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Induction or concomitant chemotherapy and radiotherapy for non-small-cell lung cancer: Myth or reality
Annals of Oncology 6 (Suppl. 3): S37-S40, 1995. C 1995 Kluwer Academic Publishers Primed in the Netherlands.
Symposium article Induction or concomitant chemotherapy and radiotherapy for non-small-cell lung cancer: Myth or reality P. Van Houtte Department of Radiotherapy, Institut Jules Bordet, Brussels, Belgium
Summary
Nowadays, the treatment of unresectable non-smallcell lung cancers remains a controversial issue. This is partially related to difference in patients selection and endpoints but also to progress in imaging procedure, surgery, chemotherapy and radiotherapy. The latter is often considered to be the treatment of choice; nevertheless, it is often regarded more as a palliative treatment rather than a curative modality: the overal 5-year survival rate varies between 5% and 10%. During the last years, the place and limits of radiotherapy are better defined tumor size, nodal involvement, host factors such as performance status and weight loss, and radiation treatment quality are some of the factors to be taken in consideration when evaluating the results. A basic radiobiological principle of radiotherapy implies that a constant fraction of cells is destroyed by a given dose of radiation. Then, there is a clear doseresponse relationship: the dose required to control a tumor increases with its size or the amount of cells present. The control of macroscopic disease (>3 cm) requires doses exceeding 70 Gy. In the 1970s, the Radiation Therapy Oncology Group (RTOG) clearly demonstrated this dose-effect and the benefit of delivering high doses in a randomized study [1, 2\. This trial evaluated total radiation doses of 40, 50 and 60 Gy delivered with 2 Gy per fraction, 5 fractions per week. This study demonstrated a direct relationship between higher total dose, better tumor control and increased long-term survival: 60 Gy induced a significant delay in the onset of local relapse or systemic metastases, and an improved 3-year survival rate, when compared to 40 Gy. The 3-year survival rates were, respectively, 6% after 40 Gy, 10% after 50 Gy and 15% after 60 Gy. Furthermore, several studies have clearly outlined the
Key words: non-small-cell chemotherapy
lung cancer,
radiotherapy,
importance and impact of treatment quality on the outcome of patients treated for lung cancer. Quality control studies reviewing the radiotherapy performed within trials demonstrated a negative impact of protocol deviation both in term of volume treated or treatment interruptions on local control and survival: in the RTOG trials, the median survival dropped from 50 weeks in patients treated according to the protocol to 23 weeks in patients with major protocol violation [3,4]. Nevertheless, even with the best available radiation schedule, failures are due both to distant metastases and in-field recurrences outlining the necessity to search to improve the local treatment and to add a systemic modality such as chemotherapy in an attempt to control the systemic spread. Combining chemotherapy and radiotherapy already is an old story: in 1951, Roswit and Kaplan published their experience with nitrogen mustard. For the last 40 years, a lot of different programs have been tested with a wide range of radiation schedules and with a large variety of drugs used as single agent or in combination. Most studies did not show any benefit due to treatment inadequacy rather than the concept itself. During the last years, positive results were reported by well conducted randomized trials. When combining drug and radiation, several aims may be pursued depending on the type of chemical agent and the sequence used. Conventional cytostatic agents may search for a spatial cooperation to control mainly the distant spread of the tumor and to achieve a possible additive effect on the primary tumor. Most often a sequential approach is used with chemotherapy separated in time from radiation to reduce the possible
Downloaded from http://annonc.oxfordjournals.org/ at New York University on July 7, 2015
If radiation therapy was often considered to be a classical treatment for locally advanced non-small-cell lung cancer, the overal results were quite dismal. Failures were related both to local recurrences and distant metastases. During the last years, several studies have clearly suggested that combining radiation with chemotherapy given as an induction
program or concurrently has led to some long term survival benefits. This paper reviews briefly the data available. Additional studies are required to better identify the optimal schedule.
