- Email: [email protected]
Radiation therapy with concomitant continuous infusion cisplatin for unresectable nonsmall cell lung carcinoma
Int. J. Radiation
Oncolog)-
Biol. Phys., Vol. 28, No. 5. pp. 1251-1256. 1994 Copyright G 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0360-30 I6194 $6.00 + .OO
Pergamon 0360-3016(93)E0058-E
??Clinical Original Contribution
RADIATION THERAPY WITH CONCOMITANT CISPLATIN FOR UNRESECTABLE NONSMALL FRANCOIS YVELISE
REBOUL,
BREWER,
M.D.,*
M.D.,*
PASCAL
CAROLINE
AND DENNIS
VINCENT,
M.D.,*
FELIX-FAURE, C. SHRIEVE,
CONTINUOUS INFUSION CELL LUNG CARCINOMA BRUNO
M.D.,*
M.D.,
CHAUVET,
MARC
M.D.,*
TAULELLE,
M.D.*
PH.D.+
*Department of Radiation Oncology, Clinique Sainte Catherine, Avignon, France: and +Department of Radiation Oncology, University of California, San Francisco, CA Purpose: This pilot study was designed to test the tolerance and effectiveness of concurrent continuous infusion cisplatin and radiotherapy in the treatment of unresectable nonsmall cell lung (NSCL) cancer. Methods and Materials: Between July 1989 and July 1991, 92 consecutive patients with either medically or technically inoperable NSCL cancer were treated with thoracic radiotherapy and concomitant chemotherapy. Radiotherapy consisted of a total dose of 70 Gy delivered in 2 Gy daily fractions over 9 weeks with a planned 2-week break after 40 Gy. During the second week of each cycle of radiotherapy, cisplatin was administered, 20 mg/m’/ day for 5 days as a continuous infusion. Eighty-five patients were evaluable. Results: Overall response rate was 81.7% (65.9% complete response). Medically operable patients were considered for curative surgical resection following 40 Gy and one cycle of chemotherapy; 11 patients underwent resection with 3/11 having no pathologic evidence of tumor. Median survival for all 85 patients was 11.4 months with a median follow-up of 27 months. Overall survival was 48.2%, 27.5%, and 25% at 12,24, and 36 months, respectively. Survival was independent of tumor stage, histology and grade, and patient age and gender. Patients having a complete response (n = 54) had a 2-year survival of 42.1% compared to 3.2% for partial-responders and nonresponders (n = 31; p <: 0.0001). Patients undergoing surgical resection (n = 11) had a 2-year survival of 75.8% compared to 20.6% for those treated with chemoradiotherapy alone (n = 74). Forty-eight patients have died of their disease. There were two treatment-related deaths, seven deaths of intercurrent disease and three of unknown causes. Eighteen of 25 patients alive at the time of analysis were without evidence of disease. Actuarial local control was 50.6% at 1 year, and 33.3% at 2 years. The distant failure rate was 47.8% at 2 years. Major acute toxicities, mainly hematologic or gastrointestinal, occurred in less than 10% of patients. Esophagitis was mild and infrequent (8.4%). Severe late
pulmonary fibrosis occurred in 5.2% of patients and resulted in two treatment-related deaths. Conclusion: Concomitant chemoradiotherapy was well tolerated, resulted in a high rate of local control, and in a survival benefit for patients demonstrating a complete response or going on to surgical resection. The incidence of distant metastases continues to be high and future strategies should be directed at improving systemic therapy. Nonsmall cell lung cancer (NSCLC), radiotherapy.
Radiotherapy,
Cisplatin,
INTRODUCTION
Reprint requests to: Francois Reboul, M.D., Clinique Chemin
du Lavarin,
B.P. 846, F84082,
modality
therapy,
Concomitant
chemo-
trol(3). Control of disseminated micrometastases requires effective systemic therapy. Cisplatin is the most effective single chemotherapeutic agent in the treatment of NSCLC. In addition, preclinical and clinical studies indicate that cisplatin may serve as an effective radiosensitizing agent (6). The continuous infusion mode of administration appears to be better tolerated and offers a basis for additional chemoradiation interactions compared to bolus injection (4). Based on these data, a pilot study combining highdose (70 Gy) thoracic RT and concomitant high-dose
Radiation therapy (RT) is considered to be the standard treatment for locally advanced or medically inoperable nonsmall cell lung cancer (NSCLC). Long-term results, however, with conventional RT (60 Gy) are poor with only 15% of patients surviving beyond 2 years (14). Both poor local control and a high rate of early distant dissemination contribute to the poor outcome. There is evidence that RT doses higher than 60 Gy may improve local con-
Catherine, France.
Combined
Accepted
Sainte Avignon,
I251
for publication
2 November
1993.
1252
I. J. Radiation Oncology 0 Biology 0 Physics
continuous infusion cisplatin in the treatment of patients with medically or technically inoperable NSCLC, was initiated in our institution.
METHODS
AND
MATERIALS
From July 1989 to July 199 1, 92 consecutive previously untreated patients with either medically or technically inoperable NSCLC were entered in the study for treatment with concomitant chemoradiotherapy. Seven patients did not receive chemotherapy and have been excluded from the analysis (two protocol violations, two refusals, three early deaths from pulmonary embolus, pulmonary edema, and atria1 fibrillation, respectively). Eighty-two patients were fully evaluable for response, toxicity, and survival. There were three early deaths from intercurrent disease (ruptured esophageal varices, cardiac arrythmia, undiagnosed simultaneous ovarian cancer), and these patients could only be evaluated for toxicity and survival. Median age was 66 years and most patients were male (91.8%). Performance status was O-2 on the WHO scale. Weight loss was not consistently registered in this study. Seventyseven point eight percent of the tumors were squamous cell, which is the usual distribution of histologic subtypes in Europe. Thirty-three point eight percent of tumors were poorly differentiated. Twelve patients (14%) were Stage I (T,_?, No) or Stage II (T,_>, N,) and medically inoperable (Table 1). Among Stage III (TI_j, N2_3) patients, 10.6% had bilateral mediastinal lymph node involvement or supraclavicular disease. Patients with malignant pleural effusions were not eligible.
