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Combined-modality treatment of non-small-cell lung cancer stages I–III (take home messages)
Lung Cancer 45 Suppl. 2 (2004) S139–S141
www.elsevier.com/locate/lungcan
Combined-modality treatment of non-small-cell lung cancer stages I–III (take home messages) Christian R¨ ube*, Jochen Fleckenstein Department of Radiotherapy and Radiation Oncology, Saarland Medical University, Kirrberger Straße, D-66421 Homburg/Saar, Germany
KEYWORDS Non-small cell lung cancer; Combined-modality treatment; Localised stages
Summary Combined-modality approaches including surgery, radiotherapy and chemotherapy have led to a clear improvement of treatment results in localised NSCLC. For stages I and II, postoperative adjuvant chemotherapy may lead to an improved progression-free survival. In stage IIIA, preoperative chemotherapy, respectively radio–chemotherapy, increases the incidence of complete resections. Compared to radio– chemotherapy alone the implementation of surgery in stage IIIA(N2)-patients leads to a better progression-free survival. For stage IIIB simultaneous radio–chemotherapy with or without additional sequential chemotherapy has become the new standard of treatment for patients in sufficient clinical condition. In the future, the implementation of further individual selection and prognostic parameters including tumour volume, location of the tumour, response to induction treatment, co-morbidities and molecular tumour analysis may contribute to further individualise the treatment approach. © 2004 Elsevier Science Ltd.
1. Introduction
2. Stages I and II
The aim of this short report is to briefly summarise the most important messages of the session “Combined-modality treatment in NSCLC stages I–III” of the Symposium on Interdisciplinary Treatment of Lung Cancer held in M¨ unster, Germany in February 2004. * Correspondence to: Christian R¨ ube MD. Department of Radiotherapy and Radiooncology, Saarland University, Kirrberger Straße, D-66421 Homburg/Saar, Germany. Tel.: +49-(6841)-16-24606; fax: +49-(6841)-16-24699. E-mail: [email protected]
Surgery is the mainstay in curative therapy in early-stage NSCLC. Complete surgical resection with radical mediastinal lymphadenectomy leads to 5-year survival rates of approximately 70–80% in stage I and 50–60% in stage II. Most tumours can be resected by lobectomy; in rare cases (e.g. with involvement of the main bronchus) pneumonectomy may be necessary. Because of the high incidence of haematogenous tumour spread, adjuvant chemotherapy was used to reduce distant metastases. Up to now, only one large randomised trial was able to show a significant
0169-5002/$ – see front matter © 2004 Published by Elsevier Ireland Ltd. doi:10.1016/j.lungcan.2004.07.000
S140 advantage for patients with an additional cisplatinbased chemotherapy after radical surgery [1]. Therefore, more data have to be awaited before a final recommendation can be given for adjuvant chemotherapy. Radiotherapy may be used in inoperable cases because of co-morbidity. Promising results with a median survival of more than 30 months can be achieved with high conformal or stereotactic extracranial techniques of either fractionated or single-dose radiotherapy [2].
3. Stage III 3.1. Resectable disease In stage IIIA, resectability with upfront surgery should be limited to cases without multilevel N2lymph-node involvement or bulky N2 disease. The positive impact of preoperative chemotherapy was shown in two small randomised trials with a total of 120 patients. Induction radio–chemotherapy also has been proven to be an effective preoperative treatment, but the definitive necessity of including radiotherapy in neoadjuvant treatment has so far not been shown. Downstaging of large tumour bulk may increase resectability, but toxicity of bimodal preoperative treatment may overcome the positive effects. Therefore selection of patients for preoperative radio–chemotherapy especially in stage IIIB has to be very careful. Concerning adjuvant chemotherapy after surgery, up to now no clear evidence for improved tumour control is available. In cases with mediastinal lymph-node involvement (N2) or incomplete resection (R1/R2) postoperative radiotherapy significantly improves local tumour control. 3.2. Unresectable disease The most important finding in the treatment of unresectable disease is the fact that simultaneous radio–chemotherapy leads to significantly better results than sequential chemo–radiotherapy [3]. No data from randomised trials are currently available concerning the addition of induction chemotherapy or consolidation chemotherapy before, respectively after, simultaneous radio–chemotherapy, but several phase-II trials indicate an advantage for the implementation of additional chemotherapy. Chemotherapy should be platinum-based with no clear advantage for any of the tested second substances with regard to tumour control but differences in treatment-related toxicities [4]. Nevertheless, the clearly higher rate of WHO grade-III and -IV toxicities mainly concerning
C. R¨ ube, J. Fleckenstein esophagitis in the simultaneous setting should play a role in selecting patients for this intensified treatment regiment. Regarding the efficacy of radiotherapy, the use of continuous hyperfractionated accelerated regimens has proven to be significantly superior over conventional fractionated radiotherapy [5]. As – due to toxicity – a combination with simultaneous chemotherapy is not possible in this treatment schedule, the additional input of sequential chemotherapy in this setting will have to be proven in the future. No results from randomised trials are available concerning dose escalation of radiotherapy, but numerous phase-II studies showed promising data with local tumour-control rates up to 70% in selected patients [6].
