities in terms of response rate, survival, and sites of relapse. Time to local and distant progression (patients with no change and with progression included) was ob-
Volume 24. Number I. 1992
served to be longer in patients treated with dailycDDP than in patients managed by RT only.
The unsatisfactory results obtained in this study may caused by the ineffectiveness of cDDP but to our scant knowledge of the optimum dose fractionation for each patient, tumor kinetics, and the best timing in combining RT and cDDP. The fact that in order to obtain a sensitizing effect cDDP must be given shortly before or after RT suggests that the critical factor could be the intracellular concentration of the drug. However, the tissue pharmacokinetics of cDDP are not very well known. Furthermore, it is common knowledge that RT has a considerable effect on tissue blood flow and protein/drug extravasation (26) and that these effects depend on the radiation dose and time between RT and drug injection. The only available data using a clinically relevant fractionation schedule (2 Gy/day, 5 days/week for 5 weeks) (27) show that in mice bearing a S.C.transplanted carcinoma the quantity of intratumoral Vincristine may vary by more than a factor of three during the RT treatment. Ongoing studies (Trovb et al.. unpublished data, June 199 1) in patients with NSCLC show that the quantity of cDDP per unit weight of tumor (as a o/oof the injected dose) is highest by a factor of about five, during fractions 4-6 of RT and that earlier and later the quantity of cDDP reaching the tumor is considerably lower. If quantity is a critical factor. the above results suggest that in protocols which combine RT with chemotherapy the pharmacokinetics of the second agent (e.g., cDDP) as modified by the first agent (radiation) should be taken into consideration. The question of the clinical effectiveness of using daily cDDP as a radioenhancer remains unanswered. The conflicting results of the clinical trials suggest that the optimum scheduling of the two modalities has not yet been achieved. The encouraging results of some of the trials and the intractability of the disease suggest that further efforts should be made to optimize clinical trial protocols, perhaps by reviewing the radiobiological and pharmacological bases of the combined treatment or by udding other chemotherapeutic agents.
REFERENCES 1. Alberti, W.: Niederle, N.; Stuschke, M.; Konietzko, N.; Sack, H. Prospective randomized study comparing immediate radiotherapy, combined chemo and radiotherapy and delayed radiotherapy (Abstr.). Lung Cancer 4: 167; 1988. 2. Anderson, G.; Deeley, T. J.: Jani, J. Comparison of radiotherapy alone and radiotherapy with chemotherapy using adriamycin and 5-fluorouracil in bronchogenic carcinoma. Thorax 36: 190- 193; 198 1. 3. Arriagada, R.; Le Chevalier, T.; Quoix. E.: Rul’lie, P.: De Cremoux, H.; Douillard, J. Y.; Tarayre. M.: Pignon. J. P.; LaPlanche, A. ASTRO plenary: Effect chemotherapy on locally advanced non-small cell lung carcinoma: A randomized study of 353 patients. Int. J. Radiat. WA. Biol. Phys. 2O:I 183-l 190;1991. 4. Bartelink, H.; Kallman, R. F.; Rapacchietta. D.: Hart.
of
A. A. Therapeutic enhancement in mice by clinically relevant dose and fractionation schedules of cis-diammine dichloroplatinum (II) and irradiation. Radiother. Oncol. 6: 61-74;1986. 5. Bonomi, P.; Rowland, K. M.; Taylor, S. G.; Pincus, M.; Reddy, S.; Lee, M. S.; Faber, L. P.: Warren, W.; Kittle, C. F. Phase II trial of therapy with etoposide, 5-fluorouracil by continuous infusion, cisplatin, and simultaneous splitcourse radiation in stage III non-small cell bronchogenic carcinoma. NC1 Monogr. 6:33 l-334; 1988. 6. Boven, E.; Tierie, A. H.; Slam, J.; Pinedo, H. M. Combined radiation therapy and daily low dose cisplatin for inoperable, locally advanced non-small cell lung cancer: Results of a phase II trial. Seminars in Oncology 15 (Suppl. 7):18I9:1988.
RT vs. RT plus cDDP in Stage III NSCLC 0 M. G. TROVEet al.
I. C&de, P.; Laval, F. Effect of cis-dichlorodiammine-platinum
8.
9.
10.
Il.
12.
13.
14.
15.
16.
17.
18.