Table 1. Patient characteristics 85 66 (35-81)
Table 2. Treatment Week Radiotherapy Chemotherapy
123456789 T T T c
T
plan
B
B C
B
Treatment methods Thoracic irradiation was delivered using external beam 18-MeV photons with minimum source axis distance of 80 cm and with lung corrections. During initial radiotherapy, the primary tumor was encompassed with a minimum margin of 2 cm. The entire mediastinum was included from the suprasternal notch to 5 cm below the carina. Lower lobe lesions required mediastinal irradiation to the diaphragm, and upper lobe lesions required irradiation of the ipsilateral supraclavicular area. Controlatera1 hilum was excluded from the irradiation field. Radiation dose was 40 Gy in 20 fractions over 4 weeks and was delivered through two opposing antero-posterior/ postero-anterior fields with custom cerrobend blocks. Surgical evaluation was carried out during a planned 2week break from treatment. In inoperable patients, a boost of 30 Gy in 15 fractions over 3 weeks was delivered to the pretreatment tumor volume with a 1-cm margin using oblique off-cord fields and computerized dosimetry based on CT scan. In operated patients, a similar boost was delivered postoperatively to the ipsilateral mediastinum only if there was residual nodal disease. Patients received cisplatin as a continuous infusion 20 mg/m’/24 h during 5 days coinciding with the second week of each RT cycle (Table 2). The second week was chosen on the basis of experimental data demonstrating enhanced penetration of cisplatin in tumors after 10 Gy irradiation (6). No maintenance chemotherapy was given and no patient received prophylactic cranial irradiation.
78
16 65 4
Hiztologic subtype Squamous Adenocarcinoma Large cell Histologic grade Well differentiated Moderately differentiated Poorly differentiated Unspecified Clinical stage I (T,_,, No) II (T,_z, N,) IIIA (TI-2, N2 or T3, NO-~) IIIB (any T, N,)
5, I994
T = Thoracic radiotherapy: 40 Gy/20 fractions/4 weeks; B = Tumor boost: 30 Gy/ 15 fractions/3 weeks; C = Continuous infusion cisplatin 20 mg/m2/day. day 1-5.
Patient characteristics
Number of patients Age, median (range) Sex Male Female WHO performance status 0
Volume 28, Number
66 11 8 21 14 33 17 8 4 64 9
Response was evaluated after 40 Gy RT and the first course of chemotherapy and 6 weeks following completion of all therapy. All patients underwent physical examination, chest X ray, CT scan of the chest and abdomen, and fiberoptic bronchoscopy with biopsy of the initial tumor site. Complete response was defined as the complete disappearance of all radiological, endoscopic, and histological abnormalities.
Statistical methods Overall survival, local control, and metastatic rate were calculated according to the Kaplan-Meier (10) method. Survival curves were compared using the log-rank test (13).
RT with cisplatin in NSCL carcinoma 0 F. REBOUL etal.
1253
RESULTS
Compliance Treatment was delivered according to protocol in most patients. The first chemoradiation cycle was administered at full dose in 90.6% of patients. The treatment break between cycles was no longer than the planned 2 weeks in 65.2% of patients, and was otherwise prolonged up to 4 weeks to allow for recovery of toxic effects. During the second phase of treatment, 84.7% of patients received full dose RT and 65.3% received full-dose chemotherapy. Eleven patients went to surgical resection. Four patients had progressive disease and died before the second treatment cycle and two patients refused the second cycle of treatment.
Response to treatment and survival Eighty-two patients were evaluable for response. Of the 11 patients taken to surgery following the first cycle of therapy, three had complete pathologic responses and received no further therapy. Eight had residual tumor, of which four had residual nodal disease and received the second cycle of chemoradiotherapy postoperatively. Fiftyfour patients (65.9%) had either pathologic or clinical complete responses. Thirteen patients ( 15.8%) had partial responses, for an overall response rate of 8 1.7%. Ten patients (12.2%) had progressive disease under treatment (Table 3). At a median follow-up time of 27 months (range, 15.7-38.9 months), the median survival for all 85 patients from the time of diagnosis was 11.4 months. Overall survival was 48.2%, 27.5%, and 25% at 12, 24, and 36 months, respectively (Fig. 1). Survival was found to be independent of patient age, gender, tumor grade, histologic subtype, or clinical stage. Patients with complete responses and those who were candidates for curative surgery had significantly better outcome. Patients who achieved a complete response had a 2-year survival of 42.1% compared to 3.2% in patients not achieving complete response (Fig. 2; p < 0.0001). Similarly, patients who underwent surgical resection had a 2-year survival
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of 75.8% compared to 20.6% in patients treated without surgery (Fig. 3; p < 0.001). Median survival was 19.6 months in complete responders and has not been reached in patients undergoing surgical resection. Nineteen patients with initial complete response had a local recurrence and local failure was associated with distant metastases in six cases. Actuarial local control was 50.6% at 12 months, and 33.3% at 24 months (Fig. 4). Thirty patients developed metastases, most commonly to brain (30%) and bone (27%). Twenty-five percent of distant failures occurred in multiple sites simultaneously. Metastasis rate was 47.8% at 24 months (Fig. 5). The mean time to local or distant failure was 9.6 months (range, 1.9-24.3 months). There have been no local or distant failures beyond 3 years of follow-up. Forty-eight patients have died of their disease. Two patients died of treatment-related toxicities and seven of intercurrent disease. The cause of death was unknown in three cases. Twenty-five patients
.S-
Fig. 1. Overall survival
24
Fig. 2. Overall survival according to response. Patients having a complete response (n = 54) had a 2-year survival of 42.1% compared to 3.2% for partial and nonresponders (p < 0.0001).