38
disease for the Finnish trial and good performance status for the Swedish study outlining the importance of patient selection [5,6]. Another negative trial was performed by the North Central Cancer Treatment Group but the MACC chemotherapy program (methotrexate, adriamycin, cytoxan and lomustine) did not include cisplatine or a vinca alcaloids [7]. In three trials, there was a clear benefit in term of long term survival. In the CALGB study, patients were randomized to radiation alone (60 Gy with 2 Gy per fraction) or a short 5-week induction program (vinblastine 5 mg/m2 x 5 and cisplatine 100 mg/m2) followed by the same radiation schedule [8]. Furthermore, the entry criteria were quite restrictive: good performance status, no supraclavicular adenopathy, no weight loss more than 5% of the body weight during the last 3 months. After the entry of 180 patients, the trial was prematurely closed as an interim analysis did demonstrate a highly significant survival benefit. The results of this trial were recently confirmed by the RTOG using exactly the same chemotherapy and radiotherapy program as well as the same patient selection criteria [9]. In the French trial, the chemoradiotherapy arm includes an induction program as well as three additional courses of chemotherapy after radiotherapy [10]. They observed a clear difference in long term survival. The study requires the following comments: the low initial response rate to the 3 cycles of chemotherapy (27%) led to a significant decrease in distant metastases (43% vs. 60%) but the local control was similar in both arms. In a recent metananalysis including data of 22 trials using a sequential chemotherapy program, there was a clear statistical benefit in favor of the combined approach: this was particularly true for chemotherapy programs including cisplatine or a vinca-alcaloi'd/etoposide drugs: there is an absolute benefit of 4% at 2 years and of 2% at 5 years [11]. The impact of the maintenance chemotherapy program or the role of the timing are unknown. In contrast to the sequential approach, the administration of chemotherapy and radiotherapy together offers the following theoretical advantages: the local
Table 1. Induction chemotherapy trials for inoperable lung cancers. Authors
Chemotherapy
Radiotherapy (Gy)
No. pts
Stage
Median survival (months)
2Y (%)
Matson Broden NCCTG
CAP
252
1,11, in i, n, in
VCPC
10 9 10 16 10 12
17
Arriagada CALGB
DDP, vinbl
RTOG
DDP, vinbl
55 S 56 C 60 C 60 C 65 C 65 C 60 C 60 C 60 C 60 C
DDP VP16 MACC
330 121
in
353
i, n, in
180
in
13.8
m
13.8 11.4
9.7 490
21 14 21 26 13
No dif. No dif. Nodrf. Statit. Benefit. Statit Benefit. StatiL Benefit
C — continuous radiation; S - split course schedule; CAP - cytoxan, adriamycin, cisplatin; MACC - methotrexate, adriamycin, cytoxan, CCNLJ; VCPC - vindesine, cytoxan, cisplatin, CCNU.
Downloaded from http://annonc.oxfordjournals.org/ at New York University on July 7, 2015
toxicity. In contrast, selected drugs given in close association with radiation may be used to search for a radiosensitizing effect For the latter, time and sequence are two important parameters. In a combined treatment, the following endpoints are of importance to assess its efficacy: survival, 'event free' survival, pattern of failure and toxicity including second primary. Response rates, especially partial response rates, appear to be soft endpoints in comparing results within or between multimodal trials. If data concerning the pattern of failure are an important endpoint for multimodal trials including a local form of treatment, then, a restaging procedure should be performed to search either for distant metastases or for local failure at the time of disease progression. This approach will avoid to report only the most striking event such as brain metastases. Furthermore, an actuarial display will give a better idea of the real risk. The term of induction therapy should be used instead of neoadjuvant or protoadjuvant therapy and is defined as a cyto-reductive therapy administered prior to a definitive locoregional treatment. This approach offers several theoretical advantages: the systemic treatment is not delayed, chemotherapy may be more effective due to better tumor vascularisation and reduce the tumor bulk improving so the effectiveness of radiotherapy or reducing the amount of normal tissue to be irradiated, the response to chemotherapy may be used to select the patients for an additional 2 to 4 cycles after the completion of the radiation. One theoretical negative impact may be the risk of recruiting tumor clonogens into active proliferation or inducing resistant clonogens to chemotherapy and later to radiation. Several phase III trials have been conducted to try to answer the question of the effectiveness of induction chemotherapy. There is no complete agreement between the different published studies including an adequate number of patients (more than 100 patients) but there is a clear suggestion of a modest but real gain in survival (Table 1). The two Scandinavian trials did not shown any survival difference but they noticed some benefits in some subgroups analysis: stage HI
39
Downloaded from http://annonc.oxfordjournals.org/ at New York University on July 7, 2015
