- Email: [email protected]
204 speaker ROLE OF ADJUVANT CHEMOTHERAPY
T UESDAY, M AY 10, 2011
S YMPOSIUM
rable in cancer outcome to lobectomy. The optimal tumors for segmentectomy are those NSCLC that are well centered in the segment of interest and sized 2.0 cm or less. In addition, a patient who has limited pulmonary function (forced expiratory volume in 1 second less than 50% of predicted) or has other lesions that will need to be resected should be given consideration for a segmental resection. The surgeon should always resect all intersegmental lymph nodes in addition to the hilar and mediastinal nodes that are routinely taken at the time of a lobectomy. Using a video-assisted thoracic surgical approach to segmentectomy decreases the morbidity and hastens the recovery of patients having this operation relative to a thoracotomy. This technique can be easily learned by surgeons who use video-assisted thoracic surgery to perform other operations. Surgery is still the only way to offer total clearing of the affected lung tissue and the possible affected local N1 and N2 lymph nodes. In selected centres VATS lobectomy/segmentectomy now is the standard operation in early stage lung cancer and in near future it must be expected to be so throughout Europe. As the surgery is more demanding it is preferable, that it is done in high volume centres by dedicated general thoracic surgeons. 202 speaker STEREOTACTIC RT. THE NEW PATIENTS WITH STAGE 1 NSCLC? F. Lagerwaard1
STANDARD
FOR
HIGH-RISK
1 VU U NIVERSITY M EDICAL C ENTER, Radiation Oncology, Amsterdam, Netherlands
Stereotactic ablative radiotherapy (SABR) or stereotactic body radiotherapy has rapidly gained acceptance by chest physicians and patients as a curative non-invasive treatment of early stage non-small cell lung cancer (NSCLC). In countries where SABR implementation has taken place, this has led to detectable survival gains in stage I NSCLC on a population level [Palma 2010]. In addition, the availability of SABR in The Netherlands resulted in a change in treatment utilization and patterns of care in elderly patients with a significant decrease in elderly patients being left untreated [Palma 2010]. Although no exact definition of SABR exists, it can be regarded as a form of high-precision image-guided radiotherapy, involving the following features: (1) an individualized incorporation of tumour mobility, e.g. using 4-dimensional CT scans or slow CT scans (2) accurate online patient setup using orthogonal imaging, on-board kV imaging (OBI), cone-beam CT-scans or fiducial markers at the treatment delivery unit, (3) the use of up to 10 or more radiation fields or intensity-modulated arcs to minimize normal tissue exposure and (5) the use of ablative doses, typically delivered in 3-5 fractions. Despite the lack of a randomized trial, superior local control rates of around 90% reported after SABR in multicenter studies, phase I-II trials and single institution series substantially exceed those obtained with conventional radiotherapy schemes. These excellent local control rates are particularly seen in series where biological effective doses of above 100 Gy10 for tumour tissue have been used. The superiority of outpatient SABR, which is typically delivered in 3-8 fractions, was confirmed by recent a meta-analysis of observational studies [Grutters 2010]. SABR is well tolerated with fatigue and mild chest wall pain the most commonly reported patient-reported early symptoms. The incidence of late toxicity is also low with symptomatic radiation-induced pneumonitis and chest wall complications including chronic pain and rib fractures each observed in less than 5% of patients. Despite early reports of excessive toxicity after SABR for centrally located lesions, the risk of such toxicity appears to be low when appropriate risk-adapted fraction schemes are used [Timmerman 2006, Haasbeek 2010]. Both pulmonary function and health-related quality of life are maintained following SABR, even in patients with considerable comorbidity [Stephans 2009, Senan 2010]. The excellent local control and low toxicity of SABR have challenged the assumption that surgery should be the preferred treatment for all potentially operable patients with Stage I NSCLC. However, randomized prospective trials comparing surgery and SABR in operable patients have not been completed. Two single-arm phase II trials of SBRT in patients who are fit to undergo surgery have been completed, and the mature results of JCOG 0403 (NCT00238875) and RTOG 0618 (NCT00551369) are awaited. Data from operable Japanese patients who elected to undergo SABR in 14 Japanese institutions over a 9-year period, reported 5-year overall survival rates of 72% and 62%, respectively, for Stage IA and IB subgroups [Onishi 2010]. Preceding the outcome of randomized trials, we observe a growing number of potentially operable patients who, after discussion within local multi-disciplinary tumor board meetings, are referred for SABR instead of surgery. The percentage of potentially operable patients in the Netherlands being referred for SABR, particularly elderly patients with an increased surgical mortality risk, has increased to 25% in recent years [Lagerwaard WCLC 2011]. In conclusion, SABR is rapidly replacing conventional radiotherapy as a curative treatment in medically inoperable patients. Until the outcome of prospective randomized clinical trials of SABR and surgery emerges, patients should be routinely informed of the option of SABR as a possible curative alternative to anatomical resection.