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Fig. 3. Overall survival according to surgical resection. Patients undergoing surgical resection (n = 11) had a 2-year survival of 75.8% compared to 20.6% for those treated with chemoradiotherapy alone (p = 0.001).
1254
I. J. Radiation Oncology 0 Biology 0 Physics
04
0
I
I
1
6
12
18
I
24
I
30
months
Fig. 4. Actuarial local control. The local control rate which is 0% at the time of diagnosis reaches the complete response rate (65.9%) at the time ofevaluation, then falls with each local failure. Actuarial local control was 33.3% at 24 months.
are living at the time of analysis, 18 with no evidence of disease, including eight patients who underwent surgery. Toxicity Acute Grade 3-4 toxicities affected less than 10% of patients and consisted of vomiting and neutropenia. Esophagitis was mild and infrequent (8.4%) as was radiation pneumonitis (9.6%). Severe late pulmonary fibrosis occurred in 5.2% of patients and accounted for one treatment-related death. The other death due to toxicity was from late pulmonary necrosis and massive hemoptysis.
DISCUSSION Approximately 40% of patients with NSCL carcinoma have locally advanced or inoperable disease at the time of diagnosis. Traditionally, treatment has been with RT alone with disappointing long-term survival (14). Radiotherapy has also been used to treat early stage NSCLC in medically inoperable patients, also with poor outcome except for patients with well-differentiated tumors (8). Analysis of long-term patterns of failure on Radiation Therapy Oncology Group (RTOG) protocol 73-O 1 demonstrated a dose-response relationship for local tumor control following RT alone (15). Patients receiving the highest RT dose (60 Gy) had a lower incidence of local failure (35%) than did patients treated with lower doses (49-58%; 40-50 Gy). However, such local control may well be overestimated in these historical studies. Local failure following RT alone may result from the presence of a large tumor cell burden, radioresistant hypoxic tumor cells or tumor cell repopulation. Recent results from the RTOG (protocol 83-l 1) using hyperfractionated radiotherapy (HFRT) to a total dose of 69.6 Gy are encouraging with 29% survival at 2 years in selected patients (3). Although an analysis of patterns of failure in that study has
Volume 28, Number 5. 1994
not yet been published, it seems that the improvement in survival seen with twice-daily RT must be attributable to better local control. In RTOG protocol 73-O 1 initial failure included extrathoracic sites in 49-65% of patients with various histologic types of NSCLC treated with RT alone: 72-79% ultimately failed with distant metastases (15). Eradication of occult distant disease present at the time of diagnosis can only be accomplished through systemic treatment. Recent studies combining RT and cisplatin-based chemotherapy have stimulated great interest (5, 12, 16). Cisplatin is not only one of the most effective chemotherapeutic agents in the treatment of metastatic NSCLC, but also has been demonstrated to have radiosensitizing properties in preclinical studies (4). Several additive and synergistic mechanisms of interaction between radiation and cisplatin have been identified when the agents are given concurrently or in close temporal relationship (6). These mechanisms include radiosensitization of hypoxic cells, inhibition of repair of potentially lethal or sublethal radiation damage and thiol depletion by cisplatin. In the clinical setting, the optimal schedule of administration of cisplatin and RT has not been clearly established. In a recently reported study of the European Organization for Research and Treatment of Cancer. daily low-dose cisplatin combined with split-course RT significantly improved overall survival compared to RT alone, with the benefit being due solely to better local control (16). It should be pointed out that in this trial, RT alone was not optimal, since 3 Gy X 10 fractions in 2 weeks followed by a 4-week break and 2.5 Gy X 10 fractions resulted in only 2% survival rate at 3 years, which is much lower than 1 l- 15% of 3year survival in patients treated with 60 Gy in 6 weeks in the USA. Similar results were reported in a Phase II trial conducted by the Southwest Oncology Group using continuous RT and concomitant daily low-dose cisplatin (9) but were not reproduced in another similar trial by Trovo et ul. (17). possibly due to the inclusion of patients with poor prognosis ( 1 1). The use of cyclic intermediate-dose
12
18
24
30
months
Fig. 5. Distant failure 47.8% at 24 months.
rate. Actuarial
distant
failure rate was
RT with cisplatin
in NSCL carcinoma
cisplatin combined with standard RT has also been associated with negative results (1). Attempts to optimize the dose of cisplatin in an effort to maximally enhance local control and eradication of distant foci of micrometastatic disease have been made. Preliminary data from a small pilot study using alternating RT and high-dose cisplatin by Gandara et al. (7) are encouraging. Although most patients had Stage IIIB disease, 2-year survival was reported to be 4 1%. In the present study, we have attempted to improve local control and to possibly lower rates of distant failure through the use of concomitant RT and high-dose cisplatin chemotherapy. Continuous infusion cisplatin administration is associated with less gastro-intestinal and renal toxicity than bolus infusion, but was also chosen for the potentially greater interaction with RT through the maintenance of higher concentrations of cisplatin free radical, as described by Aziz ct al. (2). Rates of local control achieved with this regimen are similar to those reported in other positive trials (9, 16) and suggest a substantial benefit to concomitant cisplatin-radiotherapy compared to RT alone. This was due mainly to good outcome in patients who became candidates for surgical resection or who achieved a complete clinical response. This benefit was due to improvement in local control only. The rate of local recurrence was low (22.4%) but the systemic therapy used in this trial had little or no impact on the rate of distant failure. Fifty percent of patients developed distant metastases within the first 6 months following completion of therapy. This result questions the efficacy of single agent cisplatin chemotherapy in treating distant micrometastases. Two major Phase III trials comparing standard radiation therapy alone or preceded by two or three cycles of cisplatin-based combination chemotherapy have demonstrated an advantage to such induction regimens in
0 F. REBOUL
et a/.
