- Email: [email protected]
Mitomycin, cisplatin, and vindesine followed by radiotherapy combined with cisplatin in stage III nonsmall cell lung cancer: long-term results
Int. J. Radiation Oncology Biol. Phys., Vol. 3t, No. 4, pp. 813 818, 1995 Copyright © 1995 Elsevier Science Ltd Printed in the USA. All rights reserved 0360-3016/95 $9.50 + .00
Pergamon
0360-3016(94)00575-3
•
Phase I/II Clinical Trials
M I T O M Y C I N , CISPLATIN, A N D V I N D E S I N E F O L L O W E D BY R A D I O T H E R A P Y C O M B I N E D W I T H C I S P L A T I N IN STAGE III N O N S M A L L CELL L U N G CANCER: LONG-TERM RESULTS MARTIN TEJEDOR, P H . D . , JUAN J. VALERDI,
M.D., RAFAEL
LOPEZ,
M.D.,
M1GUEL A. DOM[NGUEZ, M.D., FERNANDO ARIAS, M.D., Jos~. J. ILLARRAMENDI, PH.D. AND ENRIQUE MART~NEZ, M . D . Department of Oncology, Hospital de Navarra, 31008 Pamplona, Spain Purpose: To assess the tolerance, response rate, pattern of failure, and long-term survival of patients with unresectable nonsmail cell lung cancer treated with one cycle of induction chemotherapy followed by concurrent cisplatin and radiotherapy. Methods and Materials: From 1986 to 1988, 45 patients with histologically proven nonsmall cell lung cancer clinical Stage III (29 I l i a and 16 IIIB) were included in this study. Patients received one cycle of Mitomycin C 10 mg/m 2 day 1, Cisplatin 120 mg/m z day 1, and Vindesine 3 mg/m 2 days 1, 8, 15, and 22, by i.v. bolus
injection. Radiotherapy was started within 4 - 6 weeks after completion of chemotherapy, with a total tumor dose of 60 Gy, at 2 Gy/day. Cisplatin, 20 mg/m2/day by i.v. continous infusion was administered for days 1-5 of radiation treatment. Results: The main toxic acute effects were nausea-vomiting grade 1-3 in 38 patients (85%). Ten patients (22%) developed esophagitis grade 3. Leukopenia grade 1 - 2 was observed in 18 patients (40%), grade 3 in 12 (27%), and grade 4 in 4 (9%). Three patients (6.6%) died by granulocytopenia and sepsis. A bronchoscopic proven complete response was achieved in 9 patients (21.5%) and partial response in 28 patients (67%). With a minimum follow-up of 65 months, overall median survival was 13 months, 2-year survival was 21%, and 5-year survival was 7%, with no statistical difference between Stage I l i A and IIIB. Median survival of patients with complete response was 23.2 months, and 5-year survival was 33%. Conclusion: This treatment scheme produced a severe toxicity and in spite of a high response rate, longterm survival is poor, similar to previous studies with radiotherapy alone. Locally advanced nonsmall cell lung cancer, Induction chemotherapy, Chemoradiotherapy, Long-term results.
INTRODUCTION
and cisplatin (7, 8), with response rates greater than 50%. In these studies, survival advantage was not proven, but the high response rates observed justified the development of new trials to investigate whether induction chemotherapy could improve the survival in patients with locally advanced NSCLC. Perez et al. (16) reported that high doses of irradiation (60 Gy) yield a greater proportion of complete response, higher tumor control, and better survival in locally advanced nonsmall cell lung cancer. To increase tumoral damage of radiation and, thus, improve the local control and survival, several radiopotentiators have been investigated. In vitro studies have demostrated tumor cell radiosensitization by cisplatin (2), and clinical data of Phase II studies showed the feasibility of radiotherapy combined with cisplatin (11, 18).
The prognosis for patients with locally advanced unresectable nonsmall cell lung cancer (NSCLC) is still very poor. Radiation therapy remains the standard treatment, and median survival is 8 - 1 1 months, with long-term survival rates of 5 - 8 % (12). The presence of subclinical distant metastases at diagnosis and a high local relapse rate even after a high dose of radiotherapy, are the causes of death in these patients. In the early 1980s, several studies with new chemotherapy combinations were designed to evaluate the role of chemotherapy in patients with locally advanced NSCLC. Regimens containing cisplatin showed the highest and most reproducible response rates, and especially interesting was the combination of mitomycin C, vinca alkaloid,
Reprint requests to: Martin Tejedor, Ph.D.
Accepted for publication 25 October 1994. 813
814
I. J. Radiation Oncology• Biology• Physics Table 1. Eligibility criteria Patient characteristics
Tumor characteristics
Nonsmall cell lung cancer Karnosfky > 60% Stage III, Mo No previous tumor Leukocites > 3500/ram 3 Measurable disease Platelets > 100.000/mm3 Hemoglobin > 9 g% Creatinine clearance > 60 ml/min
Drewinko et al. (6) found that cytotoxic activity of cisplatin might be improved by increasing the duration of exposure of tumor cells to cisplatin. Furthermore, Posner et al. (17) demostrated that cisplatin administered as a continous infusion over 5 days at doses of 2 0 - 2 5 mg/m2/day was an effective chemotherapeutic treatment with less toxicity than in bolus injection. In view of these findings, a prospective study was begun in 1986 with induction chemotherapy (mitomycin, cisplatin, and vindesine) followed by radiotherapy combined with cisplatin, in patients with Stage III NSCLC. The objetives of this study were to determine the tolerrance, response rate, pattern of recurrence, and survival after a long follow-up.