S 79
203 speaker HIGH FREQUENCY ABLATION T. DeBaere Abstract not received.
204 speaker ROLE OF ADJUVANT CHEMOTHERAPY J. P. Sculier1 1 I NSTITUT JULES B ORDET (ULB), Intensive Care Brussels, Belgium
Thoracic Oncology,
Adjuvant chemotherapy is today considered in Europe and America as a standard in the management of stages II and III resected non-small cell lung cancer (NSCLC). Its theoretic advantages are the assessment of the pathological stage, the eradication of micrometastases, the lack delay for surgery in case of ineffective chemotherapy; its disadvantages are the drugs toxicity and the impossibility of delivering for patients who become unfit due to surgery. The decision to administer postoperative chemotherapy is based on the pathological TN. The level of evidence consists in multiple randomised trials and meta-analyses with regimens containing platinum derivatives (1;2). The absolute 5-year survival gain is estimated around 5 to 10 %. In Japan, by using the tegafur + uracil regimen, a benefit has been demonstrated for T1bN0M0 and stage IB NSCLC (3). Some subgroup analyses suggest for Caucasians a significant survival benefit in patients with tumour size > 4 cm (4). There is only one three-arm randomised trial having compared surgery alone or neoadjuvant or with adjuvant chemotherapy (5), including mainly stage I diseases and without survival benefit. According to meta-analyses of the literature, there seems to be no major differences between adjuvant and neoadjuvant chemotherapy (6). At very long-term, the benefit of chemotherapy seems to be cancelled by early deaths due to the occurrence of multiple diseases (7). The points that will be discussed during the presentation are the routine indications for adjuvant chemotherapy after complete resection of NSCLC, the implications of the new TNM staging system for good interpretation of the guidelines on the topic, the choice between adjuvant and neoadjuvant chemotherapy, the follow up to be performed after treatment. References: 1. Meert AP, Sculier JP. What has the meta-analysis contributed to today’s standard of care in the treatment of thoracic malignancies? Lung Cancer 2008 August;61(2):141-51. 2. Arriagada R, Auperin A, Burdett S et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010 April 10;375(9722):1267-77. 3. Hamada C, Tsuboi M, Ohta M et al. Effect of postoperative adjuvant chemotherapy with tegafur-uracil on survival in patients with stage IA non-small cell lung cancer: an exploratory analysis from a metaanalysis of six randomized controlled trials. J Thorac Oncol 2009 December;4(12):1511-6. 4. Strauss GM, Herndon JE, Maddaus MA et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008 November 1;26(31):5043-51. 5. Felip E, Rosell R, Maestre JA et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol 2010 July 1;28(19):3138-45. 6. Lim E, Harris G, Patel A et al. Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials. J Thorac Oncol 2009 November;4(11):1380-8. 7. Arriagada R, Dunant A, Pignon JP et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 2010 January 1;28(1):35-42. Adjuvant chemotherapy is today considered in Europe and America as a standard in the management of stages II and III resected non-small cell lung cancer (NSCLC). Its theoretic advantages are the assessment of the pathological stage, the eradication of micrometastases, the lack delay for surgery in case of ineffective chemotherapy; its disadvantages are the drugs toxicity and the impossibility of delivering for patients who become unfit due to surgery. The decision to administer postoperative chemotherapy is based on the pathological TN. The level of evidence consists in multiple randomised trials and
S 80
S YMPOSIUM
meta-analyses with regimens containing platinum derivatives (1;2). The absolute 5-year survival gain is estimated around 5 to 10 %. In Japan, by using the tegafur + uracil regimen, a benefit has been demonstrated for T1bN0M0 and stage IB NSCLC (3). Some subgroup analyses suggest for Caucasians a significant survival benefit in patients with tumour size > 4 cm (4). There is only one three-arm randomised trial having compared surgery alone or neoadjuvant or with adjuvant chemotherapy (5), including mainly stage I diseases and without survival benefit. According to meta-analyses of the literature, there seems to be no major differences between adjuvant and neoadjuvant chemotherapy (6). At very long-term, the benefit of chemotherapy seems to be cancelled by early deaths due to the occurrence of multiple diseases (7). The points that will be discussed during the presentation are the routine indications for adjuvant chemotherapy after complete resection of NSCLC, the implications of the new TNM staging system for good interpretation of the guidelines on the topic, the choice between adjuvant and neoadjuvant chemotherapy, the follow up to be performed after treatment. References:
T UESDAY, M AY 10, 2011
imaging modality especially suitable for monitoring of intra-tumoral changes during a course of hypofractionated radiotherapy. However, at this moment microenvironmental changes visualized and quantified by means of PETimaging need to be validated to allow interpretation of imaging techniques with intermediate resolution (such as PET/CT).
Breast cancer - What is the evidence that is being created right now? - The best of clinical trials 206 speaker UPDATE AND STATUS REPORT ON HYPOFRACTIONATION AND ACCELERATION (START AND CANADIAN STUDY) T. J. Whelan
1. Meert AP, Sculier JP. What has the meta-analysis contributed to today’s standard of care in the treatment of thoracic malignancies? Lung Cancer 2008 August;61(2):141-51.
Abstract not received.
2. Arriagada R, Auperin A, Burdett S et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010 April 10;375(9722):1267-77.
207 speaker
3. Hamada C, Tsuboi M, Ohta M et al. Effect of postoperative adjuvant chemotherapy with tegafur-uracil on survival in patients with stage IA non-small cell lung cancer: an exploratory analysis from a metaanalysis of six randomized controlled trials. J Thorac Oncol 2009 December;4(12):1511-6. 4. Strauss GM, Herndon JE, Maddaus MA et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008 November 1;26(31):5043-51. 5. Felip E, Rosell R, Maestre JA et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol 2010 July 1;28(19):3138-45. 6. Lim E, Harris G, Patel A et al. Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials. J Thorac Oncol 2009 November;4(11):1380-8. 7. Arriagada R, Dunant A, Pignon JP et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 2010 January 1;28(1):35-42.
205 speaker RADIOBIOLOGY AND MOLECULAR RESPONSE IMAGING IN HYPOFRACTIONATION J. Bussink1 1 R ADBOUD U NIVERSITY N IJMEGEN M EDICAL C ENTER, Radiation Oncology, Nijmegen, Netherlands
Introduction: One of the main microenvironmental charateristic that is responsible for treatment failure is tumor cell hypoxia. The extent of tumor cell hypoxia may have marked implication if the number of radiotherapy fractions is reduced. Therefore, the introduction of hypofractionation in clinical practice may increase the necessity to visualize these resistant hypoxic tumor areas. Hypoxia and treatment resistance: To overcome hypoxia related treatment resistance localizing and quantifying hypoxia is necessary. To reduce the negative effect of tumor cell hypoxia, radiotherapy can be combined with hypoxia mimicking agents such as nimorazole or hypoxic cytotoxins, such as tirapazamine can be applied. Also, radiotherapy can be applied together with hypoxia decreasing procedures such as hyperoxic gas breathing during treatment or stimulation tumor blood flow. The more recent introduction of Intensity Modulated RadioTherapy, IMRT, allows specific boosting of tumor subvolumes that may harbor radioresistant tumor cells. Visualizing these subvolumes by means of PET imaging for this purpose has great potential. Several PET tracers are available for hypoxia imaging. These tracers are mainly 2-nitroimidazol derivatives such as FMISO and FAZA. It was shown in several solid tumors that the amount of tracer accumulation decreased over the course of treatment before changes in conventional imaging modalities were measurable. Conclusions: One of the main advantages of PET is the potential to monitor tumor metabolism during treatment. This allows to prospectively assess changes in the tumor microenvironment that are not visible on CT. Making this
UPDATE OF THREE MAJOR PHASE III RANDOMIZED TRIALS FROM THE EORTC BREAST AND RADIOTHERAPY GROUP. H. Bartelink1 2 , S. Litiere1 2 , S. Collette1 2 , L. Collette1 2 , J. Bogaerts1 2 , E. Rutgers1 2 , N. Bijker1 2 , M. Donker1 2 , E. van Werkhoven1 2 1 T HE N ETHERLANDS C ANCER I NSTITUTE - A NTONI VAN L EEUWENHOEK H OSPITAL, Amsterdam, Netherlands 2 EORTC H EADQUARTERS, Brussels, Belgium