1255
terms of survival (5) and reduced incidence of distant metastases ( 12). Dillman et al. (5) reported a doubling in 2year survival (26% vs. 13%) for neoadjuvant vinblastine, cisplatin chemotherapy followed by radiation compared to RT alone. Le Chevalier et al. ( 12) demonstrated a 20% decrease in tile rate of distant metastases with three cycles of neoadjuvant combination cisplatin-based chemotherapy followed by RT. Improvement in survival was partially obscured by the high incidence of local failure. The results of this single institution trial of high-dose RT and concomitant high-dose continuous infusion cisplatin chemotherapy indicate that this regimen is well tolerated. The response rate was high, resulting in improved local control and encouraging long-term survival. The high rate of distant failure indicates a need to address this problem by adding a second active systemic agent to the treatment plan. The currently active RTOG protocol 9204 compares neoadjuvant cisplatin-vinblastine chemotherapy followed by conventional RT plus concurrent cisplatin to HFRT with concurrent cisplatin-oral etoposide chemotherapy (Komaki, R., RTOG 92-04: Randomized phase II study of chemotherapy-radiotherapy combination for favorable patients with locally advanced inoperable NSCLC. Unpublished-personal communication). This protocol addresses the need for improved local control by including concurrent chemoradiotherapy with cisplatin and either conventional RT or HFRT. In addition, each arm includes a second active chemotherapeutic agent that may reduce the frequency ofdistant failure. These treatment regimens offer the hope for significant improvement in overall survival in patients with locally advanced NSCLC. In our institution, such patients are currently being treated with a regimen of conventional RT with concurrent cisplatin-etoposide chemotherapy which might work as a radiosensitizer by synergetic mechanism in addition to the systemic effectiveness.
REFERENCES Ansari, R.; Tokars, R.; Fisher. W.; Pennington, K.: Mantravadi, R.; O’Connor, T.; Rynard, S.; Miller, M.; Einhorn. L. A phase III study of thoracic irradiation with or without concomitant cisplatin on locoregional unresectable nonsmall cell lung cancer: A Hoosier Oncology Group protocol (Abstract). Proc. Am. Sot. Clin. Oncol. IO:24 1; 199 1. Aziz. H.; Rosenthal, C. J.; Potters, L.; Nuthakki, M.; Rotman, M. Radiopotentiation by cisplatin in continuous infusion: Nonsmall cell carcinoma of the lung. In: Rotman, M., Rosenthal, C. J., eds. Concomitant continuous infusion chemotherapy and radiation. Berlin. Heidelberg, New York: Springer-Verlag; 199 1:223-228. Cox, J. D.; Azamia. N.: Byhardt, R. W.; Shin, K. H.; Emami, B.: Pajak, T. F. A randomized Phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 to 79.2 Gy: Possible survival benefit with 69.6 Gy in favorable patients with Radiation Therapy Oncology Group Stage III nonsmall cell lung carcinoma. J. Clin. Oncol. 8: 1543- 1555; 1990. Dewit, L. Combined treatment of radiation and cis-diamminedichloroplatinum (II): A review of experimental and
clinical data. Int. J. Radiat. Oncol. Biol. Phys. 13:403-426: 1987. Dillman, R. 0.; Seagreen, 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 vs. radiation alone in stage III nonsmallcell lung cancer. N. Engl. J. Med. 323:940-945; 1990. Douple, E. B. Keynote address: Platinum-radiation interactions. NC1 Monographs. 6:3 15-3 19: 1988. Gandara, D. R.; Valone, F. H.; Deisseroth, A. B.; Roach, M.; Ahn, D. K.; Phillips, T. L. Rapidly alternating radiotherapy and high dose cisplatin chemotherapy in Stage BIB nonsmall cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 20:1047-1052; 1991. 8. Haffty, B. G. Can lung cancer be cured by radiation alone? Int. J. Radiat. Oncol. Biol. Phys. 24: 18 l-182; 1992. 9. Hazuka, M.; Crowley, J.; Bunn, P.; Livingston, R. Concurrent daily low-dose cisplatin (LDCP) combined with chest irradiation (RT) in locally advanced nonsmall cell lung cancer: Preliminary results of a Southwest Oncology Group
1256
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11.
12.
13.
14.
I. J. Radiation Oncology 0 Biology 0 Physics
(SWOG) study (Abstract). Proc. Am. Sot. Clin. Oncol. 11: 295; 1992. Kaplan, E. L.; Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53:457-48 1; 1958. Komaki, R. Is concomitant cisplatin and radiotherapy more efficacious treatment than radiotherapy alone in Stage III nonsmall cell lung cancer? Int. J. Radiat. Oncol. Biol. Phys. 24:185-186: 1992. Le Chevalier, T.; Arriagada, R.; Quoix, E.; RuffiC, 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 of 353 patients. JNCI 83:417-423; 199 1. Mantel, N. Evaluation of survival data and two new rank order statistics arising from its consideration. Cancer Chemother. Rep. 50: 163-l 70; 1966. Perez, C. A.; Bauer, M.; Edelstein, S.; Gillespie, B. W.: Birch.
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28. Number
5, 1994
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. 15. Perez. C. A.; Pajak, T. F.; Rubin, P.; Simpson. J. R.; Mohiuddin, M.: Brady, L. W.; Perez-Tamayo, R.; Rotman, M. Long-term observations of the patterns of failure in patients with unresectable nonoat cell carcinoma of the lung treated with definitive radiotherapy. Cancer 59: 1874-l 88 I ; 1987. 16. Schaake-Koning, C.; van den Bogaert, W.: Dalesio, 0.; Festen, J.; Hoogenhout. J.; van Houtte. P.; Kirkpatrick, A.; Scuher, J. P.: van Zandwijk, N.; Bartelink, H. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall-cell lung cancer. N. Eng. J. Med. 326:524-530; 1992. 17. Trovo, M. G.; Minatel, E.: Franchin, G.; Boccieri, M. G.; Nascimben, 0.; Bolzicco, G.: Pizzi. G.: Torretta, A.: Veronesi. A.: Gobitti, C.: Zanelli, D. J.; Monfardini, S. Radiotherapy vs. radiotherapy enhanced by cisplatin in Stage III nonsmall cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 24:11-15: 1992.