METHODS AND MATERIALS Patient population From 1986 to 1988, 45 patients with histologically proven NSCLC were included into the study. Eligibility criteria are shown in Table 1. Initial evaluation included a physical examination, hematological and biochemical studies, chest x-ray, bronchoscopy, and computed tomography scan of the thorax and abdomen. Bone scintigraphy and computed tomography scan of the brain were performed only in clinical indications. Minimum follow-up was 65 months. All patients gave informed written conset. The patients's characteristics are shown in Table 2. Treatment scheme Induction chemotherapy consisted of one cycle with: mitomycin C, 10 mg/m 2 by intravenous bolus injection on day 1, cisplatin 120 mg/m 2 by intravenous bolus injection on day 1, and vindesine, 3 mg/m 2 by intravenous bolus injection on days 1, 8, 15, and 22. Radiation treatment was initiated 4 - 6 weeks after chemotherapy, and was delivered with a Cobalt-60 unit. 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. Supraclavicular nodes were included when involved or when tumor was localized in the upper lobes. Inferior mediastinum was included in the case of tumor in lower lobe. The primary tumor and involved nodal region received 60 Gy, at 2 Gy/day for 6 weeks, with opposing anterior and posterior shaped fields to 40
Volume 31, Number 4, 1995 Gy, and oblique fields to complete total dosage. The dose to spinal cord was kept below 45 Gy. Cisplatin, 20 mg/ mZ/day by i.v. continous infusion, was administered for days 1 - 5 of radiotherapy.
Criteria for response and toxicity Response and toxicity were evaluated according to the WHO criteria (23). To assess the response to induction chemotherapy, a chest x-ray was performed. Postradiotherapy evaluation of response was performed 4 to 6 weeks after completion of treatment, and included a computed tomography scan of the thorax and a bronchoscopy when a complete response was observed. Statistical methods Survival was calculated according to the method of Kaplan and Meier (10), and the log rank test (15) was used to compare prognostic variables. RESULTS Toxicity All patients included in the study were evaluable for toxicity. Toxic effects according to the WHO are shown in Table 3. The main toxic reactions during treatment were nausea-vomiting (85%). Three patients (6.6%) with granulocytopenia grade 4 died by sepsis after induction chemotherapy. Reversible alopecia was seen in all patients. Patients with long-term survival showed lung fibrosis in treatment volume. Response Three patients died before radiotherapy. Forty-two patients completed the treatment and were evaluable for response. After neoadjuvant chemotherapy, 1 patient (2.4%) achieved a radiographic complete response, and 15 patients (36%) a partial response. Following radiotherapy, 10 patients (24%) had a radiographic complete response. The bronchoscopy-biopsy was performed in all Table 2. Patient characteristics Age (years) Median Range Sex Male Female Histology Squamous cell Adenocarcinoma Undifferentiated or Large cell Stage Ill A III B Performance status Karnosfky 70-80% Karnosfky 90-100%
63 37-75 42 3 35 7 3 29 16 26 19
Chemotherapy in NSCLC • M. TEJEDORet al. Table 3. Acute toxicity of indution chemotherapy and concomitant cisplatin and radiotherapy (n = 45)
815
difference in overall survival was found between Stage I I I A and Stage III B (Fig. 3).
WHO Grade
I-II
III
IV
Leukopenia Trombopenia Anemia Infection Renal Nausea/vomiting Mucositis/esophagitis
18 4 12 0 3 30 12
12 1 2 1 0 8 10
4 0 0 3 0 0 0
complete responders, and showed tumor persistance in one patient. Nine patients (21.4%) had a radiographic and bronchoscopy-biopsy complete response and 28 patients (67%) a partial response. Survival
Median survival time was 13 months, with 2-year survival of 21% and 5-year survival of 7% (Fig. 1). Three patients with Stage III A are alive at 65, 78, and 84 months. One patient (Stage III A) was lost at follow-up at 17 months without evidence of recurrence. Forty-two patients received complete treatment and 38 are dead: 31 patients (74%) with disease progression and 7 from other causes (5 by cardiopulmonary disease, 1 from bladder carcinoma, and 1 from cerebrovascular accident). The primary tumor site was the first site of failure in 10 patients; local and distant failure was observed in 6 patients, and distant progression only in 15 patients. Patients with complete response showed a significantly (p < 0.01) longer survival, with a median survival time of 23.2 months and 5-year survival of 33% (Fig. 2). No statistical
DISCUSSION The main end point of this study was to analyze if long-term survival of patients with locally advanced NSCLC could be improved with a combined chemoradiotherapy treatment. Since we started this trial in 1986, several studies with induction chemotherapy followed by radical radiotherapy or concurrent chemoradiotherapy, have been published. In four randomized studies (3, 4, 9, 14) induction chemotherapy with two to three cycles of cisplatin-based regimens and radiotherapy was compared with radiation treatment alone. Gregor e t al. (9) did not find survival difference, and the other three studies (3, 4, 14) reported a moderate benefit in survival with the combined treatment, but only Dillman e t al. (4) had a statistical significant difference, with a median survival time of 13.8 months vs. 9.7 months. Concurrent cisplatin by bolus injection and radiotherapy vs. radiotherapy alone have been investigated in three randomized studies (19-21). Soresi et al. (20) reported a higher local control and improved survival (16 vs. 11 months), without statistical significance, in the group treated with 50 Gy plus cisplatin 15 mg/m 2 i.v. weekly. Schaake-Koning e t al. (19) designed a randomized trial with three arms: radiotherapy alone (55 Gy), radiotherapy plus cisplatin 30 mg/m 2 weekly, or radiotherapy combined with 6 mg/m2/daily. In this study, patients with cisplatin and radiotherapy had a better local control and survival, with statistical significance only in the group
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
2
3
I
I
4 Years
5
Fig. 1. Overall survival (n = 45).