Three major Phase III randomized trials from The EORTC Breast and Radiotherapy group were updated, all three trials investigated the role of radiotherapy in early breast cancer. 1. Comparing radical mastectomy (RM) with breast conserving therapy (BCT) In this trial 902 patients were randomized between RM and BCT, the previous analysis revealed a significant higher loco-regional recurrence rate but no difference in overall survival or the time to distant metastasis rate after a median follow-up of 13.4 years. This updated analysis demonstrated that with a median follow-up of 22.1 years, the BCT and mastectomy groups had similar curves with respect to time to DM and overall survival (p = 0.23 and p = 0.23 respectively). Adjustment for clinical tumor size (≤ 2cm versus > 2cm), pathologic axillary lymph node status (negative versus positive) and age (≥ 50 years old versus <50 years old) did not change these conclusions. 2. Breast-Conserving Treatment With or Without Radiotherapy in Ductal Carcinoma-In-Situ: After complete local excision (LE), 1010 women with DCIS were randomly assigned to no further treatment or radiotherapy (50Gy). One thousand ten women with mostly (71%) mammographically detected DCIS were included. The 10 years follow up data demonstrated that radiotherapy after LE for DCIS continued to reduce the risk of LR, with a 47% reduction at 10 years. All patient subgroups benefited from radiotherapy. If mature for analysis, data from a recent update will be presented at the meeting Data from 15year follow up data will be presented at the meeting. 3. Boost versus no Boost trial in stage I and II breast cancer A total of 5,318 patients with microscopically complete excision followed by whole-breast irradiation of 50 Gy were randomly assigned to receive either a boost dose of 16 Gy (2,661 patients) or no boost dose (2,657 patients), with a median follow-up of 10.8 years. A nomogram was developed for predicting the cost benefit for giving a boost dose predicting the individual chance on fibrosis and local recurrence. For local recurrence the following factors associated with local recurrence were included in the nomogram: diameter (per mm: HR 1.01), the presence of accompanying DCIS (HR 1.96) and histological high grade (HR 1.21), systemic treatment with hormones (HR 0.59) or chemotherapy (HR 0.68), treatment with boost (HR 0.49) with age as the most dominant factor (HR 0.4 for older than 50 years). J.A. van Dongen, A.C. Voogd, I.S. Fentiman, C. Legrand, R. Sylvester, D. Tong, E. van der Schueren, P.A. Helle, K. van Zijl, H. Bartelink. (2000) Longterm Results of a Randomized Trial Comparing Breast-Conserving Therapy with Mastectomy: European Organization for Research and Treatment of Cancer 10801 Trial. Journal of the National Cancer Institute 92(14) pp 11431150. Bijker N, Meijnen P, Peterse JL, Bogaerts J, Van Hoorebeeck I, Julien JP, Gennaro M, Rouanet P, Avril A, Fentiman IS, Bartelink H, Rutgers EJ. EORTC Breast Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853–a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group.Cancer Cooperative Group. J Clin Oncol. 2006 Jul 20;24(21):3381-7. Harry Bartelink, Jean-Claude Horiot, Philip M. Poortmans, Henk Struikmans, Walter Van den Bogaert, Alain Fourquet, Jos J. Jager, Willem J. Hoogenraad, S. Bing Oei, Carla C. Warlam-Rodenhuis,Marianne Pierart, and Laurence Collette Impact of a Higher Radiation Dose on Local Control and Survival in Breast-
S YMPOSIUM
rable in cancer outcome to lobectomy. The optimal tumors for segmentectomy are those NSCLC that are well centered in the segment of interest and sized 2.0 cm or less. In addition, a patient who has limited pulmonary function (forced expiratory volume in 1 second less than 50% of predicted) or has other lesions that will need to be resected should be given consideration for a segmental resection. The surgeon should always resect all intersegmental lymph nodes in addition to the hilar and mediastinal nodes that are routinely taken at the time of a lobectomy. Using a video-assisted thoracic surgical approach to segmentectomy decreases the morbidity and hastens the recovery of patients having this operation relative to a thoracotomy. This technique can be easily learned by surgeons who use video-assisted thoracic surgery to perform other operations. Surgery is still the only way to offer total clearing of the affected lung tissue and the possible affected local N1 and N2 lymph nodes. In selected centres VATS lobectomy/segmentectomy now is the standard operation in early stage lung cancer and in near future it must be expected to be so throughout Europe. As the surgery is more demanding it is preferable, that it is done in high volume centres by dedicated general thoracic surgeons. 202 speaker STEREOTACTIC RT. THE NEW PATIENTS WITH STAGE 1 NSCLC? F. Lagerwaard1