II and x-rays on mammation cell survival. Int. J. Radiat. Oncol. Biol. Phys. 17:929-933; 198 1. Crino, L.; Marazano, E.; Corgna, E.; Meacci, L.; Checcaglini, F.; Darwish, S.; Ariestei, C.; Latini, P.; Tonato, M. Combined modality treatment for locally advanced non small cell lung cancer. A randomized trial (Abstr.). Lung Cancer 4:164;1988. Dewit, L. Combined treatment of radiation and cisdiammine dichloroplatinum (II): A review of experimental and clinical data. Int. J. Radiat. Oncol. Biol. Phys. 13:403-426; 1987. Dillman, R. 0.; Seagren, S. L.; Propert, K. J.; Guerra, J.; Eaton, W. L.; Perry, M. C.; Carey, R. W.; Frei, E. F.; Green, M. R. 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. 323:940-945;1990. Douple, E. B.; Richmond, R. C. Enhancement of the potentiation of radiotherapy by platinum drugs in a mouse tumor. Int. J. Radiat. Oncol. Biol. Phys. 8:501-503;1982. Eagan, R. T.; Fleming, T. R.; Schoonover, V. Evaluation of response criteria in advanced lung cancer. Cancer 44: 1125-1128;1979. International Union Against Cancer (UICC). TNM classification of malignant tumors, 3rd edition. Geneva: International Union Against Cancer; 1978:41-45. Johnson, D. H.; Einhorn, L. H.; Bartolucci, A.; Birch, R.; Omura, G.; Perez, C. A.; Greco, F. A. Thoracic radiotherapy does not prolong survival in patients with locally advanced unresectable non-small cell lung cancer. Ann. Int. Med. 113: 33-38;1990. Keizer, H. J.; Karim, A. B. M. F.; Njo, K. H.; Tierie, A. H., Snow, G.; Vermoken, J. B.; Pinedo, H. M. Feasibility study on daily administration of cis-dichlorodiammineplatinum (II) in combination with radiotherapy. Radiother. Oncol. 1~227-234; 1984. Lelieveld, P.; Stoles, M. A.; Brown, J. M.; Kallmann, R. F. The effect of treatment in fractionated schedules with the combination of x-irradiation and six cytostatic drugs on the RFI-1 tumor and normal mouse skin. Int. J. Radiat. Oncol. Biol. Phys. 1l:ll l-121;1984. Mattson, K.; Holsti, L.; Holst, P.; Jakobsson, M.; Kajant, 1. M.; Liippo, K.; Mantyla, M.; Niitano-Korhone, N. S.; Nikkanen, V.; Nordman, E.; Platin, L. H.; Pyrhonen, S.; Romppanen, M. L.; Salmi, T.; Tammiletho, L.; Taskinen, P. J. Inoperable non small cell lung cancer: Radiation with or without chemotherapy. Eur. J. Cancer Clin. Oncol. 24: 477-482;1988. Miller, A. B.; Hoogstraten, B.; Staquet, M.; Winkler, A. Re-
19.
20.
21.
22.
23.
24.
25.
26.
27.
15
porting results of cancer treatment. Cancer 47:207214;1981. Morton, R. F.; Jett, R.; Maher, C.; Therneau, T. Randomized trial of thoracic radiation therapy with or without chemotherapy for treatment of locally unresectable non-small cell lung cancer (Abstr.). Proc. Am. Sot. Clin. Oncol. 7: 200;1988. Perez, C. A.; Bauer, M.; Edelstein, S.; Gillespie, B. W.; Birch, R. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int. J. Radiat. Oncol. Biol. Phys. 12:539-547;1986. Pinedo, H. M.; Karim, A. B. M. F.; van Vliet, W. H.; Snow, G. B.; Vermoken, J. B. Daily cis-dichlorodiammineplatinum (II) as a radioenhancer: a preliminary toxicity report. J. Cancer Res. CIin. Oncol. 105:79-82;1983. Schaake-Koning, C.; Maat, B.; van Houtte, P.; van der Bogaert, W.; Dalesio, 0.; Kirkpatrick, A.; Bartelink, H. Radiotherapy combined with low-dose cis-diammine dichloroplatinum (II) (CDDP) in inoperable nonmetastatic nonsmall cell lung cancer (NSCLC): a randomized three arm phase II study of the EORTC Lung Cancer and Radiotherapy Cooperative Groups. Int. J. Radiat. Oncol. Biol. Phys. 19:967-972;1990. Simpson, J. R.; Bauer, M.; Perez, C. A.; Wasserman, T. H.; Emami, B.; Scott Doggett, R. L.; Byhardt, R. W.; Phillips, T. L.; Ager Mowry, P. Radiation therapy alone or combined with misonidazole in the treatment of locally advanced nonoat cell lung cancer: Report of an RTOG prospective randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 16:14831491;1989. Soresi, E.; Clerici, M.; Grilli, R.; Borghini, U.; Zucali, R.; Leoni, M.; Botturi, M.; Vergari, C.; Luporini, G.; Scoccia, S. A randomized clinical trial comparing radiation therapy vs radiation therapy plus cis-dicholorodiammine platinum (II) in the treatment of locally advanced non-small cell lung cancer. Sem. Oncol. lS(Supp1. 7):20-25;1988. Trove, M. G.; Minatel, E.; Veronesi, A.; Roncadin, M.; De Paoli, A.; Franchin, G.; Magri, M. D.; Tirelli, U.; Carbone, A.; Grigoletto, E. Combined radiotherapy and chemotherapy versus radiotherapy alone in locally advanced epidermoid bronchogenic carcinoma: A randomized study. Cancer 65:400-404; 1990. Zanelli, G. D.; Rota, L.; Trovb, M. G.; Grigoletto, E.; Roncadin, M. The uptake of 3H Vincristine by a mouse carcinoma during a course of fractionated radiotherapy. Br. J. Cancer 60:310-314;1989. Zanelli, G. D.; Rota, L.; Innocente, R.; Trove, M. G. The effect of timing of Vincristine administration during a course of fractionated radiotherapy in a mouse carcinoma. Eur. J. Cancer 28:64-66; 1992.