__
I
6
.
I
7
8
816
I.J. Radiation Oncology • Biology • Physics
0.9
Volume31, Number 4, 1995
COMPLETE RESPONSE
~
* r
o
0.8 i 0.7
'
NO COMPLETE RESPONSE
\
-\
O
r t
O. 6
r,
0.5
,-
0.4 i
i vi
0.3.
g
0.2
i o
I
"/ '
~'
',\
,~
',~ \\
"
0.1, 0 I
J_
0
1
~i
2
::;.®
3
4 Years
t
5
I
6
7
__
8
Fig. 2. Survival according to response to the treatment. Complete response n = 9, no complete response n = 33. (p < 0.01). with cisplatin given daily (16% vs. 2% at 3 years). However, Trov6 et al. (21) with a treatment scheme similar to the Schaake-Koning et al. (19), 45 Gy and cisplatin 6 mg/m 2 daily compared with radiotherapy alone, did not observe differences in the pattern of relapse and median survival time (10.3 vs. 9.9 months). T w o nonrandomized studies (13, 22) of more than 40 patients agressively treated with radiotherapy concurrent with cisplatin plus other two drugs, reported a median survival of 14 months (13) and 12 months (22), respectively.
0.9
The most of series cited with combined chemotherapy have a short follow-up and 5-year survival is not specified. Dillman e t al. (5) have recently reported the results of induction chemotherapy plus radiotherapy vs. radiotherapy alone after a 5-year follow-up, and the median survival time remains favorable to the group with induction chemotherapy (13.7 vs. 9.6 months) with statistical significance. By administering one cycle of induction chemotherapy and radiotherapy concurrent with continuous infusion of cisplatin, we achieved a high response rate (88%), but
STAGE III A
~
STAGE III B
0.8]
" ~I
0.7-
~', ® ,
0.6 -
~"~
:!
o3°4J
.
0.21 0.1~ O'
J
0
1
2
I
~ ±,o
I
3
4 Years
5
J . . . .
6
7
8
Fig. 3. Survival according to stage. Stage IIIA n = 29, Stage IIIB n = 16 (p = NS).
Chemotherapy in NSCLC • M. TEJEDORet al. the 5-year survival (7%) is very poor. Our results on local control and median survival are similar to previous studies with two or more cycles of induction chemotherapy and radiotherapy (3, 4, 9, 14, 22) or concurrent cisplatin by bolus injection plus radiotherapy (13, 1 9 - 2 1 ) , and in spite of the agressive treatment, patients with unresectable N S C L C died by local failure and distant metastases. Moreover, Ball e t al. (1) and Wtirschmidt e t al. (24) have recently reported a median survival o f 14.5 and 13.2 months and 5-year survival o f 7 and 4%, respectively, in patients with Stage III nonsmall cell lung cancer treated with high dose o f radiotherapy alone after a long follow-up. The c o m b i n e d c h e m o r a d i o t h e r a p y treatment caused an increase in the acute toxicity, mainly esophagitis, n a u s e a - v o m i t i n g , and hematological toxicity, in all studies published (3, 4, 9, 13, 14, 1 9 - 2 2 ) . In our study,
817
there were three treatment-related deaths due to sepsis, that, analyzed critically, could have been prevented with a more rigourous patient selection and better supportive care. The benefit o f c h e m o r a d i o t h e r a p y in patients with locally advanced N S C L C remains controversial, and perhaps, a metaanalysis could elucidate this question, but the possible advantage on survival is clearly associated with an increase in the morbidity. With a median survival time of aproximately 1 year, the treatment in patients with locally advanced nonsmall cell lung cancer is mainly palliative, and the primary objectives o f the treatment must be to improve the s y m p t o m a t i c control and quality o f life. In future r a n d o m i z e d studies with new aggressive treatments, the quality o f life should be measured to assess the risk benefit.