STANDARD
FOR
HIGH-RISK
1 VU U NIVERSITY M EDICAL C ENTER, Radiation Oncology, Amsterdam, Netherlands
Stereotactic ablative radiotherapy (SABR) or stereotactic body radiotherapy has rapidly gained acceptance by chest physicians and patients as a curative non-invasive treatment of early stage non-small cell lung cancer (NSCLC). In countries where SABR implementation has taken place, this has led to detectable survival gains in stage I NSCLC on a population level [Palma 2010]. In addition, the availability of SABR in The Netherlands resulted in a change in treatment utilization and patterns of care in elderly patients with a significant decrease in elderly patients being left untreated [Palma 2010]. Although no exact definition of SABR exists, it can be regarded as a form of high-precision image-guided radiotherapy, involving the following features: (1) an individualized incorporation of tumour mobility, e.g. using 4-dimensional CT scans or slow CT scans (2) accurate online patient setup using orthogonal imaging, on-board kV imaging (OBI), cone-beam CT-scans or fiducial markers at the treatment delivery unit, (3) the use of up to 10 or more radiation fields or intensity-modulated arcs to minimize normal tissue exposure and (5) the use of ablative doses, typically delivered in 3-5 fractions. Despite the lack of a randomized trial, superior local control rates of around 90% reported after SABR in multicenter studies, phase I-II trials and single institution series substantially exceed those obtained with conventional radiotherapy schemes. These excellent local control rates are particularly seen in series where biological effective doses of above 100 Gy10 for tumour tissue have been used. The superiority of outpatient SABR, which is typically delivered in 3-8 fractions, was confirmed by recent a meta-analysis of observational studies [Grutters 2010]. SABR is well tolerated with fatigue and mild chest wall pain the most commonly reported patient-reported early symptoms. The incidence of late toxicity is also low with symptomatic radiation-induced pneumonitis and chest wall complications including chronic pain and rib fractures each observed in less than 5% of patients. Despite early reports of excessive toxicity after SABR for centrally located lesions, the risk of such toxicity appears to be low when appropriate risk-adapted fraction schemes are used [Timmerman 2006, Haasbeek 2010]. Both pulmonary function and health-related quality of life are maintained following SABR, even in patients with considerable comorbidity [Stephans 2009, Senan 2010]. The excellent local control and low toxicity of SABR have challenged the assumption that surgery should be the preferred treatment for all potentially operable patients with Stage I NSCLC. However, randomized prospective trials comparing surgery and SABR in operable patients have not been completed. Two single-arm phase II trials of SBRT in patients who are fit to undergo surgery have been completed, and the mature results of JCOG 0403 (NCT00238875) and RTOG 0618 (NCT00551369) are awaited. Data from operable Japanese patients who elected to undergo SABR in 14 Japanese institutions over a 9-year period, reported 5-year overall survival rates of 72% and 62%, respectively, for Stage IA and IB subgroups [Onishi 2010]. Preceding the outcome of randomized trials, we observe a growing number of potentially operable patients who, after discussion within local multi-disciplinary tumor board meetings, are referred for SABR instead of surgery. The percentage of potentially operable patients in the Netherlands being referred for SABR, particularly elderly patients with an increased surgical mortality risk, has increased to 25% in recent years [Lagerwaard WCLC 2011]. In conclusion, SABR is rapidly replacing conventional radiotherapy as a curative treatment in medically inoperable patients. Until the outcome of prospective randomized clinical trials of SABR and surgery emerges, patients should be routinely informed of the option of SABR as a possible curative alternative to anatomical resection.