0360.3016192 $5.00 t .M) C’opyght 1’ 1992 Pergamon Press Ltd.
0 Clinical Original Contribution RADIOTHERAPY VERSUS RADIOTHERAPY ENHANCED BY CISPLATIN IN STAGE III NON-SMALL CELL LUNG CANCER MAURO MARIA
G.
G. TROVE, BOCCIERI,
GIANBEPPI
CARLO
PIZZI,
GOBITTI,
M.D.,’
M.D.,*
M.D.,’ M.D.,’
EMILIO MINATEL,
OTTORINO
ALESSANDRO
M.D.,’
NASCIMBEN,
TORRETTA,
DALI J. ZANELLI,
PH.D.’
M.D.,3
M.D.,6
Oncologico
FRANCHIN,
GIANPAOLO
ANDREA
(C.R.O.) Aviano,
Operation Pordenone,
M.D.,’
BOLZICCO,
VERONESI,
AND SILVIO MONFARDINI,
North-Eastern Italian Oncology Group (G.O.C.C.N.E.), Centro di Riferimento
GIOVANNI
M.D.,4
M.D.,7 M.D.9
Office, Italy
Between January 1987 and June 1991, 173 patients with inoperable non-small cell lung cancer, Stage III, were entered into a randomized trial comparing radiotherapy only (RT) (45 Gy/15 fractions/3 weeks) (arm A) versus RT and a daily low dose of cDDP (6 mg/m’) (arm B). An overall response rate of 58.9% was observed in arm A and 50.6% in arm B, respectively. No differences in the pattern of relapse were noted between the two treatment groups. Median time to progression was 10.6 months for arm A and 14.2 months for arm B. Median survivals were 10.3 months and 9.97 months, respectively. Toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant advantage of the combined treatment over radiation therapy only was found. The encouraging results achieved in some trials together with the intractability of the disease suggest that further efforts should be made to optimize clinical trial protocols, perhaps by reviewing the radiobiological and pharmacological basis of the combined treatment. Non-small cell lung cancer, cDDP, Radiotherapy, Radiosensitizer. INTRODUCTION
(6, 1.5, 2 1, 22) using different dosages and schedules. From such non-randomized trials it is not possible to assess the resulting therapeutic gain. Recently, two randomized studies have been published and both have reported some favorable results. In one study, either daily low doses or weekly doses of cDDP plus RT (22) were used and in another study the cDDP was given weekly during the RT course (24). In both studies, the combined modality treatment was compared with RT only in patients with inoperable non-metastatic NSCLC. Experimental data (4, 16) suggest that a daily low dose of cDDP during fractionated RT might lead to higher therapeutic gains. Pinedo et al. (2 1) demonstrated the effectiveness of cDDP as radiosensitizer when administered at daily 8 mg/ m2 doses, but recorded that this was accompanied, 3 to 5 months from the beginning of treatment, by increased hemathologic toxicity. On the other hand, Keizer et al. tumors
The treatment of patients with primary unresectable bronchogenic carcinoma still remains a serious clinical challenge to oncologists involved in the care of these patients. The task of the medical community therefore is to continue to explore new modalities of therapy to improve the present survival rates. A recently developed strategy for the treatment of nonsmall cell lung cancer (NSCLC) consists of a combination of radiotherapy (RT) and radiosensitizer drugs, such as Cisplatin (cDDP). The interaction of cDDP and RT has been investigated mainly in vitro and the probably mechanisms of enhancement are hypoxic cell radiosensitization and inhibition of cellular repair mechanisms (7, 9, 11). In the literature, favorable results are reported in Phase I-II studies involving RT and cDDP in locally advanced
’ Scientific Director, Centro di Riferimento Oncologico (C.R.O.), Aviano (PN), Italy. Reprint requests to: Dr. Mauro G. Trov6, Radiotherapy Division, Centro di Riferimento Oncologico, 3308 1 Aviano (PN), Italy. Acknowledgements-The authors thank Mrs. Michilin Daniela for secretarial assistance and help in the preparation of the manuscript. Accepted for publication 5 March 1992.