REFERENCES 1. Ball, D.; Matthews, J.; Worotniuk, V.; Crennan, E. Longer survival with higher doses of thoracic radiotherapy in patients with limited nonsmall cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 25:599-604; 1993. 2. Carde, P.; Laval, F. Effect of cis-dichlorodiammine-platinum II and X-rays on mammation celll survival. Int. J. Radiat. Oncol. Biol. Phys. 17:929-933; 1981. 3. Crin6, L.; Latini, P.; Meacci, M.; Corgna, E.; Maranzano, E.: Darwish, S.; Minotti, V.; Santucci, A.; Tonato, M. Induction chemotherapy plus high-dose radiotherapy vs. radiotherapy alone in locally advanced unresectable nonsmall cell lung cancer. Ann. Oncol. 4:847-851; 1993. 4. Dillman, R. O.; Seagren, S. L.; Propert, K. L.; 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 vs. radiation alone in stage III nonsmall cell lung cancer. N. Engl. J. Med. 323:940-945; 1990. 5. Dillman, R. O.; Seagren, S. L.; Porpert, K. L.; Guerra, J.; Eaton, W. L.; Perry, M. C.; Carey, R. W.; Frei, E. F.; Green, M. R. Randomized trial of induction chemotherapy plus radiation therapy vs. RT alone in stage III nonsmallcell lung cancer (NSCLC): Five year follow-up of CALGB (Abstr.). Proc. Am. Soc. Clin. Oncol. 12:329; 1993. 6. Drewinko, B.; Brown, B. W.; Gottlies, J. A. The effect of cis-diamminedichloroplatinum(II) on cultured human lymphoma cells and its therapeutic implications. Cancer Res 33:3091-3095; 1973. 7. Folman, R.; Rosman, M.; Auerbach, S. Mitomycin-C, vinblastine, and cisplatinum in the combined modality treatment of nonsmall cell lung cancer (Abstr.). Proc. Am. Soc. Clin. Oncol. 3:232; 1984. 8. Gralla, R. J.; Kris, M. G.; Burke, M. T.; Wertheim, M. S. The influence of addition of mitomycin to vindesine plus cisplatin in a random assignment trial in 120 patients with nonsmall celll lung cancer (Abstr.). Proc. Am. Soc. Clin. Oncol. 5:182; 1986. 9. Gregor, A.; Macbeth, F. R.; Paul, J.; Cram, L.; Hansen, H. H. Radical radiotherapy and chemotherapy in localized inoperable nonsmall-cell lung cancer: A randomized trial. J. Natl. Cancer Inst. 85:997-999; 1993. 10. Kaplan, E. L.; Meier, P. Nonparametric estimation from
incomplete observations. J. Am. Stat. Assoc. 4:57-81; 1958. 11. 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-dicholodiammineplatinum (II) in combination with radiotherapy. Radiother. Oncol. 1:227-234; 1984. 12. Komaki, R.; Cox, J. D.; Hartz, A. J.; Byhardt, R. W.; PerezTamayo, C.; Clowry, L.; Choi, H.; Wilson, F.; Lopes de Conceicao, A.; Rangala, N. Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am. J. Clin. Oncol. 8:362-370; 1985. 13. Langer, C. J.; Curran, W. J.; Keller, S. M.; Catalano, R.; Fowler, W.; Blankstein, K.; Litwin, S.; Bagchi, P.; Nash, S.; Comis, R. Report of phase II trial of concurrent chemoradiotherapy with radical thoracic irradiation (60 Gy), infusional fluorouracil, bolus cisplatin and etoposide for clinical stage IIIB and bulky stage IIIA nonsmall cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 26:469-478; 1993. 14. Le Chevalier, T.; Arriagada, R.; Quoix, E.; Ruffle, P.; Martin, M.; Tarayre, M.; Lacombe-Terrier, M. J.; Douillard, J. Y.; Laplanche, A. Radiotherapy alone vs. combined chemotherapy and radiotherapy in nonresectable nonsmall cell lung cancer: First analysis of a randomized trial in 353 patients. J. Natl. Cancer Inst. 83:417-423; 1991. 15. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 50:163-170; 1966. 16. Perez, C. A.; Bauer, M.; Edelstein, S.; Gillespie, B. W.; Birch, R. Impact of tumor control on survival on carcinoma of the lung treated with irradiation. Int. J. Radiat. Oncol. Biol. Phys. 12:539-547; 1986. 17. Posner, M. R.; Skarin, A. T.; Clark, J.; Fruin, T. J. Phase I study of continous-infusion cisplatin. Cancer Treat. Rep. 70:847-850; 1986. 18. Schaake-Koning, C.; Bartelink, H.; Hora Adema, B.; Schuster-Uitterhoeve, L.; van Zandwijk, N. Radiotherapy and cis-diammine dichloroplatinum (II) as a combined treatment modality for inoperable nonsmall cell lung cancer: A dose finding study. Int. J. Radiat. Oncol. Biol. Phys. 12:379-383; 1986. 19. Schaake-Koning, C.; van der Bogaert, W.; Dalesio, O.; Festen, J.; Hoogenhout, J.; van Houtte, P.; Kirkpatrick, A.;
818
I.J. Radiation Oncology • Biology • Physics
Koolen, M.; Maat, B.; Nijs, A.; Renaud, A.; Rodrigus, P.; Schuster-Uitterhoeve, L.; Sculler, J. P.; van Zandwijk, N.; Bartelink, H. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall cell lung cancer. N. Engl. J. Med. 326:524-530; 1992. 20. 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 nonsmall cell lung cancer. Semin. Oncol. 15(Suppl. 7):20-25; 1988. 21. Troy6, M. G.; Minatel, E.; Franchin, G.; Boccieri, M. G.; Nascimbem, O.; Bolziceo, G.; Pizzi, G.; Torretta, A.; Veronesi, A.; Gobitti, C.; Zanelli, D. J.; Monfardini, S. Radiotherapy vs. radiotherapy enhanced by eisplatin in stage III
Volume 31, Number 4, 1995 nonsmall celll lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 24:11-15; 1992. 22. Umsawasdi, T.; Valdivieso, M.; Barkley, H. T.; Chen, T.; Booser, D. J.; Chiuten, D. F.; Dhingra, H. M.; Murphy, W. K.; Carr, D. T. Combined chemoradiotherapy in limiteddisease, inoperable nonsmall cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 14:43-48: 1988. 23. WHO handbook for reporting results of cancer treatment. Neoplasma 27(5):607-619; 1980. 24. Wtirschmidt, F.; Btinemann, H.; Btinemann, C.; BeckBornholdt, H. P.; Heilman, H. P. Inoperable nonsmall cell lung cancer: A retrospective analysis of 427 patients treated with high-dose radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 28:583-588; 1994.