treatment as well as the systemic treatment are not Table 2. Cisplatin and thoracic radiation for NSC lung cancer deleted; the use of cytotoxic drugs may be used for randomized trials. their radiosensitizing properties and so cause a supraSoresi Ansari Trovo Schaake additive cell killing by different specific interactions between the two modalities. Nevertheless, the main Cisplatine concern with such an approach is the risk of an inDose (mg/m2) 15 70 6 6 30 Fractions 5 3 15 20 4 creased toxicity on normal tissues, reducing the anti50 50 45 55 55 cipated gain on the tumor. Several approaches have Radiation Gy No. of patients 95 183 173 318 been explored: single agent chemotherapy such as low- Survival dose cisplatine, high-dose single agent, combination Median (months) chemotherapy. Rt 11 9.5 10.3 12 Rt + DDP 16 8.1 10 12 12 The large majority of recent reports in NSCL cancer 2 years (%) are phase I—II studies. They can only provide useful Rt 25 9 15 13 information with regard to the feasability and toxicity. 35 15 Rt + DDP 15 19 26' Cytotoxic chemotherapy program has been combined Local Failure6 (%) Rt 58 50 54 with different types of radiation schedules. The re44 Rt + DDP 48' 60 41' sponse rate is often quite impressive with figures in excess of 60%. Nevertheless, most groups have also re" Statistical significant difference with the radiation control group. ported a large proportion of severe acute hematologi- b Different definition of local failure. cal, lung or esophageal toxicity. The latter toxicity appears to become a limiting factor in accelerated radiation programs using daily dose in excess of 2 Gy. radiation plus daily cisplatine (6 mg/m2) [19]. Survival The acute toxicity of such an approach is higher than was significantly improved in the combined arms, espethe one reported with single drugs used more for their cially with the daily cisplatine (p = 0.0009). This benefit radiosensity properties. For example, two recent phase in survival was only due to an improvement in local II studies used both a combination of cisplatine and control. The major criticism to this EORTC trial is etoposide with a course of definitive radiotherapy (60 related to the radiation schedule used: a split course Gy or more) [12,13]. The 2-year survival rates are regimen which is no more considered to be the optimal quite impressive with figures as high as 42% and 45%; treatment. Indeed, the long rest period between the two by contrast, the reported 2-year survival rates were radiation courses, 3 weeks, may allow for tumor re15% with radiation alone in the large metaanalysis and population. This brief review of the available results for com25% with the CALGB induction program. If those preliminary results may be encouraging, the RTOG has bined treatments suggests a small but significant benefit started a phase HI study comparing two induction pro- in term of survival due to a reduction of distant metasgrams, cisplatine-vinblastine and cisplatine-etoposide tases by the induction program and to a better local to a concomitant program with the latter chemotherapy control by a concurrent administration of cisplatine and radiation. Nevertheless, those treatments should program. The recent published phase III trials with concurrent not be applied to all patients with an unresectable nontreatments have analysed the impact of single agent small-cell lung cancer. Indeed, in all positive trials, either vinca alcaloids or cisplatine. Both agents are well patient selection criteria were quite rigorous including known for their radiosensitizing properties in animal only patients with a good performance status and with experiments. The study of Johnson with vindesine did minimal weight loss (less than 5%). Furthermore, several trials comparing radiation to not show any benefit; more than 30% of the patients included in this trial had either a weight loss of more chemotherapy failed to show any difference but the than 10% or a performance status of less than 70% trial design allowed to cross over the treatment in case (two bad prognostic factors) [14]. Vinblastine was used of tumor progression. Currently, we are completing a by Schallier in a trial including a limited number of randomized study evaluating the role of radiotherapy patients; an improvement in local control was reported after induction chemotherapy: after three cycles of MIP (mitomycine C, cisplatine and iphosphamide), patients [15]. Cisplatine has ben evaluated in 4 different trials with at least a partial response are randomized between using different forms of drug administration and radia- a course of radiation and 3 additional cycles of the MIP tion schedule (Table 2) [16-19]. The two largest trials program [20]. Another important issue is certainly the high rate of explored the impact of low daily doses of cisplatine (6 mg/m2) given 1 hour before the radiation [18,19]. local failure even with the best radiation schedule: in Trovo did not observe any difference in term of sur- the well-documented French trial, the local control vival, response rate and pattern of failure in his trial after 65 Gy assessed through a complete work-up including 173 patients [18]. In contrast, the EORTC including repeated fiberbronchoscopy was quite low trial has compared 3 groups treated with radiation (17%) [10]. Intensification of local treatment is another alone, radiation plus weekly cisplatine (30 mg/m2) and important issue (hyperfractionated programs, acceler-
40
References 1. Perez CA, Bauer M, Edelstein S et al. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 1986; 12:539-47. 2. Perez CA, Pajak TF, Rubin P et al. Long-term observations of the patterns of failure in patients with unresectable non oat-cell carcinoma of the lung treated with definitive radiotherapy. Cancer 1987; 59: 1874-81. 3. Perez CA, Stanley K, Grundy G et al. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung. Report by the Radiation Therapy Oncology Group. Cancer 1982; 50: 1091-9. 4. Cox JD, Pajak TF, Asbell S et al. Interruptions of high-dose radiation therapy decrease long-term survival of favorable patients with unresectable non-small cell carcinoma of the lung: Analysis of 1244 cases from 3 Radiation Therapy Oncology Group (RTOG) trials. Int J Radiat Oncol Biol Phys 1993; 27:493-8. 5. Mattson K, Holsti LR, Hoist P et al. Inoperable non small cell lung cancer: Radiation with or without chemotherapy. Eur J Cancer Clin Oncol 1988; 24: 477-82.