S 79
203 speaker HIGH FREQUENCY ABLATION T. DeBaere Abstract not received.
204 speaker ROLE OF ADJUVANT CHEMOTHERAPY J. P. Sculier1 1 I NSTITUT JULES B ORDET (ULB), Intensive Care Brussels, Belgium
Thoracic Oncology,
Adjuvant chemotherapy is today considered in Europe and America as a standard in the management of stages II and III resected non-small cell lung cancer (NSCLC). Its theoretic advantages are the assessment of the pathological stage, the eradication of micrometastases, the lack delay for surgery in case of ineffective chemotherapy; its disadvantages are the drugs toxicity and the impossibility of delivering for patients who become unfit due to surgery. The decision to administer postoperative chemotherapy is based on the pathological TN. The level of evidence consists in multiple randomised trials and meta-analyses with regimens containing platinum derivatives (1;2). The absolute 5-year survival gain is estimated around 5 to 10 %. In Japan, by using the tegafur + uracil regimen, a benefit has been demonstrated for T1bN0M0 and stage IB NSCLC (3). Some subgroup analyses suggest for Caucasians a significant survival benefit in patients with tumour size > 4 cm (4). There is only one three-arm randomised trial having compared surgery alone or neoadjuvant or with adjuvant chemotherapy (5), including mainly stage I diseases and without survival benefit. According to meta-analyses of the literature, there seems to be no major differences between adjuvant and neoadjuvant chemotherapy (6). At very long-term, the benefit of chemotherapy seems to be cancelled by early deaths due to the occurrence of multiple diseases (7). The points that will be discussed during the presentation are the routine indications for adjuvant chemotherapy after complete resection of NSCLC, the implications of the new TNM staging system for good interpretation of the guidelines on the topic, the choice between adjuvant and neoadjuvant chemotherapy, the follow up to be performed after treatment. References: 1. Meert AP, Sculier JP. What has the meta-analysis contributed to today’s standard of care in the treatment of thoracic malignancies? Lung Cancer 2008 August;61(2):141-51. 2. Arriagada R, Auperin A, Burdett S et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010 April 10;375(9722):1267-77. 3. Hamada C, Tsuboi M, Ohta M et al. Effect of postoperative adjuvant chemotherapy with tegafur-uracil on survival in patients with stage IA non-small cell lung cancer: an exploratory analysis from a metaanalysis of six randomized controlled trials. J Thorac Oncol 2009 December;4(12):1511-6. 4. Strauss GM, Herndon JE, Maddaus MA et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008 November 1;26(31):5043-51. 5. Felip E, Rosell R, Maestre JA et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol 2010 July 1;28(19):3138-45. 6. Lim E, Harris G, Patel A et al. Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials. J Thorac Oncol 2009 November;4(11):1380-8. 7. Arriagada R, Dunant A, Pignon JP et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 2010 January 1;28(1):35-42. Adjuvant chemotherapy is today considered in Europe and America as a standard in the management of stages II and III resected non-small cell lung cancer (NSCLC). Its theoretic advantages are the assessment of the pathological stage, the eradication of micrometastases, the lack delay for surgery in case of ineffective chemotherapy; its disadvantages are the drugs toxicity and the impossibility of delivering for patients who become unfit due to surgery. The decision to administer postoperative chemotherapy is based on the pathological TN. The level of evidence consists in multiple randomised trials and
S 80
S YMPOSIUM
meta-analyses with regimens containing platinum derivatives (1;2). The absolute 5-year survival gain is estimated around 5 to 10 %. In Japan, by using the tegafur + uracil regimen, a benefit has been demonstrated for T1bN0M0 and stage IB NSCLC (3). Some subgroup analyses suggest for Caucasians a significant survival benefit in patients with tumour size > 4 cm (4). There is only one three-arm randomised trial having compared surgery alone or neoadjuvant or with adjuvant chemotherapy (5), including mainly stage I diseases and without survival benefit. According to meta-analyses of the literature, there seems to be no major differences between adjuvant and neoadjuvant chemotherapy (6). At very long-term, the benefit of chemotherapy seems to be cancelled by early deaths due to the occurrence of multiple diseases (7). The points that will be discussed during the presentation are the routine indications for adjuvant chemotherapy after complete resection of NSCLC, the implications of the new TNM staging system for good interpretation of the guidelines on the topic, the choice between adjuvant and neoadjuvant chemotherapy, the follow up to be performed after treatment. References:
T UESDAY, M AY 10, 2011
imaging modality especially suitable for monitoring of intra-tumoral changes during a course of hypofractionated radiotherapy. However, at this moment microenvironmental changes visualized and quantified by means of PETimaging need to be validated to allow interpretation of imaging techniques with intermediate resolution (such as PET/CT).