Pergamon
0360-3016(94)00575-3
•
Phase I/II Clinical Trials
M I T O M Y C I N , CISPLATIN, A N D V I N D E S I N E F O L L O W E D BY R A D I O T H E R A P Y C O M B I N E D W I T H C I S P L A T I N IN STAGE III N O N S M A L L CELL L U N G CANCER: LONG-TERM RESULTS MARTIN TEJEDOR, P H . D . , JUAN J. VALERDI,
M.D., RAFAEL
LOPEZ,
M.D.,
M1GUEL A. DOM[NGUEZ, M.D., FERNANDO ARIAS, M.D., Jos~. J. ILLARRAMENDI, PH.D. AND ENRIQUE MART~NEZ, M . D . Department of Oncology, Hospital de Navarra, 31008 Pamplona, Spain Purpose: To assess the tolerance, response rate, pattern of failure, and long-term survival of patients with unresectable nonsmail cell lung cancer treated with one cycle of induction chemotherapy followed by concurrent cisplatin and radiotherapy. Methods and Materials: From 1986 to 1988, 45 patients with histologically proven nonsmall cell lung cancer clinical Stage III (29 I l i a and 16 IIIB) were included in this study. Patients received one cycle of Mitomycin C 10 mg/m 2 day 1, Cisplatin 120 mg/m z day 1, and Vindesine 3 mg/m 2 days 1, 8, 15, and 22, by i.v. bolus
injection. Radiotherapy was started within 4 - 6 weeks after completion of chemotherapy, with a total tumor dose of 60 Gy, at 2 Gy/day. Cisplatin, 20 mg/m2/day by i.v. continous infusion was administered for days 1-5 of radiation treatment. Results: The main toxic acute effects were nausea-vomiting grade 1-3 in 38 patients (85%). Ten patients (22%) developed esophagitis grade 3. Leukopenia grade 1 - 2 was observed in 18 patients (40%), grade 3 in 12 (27%), and grade 4 in 4 (9%). Three patients (6.6%) died by granulocytopenia and sepsis. A bronchoscopic proven complete response was achieved in 9 patients (21.5%) and partial response in 28 patients (67%). With a minimum follow-up of 65 months, overall median survival was 13 months, 2-year survival was 21%, and 5-year survival was 7%, with no statistical difference between Stage I l i A and IIIB. Median survival of patients with complete response was 23.2 months, and 5-year survival was 33%. Conclusion: This treatment scheme produced a severe toxicity and in spite of a high response rate, longterm survival is poor, similar to previous studies with radiotherapy alone. Locally advanced nonsmall cell lung cancer, Induction chemotherapy, Chemoradiotherapy, Long-term results.
INTRODUCTION
and cisplatin (7, 8), with response rates greater than 50%. In these studies, survival advantage was not proven, but the high response rates observed justified the development of new trials to investigate whether induction chemotherapy could improve the survival in patients with locally advanced NSCLC. Perez et al. (16) reported that high doses of irradiation (60 Gy) yield a greater proportion of complete response, higher tumor control, and better survival in locally advanced nonsmall cell lung cancer. To increase tumoral damage of radiation and, thus, improve the local control and survival, several radiopotentiators have been investigated. In vitro studies have demostrated tumor cell radiosensitization by cisplatin (2), and clinical data of Phase II studies showed the feasibility of radiotherapy combined with cisplatin (11, 18).
The prognosis for patients with locally advanced unresectable nonsmall cell lung cancer (NSCLC) is still very poor. Radiation therapy remains the standard treatment, and median survival is 8 - 1 1 months, with long-term survival rates of 5 - 8 % (12). The presence of subclinical distant metastases at diagnosis and a high local relapse rate even after a high dose of radiotherapy, are the causes of death in these patients. In the early 1980s, several studies with new chemotherapy combinations were designed to evaluate the role of chemotherapy in patients with locally advanced NSCLC. Regimens containing cisplatin showed the highest and most reproducible response rates, and especially interesting was the combination of mitomycin C, vinca alkaloid,
Reprint requests to: Martin Tejedor, Ph.D.
Accepted for publication 25 October 1994. 813
814
I. J. Radiation Oncology• Biology• Physics Table 1. Eligibility criteria Patient characteristics
Tumor characteristics
Nonsmall cell lung cancer Karnosfky > 60% Stage III, Mo No previous tumor Leukocites > 3500/ram 3 Measurable disease Platelets > 100.000/mm3 Hemoglobin > 9 g% Creatinine clearance > 60 ml/min
Drewinko et al. (6) found that cytotoxic activity of cisplatin might be improved by increasing the duration of exposure of tumor cells to cisplatin. Furthermore, Posner et al. (17) demostrated that cisplatin administered as a continous infusion over 5 days at doses of 2 0 - 2 5 mg/m2/day was an effective chemotherapeutic treatment with less toxicity than in bolus injection. In view of these findings, a prospective study was begun in 1986 with induction chemotherapy (mitomycin, cisplatin, and vindesine) followed by radiotherapy combined with cisplatin, in patients with Stage III NSCLC. The objetives of this study were to determine the tolerrance, response rate, pattern of recurrence, and survival after a long follow-up.