6. Broden O, Nou E. Patients with nonresectable squamous cell carcinoma of the lung . A prospective randomized study. Lung Cancer 1991; (Suppl 7): 161. 7. Morton RF, Jett JR, McGinnis WK et al. Thoracic radiation therapy alone compared with combined chemotherapy for locally unresectable non-small cell lung cancer. A randomized phase III trials. Ann Intern Med 1991; 115: 681-6. 8. Dillman RO, Seagren SL, Propert KJ et al. A randomized trial of induction chemotherapy plus high-dose versus radiation alone in stage HI non-small cell lung cancer. N Engl J Med 1990; 323: 940-5. 9. Sause W, Scott C, Taylor S et al. RTOG 8808 ECOG 4588 Preliminary analysis of a phase III trial in regionally advanced unresectable non-small cell lung cancer (Abstract). Lung Cancer 1994; 11 (Suppl 1): 179. 10. Arriagada R, Le Chevalier T, Quoix E et al. Effect of chemotherapy on locally advanced non-small lung carcinoma: A randomized study of 353 patients. Int J Radiat Oncol Biol Phys 1991; 20:1183-90. 11. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated individual patient data from 52 randomised clinical trials. Paper submitted for publication. 12. Komaki R, Scott C, Lee JS et al. Phase I/II study of combined chemoradiation therapy with cisplatin plus oral etoposide for patients with locally advanced inoperable non-small cell lung cancer (NSCLC): RTOG 91-06 (Abstract). Lung Cancer 1994; 11 (Suppl 1): 178. 13. Reboul F, Brewer Y, Vincent P et al. Concurrent chemoradiation for stage III non-small cell lung cancer (NSCLC): From cisplatin alone to cisplatin + etoposide (Abstract). Lung Cancer 1994; 11 (Suppl 1): 177. 14. Johnson DH, Einhorn LH, Bartolucci A et al. Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Ann Intern Med 1990; 113: 33-8. 15. Schallier DC, de Neve WJ, de Greve JL et al. Is adjuvant treatment with vinblastine effective in reducing the occurrence of distant metastases in limited squamous cell lung cancer? A randomized study. Clin Exp Metastasis 1988; 6: 39-48. 16. Ansari R, Tokars R, Fisher W et al. A phase III study of thoracic irradiation with or without concomitant cisplatin in locoregional unresectable non-small cell lung cancer. Proc Am Soc Clin Oncol 1991; 10: 241. 17. Soresi E, Clerici M, Grilli R et al. A randomized clinical trial comparing radiation vs radiation therapy plus cis-dichlorodiammine platinum in the treatment of locally advanced nonsmall cell lung cancer. Semin Oncol 1988; 15: 20-5. 18. Trovo M, Minatel E, Franchin G et al. Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1992; 24: 11-5. 19. Schaake-Koning C, van den Bogaert W, Dalesio O et al. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall cell lung cancer. N Engl J Med 1992; 326: 524-30. 20. Giner V, Sculier JP, Opalka P et al. A phase III randomized study comparing 6 courses of chemotherapy alone versus 3 courses of chemotherapy followed by locoregional irradiation in patients with non metastatic unresectable non small cell lung cancer (NSCLC): Report on activity of induction chemotherapy (Abstract). Lung Cancer 1994; 11 (Suppl 1): 127. 21. Van Houtte P. Postoperative radiotherapy for lung cancer. Lung Cancer 1991; 7: 5 7-64.
Correspondence to: Dr. P. Van Houtte Department of Radiotherapy Institut Jules Bordet Heger Bordet Street 1 1000 Brussels, Belgium
Downloaded from http://annonc.oxfordjournals.org/ at New York University on July 7, 2015
ated radiation, radiosensitisers) are a few roads to be explored. From a theoretical point of view, the best locoregional control should be achieved through the association of surgery and radiotherapy. The rationale for combining both modalities implies that the failures are due to different mechanisms. Indeed, there is a well-known dose response relationship for radiation, with failures occurring most often in the central part of the tumor where there is a large volume of cells often under hypoxic conditions and not at the periphery where there are fewer cells with an adequate blood supply providing oxic conditions. In contrast, the main limitation of surgery is the need for preserving vital normal tissue adjacent to the tumor; the failures will often be seen at the resection periphery where the quantity of cells is limited. In our own experience with postoperative irradiation for pathological stage HI disease, the local failure rate was as low as 10% provided a complete resection was performed [21]. So, this is certainly not a justification to carry on debulking surgery: in the different studies using a form of induction program before a surgical resection, long-term survival was only observed after a complete resection. Once again, the key question remains our ability to identify the right group of patients who may benefit from such an aggressive multimodal treatment approach. In conclusion, combined treatments for locally advanced non-small lung cancers are more and more a reality which has led to some survival benefit. In the absence of an effective screening program or of an adequate prevention campaign, the treatment of lung cancer still will require a close collaboration between all specialities to identify for each individual patient the best approach taking into account the different prognostic factors and the limitations of each treatment modality.