’Radiotherapy Div., Centro di Riferimento Oncologico (C.R.O.), Aviano (PN, Italy). * Pneumology Div., General Hospital, Pordenone, Italy. 3 Radiotherapy Div., General Hospital, Mestre (Ve), Italy. 4 Radiotherapy Div., General Hospital, Vicenza, Italy. 5 Radiotherapy Div., General Hospital, Udine, Italy. ’ Radiotherapy Div., General Hospital, Trieste, Italy. ’ Medical Oncology Div., General Hospital, Gorizia, Italy. * Radiochemistry Div., Clinical Research Centre, Harrow, UK. II
12
1. J. Radiation Oncology 0 Biology 0 Physics
( 15) have reported no severe hemathologic toxicity when cDDP at daily low doses of 6 mg/m* were combined with fractionated RT. In light of these data, a pilot study undertaken from January 1984 to December 1986 was carried out at our institute to assess the effectiveness of the combination of cDDP at daily low doses (6 mg/m*) and short-course RT (45 Gy/l5 fractions/3 weeks) in patients with Stage III inoperable NSCLC (Trove et al. in press). After the encouraging results of our pilot study in which 90 evaluable patients were assessed for tolerance and efficacy ( 15 complete remissions and 34 partial remissions) a randomized cooperative trial was started comparing RT only versus daily low-dose cDDP (6 mg/m*) and RT. The study was designed to assess the superiority of the combined treatment over RT only. METHODS
AND MATERIALS
From January 1987 until June 199 1, 173 patients with inoperable NSCLC Stage III were entered into the present randomized trial. Five institutes participated in the trial. Patients were considered eligible for entry provided the following criteria were met: Diagnosis of NSCLC established by bronchial biopsy and/or transparietal biopsy, limited unresectable disease (Stage III, according to the TNM classification) ( 13) or ipsilateral supraclavicular nodal metastasis without pleural effusion, Karnofsky score greater than 50, age less than 70 years, creatinine < 1.5 mg/ 100 mL, absence of superior vena cava obstructions, absence of life-threatening haemoptysis. Pre-treatment evaluation included clinical examination, chest x-ray, tracheobronchoscopy, routine blood analysis, renal and respiratory function tests, bone scintiscan, brain and chest CT scan, liver ultrasound, or abdominal CT scan. After staging, the patients were randomized to RT only or cDDP and RT. Informed oral consent was obtained from all patients. About 1 hour before each RT fraction, 6 mg/m* cDDP was administered by i.v. injection. No special pre-hydration was used unless patients were unable to have an oral intake of 1.5-2 liters of fluids daily. Antiemetics were not routinely used for vomiting and nausea control. cDDP was discontinued during RT if serum creatinine, measured weekly, was greater than 1.5 mg/ 100 mL. RT was delivered with high energy photon beams either from Cobalt 60 units or from 6 MeV linear accelerators. The total dose delivered was 45 Gy in 15 daily fractions, 5 fractions per week. The target volume included the primary tumor, with 2 cm margins, ipsilateral hilum and mediastinum from the sternal notch to 5 cm below the carina. Inferior mediastinal nodes were included in cases of lower lobe tumors and the supraclavicular nodes were included when the upper lobe bronchus was involved by the primary tumor or when the supraclavicular nodes were involved. The patients were treated using antero-posterior
Volume 24. Number I. 1992
fields during the first 10 fractions and subsequently with two to three computer planned fields. Supraclavicular nodes were treated with an anterior port using an 8 MeV electron beam. The maximum permissible dose to the spinal cord was 36 Gy. Dose distributions were plotted using a linear program. Response and toxicity were evaluated according to the WHO criteria ( 18) during followup. In case of bidimensional unmeasurable lesions, the criteria outlined by Eagan et al. ( 12) were employed. Chest x-rays and CT scans were used for the assessment of response. Histologic and cytologic confirmation were not mandatory for the definition of complete response. After treatment, patients were clinically examined at 2-month intervals during the first year and at 3-month intervals thereafter. The minimum follow-up period at the time of analysis for evaluable patients was 6 months. Progression free interval (from start of treatment to detection of first failure) and survival (from start of treatment to death) were analyzed using the actuarial life-table method. For the comparison of the two survival curves, the log-rank test was used.