4. Future developments In stage I, II and IIIA, additional trials will have to confirm the advantage for patients receiving adjuvant or neoadjuvant chemotherapy after R0 resection. In stage IIIA (N2), the impact of radio– chemotherapy as a potential alternative to surgery will have to be underlined in future studies. In stage IIIB, the combination of simultaneous radio–chemotherapy with upfront induction chemotherapy or “adjuvant” consolidating chemotherapy is currently being tested in several trials. In patients with unresectable disease there is a large subpopulation which does not qualify for intensive simultaneous radio–chemotherapy regimens because of co-morbidity. For these patients, clear evidencebased treatment recommendations including the combination of reduced doses of radiotherapy and chemotherapy in a palliative setting will have to be developed. Regarding radiotherapy regiments and techniques, new target volume concepts, omitting elective lymph-node irradiation as well as conformal 3D treatment planning will have to be implemented as standard treatments. Dose escalation will have to show whether or not it has the potential not only to improve local tumour control but also to improve overall survival. In all localised stages new additional molecular targeted drugs such as EGFR antibodies or EGFR tyrosine-kinase inhibitors will be added to the treatment schedules pointed out above. The improvement of patient selection for the different treatment options available by individual functional and biological parameters will be the major challenge in the near future.
Combined-modality treatment of non-small-cell lung cancer stages I–III (take home messages)
References 1. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non–small-cell lung cancer. N Engl J Med 2004;350:351–60. 2. Jeremic B, Classen J, Bamberg M. Radiotherapy alone in technically operable, medically inoperable, early-stage (I/II) non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002;54:119–30. 3. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17:2692–9. 4. Vokes EE, Herndon 2nd JE, Crawford J, et al. Randomized
S141
phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: Cancer and Leukaemia Group B Study 9431. J Clin Oncol 2002;20:4191–8. 5. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet 1997;350:161–5. 6. Thirion P, Holmberg O, Collins CD, et al. Escalated dose for non-small-cell lung cancer with accelerated hypofractionated three-dimensional conformal radiation therapy. Radiother Oncol 2004;71:163–6.
www.elsevier.com/locate/lungcan
Combined-modality treatment of non-small-cell lung cancer stages I–III (take home messages) Christian R¨ ube*, Jochen Fleckenstein Department of Radiotherapy and Radiation Oncology, Saarland Medical University, Kirrberger Straße, D-66421 Homburg/Saar, Germany
KEYWORDS Non-small cell lung cancer; Combined-modality treatment; Localised stages
Summary Combined-modality approaches including surgery, radiotherapy and chemotherapy have led to a clear improvement of treatment results in localised NSCLC. For stages I and II, postoperative adjuvant chemotherapy may lead to an improved progression-free survival. In stage IIIA, preoperative chemotherapy, respectively radio–chemotherapy, increases the incidence of complete resections. Compared to radio– chemotherapy alone the implementation of surgery in stage IIIA(N2)-patients leads to a better progression-free survival. For stage IIIB simultaneous radio–chemotherapy with or without additional sequential chemotherapy has become the new standard of treatment for patients in sufficient clinical condition. In the future, the implementation of further individual selection and prognostic parameters including tumour volume, location of the tumour, response to induction treatment, co-morbidities and molecular tumour analysis may contribute to further individualise the treatment approach. © 2004 Elsevier Science Ltd.
1. Introduction
2. Stages I and II
The aim of this short report is to briefly summarise the most important messages of the session “Combined-modality treatment in NSCLC stages I–III” of the Symposium on Interdisciplinary Treatment of Lung Cancer held in M¨ unster, Germany in February 2004. * Correspondence to: Christian R¨ ube MD. Department of Radiotherapy and Radiooncology, Saarland University, Kirrberger Straße, D-66421 Homburg/Saar, Germany. Tel.: +49-(6841)-16-24606; fax: +49-(6841)-16-24699. E-mail: [email protected]
Surgery is the mainstay in curative therapy in early-stage NSCLC. Complete surgical resection with radical mediastinal lymphadenectomy leads to 5-year survival rates of approximately 70–80% in stage I and 50–60% in stage II. Most tumours can be resected by lobectomy; in rare cases (e.g. with involvement of the main bronchus) pneumonectomy may be necessary. Because of the high incidence of haematogenous tumour spread, adjuvant chemotherapy was used to reduce distant metastases. Up to now, only one large randomised trial was able to show a significant
0169-5002/$ – see front matter © 2004 Published by Elsevier Ireland Ltd. doi:10.1016/j.lungcan.2004.07.000
S140 advantage for patients with an additional cisplatinbased chemotherapy after radical surgery [1]. Therefore, more data have to be awaited before a final recommendation can be given for adjuvant chemotherapy. Radiotherapy may be used in inoperable cases because of co-morbidity. Promising results with a median survival of more than 30 months can be achieved with high conformal or stereotactic extracranial techniques of either fractionated or single-dose radiotherapy [2].