Symposium article Induction or concomitant chemotherapy and radiotherapy for non-small-cell lung cancer: Myth or reality P. Van Houtte Department of Radiotherapy, Institut Jules Bordet, Brussels, Belgium
Summary
Nowadays, the treatment of unresectable non-smallcell lung cancers remains a controversial issue. This is partially related to difference in patients selection and endpoints but also to progress in imaging procedure, surgery, chemotherapy and radiotherapy. The latter is often considered to be the treatment of choice; nevertheless, it is often regarded more as a palliative treatment rather than a curative modality: the overal 5-year survival rate varies between 5% and 10%. During the last years, the place and limits of radiotherapy are better defined tumor size, nodal involvement, host factors such as performance status and weight loss, and radiation treatment quality are some of the factors to be taken in consideration when evaluating the results. A basic radiobiological principle of radiotherapy implies that a constant fraction of cells is destroyed by a given dose of radiation. Then, there is a clear doseresponse relationship: the dose required to control a tumor increases with its size or the amount of cells present. The control of macroscopic disease (>3 cm) requires doses exceeding 70 Gy. In the 1970s, the Radiation Therapy Oncology Group (RTOG) clearly demonstrated this dose-effect and the benefit of delivering high doses in a randomized study [1, 2\. This trial evaluated total radiation doses of 40, 50 and 60 Gy delivered with 2 Gy per fraction, 5 fractions per week. This study demonstrated a direct relationship between higher total dose, better tumor control and increased long-term survival: 60 Gy induced a significant delay in the onset of local relapse or systemic metastases, and an improved 3-year survival rate, when compared to 40 Gy. The 3-year survival rates were, respectively, 6% after 40 Gy, 10% after 50 Gy and 15% after 60 Gy. Furthermore, several studies have clearly outlined the
Key words: non-small-cell chemotherapy
lung cancer,
radiotherapy,
importance and impact of treatment quality on the outcome of patients treated for lung cancer. Quality control studies reviewing the radiotherapy performed within trials demonstrated a negative impact of protocol deviation both in term of volume treated or treatment interruptions on local control and survival: in the RTOG trials, the median survival dropped from 50 weeks in patients treated according to the protocol to 23 weeks in patients with major protocol violation [3,4]. Nevertheless, even with the best available radiation schedule, failures are due both to distant metastases and in-field recurrences outlining the necessity to search to improve the local treatment and to add a systemic modality such as chemotherapy in an attempt to control the systemic spread. Combining chemotherapy and radiotherapy already is an old story: in 1951, Roswit and Kaplan published their experience with nitrogen mustard. For the last 40 years, a lot of different programs have been tested with a wide range of radiation schedules and with a large variety of drugs used as single agent or in combination. Most studies did not show any benefit due to treatment inadequacy rather than the concept itself. During the last years, positive results were reported by well conducted randomized trials. When combining drug and radiation, several aims may be pursued depending on the type of chemical agent and the sequence used. Conventional cytostatic agents may search for a spatial cooperation to control mainly the distant spread of the tumor and to achieve a possible additive effect on the primary tumor. Most often a sequential approach is used with chemotherapy separated in time from radiation to reduce the possible
Downloaded from http://annonc.oxfordjournals.org/ at New York University on July 7, 2015
If radiation therapy was often considered to be a classical treatment for locally advanced non-small-cell lung cancer, the overal results were quite dismal. Failures were related both to local recurrences and distant metastases. During the last years, several studies have clearly suggested that combining radiation with chemotherapy given as an induction
program or concurrently has led to some long term survival benefits. This paper reviews briefly the data available. Additional studies are required to better identify the optimal schedule.