METHODS AND MATERIALS Patient population From 1986 to 1988, 45 patients with histologically proven NSCLC were included into the study. Eligibility criteria are shown in Table 1. Initial evaluation included a physical examination, hematological and biochemical studies, chest x-ray, bronchoscopy, and computed tomography scan of the thorax and abdomen. Bone scintigraphy and computed tomography scan of the brain were performed only in clinical indications. Minimum follow-up was 65 months. All patients gave informed written conset. The patients's characteristics are shown in Table 2. Treatment scheme Induction chemotherapy consisted of one cycle with: mitomycin C, 10 mg/m 2 by intravenous bolus injection on day 1, cisplatin 120 mg/m 2 by intravenous bolus injection on day 1, and vindesine, 3 mg/m 2 by intravenous bolus injection on days 1, 8, 15, and 22. Radiation treatment was initiated 4 - 6 weeks after chemotherapy, and was delivered with a Cobalt-60 unit. 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. Supraclavicular nodes were included when involved or when tumor was localized in the upper lobes. Inferior mediastinum was included in the case of tumor in lower lobe. The primary tumor and involved nodal region received 60 Gy, at 2 Gy/day for 6 weeks, with opposing anterior and posterior shaped fields to 40
Volume 31, Number 4, 1995 Gy, and oblique fields to complete total dosage. The dose to spinal cord was kept below 45 Gy. Cisplatin, 20 mg/ mZ/day by i.v. continous infusion, was administered for days 1 - 5 of radiotherapy.
Criteria for response and toxicity Response and toxicity were evaluated according to the WHO criteria (23). To assess the response to induction chemotherapy, a chest x-ray was performed. Postradiotherapy evaluation of response was performed 4 to 6 weeks after completion of treatment, and included a computed tomography scan of the thorax and a bronchoscopy when a complete response was observed. Statistical methods Survival was calculated according to the method of Kaplan and Meier (10), and the log rank test (15) was used to compare prognostic variables. RESULTS Toxicity All patients included in the study were evaluable for toxicity. Toxic effects according to the WHO are shown in Table 3. The main toxic reactions during treatment were nausea-vomiting (85%). Three patients (6.6%) with granulocytopenia grade 4 died by sepsis after induction chemotherapy. Reversible alopecia was seen in all patients. Patients with long-term survival showed lung fibrosis in treatment volume. Response Three patients died before radiotherapy. Forty-two patients completed the treatment and were evaluable for response. After neoadjuvant chemotherapy, 1 patient (2.4%) achieved a radiographic complete response, and 15 patients (36%) a partial response. Following radiotherapy, 10 patients (24%) had a radiographic complete response. The bronchoscopy-biopsy was performed in all Table 2. Patient characteristics Age (years) Median Range Sex Male Female Histology Squamous cell Adenocarcinoma Undifferentiated or Large cell Stage Ill A III B Performance status Karnosfky 70-80% Karnosfky 90-100%
63 37-75 42 3 35 7 3 29 16 26 19
Chemotherapy in NSCLC • M. TEJEDORet al. Table 3. Acute toxicity of indution chemotherapy and concomitant cisplatin and radiotherapy (n = 45)
815
difference in overall survival was found between Stage I I I A and Stage III B (Fig. 3).
WHO Grade
I-II
III
IV
Leukopenia Trombopenia Anemia Infection Renal Nausea/vomiting Mucositis/esophagitis
18 4 12 0 3 30 12
12 1 2 1 0 8 10
4 0 0 3 0 0 0
complete responders, and showed tumor persistance in one patient. Nine patients (21.4%) had a radiographic and bronchoscopy-biopsy complete response and 28 patients (67%) a partial response. Survival
Median survival time was 13 months, with 2-year survival of 21% and 5-year survival of 7% (Fig. 1). Three patients with Stage III A are alive at 65, 78, and 84 months. One patient (Stage III A) was lost at follow-up at 17 months without evidence of recurrence. Forty-two patients received complete treatment and 38 are dead: 31 patients (74%) with disease progression and 7 from other causes (5 by cardiopulmonary disease, 1 from bladder carcinoma, and 1 from cerebrovascular accident). The primary tumor site was the first site of failure in 10 patients; local and distant failure was observed in 6 patients, and distant progression only in 15 patients. Patients with complete response showed a significantly (p < 0.01) longer survival, with a median survival time of 23.2 months and 5-year survival of 33% (Fig. 2). No statistical
DISCUSSION The main end point of this study was to analyze if long-term survival of patients with locally advanced NSCLC could be improved with a combined chemoradiotherapy treatment. Since we started this trial in 1986, several studies with induction chemotherapy followed by radical radiotherapy or concurrent chemoradiotherapy, have been published. In four randomized studies (3, 4, 9, 14) induction chemotherapy with two to three cycles of cisplatin-based regimens and radiotherapy was compared with radiation treatment alone. Gregor e t al. (9) did not find survival difference, and the other three studies (3, 4, 14) reported a moderate benefit in survival with the combined treatment, but only Dillman e t al. (4) had a statistical significant difference, with a median survival time of 13.8 months vs. 9.7 months. Concurrent cisplatin by bolus injection and radiotherapy vs. radiotherapy alone have been investigated in three randomized studies (19-21). Soresi et al. (20) reported a higher local control and improved survival (16 vs. 11 months), without statistical significance, in the group treated with 50 Gy plus cisplatin 15 mg/m 2 i.v. weekly. Schaake-Koning e t al. (19) designed a randomized trial with three arms: radiotherapy alone (55 Gy), radiotherapy plus cisplatin 30 mg/m 2 weekly, or radiotherapy combined with 6 mg/m2/daily. In this study, patients with cisplatin and radiotherapy had a better local control and survival, with statistical significance only in the group
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
2
3
I
I
4 Years
5
Fig. 1. Overall survival (n = 45).