RESULTS Out of the 173 randomized patients with unresectable Stage III NSCLC, four patients (three in the RT group and one in the combined treatment group) were subsequently found to be ineligible for the following reasons: metastatic disease at the time of randomization (two patients), small-cell histology (one patient), previous treatment (one patient). Twenty-one patients were not evaluable for response and toxicity (10 in the RT group and 11 in the combined treatment group) and two patients
Table I. Patient characteristics
Total number of patients M/F ratio Median age (range) Median P.S. Histology Squamous Adeno Large cell Weight loss > 10% Patients not eligible Patients not evaluable Patients not yet evaluable Patients evaluable Recruitment distribution per year 1987 1988 1989 1990 1991
RT
RT + cDDP
88 81/7 61 (43-70) 80
85 7411 I 62 (36-69) 80
62 16
62
11 3 10 2 73
13 11 73
35 22 10 19 2
29 26 12 16 2
15
RT vs. RT plus cDDP in Stage III NSCLC 0
Table 2. Response
to treatment
Complete remission Partial remission Stable disease Progression Total
;;I
(146 evaluable
TROVO
13
et al.
patients)
RT
RT + cDDP
(58.9%)
;!$ (50.6%)
24J 6 73
G.
M.
33’ 3 73 .23?3
are not yet evaluable (Table 1). One hundred and fortysix patients (73 in each group) are evaluable for response and toxicity; 167 for survival. Patient characteristics are shown in Table 1. One hundred and fifty-five patients were males and 18 females with a median age of 6 1.5 years and a median performance status of 80. One hundred and twenty-four patients had squamous cell carcinoma, 3 1 adenocarcinoma, and 14 large cell carcinoma. All the 146 evaluable patients completed the planned treatment. The two groups of patients were homogeneous for age, sex, performance status, and weight loss during the previous 6 months. An overall response rate of 58.9% was observed in the RT only group and 50.6% in the combined treatment group, a difference which is not statistically significant. Patterns of response are shown in Table 2. The most frequent sites of distant metastases were recorded to be the following, respectively ,for the RT and RT -I- cDDP arm: bone (IO/l I), brain (7/ I l), lung (2/3), liver (2/2), supraclavicular lymphnodes (2/3). The sites of disease progression are shown in Table 3. No obvious difference in the pattern of relapse was noted in the two treatment groups. Time to local and distant progression curves (patients with no change and with progression included) for patients receiving RT only versus the cDDP and RT group are shown in Figure 1. There is no significant difference in median survival time for the two groups of patients (10.3 months for RT only and 9.97 for cDDP and RT) (Fig. 2). In both groups, 66% of patients developed esophagitis after RT. Severe reversible esophagitis (grade III) was observed in 8% with RT only and in 16% with cDDP and RT. Severe nausea and vomiting (grade III) was observed in one patient and renal toxicity (grade I) in three patients in the combined treatment group. The patterns of acute toxicity are shown in Table 4. No late renal toxicity was documented. Patients with longer survival showed signs of typical, asymptomatic radiation fibrosis on the chest radiograph.