Breast cancer - What is the evidence that is being created right now? - The best of clinical trials 206 speaker UPDATE AND STATUS REPORT ON HYPOFRACTIONATION AND ACCELERATION (START AND CANADIAN STUDY) T. J. Whelan
1. Meert AP, Sculier JP. What has the meta-analysis contributed to today’s standard of care in the treatment of thoracic malignancies? Lung Cancer 2008 August;61(2):141-51.
Abstract not received.
2. Arriagada R, Auperin A, Burdett S et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010 April 10;375(9722):1267-77.
207 speaker
3. Hamada C, Tsuboi M, Ohta M et al. Effect of postoperative adjuvant chemotherapy with tegafur-uracil on survival in patients with stage IA non-small cell lung cancer: an exploratory analysis from a metaanalysis of six randomized controlled trials. J Thorac Oncol 2009 December;4(12):1511-6. 4. Strauss GM, Herndon JE, Maddaus MA et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008 November 1;26(31):5043-51. 5. Felip E, Rosell R, Maestre JA et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol 2010 July 1;28(19):3138-45. 6. Lim E, Harris G, Patel A et al. Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials. J Thorac Oncol 2009 November;4(11):1380-8. 7. Arriagada R, Dunant A, Pignon JP et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 2010 January 1;28(1):35-42.
205 speaker RADIOBIOLOGY AND MOLECULAR RESPONSE IMAGING IN HYPOFRACTIONATION J. Bussink1 1 R ADBOUD U NIVERSITY N IJMEGEN M EDICAL C ENTER, Radiation Oncology, Nijmegen, Netherlands
Introduction: One of the main microenvironmental charateristic that is responsible for treatment failure is tumor cell hypoxia. The extent of tumor cell hypoxia may have marked implication if the number of radiotherapy fractions is reduced. Therefore, the introduction of hypofractionation in clinical practice may increase the necessity to visualize these resistant hypoxic tumor areas. Hypoxia and treatment resistance: To overcome hypoxia related treatment resistance localizing and quantifying hypoxia is necessary. To reduce the negative effect of tumor cell hypoxia, radiotherapy can be combined with hypoxia mimicking agents such as nimorazole or hypoxic cytotoxins, such as tirapazamine can be applied. Also, radiotherapy can be applied together with hypoxia decreasing procedures such as hyperoxic gas breathing during treatment or stimulation tumor blood flow. The more recent introduction of Intensity Modulated RadioTherapy, IMRT, allows specific boosting of tumor subvolumes that may harbor radioresistant tumor cells. Visualizing these subvolumes by means of PET imaging for this purpose has great potential. Several PET tracers are available for hypoxia imaging. These tracers are mainly 2-nitroimidazol derivatives such as FMISO and FAZA. It was shown in several solid tumors that the amount of tracer accumulation decreased over the course of treatment before changes in conventional imaging modalities were measurable. Conclusions: One of the main advantages of PET is the potential to monitor tumor metabolism during treatment. This allows to prospectively assess changes in the tumor microenvironment that are not visible on CT. Making this
UPDATE OF THREE MAJOR PHASE III RANDOMIZED TRIALS FROM THE EORTC BREAST AND RADIOTHERAPY GROUP. H. Bartelink1 2 , S. Litiere1 2 , S. Collette1 2 , L. Collette1 2 , J. Bogaerts1 2 , E. Rutgers1 2 , N. Bijker1 2 , M. Donker1 2 , E. van Werkhoven1 2 1 T HE N ETHERLANDS C ANCER I NSTITUTE - A NTONI VAN L EEUWENHOEK H OSPITAL, Amsterdam, Netherlands 2 EORTC H EADQUARTERS, Brussels, Belgium