38
disease for the Finnish trial and good performance status for the Swedish study outlining the importance of patient selection [5,6]. Another negative trial was performed by the North Central Cancer Treatment Group but the MACC chemotherapy program (methotrexate, adriamycin, cytoxan and lomustine) did not include cisplatine or a vinca alcaloids [7]. In three trials, there was a clear benefit in term of long term survival. In the CALGB study, patients were randomized to radiation alone (60 Gy with 2 Gy per fraction) or a short 5-week induction program (vinblastine 5 mg/m2 x 5 and cisplatine 100 mg/m2) followed by the same radiation schedule [8]. Furthermore, the entry criteria were quite restrictive: good performance status, no supraclavicular adenopathy, no weight loss more than 5% of the body weight during the last 3 months. After the entry of 180 patients, the trial was prematurely closed as an interim analysis did demonstrate a highly significant survival benefit. The results of this trial were recently confirmed by the RTOG using exactly the same chemotherapy and radiotherapy program as well as the same patient selection criteria [9]. In the French trial, the chemoradiotherapy arm includes an induction program as well as three additional courses of chemotherapy after radiotherapy [10]. They observed a clear difference in long term survival. The study requires the following comments: the low initial response rate to the 3 cycles of chemotherapy (27%) led to a significant decrease in distant metastases (43% vs. 60%) but the local control was similar in both arms. In a recent metananalysis including data of 22 trials using a sequential chemotherapy program, there was a clear statistical benefit in favor of the combined approach: this was particularly true for chemotherapy programs including cisplatine or a vinca-alcaloi'd/etoposide drugs: there is an absolute benefit of 4% at 2 years and of 2% at 5 years [11]. The impact of the maintenance chemotherapy program or the role of the timing are unknown. In contrast to the sequential approach, the administration of chemotherapy and radiotherapy together offers the following theoretical advantages: the local
Table 1. Induction chemotherapy trials for inoperable lung cancers. Authors
Chemotherapy
Radiotherapy (Gy)
No. pts
Stage
Median survival (months)
2Y (%)
Matson Broden NCCTG
CAP
252
1,11, in i, n, in
VCPC
10 9 10 16 10 12
17
Arriagada CALGB
DDP, vinbl
RTOG
DDP, vinbl
55 S 56 C 60 C 60 C 65 C 65 C 60 C 60 C 60 C 60 C
DDP VP16 MACC
330 121
in
353
i, n, in
180
in
13.8
m
13.8 11.4
9.7 490
21 14 21 26 13
No dif. No dif. Nodrf. Statit. Benefit. Statit Benefit. StatiL Benefit
C — continuous radiation; S - split course schedule; CAP - cytoxan, adriamycin, cisplatin; MACC - methotrexate, adriamycin, cytoxan, CCNLJ; VCPC - vindesine, cytoxan, cisplatin, CCNU.
Downloaded from http://annonc.oxfordjournals.org/ at New York University on July 7, 2015
toxicity. In contrast, selected drugs given in close association with radiation may be used to search for a radiosensitizing effect For the latter, time and sequence are two important parameters. In a combined treatment, the following endpoints are of importance to assess its efficacy: survival, 'event free' survival, pattern of failure and toxicity including second primary. Response rates, especially partial response rates, appear to be soft endpoints in comparing results within or between multimodal trials. If data concerning the pattern of failure are an important endpoint for multimodal trials including a local form of treatment, then, a restaging procedure should be performed to search either for distant metastases or for local failure at the time of disease progression. This approach will avoid to report only the most striking event such as brain metastases. Furthermore, an actuarial display will give a better idea of the real risk. The term of induction therapy should be used instead of neoadjuvant or protoadjuvant therapy and is defined as a cyto-reductive therapy administered prior to a definitive locoregional treatment. This approach offers several theoretical advantages: the systemic treatment is not delayed, chemotherapy may be more effective due to better tumor vascularisation and reduce the tumor bulk improving so the effectiveness of radiotherapy or reducing the amount of normal tissue to be irradiated, the response to chemotherapy may be used to select the patients for an additional 2 to 4 cycles after the completion of the radiation. One theoretical negative impact may be the risk of recruiting tumor clonogens into active proliferation or inducing resistant clonogens to chemotherapy and later to radiation. Several phase III trials have been conducted to try to answer the question of the effectiveness of induction chemotherapy. There is no complete agreement between the different published studies including an adequate number of patients (more than 100 patients) but there is a clear suggestion of a modest but real gain in survival (Table 1). The two Scandinavian trials did not shown any survival difference but they noticed some benefits in some subgroups analysis: stage HI
39
Downloaded from http://annonc.oxfordjournals.org/ at New York University on July 7, 2015