Oncolog)-
Biol. Phys., Vol. 28, No. 5. pp. 1251-1256. 1994 Copyright G 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0360-30 I6194 $6.00 + .OO
Pergamon 0360-3016(93)E0058-E
??Clinical Original Contribution
RADIATION THERAPY WITH CONCOMITANT CISPLATIN FOR UNRESECTABLE NONSMALL FRANCOIS YVELISE
REBOUL,
BREWER,
M.D.,*
M.D.,*
PASCAL
CAROLINE
AND DENNIS
VINCENT,
M.D.,*
FELIX-FAURE, C. SHRIEVE,
CONTINUOUS INFUSION CELL LUNG CARCINOMA BRUNO
M.D.,*
M.D.,
CHAUVET,
MARC
M.D.,*
TAULELLE,
M.D.*
PH.D.+
*Department of Radiation Oncology, Clinique Sainte Catherine, Avignon, France: and +Department of Radiation Oncology, University of California, San Francisco, CA Purpose: This pilot study was designed to test the tolerance and effectiveness of concurrent continuous infusion cisplatin and radiotherapy in the treatment of unresectable nonsmall cell lung (NSCL) cancer. Methods and Materials: Between July 1989 and July 1991, 92 consecutive patients with either medically or technically inoperable NSCL cancer were treated with thoracic radiotherapy and concomitant chemotherapy. Radiotherapy consisted of a total dose of 70 Gy delivered in 2 Gy daily fractions over 9 weeks with a planned 2-week break after 40 Gy. During the second week of each cycle of radiotherapy, cisplatin was administered, 20 mg/m’/ day for 5 days as a continuous infusion. Eighty-five patients were evaluable. Results: Overall response rate was 81.7% (65.9% complete response). Medically operable patients were considered for curative surgical resection following 40 Gy and one cycle of chemotherapy; 11 patients underwent resection with 3/11 having no pathologic evidence of tumor. Median survival for all 85 patients was 11.4 months with a median follow-up of 27 months. Overall survival was 48.2%, 27.5%, and 25% at 12,24, and 36 months, respectively. Survival was independent of tumor stage, histology and grade, and patient age and gender. Patients having a complete response (n = 54) had a 2-year survival of 42.1% compared to 3.2% for partial-responders and nonresponders (n = 31; p <: 0.0001). Patients undergoing surgical resection (n = 11) had a 2-year survival of 75.8% compared to 20.6% for those treated with chemoradiotherapy alone (n = 74). Forty-eight patients have died of their disease. There were two treatment-related deaths, seven deaths of intercurrent disease and three of unknown causes. Eighteen of 25 patients alive at the time of analysis were without evidence of disease. Actuarial local control was 50.6% at 1 year, and 33.3% at 2 years. The distant failure rate was 47.8% at 2 years. Major acute toxicities, mainly hematologic or gastrointestinal, occurred in less than 10% of patients. Esophagitis was mild and infrequent (8.4%). Severe late
pulmonary fibrosis occurred in 5.2% of patients and resulted in two treatment-related deaths. Conclusion: Concomitant chemoradiotherapy was well tolerated, resulted in a high rate of local control, and in a survival benefit for patients demonstrating a complete response or going on to surgical resection. The incidence of distant metastases continues to be high and future strategies should be directed at improving systemic therapy. Nonsmall cell lung cancer (NSCLC), radiotherapy.
Radiotherapy,
Cisplatin,
INTRODUCTION
Reprint requests to: Francois Reboul, M.D., Clinique Chemin
du Lavarin,
B.P. 846, F84082,
modality
therapy,
Concomitant
chemo-
trol(3). Control of disseminated micrometastases requires effective systemic therapy. Cisplatin is the most effective single chemotherapeutic agent in the treatment of NSCLC. In addition, preclinical and clinical studies indicate that cisplatin may serve as an effective radiosensitizing agent (6). The continuous infusion mode of administration appears to be better tolerated and offers a basis for additional chemoradiation interactions compared to bolus injection (4). Based on these data, a pilot study combining highdose (70 Gy) thoracic RT and concomitant high-dose
Radiation therapy (RT) is considered to be the standard treatment for locally advanced or medically inoperable nonsmall cell lung cancer (NSCLC). Long-term results, however, with conventional RT (60 Gy) are poor with only 15% of patients surviving beyond 2 years (14). Both poor local control and a high rate of early distant dissemination contribute to the poor outcome. There is evidence that RT doses higher than 60 Gy may improve local con-
Catherine, France.
Combined
Accepted
Sainte Avignon,
I251
for publication
2 November
1993.
1252
I. J. Radiation Oncology 0 Biology 0 Physics
continuous infusion cisplatin in the treatment of patients with medically or technically inoperable NSCLC, was initiated in our institution.
METHODS
AND
MATERIALS
From July 1989 to July 199 1, 92 consecutive previously untreated patients with either medically or technically inoperable NSCLC were entered in the study for treatment with concomitant chemoradiotherapy. Seven patients did not receive chemotherapy and have been excluded from the analysis (two protocol violations, two refusals, three early deaths from pulmonary embolus, pulmonary edema, and atria1 fibrillation, respectively). Eighty-two patients were fully evaluable for response, toxicity, and survival. There were three early deaths from intercurrent disease (ruptured esophageal varices, cardiac arrythmia, undiagnosed simultaneous ovarian cancer), and these patients could only be evaluated for toxicity and survival. Median age was 66 years and most patients were male (91.8%). Performance status was O-2 on the WHO scale. Weight loss was not consistently registered in this study. Seventyseven point eight percent of the tumors were squamous cell, which is the usual distribution of histologic subtypes in Europe. Thirty-three point eight percent of tumors were poorly differentiated. Twelve patients (14%) were Stage I (T,_?, No) or Stage II (T,_>, N,) and medically inoperable (Table 1). Among Stage III (TI_j, N2_3) patients, 10.6% had bilateral mediastinal lymph node involvement or supraclavicular disease. Patients with malignant pleural effusions were not eligible.