3. Stage III 3.1. Resectable disease In stage IIIA, resectability with upfront surgery should be limited to cases without multilevel N2lymph-node involvement or bulky N2 disease. The positive impact of preoperative chemotherapy was shown in two small randomised trials with a total of 120 patients. Induction radio–chemotherapy also has been proven to be an effective preoperative treatment, but the definitive necessity of including radiotherapy in neoadjuvant treatment has so far not been shown. Downstaging of large tumour bulk may increase resectability, but toxicity of bimodal preoperative treatment may overcome the positive effects. Therefore selection of patients for preoperative radio–chemotherapy especially in stage IIIB has to be very careful. Concerning adjuvant chemotherapy after surgery, up to now no clear evidence for improved tumour control is available. In cases with mediastinal lymph-node involvement (N2) or incomplete resection (R1/R2) postoperative radiotherapy significantly improves local tumour control. 3.2. Unresectable disease The most important finding in the treatment of unresectable disease is the fact that simultaneous radio–chemotherapy leads to significantly better results than sequential chemo–radiotherapy [3]. No data from randomised trials are currently available concerning the addition of induction chemotherapy or consolidation chemotherapy before, respectively after, simultaneous radio–chemotherapy, but several phase-II trials indicate an advantage for the implementation of additional chemotherapy. Chemotherapy should be platinum-based with no clear advantage for any of the tested second substances with regard to tumour control but differences in treatment-related toxicities [4]. Nevertheless, the clearly higher rate of WHO grade-III and -IV toxicities mainly concerning
C. R¨ ube, J. Fleckenstein esophagitis in the simultaneous setting should play a role in selecting patients for this intensified treatment regiment. Regarding the efficacy of radiotherapy, the use of continuous hyperfractionated accelerated regimens has proven to be significantly superior over conventional fractionated radiotherapy [5]. As – due to toxicity – a combination with simultaneous chemotherapy is not possible in this treatment schedule, the additional input of sequential chemotherapy in this setting will have to be proven in the future. No results from randomised trials are available concerning dose escalation of radiotherapy, but numerous phase-II studies showed promising data with local tumour-control rates up to 70% in selected patients [6].
4. Future developments In stage I, II and IIIA, additional trials will have to confirm the advantage for patients receiving adjuvant or neoadjuvant chemotherapy after R0 resection. In stage IIIA (N2), the impact of radio– chemotherapy as a potential alternative to surgery will have to be underlined in future studies. In stage IIIB, the combination of simultaneous radio–chemotherapy with upfront induction chemotherapy or “adjuvant” consolidating chemotherapy is currently being tested in several trials. In patients with unresectable disease there is a large subpopulation which does not qualify for intensive simultaneous radio–chemotherapy regimens because of co-morbidity. For these patients, clear evidencebased treatment recommendations including the combination of reduced doses of radiotherapy and chemotherapy in a palliative setting will have to be developed. Regarding radiotherapy regiments and techniques, new target volume concepts, omitting elective lymph-node irradiation as well as conformal 3D treatment planning will have to be implemented as standard treatments. Dose escalation will have to show whether or not it has the potential not only to improve local tumour control but also to improve overall survival. In all localised stages new additional molecular targeted drugs such as EGFR antibodies or EGFR tyrosine-kinase inhibitors will be added to the treatment schedules pointed out above. The improvement of patient selection for the different treatment options available by individual functional and biological parameters will be the major challenge in the near future.
Combined-modality treatment of non-small-cell lung cancer stages I–III (take home messages)
References 1. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non–small-cell lung cancer. N Engl J Med 2004;350:351–60. 2. Jeremic B, Classen J, Bamberg M. Radiotherapy alone in technically operable, medically inoperable, early-stage (I/II) non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002;54:119–30. 3. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17:2692–9. 4. Vokes EE, Herndon 2nd JE, Crawford J, et al. Randomized
S141
phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: Cancer and Leukaemia Group B Study 9431. J Clin Oncol 2002;20:4191–8. 5. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet 1997;350:161–5. 6. Thirion P, Holmberg O, Collins CD, et al. Escalated dose for non-small-cell lung cancer with accelerated hypofractionated three-dimensional conformal radiation therapy. Radiother Oncol 2004;71:163–6.