QV 0
Y4
6lzia249JF,v248
Fig. 1. Time to local and distant progression change and with progression included).
m-e ms~
(patients
with no
DISCUSSION
In NSCLC, local control remains an important goal that has been shown to contribute to the improvement of the overall survival rates (20). Several trials in which chemotherapy was combined with standard RT have been conducted (1-3, 5, 8, 10, 14, 17, 19. 25) but no clear evidence in favor of this approach has emerged. Higher RT doses or their biological equivalent in combined modality therapy may be necessary to improve local control. However, the true efficacy of sensitizers in the treatment of lung cancer has not yet been assessed in patients. Dose limitations caused by the side effects of the chemotherapeutic agents preclude the use of optimum dose levels (23). An agent that deserves special attention as a radioenhancing drug is cDDP, but its real effectiveness on local control and the best timing of the combined treatment have yet to be assessed. In the randomized Phase II study by Shaake-Koning et al. (22) although the number of patients is too small to
SURVlVA4
kdlal
10.3 mm
83 uts
RT + DDP **.#“**l..*lcdlal
9.97 NJ%
e4 m.?
RT
_
I AlIve X2 1 - om
Table 3. Progression
Overall Local Local + distant Distant
sites (146 evaluable
P - 0.89
patients)
RT
RT + cDDP
46173 20146 3146 23146
43173 21143 5143 17143
0
6
12
16
24
30
36
42
Fig. 2. Overall survival time.
98
50
14
I. J. Radiation Oncology 0 Biology 0 Physics Table 4. Toxicity ( 146 evaluable
patients)
RT Esophagitis (Grade III) Nausea and vomiting (Grade III) Renal toxicity (Grade I) Hemoglobin (Grade I, II) Leukopenia
RT + cDDP
48 (6) U)
(;;) 21 (I)
(0) 3
(3) 4
2
3
allow conclusions to be drawn, complete responses were observed more frequently in the group of patients treated with RT and daily cDDP. Furthermore, local progression
was observed at a later time in patients treated with daily cDDP than in patients treated with either RT only or RT and weekly cDDP (p = 0.057). Soresi et al. (24) reported that although no statistically significant differences in median survival time and progression-free interval were seen when RT only and RT combined with weekly cDDP, a smaller number of intrathoracic relapses was observed in the combined treatment group. The forthcoming results of the E.O.R.T.C. Phase III study should either confirm or deny the hypothesis for a better tumor response, less recurrences, and improved survival in the daily cDDP arm. In our previous experience, we concluded that the combined treatment was well tolerated and yielded some encouraging results on response rate even though the real efficacy of the combined modality approach was not clearly ascertained. In this cooperative randomized study, the results of the combined treatment group confirm those obtained in the previous pilot study as regards both response rate and survival, but without showing any statistically significant differences for the two treatment modalities in terms of response rate, survival, and sites of relapse. Time to local and distant progression (patients with no change and with progression included) was ob-
Volume 24. Number I. 1992
served to be longer in patients treated with dailycDDP than in patients managed by RT only.
The unsatisfactory results obtained in this study may caused by the ineffectiveness of cDDP but to our scant knowledge of the optimum dose fractionation for each patient, tumor kinetics, and the best timing in combining RT and cDDP. The fact that in order to obtain a sensitizing effect cDDP must be given shortly before or after RT suggests that the critical factor could be the intracellular concentration of the drug. However, the tissue pharmacokinetics of cDDP are not very well known. Furthermore, it is common knowledge that RT has a considerable effect on tissue blood flow and protein/drug extravasation (26) and that these effects depend on the radiation dose and time between RT and drug injection. The only available data using a clinically relevant fractionation schedule (2 Gy/day, 5 days/week for 5 weeks) (27) show that in mice bearing a S.C.transplanted carcinoma the quantity of intratumoral Vincristine may vary by more than a factor of three during the RT treatment. Ongoing studies (Trovb et al.. unpublished data, June 199 1) in patients with NSCLC show that the quantity of cDDP per unit weight of tumor (as a o/oof the injected dose) is highest by a factor of about five, during fractions 4-6 of RT and that earlier and later the quantity of cDDP reaching the tumor is considerably lower. If quantity is a critical factor. the above results suggest that in protocols which combine RT with chemotherapy the pharmacokinetics of the second agent (e.g., cDDP) as modified by the first agent (radiation) should be taken into consideration. The question of the clinical effectiveness of using daily cDDP as a radioenhancer remains unanswered. The conflicting results of the clinical trials suggest that the optimum scheduling of the two modalities has not yet been achieved. The encouraging results of some of the trials and the intractability of the disease suggest that further efforts should be made to optimize clinical trial protocols, perhaps by reviewing the radiobiological and pharmacological bases of the combined treatment or by udding other chemotherapeutic agents.