Table 1. Patient characteristics 85 66 (35-81)
Table 2. Treatment Week Radiotherapy Chemotherapy
123456789 T T T c
T
plan
B
B C
B
Treatment methods Thoracic irradiation was delivered using external beam 18-MeV photons with minimum source axis distance of 80 cm and with lung corrections. During initial radiotherapy, the primary tumor was encompassed with a minimum margin of 2 cm. The entire mediastinum was included from the suprasternal notch to 5 cm below the carina. Lower lobe lesions required mediastinal irradiation to the diaphragm, and upper lobe lesions required irradiation of the ipsilateral supraclavicular area. Controlatera1 hilum was excluded from the irradiation field. Radiation dose was 40 Gy in 20 fractions over 4 weeks and was delivered through two opposing antero-posterior/ postero-anterior fields with custom cerrobend blocks. Surgical evaluation was carried out during a planned 2week break from treatment. In inoperable patients, a boost of 30 Gy in 15 fractions over 3 weeks was delivered to the pretreatment tumor volume with a 1-cm margin using oblique off-cord fields and computerized dosimetry based on CT scan. In operated patients, a similar boost was delivered postoperatively to the ipsilateral mediastinum only if there was residual nodal disease. Patients received cisplatin as a continuous infusion 20 mg/m’/24 h during 5 days coinciding with the second week of each RT cycle (Table 2). The second week was chosen on the basis of experimental data demonstrating enhanced penetration of cisplatin in tumors after 10 Gy irradiation (6). No maintenance chemotherapy was given and no patient received prophylactic cranial irradiation.
78
16 65 4
Hiztologic subtype Squamous Adenocarcinoma Large cell Histologic grade Well differentiated Moderately differentiated Poorly differentiated Unspecified Clinical stage I (T,_,, No) II (T,_z, N,) IIIA (TI-2, N2 or T3, NO-~) IIIB (any T, N,)
5, I994
T = Thoracic radiotherapy: 40 Gy/20 fractions/4 weeks; B = Tumor boost: 30 Gy/ 15 fractions/3 weeks; C = Continuous infusion cisplatin 20 mg/m2/day. day 1-5.
Patient characteristics
Number of patients Age, median (range) Sex Male Female WHO performance status 0
Volume 28, Number
66 11 8 21 14 33 17 8 4 64 9
Response was evaluated after 40 Gy RT and the first course of chemotherapy and 6 weeks following completion of all therapy. All patients underwent physical examination, chest X ray, CT scan of the chest and abdomen, and fiberoptic bronchoscopy with biopsy of the initial tumor site. Complete response was defined as the complete disappearance of all radiological, endoscopic, and histological abnormalities.
Statistical methods Overall survival, local control, and metastatic rate were calculated according to the Kaplan-Meier (10) method. Survival curves were compared using the log-rank test (13).
RT with cisplatin in NSCL carcinoma 0 F. REBOUL etal.
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RESULTS
Compliance Treatment was delivered according to protocol in most patients. The first chemoradiation cycle was administered at full dose in 90.6% of patients. The treatment break between cycles was no longer than the planned 2 weeks in 65.2% of patients, and was otherwise prolonged up to 4 weeks to allow for recovery of toxic effects. During the second phase of treatment, 84.7% of patients received full dose RT and 65.3% received full-dose chemotherapy. Eleven patients went to surgical resection. Four patients had progressive disease and died before the second treatment cycle and two patients refused the second cycle of treatment.
Response to treatment and survival Eighty-two patients were evaluable for response. Of the 11 patients taken to surgery following the first cycle of therapy, three had complete pathologic responses and received no further therapy. Eight had residual tumor, of which four had residual nodal disease and received the second cycle of chemoradiotherapy postoperatively. Fiftyfour patients (65.9%) had either pathologic or clinical complete responses. Thirteen patients ( 15.8%) had partial responses, for an overall response rate of 8 1.7%. Ten patients (12.2%) had progressive disease under treatment (Table 3). At a median follow-up time of 27 months (range, 15.7-38.9 months), the median survival for all 85 patients from the time of diagnosis was 11.4 months. Overall survival was 48.2%, 27.5%, and 25% at 12, 24, and 36 months, respectively (Fig. 1). Survival was found to be independent of patient age, gender, tumor grade, histologic subtype, or clinical stage. Patients with complete responses and those who were candidates for curative surgery had significantly better outcome. Patients who achieved a complete response had a 2-year survival of 42.1% compared to 3.2% in patients not achieving complete response (Fig. 2; p < 0.0001). Similarly, patients who underwent surgical resection had a 2-year survival
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of 75.8% compared to 20.6% in patients treated without surgery (Fig. 3; p < 0.001). Median survival was 19.6 months in complete responders and has not been reached in patients undergoing surgical resection. Nineteen patients with initial complete response had a local recurrence and local failure was associated with distant metastases in six cases. Actuarial local control was 50.6% at 12 months, and 33.3% at 24 months (Fig. 4). Thirty patients developed metastases, most commonly to brain (30%) and bone (27%). Twenty-five percent of distant failures occurred in multiple sites simultaneously. Metastasis rate was 47.8% at 24 months (Fig. 5). The mean time to local or distant failure was 9.6 months (range, 1.9-24.3 months). There have been no local or distant failures beyond 3 years of follow-up. Forty-eight patients have died of their disease. Two patients died of treatment-related toxicities and seven of intercurrent disease. The cause of death was unknown in three cases. Twenty-five patients
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Fig. 2. Overall survival according to response. Patients having a complete response (n = 54) had a 2-year survival of 42.1% compared to 3.2% for partial and nonresponders (p < 0.0001).