treatment as well as the systemic treatment are not Table 2. Cisplatin and thoracic radiation for NSC lung cancer deleted; the use of cytotoxic drugs may be used for randomized trials. their radiosensitizing properties and so cause a supraSoresi Ansari Trovo Schaake additive cell killing by different specific interactions between the two modalities. Nevertheless, the main Cisplatine concern with such an approach is the risk of an inDose (mg/m2) 15 70 6 6 30 Fractions 5 3 15 20 4 creased toxicity on normal tissues, reducing the anti50 50 45 55 55 cipated gain on the tumor. Several approaches have Radiation Gy No. of patients 95 183 173 318 been explored: single agent chemotherapy such as low- Survival dose cisplatine, high-dose single agent, combination Median (months) chemotherapy. Rt 11 9.5 10.3 12 Rt + DDP 16 8.1 10 12 12 The large majority of recent reports in NSCL cancer 2 years (%) are phase I—II studies. They can only provide useful Rt 25 9 15 13 information with regard to the feasability and toxicity. 35 15 Rt + DDP 15 19 26' Cytotoxic chemotherapy program has been combined Local Failure6 (%) Rt 58 50 54 with different types of radiation schedules. The re44 Rt + DDP 48' 60 41' sponse rate is often quite impressive with figures in excess of 60%. Nevertheless, most groups have also re" Statistical significant difference with the radiation control group. ported a large proportion of severe acute hematologi- b Different definition of local failure. cal, lung or esophageal toxicity. The latter toxicity appears to become a limiting factor in accelerated radiation programs using daily dose in excess of 2 Gy. radiation plus daily cisplatine (6 mg/m2) [19]. Survival The acute toxicity of such an approach is higher than was significantly improved in the combined arms, espethe one reported with single drugs used more for their cially with the daily cisplatine (p = 0.0009). This benefit radiosensity properties. For example, two recent phase in survival was only due to an improvement in local II studies used both a combination of cisplatine and control. The major criticism to this EORTC trial is etoposide with a course of definitive radiotherapy (60 related to the radiation schedule used: a split course Gy or more) [12,13]. The 2-year survival rates are regimen which is no more considered to be the optimal quite impressive with figures as high as 42% and 45%; treatment. Indeed, the long rest period between the two by contrast, the reported 2-year survival rates were radiation courses, 3 weeks, may allow for tumor re15% with radiation alone in the large metaanalysis and population. This brief review of the available results for com25% with the CALGB induction program. If those preliminary results may be encouraging, the RTOG has bined treatments suggests a small but significant benefit started a phase HI study comparing two induction pro- in term of survival due to a reduction of distant metasgrams, cisplatine-vinblastine and cisplatine-etoposide tases by the induction program and to a better local to a concomitant program with the latter chemotherapy control by a concurrent administration of cisplatine and radiation. Nevertheless, those treatments should program. The recent published phase III trials with concurrent not be applied to all patients with an unresectable nontreatments have analysed the impact of single agent small-cell lung cancer. Indeed, in all positive trials, either vinca alcaloids or cisplatine. Both agents are well patient selection criteria were quite rigorous including known for their radiosensitizing properties in animal only patients with a good performance status and with experiments. The study of Johnson with vindesine did minimal weight loss (less than 5%). Furthermore, several trials comparing radiation to not show any benefit; more than 30% of the patients included in this trial had either a weight loss of more chemotherapy failed to show any difference but the than 10% or a performance status of less than 70% trial design allowed to cross over the treatment in case (two bad prognostic factors) [14]. Vinblastine was used of tumor progression. Currently, we are completing a by Schallier in a trial including a limited number of randomized study evaluating the role of radiotherapy patients; an improvement in local control was reported after induction chemotherapy: after three cycles of MIP (mitomycine C, cisplatine and iphosphamide), patients [15]. Cisplatine has ben evaluated in 4 different trials with at least a partial response are randomized between using different forms of drug administration and radia- a course of radiation and 3 additional cycles of the MIP tion schedule (Table 2) [16-19]. The two largest trials program [20]. Another important issue is certainly the high rate of explored the impact of low daily doses of cisplatine (6 mg/m2) given 1 hour before the radiation [18,19]. local failure even with the best radiation schedule: in Trovo did not observe any difference in term of sur- the well-documented French trial, the local control vival, response rate and pattern of failure in his trial after 65 Gy assessed through a complete work-up including 173 patients [18]. In contrast, the EORTC including repeated fiberbronchoscopy was quite low trial has compared 3 groups treated with radiation (17%) [10]. Intensification of local treatment is another alone, radiation plus weekly cisplatine (30 mg/m2) and important issue (hyperfractionated programs, acceler-