__
I
6
.
I
7
8
816
I.J. Radiation Oncology • Biology • Physics
0.9
Volume31, Number 4, 1995
COMPLETE RESPONSE
~
* r
o
0.8 i 0.7
'
NO COMPLETE RESPONSE
\
-\
O
r t
O. 6
r,
0.5
,-
0.4 i
i vi
0.3.
g
0.2
i o
I
"/ '
~'
',\
,~
',~ \\
"
0.1, 0 I
J_
0
1
~i
2
::;.®
3
4 Years
t
5
I
6
7
__
8
Fig. 2. Survival according to response to the treatment. Complete response n = 9, no complete response n = 33. (p < 0.01). with cisplatin given daily (16% vs. 2% at 3 years). However, Trov6 et al. (21) with a treatment scheme similar to the Schaake-Koning et al. (19), 45 Gy and cisplatin 6 mg/m 2 daily compared with radiotherapy alone, did not observe differences in the pattern of relapse and median survival time (10.3 vs. 9.9 months). T w o nonrandomized studies (13, 22) of more than 40 patients agressively treated with radiotherapy concurrent with cisplatin plus other two drugs, reported a median survival of 14 months (13) and 12 months (22), respectively.
0.9
The most of series cited with combined chemotherapy have a short follow-up and 5-year survival is not specified. Dillman e t al. (5) have recently reported the results of induction chemotherapy plus radiotherapy vs. radiotherapy alone after a 5-year follow-up, and the median survival time remains favorable to the group with induction chemotherapy (13.7 vs. 9.6 months) with statistical significance. By administering one cycle of induction chemotherapy and radiotherapy concurrent with continuous infusion of cisplatin, we achieved a high response rate (88%), but
STAGE III A
~
STAGE III B
0.8]
" ~I
0.7-
~', ® ,
0.6 -
~"~
:!
o3°4J
.
0.21 0.1~ O'
J
0
1
2
I
~ ±,o
I
3
4 Years
5
J . . . .
6
7
8
Fig. 3. Survival according to stage. Stage IIIA n = 29, Stage IIIB n = 16 (p = NS).
Chemotherapy in NSCLC • M. TEJEDORet al. the 5-year survival (7%) is very poor. Our results on local control and median survival are similar to previous studies with two or more cycles of induction chemotherapy and radiotherapy (3, 4, 9, 14, 22) or concurrent cisplatin by bolus injection plus radiotherapy (13, 1 9 - 2 1 ) , and in spite of the agressive treatment, patients with unresectable N S C L C died by local failure and distant metastases. Moreover, Ball e t al. (1) and Wtirschmidt e t al. (24) have recently reported a median survival o f 14.5 and 13.2 months and 5-year survival o f 7 and 4%, respectively, in patients with Stage III nonsmall cell lung cancer treated with high dose o f radiotherapy alone after a long follow-up. The c o m b i n e d c h e m o r a d i o t h e r a p y treatment caused an increase in the acute toxicity, mainly esophagitis, n a u s e a - v o m i t i n g , and hematological toxicity, in all studies published (3, 4, 9, 13, 14, 1 9 - 2 2 ) . In our study,
817
there were three treatment-related deaths due to sepsis, that, analyzed critically, could have been prevented with a more rigourous patient selection and better supportive care. The benefit o f c h e m o r a d i o t h e r a p y in patients with locally advanced N S C L C remains controversial, and perhaps, a metaanalysis could elucidate this question, but the possible advantage on survival is clearly associated with an increase in the morbidity. With a median survival time of aproximately 1 year, the treatment in patients with locally advanced nonsmall cell lung cancer is mainly palliative, and the primary objectives o f the treatment must be to improve the s y m p t o m a t i c control and quality o f life. In future r a n d o m i z e d studies with new aggressive treatments, the quality o f life should be measured to assess the risk benefit.