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1254
I. J. Radiation Oncology 0 Biology 0 Physics
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Fig. 4. Actuarial local control. The local control rate which is 0% at the time of diagnosis reaches the complete response rate (65.9%) at the time ofevaluation, then falls with each local failure. Actuarial local control was 33.3% at 24 months.
are living at the time of analysis, 18 with no evidence of disease, including eight patients who underwent surgery. Toxicity Acute Grade 3-4 toxicities affected less than 10% of patients and consisted of vomiting and neutropenia. Esophagitis was mild and infrequent (8.4%) as was radiation pneumonitis (9.6%). Severe late pulmonary fibrosis occurred in 5.2% of patients and accounted for one treatment-related death. The other death due to toxicity was from late pulmonary necrosis and massive hemoptysis.
DISCUSSION Approximately 40% of patients with NSCL carcinoma have locally advanced or inoperable disease at the time of diagnosis. Traditionally, treatment has been with RT alone with disappointing long-term survival (14). Radiotherapy has also been used to treat early stage NSCLC in medically inoperable patients, also with poor outcome except for patients with well-differentiated tumors (8). Analysis of long-term patterns of failure on Radiation Therapy Oncology Group (RTOG) protocol 73-O 1 demonstrated a dose-response relationship for local tumor control following RT alone (15). Patients receiving the highest RT dose (60 Gy) had a lower incidence of local failure (35%) than did patients treated with lower doses (49-58%; 40-50 Gy). However, such local control may well be overestimated in these historical studies. Local failure following RT alone may result from the presence of a large tumor cell burden, radioresistant hypoxic tumor cells or tumor cell repopulation. Recent results from the RTOG (protocol 83-l 1) using hyperfractionated radiotherapy (HFRT) to a total dose of 69.6 Gy are encouraging with 29% survival at 2 years in selected patients (3). Although an analysis of patterns of failure in that study has
Volume 28, Number 5. 1994
not yet been published, it seems that the improvement in survival seen with twice-daily RT must be attributable to better local control. In RTOG protocol 73-O 1 initial failure included extrathoracic sites in 49-65% of patients with various histologic types of NSCLC treated with RT alone: 72-79% ultimately failed with distant metastases (15). Eradication of occult distant disease present at the time of diagnosis can only be accomplished through systemic treatment. Recent studies combining RT and cisplatin-based chemotherapy have stimulated great interest (5, 12, 16). Cisplatin is not only one of the most effective chemotherapeutic agents in the treatment of metastatic NSCLC, but also has been demonstrated to have radiosensitizing properties in preclinical studies (4). Several additive and synergistic mechanisms of interaction between radiation and cisplatin have been identified when the agents are given concurrently or in close temporal relationship (6). These mechanisms include radiosensitization of hypoxic cells, inhibition of repair of potentially lethal or sublethal radiation damage and thiol depletion by cisplatin. In the clinical setting, the optimal schedule of administration of cisplatin and RT has not been clearly established. In a recently reported study of the European Organization for Research and Treatment of Cancer. daily low-dose cisplatin combined with split-course RT significantly improved overall survival compared to RT alone, with the benefit being due solely to better local control (16). It should be pointed out that in this trial, RT alone was not optimal, since 3 Gy X 10 fractions in 2 weeks followed by a 4-week break and 2.5 Gy X 10 fractions resulted in only 2% survival rate at 3 years, which is much lower than 1 l- 15% of 3year survival in patients treated with 60 Gy in 6 weeks in the USA. Similar results were reported in a Phase II trial conducted by the Southwest Oncology Group using continuous RT and concomitant daily low-dose cisplatin (9) but were not reproduced in another similar trial by Trovo et ul. (17). possibly due to the inclusion of patients with poor prognosis ( 1 1). The use of cyclic intermediate-dose
12
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Fig. 5. Distant failure 47.8% at 24 months.
rate. Actuarial
distant
failure rate was
RT with cisplatin
in NSCL carcinoma
cisplatin combined with standard RT has also been associated with negative results (1). Attempts to optimize the dose of cisplatin in an effort to maximally enhance local control and eradication of distant foci of micrometastatic disease have been made. Preliminary data from a small pilot study using alternating RT and high-dose cisplatin by Gandara et al. (7) are encouraging. Although most patients had Stage IIIB disease, 2-year survival was reported to be 4 1%. In the present study, we have attempted to improve local control and to possibly lower rates of distant failure through the use of concomitant RT and high-dose cisplatin chemotherapy. Continuous infusion cisplatin administration is associated with less gastro-intestinal and renal toxicity than bolus infusion, but was also chosen for the potentially greater interaction with RT through the maintenance of higher concentrations of cisplatin free radical, as described by Aziz ct al. (2). Rates of local control achieved with this regimen are similar to those reported in other positive trials (9, 16) and suggest a substantial benefit to concomitant cisplatin-radiotherapy compared to RT alone. This was due mainly to good outcome in patients who became candidates for surgical resection or who achieved a complete clinical response. This benefit was due to improvement in local control only. The rate of local recurrence was low (22.4%) but the systemic therapy used in this trial had little or no impact on the rate of distant failure. Fifty percent of patients developed distant metastases within the first 6 months following completion of therapy. This result questions the efficacy of single agent cisplatin chemotherapy in treating distant micrometastases. Two major Phase III trials comparing standard radiation therapy alone or preceded by two or three cycles of cisplatin-based combination chemotherapy have demonstrated an advantage to such induction regimens in
0 F. REBOUL
et a/.