40
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6. Broden O, Nou E. Patients with nonresectable squamous cell carcinoma of the lung . A prospective randomized study. Lung Cancer 1991; (Suppl 7): 161. 7. Morton RF, Jett JR, McGinnis WK et al. Thoracic radiation therapy alone compared with combined chemotherapy for locally unresectable non-small cell lung cancer. A randomized phase III trials. Ann Intern Med 1991; 115: 681-6. 8. Dillman RO, Seagren SL, Propert KJ et al. A randomized trial of induction chemotherapy plus high-dose versus radiation alone in stage HI non-small cell lung cancer. N Engl J Med 1990; 323: 940-5. 9. Sause W, Scott C, Taylor S et al. RTOG 8808 ECOG 4588 Preliminary analysis of a phase III trial in regionally advanced unresectable non-small cell lung cancer (Abstract). Lung Cancer 1994; 11 (Suppl 1): 179. 10. Arriagada R, Le Chevalier T, Quoix E et al. Effect of chemotherapy on locally advanced non-small lung carcinoma: A randomized study of 353 patients. Int J Radiat Oncol Biol Phys 1991; 20:1183-90. 11. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated individual patient data from 52 randomised clinical trials. Paper submitted for publication. 12. Komaki R, Scott C, Lee JS et al. Phase I/II study of combined chemoradiation therapy with cisplatin plus oral etoposide for patients with locally advanced inoperable non-small cell lung cancer (NSCLC): RTOG 91-06 (Abstract). Lung Cancer 1994; 11 (Suppl 1): 178. 13. Reboul F, Brewer Y, Vincent P et al. Concurrent chemoradiation for stage III non-small cell lung cancer (NSCLC): From cisplatin alone to cisplatin + etoposide (Abstract). Lung Cancer 1994; 11 (Suppl 1): 177. 14. Johnson DH, Einhorn LH, Bartolucci A et al. Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Ann Intern Med 1990; 113: 33-8. 15. Schallier DC, de Neve WJ, de Greve JL et al. Is adjuvant treatment with vinblastine effective in reducing the occurrence of distant metastases in limited squamous cell lung cancer? A randomized study. Clin Exp Metastasis 1988; 6: 39-48. 16. Ansari R, Tokars R, Fisher W et al. A phase III study of thoracic irradiation with or without concomitant cisplatin in locoregional unresectable non-small cell lung cancer. Proc Am Soc Clin Oncol 1991; 10: 241. 17. Soresi E, Clerici M, Grilli R et al. A randomized clinical trial comparing radiation vs radiation therapy plus cis-dichlorodiammine platinum in the treatment of locally advanced nonsmall cell lung cancer. Semin Oncol 1988; 15: 20-5. 18. Trovo M, Minatel E, Franchin G et al. Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1992; 24: 11-5. 19. Schaake-Koning C, van den Bogaert W, Dalesio O et al. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall cell lung cancer. N Engl J Med 1992; 326: 524-30. 20. Giner V, Sculier JP, Opalka P et al. A phase III randomized study comparing 6 courses of chemotherapy alone versus 3 courses of chemotherapy followed by locoregional irradiation in patients with non metastatic unresectable non small cell lung cancer (NSCLC): Report on activity of induction chemotherapy (Abstract). Lung Cancer 1994; 11 (Suppl 1): 127. 21. Van Houtte P. Postoperative radiotherapy for lung cancer. Lung Cancer 1991; 7: 5 7-64.
Correspondence to: Dr. P. Van Houtte Department of Radiotherapy Institut Jules Bordet Heger Bordet Street 1 1000 Brussels, Belgium
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ated radiation, radiosensitisers) are a few roads to be explored. From a theoretical point of view, the best locoregional control should be achieved through the association of surgery and radiotherapy. The rationale for combining both modalities implies that the failures are due to different mechanisms. Indeed, there is a well-known dose response relationship for radiation, with failures occurring most often in the central part of the tumor where there is a large volume of cells often under hypoxic conditions and not at the periphery where there are fewer cells with an adequate blood supply providing oxic conditions. In contrast, the main limitation of surgery is the need for preserving vital normal tissue adjacent to the tumor; the failures will often be seen at the resection periphery where the quantity of cells is limited. In our own experience with postoperative irradiation for pathological stage HI disease, the local failure rate was as low as 10% provided a complete resection was performed [21]. So, this is certainly not a justification to carry on debulking surgery: in the different studies using a form of induction program before a surgical resection, long-term survival was only observed after a complete resection. Once again, the key question remains our ability to identify the right group of patients who may benefit from such an aggressive multimodal treatment approach. In conclusion, combined treatments for locally advanced non-small lung cancers are more and more a reality which has led to some survival benefit. In the absence of an effective screening program or of an adequate prevention campaign, the treatment of lung cancer still will require a close collaboration between all specialities to identify for each individual patient the best approach taking into account the different prognostic factors and the limitations of each treatment modality.