Three major Phase III randomized trials from The EORTC Breast and Radiotherapy group were updated, all three trials investigated the role of radiotherapy in early breast cancer. 1. Comparing radical mastectomy (RM) with breast conserving therapy (BCT) In this trial 902 patients were randomized between RM and BCT, the previous analysis revealed a significant higher loco-regional recurrence rate but no difference in overall survival or the time to distant metastasis rate after a median follow-up of 13.4 years. This updated analysis demonstrated that with a median follow-up of 22.1 years, the BCT and mastectomy groups had similar curves with respect to time to DM and overall survival (p = 0.23 and p = 0.23 respectively). Adjustment for clinical tumor size (≤ 2cm versus > 2cm), pathologic axillary lymph node status (negative versus positive) and age (≥ 50 years old versus <50 years old) did not change these conclusions. 2. Breast-Conserving Treatment With or Without Radiotherapy in Ductal Carcinoma-In-Situ: After complete local excision (LE), 1010 women with DCIS were randomly assigned to no further treatment or radiotherapy (50Gy). One thousand ten women with mostly (71%) mammographically detected DCIS were included. The 10 years follow up data demonstrated that radiotherapy after LE for DCIS continued to reduce the risk of LR, with a 47% reduction at 10 years. All patient subgroups benefited from radiotherapy. If mature for analysis, data from a recent update will be presented at the meeting Data from 15year follow up data will be presented at the meeting. 3. Boost versus no Boost trial in stage I and II breast cancer A total of 5,318 patients with microscopically complete excision followed by whole-breast irradiation of 50 Gy were randomly assigned to receive either a boost dose of 16 Gy (2,661 patients) or no boost dose (2,657 patients), with a median follow-up of 10.8 years. A nomogram was developed for predicting the cost benefit for giving a boost dose predicting the individual chance on fibrosis and local recurrence. For local recurrence the following factors associated with local recurrence were included in the nomogram: diameter (per mm: HR 1.01), the presence of accompanying DCIS (HR 1.96) and histological high grade (HR 1.21), systemic treatment with hormones (HR 0.59) or chemotherapy (HR 0.68), treatment with boost (HR 0.49) with age as the most dominant factor (HR 0.4 for older than 50 years). J.A. van Dongen, A.C. Voogd, I.S. Fentiman, C. Legrand, R. Sylvester, D. Tong, E. van der Schueren, P.A. Helle, K. van Zijl, H. Bartelink. (2000) Longterm Results of a Randomized Trial Comparing Breast-Conserving Therapy with Mastectomy: European Organization for Research and Treatment of Cancer 10801 Trial. Journal of the National Cancer Institute 92(14) pp 11431150. Bijker N, Meijnen P, Peterse JL, Bogaerts J, Van Hoorebeeck I, Julien JP, Gennaro M, Rouanet P, Avril A, Fentiman IS, Bartelink H, Rutgers EJ. EORTC Breast Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853–a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group.Cancer Cooperative Group. J Clin Oncol. 2006 Jul 20;24(21):3381-7. Harry Bartelink, Jean-Claude Horiot, Philip M. Poortmans, Henk Struikmans, Walter Van den Bogaert, Alain Fourquet, Jos J. Jager, Willem J. Hoogenraad, S. Bing Oei, Carla C. Warlam-Rodenhuis,Marianne Pierart, and Laurence Collette Impact of a Higher Radiation Dose on Local Control and Survival in Breast-