REFERENCES 1. Ball, D.; Matthews, J.; Worotniuk, V.; Crennan, E. Longer survival with higher doses of thoracic radiotherapy in patients with limited nonsmall cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 25:599-604; 1993. 2. Carde, P.; Laval, F. Effect of cis-dichlorodiammine-platinum II and X-rays on mammation celll survival. Int. J. Radiat. Oncol. Biol. Phys. 17:929-933; 1981. 3. Crin6, L.; Latini, P.; Meacci, M.; Corgna, E.; Maranzano, E.: Darwish, S.; Minotti, V.; Santucci, A.; Tonato, M. Induction chemotherapy plus high-dose radiotherapy vs. radiotherapy alone in locally advanced unresectable nonsmall cell lung cancer. Ann. Oncol. 4:847-851; 1993. 4. Dillman, R. O.; Seagren, S. L.; Propert, K. L.; 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 vs. radiation alone in stage III nonsmall cell lung cancer. N. Engl. J. Med. 323:940-945; 1990. 5. Dillman, R. O.; Seagren, S. L.; Porpert, K. L.; Guerra, J.; Eaton, W. L.; Perry, M. C.; Carey, R. W.; Frei, E. F.; Green, M. R. Randomized trial of induction chemotherapy plus radiation therapy vs. RT alone in stage III nonsmallcell lung cancer (NSCLC): Five year follow-up of CALGB (Abstr.). Proc. Am. Soc. Clin. Oncol. 12:329; 1993. 6. Drewinko, B.; Brown, B. W.; Gottlies, J. A. The effect of cis-diamminedichloroplatinum(II) on cultured human lymphoma cells and its therapeutic implications. Cancer Res 33:3091-3095; 1973. 7. Folman, R.; Rosman, M.; Auerbach, S. Mitomycin-C, vinblastine, and cisplatinum in the combined modality treatment of nonsmall cell lung cancer (Abstr.). Proc. Am. Soc. Clin. Oncol. 3:232; 1984. 8. Gralla, R. J.; Kris, M. G.; Burke, M. T.; Wertheim, M. S. The influence of addition of mitomycin to vindesine plus cisplatin in a random assignment trial in 120 patients with nonsmall celll lung cancer (Abstr.). Proc. Am. Soc. Clin. Oncol. 5:182; 1986. 9. Gregor, A.; Macbeth, F. R.; Paul, J.; Cram, L.; Hansen, H. H. Radical radiotherapy and chemotherapy in localized inoperable nonsmall-cell lung cancer: A randomized trial. J. Natl. Cancer Inst. 85:997-999; 1993. 10. Kaplan, E. L.; Meier, P. Nonparametric estimation from
incomplete observations. J. Am. Stat. Assoc. 4:57-81; 1958. 11. 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-dicholodiammineplatinum (II) in combination with radiotherapy. Radiother. Oncol. 1:227-234; 1984. 12. Komaki, R.; Cox, J. D.; Hartz, A. J.; Byhardt, R. W.; PerezTamayo, C.; Clowry, L.; Choi, H.; Wilson, F.; Lopes de Conceicao, A.; Rangala, N. Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am. J. Clin. Oncol. 8:362-370; 1985. 13. Langer, C. J.; Curran, W. J.; Keller, S. M.; Catalano, R.; Fowler, W.; Blankstein, K.; Litwin, S.; Bagchi, P.; Nash, S.; Comis, R. Report of phase II trial of concurrent chemoradiotherapy with radical thoracic irradiation (60 Gy), infusional fluorouracil, bolus cisplatin and etoposide for clinical stage IIIB and bulky stage IIIA nonsmall cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 26:469-478; 1993. 14. Le Chevalier, T.; Arriagada, R.; Quoix, E.; Ruffle, P.; Martin, M.; Tarayre, M.; Lacombe-Terrier, M. J.; Douillard, J. Y.; Laplanche, A. Radiotherapy alone vs. combined chemotherapy and radiotherapy in nonresectable nonsmall cell lung cancer: First analysis of a randomized trial in 353 patients. J. Natl. Cancer Inst. 83:417-423; 1991. 15. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 50:163-170; 1966. 16. Perez, C. A.; Bauer, M.; Edelstein, S.; Gillespie, B. W.; Birch, R. Impact of tumor control on survival on carcinoma of the lung treated with irradiation. Int. J. Radiat. Oncol. Biol. Phys. 12:539-547; 1986. 17. Posner, M. R.; Skarin, A. T.; Clark, J.; Fruin, T. J. Phase I study of continous-infusion cisplatin. Cancer Treat. Rep. 70:847-850; 1986. 18. Schaake-Koning, C.; Bartelink, H.; Hora Adema, B.; Schuster-Uitterhoeve, L.; van Zandwijk, N. Radiotherapy and cis-diammine dichloroplatinum (II) as a combined treatment modality for inoperable nonsmall cell lung cancer: A dose finding study. Int. J. Radiat. Oncol. Biol. Phys. 12:379-383; 1986. 19. Schaake-Koning, C.; van der Bogaert, W.; Dalesio, O.; Festen, J.; Hoogenhout, J.; van Houtte, P.; Kirkpatrick, A.;
818
I.J. Radiation Oncology • Biology • Physics
Koolen, M.; Maat, B.; Nijs, A.; Renaud, A.; Rodrigus, P.; Schuster-Uitterhoeve, L.; Sculler, J. P.; van Zandwijk, N.; Bartelink, H. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall cell lung cancer. N. Engl. J. Med. 326:524-530; 1992. 20. 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 nonsmall cell lung cancer. Semin. Oncol. 15(Suppl. 7):20-25; 1988. 21. Troy6, M. G.; Minatel, E.; Franchin, G.; Boccieri, M. G.; Nascimbem, O.; Bolziceo, G.; Pizzi, G.; Torretta, A.; Veronesi, A.; Gobitti, C.; Zanelli, D. J.; Monfardini, S. Radiotherapy vs. radiotherapy enhanced by eisplatin in stage III
Volume 31, Number 4, 1995 nonsmall celll lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 24:11-15; 1992. 22. Umsawasdi, T.; Valdivieso, M.; Barkley, H. T.; Chen, T.; Booser, D. J.; Chiuten, D. F.; Dhingra, H. M.; Murphy, W. K.; Carr, D. T. Combined chemoradiotherapy in limiteddisease, inoperable nonsmall cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 14:43-48: 1988. 23. WHO handbook for reporting results of cancer treatment. Neoplasma 27(5):607-619; 1980. 24. Wtirschmidt, F.; Btinemann, H.; Btinemann, C.; BeckBornholdt, H. P.; Heilman, H. P. Inoperable nonsmall cell lung cancer: A retrospective analysis of 427 patients treated with high-dose radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 28:583-588; 1994.