1255
terms of survival (5) and reduced incidence of distant metastases ( 12). Dillman et al. (5) reported a doubling in 2year survival (26% vs. 13%) for neoadjuvant vinblastine, cisplatin chemotherapy followed by radiation compared to RT alone. Le Chevalier et al. ( 12) demonstrated a 20% decrease in tile rate of distant metastases with three cycles of neoadjuvant combination cisplatin-based chemotherapy followed by RT. Improvement in survival was partially obscured by the high incidence of local failure. The results of this single institution trial of high-dose RT and concomitant high-dose continuous infusion cisplatin chemotherapy indicate that this regimen is well tolerated. The response rate was high, resulting in improved local control and encouraging long-term survival. The high rate of distant failure indicates a need to address this problem by adding a second active systemic agent to the treatment plan. The currently active RTOG protocol 9204 compares neoadjuvant cisplatin-vinblastine chemotherapy followed by conventional RT plus concurrent cisplatin to HFRT with concurrent cisplatin-oral etoposide chemotherapy (Komaki, R., RTOG 92-04: Randomized phase II study of chemotherapy-radiotherapy combination for favorable patients with locally advanced inoperable NSCLC. Unpublished-personal communication). This protocol addresses the need for improved local control by including concurrent chemoradiotherapy with cisplatin and either conventional RT or HFRT. In addition, each arm includes a second active chemotherapeutic agent that may reduce the frequency ofdistant failure. These treatment regimens offer the hope for significant improvement in overall survival in patients with locally advanced NSCLC. In our institution, such patients are currently being treated with a regimen of conventional RT with concurrent cisplatin-etoposide chemotherapy which might work as a radiosensitizer by synergetic mechanism in addition to the systemic effectiveness.
REFERENCES Ansari, R.; Tokars, R.; Fisher. W.; Pennington, K.: Mantravadi, R.; O’Connor, T.; Rynard, S.; Miller, M.; Einhorn. L. A phase III study of thoracic irradiation with or without concomitant cisplatin on locoregional unresectable nonsmall cell lung cancer: A Hoosier Oncology Group protocol (Abstract). Proc. Am. Sot. Clin. Oncol. IO:24 1; 199 1. Aziz. H.; Rosenthal, C. J.; Potters, L.; Nuthakki, M.; Rotman, M. Radiopotentiation by cisplatin in continuous infusion: Nonsmall cell carcinoma of the lung. In: Rotman, M., Rosenthal, C. J., eds. Concomitant continuous infusion chemotherapy and radiation. Berlin. Heidelberg, New York: Springer-Verlag; 199 1:223-228. Cox, J. D.; Azamia. N.: Byhardt, R. W.; Shin, K. H.; Emami, B.: Pajak, T. F. A randomized Phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 to 79.2 Gy: Possible survival benefit with 69.6 Gy in favorable patients with Radiation Therapy Oncology Group Stage III nonsmall cell lung carcinoma. J. Clin. Oncol. 8: 1543- 1555; 1990. Dewit, L. Combined treatment of radiation and cis-diamminedichloroplatinum (II): A review of experimental and
clinical data. Int. J. Radiat. Oncol. Biol. Phys. 13:403-426: 1987. Dillman, R. 0.; Seagreen, 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 vs. radiation alone in stage III nonsmallcell lung cancer. N. Engl. J. Med. 323:940-945; 1990. Douple, E. B. Keynote address: Platinum-radiation interactions. NC1 Monographs. 6:3 15-3 19: 1988. Gandara, D. R.; Valone, F. H.; Deisseroth, A. B.; Roach, M.; Ahn, D. K.; Phillips, T. L. Rapidly alternating radiotherapy and high dose cisplatin chemotherapy in Stage BIB nonsmall cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 20:1047-1052; 1991. 8. Haffty, B. G. Can lung cancer be cured by radiation alone? Int. J. Radiat. Oncol. Biol. Phys. 24: 18 l-182; 1992. 9. Hazuka, M.; Crowley, J.; Bunn, P.; Livingston, R. Concurrent daily low-dose cisplatin (LDCP) combined with chest irradiation (RT) in locally advanced nonsmall cell lung cancer: Preliminary results of a Southwest Oncology Group
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(SWOG) study (Abstract). Proc. Am. Sot. Clin. Oncol. 11: 295; 1992. Kaplan, E. L.; Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53:457-48 1; 1958. Komaki, R. Is concomitant cisplatin and radiotherapy more efficacious treatment than radiotherapy alone in Stage III nonsmall cell lung cancer? Int. J. Radiat. Oncol. Biol. Phys. 24:185-186: 1992. Le Chevalier, T.; Arriagada, R.; Quoix, E.; RuffiC, 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 of 353 patients. JNCI 83:417-423; 199 1. Mantel, N. Evaluation of survival data and two new rank order statistics arising from its consideration. Cancer Chemother. Rep. 50: 163-l 70; 1966. Perez, C. A.; Bauer, M.; Edelstein, S.; Gillespie, B. W.: Birch.
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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. 15. Perez. C. A.; Pajak, T. F.; Rubin, P.; Simpson. J. R.; Mohiuddin, M.: Brady, L. W.; Perez-Tamayo, R.; Rotman, M. Long-term observations of the patterns of failure in patients with unresectable nonoat cell carcinoma of the lung treated with definitive radiotherapy. Cancer 59: 1874-l 88 I ; 1987. 16. Schaake-Koning, C.; van den Bogaert, W.: Dalesio, 0.; Festen, J.; Hoogenhout. J.; van Houtte. P.; Kirkpatrick, A.; Scuher, J. P.: van Zandwijk, N.; Bartelink, H. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall-cell lung cancer. N. Eng. J. Med. 326:524-530; 1992. 17. Trovo, M. G.; Minatel, E.: Franchin, G.; Boccieri, M. G.; Nascimben, 0.; Bolzicco, G.: Pizzi. G.: Torretta, A.: Veronesi. A.: Gobitti, C.: Zanelli, D. J.; Monfardini, S. Radiotherapy vs. radiotherapy enhanced by cisplatin in Stage III nonsmall cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 24:11-15: 1992.