REFERENCES 1. Alberti, W.: Niederle, N.; Stuschke, M.; Konietzko, N.; Sack, H. Prospective randomized study comparing immediate radiotherapy, combined chemo and radiotherapy and delayed radiotherapy (Abstr.). Lung Cancer 4: 167; 1988. 2. Anderson, G.; Deeley, T. J.: Jani, J. Comparison of radiotherapy alone and radiotherapy with chemotherapy using adriamycin and 5-fluorouracil in bronchogenic carcinoma. Thorax 36: 190- 193; 198 1. 3. Arriagada, R.; Le Chevalier, T.; Quoix. E.: Rul’lie, P.: De Cremoux, H.; Douillard, J. Y.; Tarayre. M.: Pignon. J. P.; LaPlanche, A. ASTRO plenary: Effect chemotherapy on locally advanced non-small cell lung carcinoma: A randomized study of 353 patients. Int. J. Radiat. WA. Biol. Phys. 2O:I 183-l 190;1991. 4. Bartelink, H.; Kallman, R. F.; Rapacchietta. D.: Hart.
of
A. A. Therapeutic enhancement in mice by clinically relevant dose and fractionation schedules of cis-diammine dichloroplatinum (II) and irradiation. Radiother. Oncol. 6: 61-74;1986. 5. Bonomi, P.; Rowland, K. M.; Taylor, S. G.; Pincus, M.; Reddy, S.; Lee, M. S.; Faber, L. P.: Warren, W.; Kittle, C. F. Phase II trial of therapy with etoposide, 5-fluorouracil by continuous infusion, cisplatin, and simultaneous splitcourse radiation in stage III non-small cell bronchogenic carcinoma. NC1 Monogr. 6:33 l-334; 1988. 6. Boven, E.; Tierie, A. H.; Slam, J.; Pinedo, H. M. Combined radiation therapy and daily low dose cisplatin for inoperable, locally advanced non-small cell lung cancer: Results of a phase II trial. Seminars in Oncology 15 (Suppl. 7):18I9:1988.
RT vs. RT plus cDDP in Stage III NSCLC 0 M. G. TROVEet al.
I. C&de, P.; Laval, F. Effect of cis-dichlorodiammine-platinum
8.
9.
10.
Il.
12.
13.
14.
15.
16.
17.
18.
II and x-rays on mammation cell survival. Int. J. Radiat. Oncol. Biol. Phys. 17:929-933; 198 1. Crino, L.; Marazano, E.; Corgna, E.; Meacci, L.; Checcaglini, F.; Darwish, S.; Ariestei, C.; Latini, P.; Tonato, M. Combined modality treatment for locally advanced non small cell lung cancer. A randomized trial (Abstr.). Lung Cancer 4:164;1988. Dewit, L. Combined treatment of radiation and cisdiammine dichloroplatinum (II): A review of experimental and clinical data. Int. J. Radiat. Oncol. Biol. Phys. 13:403-426; 1987. Dillman, R. 0.; Seagren, S. L.; Propert, K. J.; Guerra, J.; Eaton, W. L.; Perry, M. C.; Carey, R. W.; Frei, E. F.; Green, M. R. 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. 323:940-945;1990. Douple, E. B.; Richmond, R. C. Enhancement of the potentiation of radiotherapy by platinum drugs in a mouse tumor. Int. J. Radiat. Oncol. Biol. Phys. 8:501-503;1982. Eagan, R. T.; Fleming, T. R.; Schoonover, V. Evaluation of response criteria in advanced lung cancer. Cancer 44: 1125-1128;1979. International Union Against Cancer (UICC). TNM classification of malignant tumors, 3rd edition. Geneva: International Union Against Cancer; 1978:41-45. Johnson, D. H.; Einhorn, L. H.; Bartolucci, A.; Birch, R.; Omura, G.; Perez, C. A.; Greco, F. A. Thoracic radiotherapy does not prolong survival in patients with locally advanced unresectable non-small cell lung cancer. Ann. Int. Med. 113: 33-38;1990. Keizer, H. J.; Karim, A. B. M. F.; Njo, K. H.; Tierie, A. H., Snow, G.; Vermoken, J. B.; Pinedo, H. M. Feasibility study on daily administration of cis-dichlorodiammineplatinum (II) in combination with radiotherapy. Radiother. Oncol. 1~227-234; 1984. Lelieveld, P.; Stoles, M. A.; Brown, J. M.; Kallmann, R. F. The effect of treatment in fractionated schedules with the combination of x-irradiation and six cytostatic drugs on the RFI-1 tumor and normal mouse skin. Int. J. Radiat. Oncol. Biol. Phys. 1l:ll l-121;1984. Mattson, K.; Holsti, L.; Holst, P.; Jakobsson, M.; Kajant, 1. M.; Liippo, K.; Mantyla, M.; Niitano-Korhone, N. S.; Nikkanen, V.; Nordman, E.; Platin, L. H.; Pyrhonen, S.; Romppanen, M. L.; Salmi, T.; Tammiletho, L.; Taskinen, P. J. Inoperable non small cell lung cancer: Radiation with or without chemotherapy. Eur. J. Cancer Clin. Oncol. 24: 477-482;1988. Miller, A. B.; Hoogstraten, B.; Staquet, M.; Winkler, A. Re-
19.
20.
21.
22.
23.
24.
25.
26.
27.
15
porting results of cancer treatment. Cancer 47:207214;1981. Morton, R. F.; Jett, R.; Maher, C.; Therneau, T. Randomized trial of thoracic radiation therapy with or without chemotherapy for treatment of locally unresectable non-small cell lung cancer (Abstr.). Proc. Am. Sot. Clin. Oncol. 7: 200;1988. Perez, C. A.; Bauer, M.; Edelstein, S.; Gillespie, B. W.; Birch, R. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int. J. Radiat. Oncol. Biol. Phys. 12:539-547;1986. Pinedo, H. M.; Karim, A. B. M. F.; van Vliet, W. H.; Snow, G. B.; Vermoken, J. B. Daily cis-dichlorodiammineplatinum (II) as a radioenhancer: a preliminary toxicity report. J. Cancer Res. CIin. Oncol. 105:79-82;1983. Schaake-Koning, C.; Maat, B.; van Houtte, P.; van der Bogaert, W.; Dalesio, 0.; Kirkpatrick, A.; Bartelink, H. Radiotherapy combined with low-dose cis-diammine dichloroplatinum (II) (CDDP) in inoperable nonmetastatic nonsmall cell lung cancer (NSCLC): a randomized three arm phase II study of the EORTC Lung Cancer and Radiotherapy Cooperative Groups. Int. J. Radiat. Oncol. Biol. Phys. 19:967-972;1990. Simpson, J. R.; Bauer, M.; Perez, C. A.; Wasserman, T. H.; Emami, B.; Scott Doggett, R. L.; Byhardt, R. W.; Phillips, T. L.; Ager Mowry, P. Radiation therapy alone or combined with misonidazole in the treatment of locally advanced nonoat cell lung cancer: Report of an RTOG prospective randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 16:14831491;1989. Soresi, E.; Clerici, M.; Grilli, R.; Borghini, U.; Zucali, R.; Leoni, M.; Botturi, M.; Vergari, C.; Luporini, G.; Scoccia, S. A randomized clinical trial comparing radiation therapy vs radiation therapy plus cis-dicholorodiammine platinum (II) in the treatment of locally advanced non-small cell lung cancer. Sem. Oncol. lS(Supp1. 7):20-25;1988. Trove, M. G.; Minatel, E.; Veronesi, A.; Roncadin, M.; De Paoli, A.; Franchin, G.; Magri, M. D.; Tirelli, U.; Carbone, A.; Grigoletto, E. Combined radiotherapy and chemotherapy versus radiotherapy alone in locally advanced epidermoid bronchogenic carcinoma: A randomized study. Cancer 65:400-404; 1990. Zanelli, G. D.; Rota, L.; Trovb, M. G.; Grigoletto, E.; Roncadin, M. The uptake of 3H Vincristine by a mouse carcinoma during a course of fractionated radiotherapy. Br. J. Cancer 60:310-314;1989. Zanelli, G. D.; Rota, L.; Innocente, R.; Trove, M. G. The effect of timing of Vincristine administration during a course of fractionated radiotherapy in a mouse carcinoma. Eur. J. Cancer 28:64-66; 1992.
