UPDATED OF POSTOPERATIVE RADIATION THERAPY. Francesc Casas

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1 UPDATED OF POSTOPERATIVE RADIATION THERAPY Francesc Casas

2 1. Introducción (I) The Röntgenology was born in 1896, the same year X rays were discovered [1]. At the beginning the main therapeutic concepts of modern radiation therapy radical or curative, postoperative or adjuvant and palliative intervention were established: neoplasias inoperables, como última esperanza de curación, pocas veces realizada, ó como paliativo insustituible (desaparición del dolor y de la secreción saniosa, cicatrización parcial de las partes ulceradas, etc), procurando evitar en lo posible, la determinación de reacciones intensas. Recidivas recientes de los casos operados, consiguiéndose con frecuencia detenerlas ó hacerlas desaparecer. Cicatrices operatorias consecutivas á la extirpación de un cáncer; aunque la acción de los rayos Röntgen no está suficientemente comprobada en estos casos, creemos que de esta manera se ha de limitar generalmente el número de recidivas [2] [1] Casas F. De la Röntgenologia a l Oncologia Radioteràpica.Contribució a cent anys de lluita contra el càncer a Catalunya ( ). Editorial Barguñó. Barcelona [2] Comas C, Prió A. Los Rayos Roentgen en el tratamiento del cáncer. Resultados e indicaciones. Revista Ibero-Americana de Ciencias Médicas 1906;

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5 1. Introducción (II) During XX century these concepts have been confirmed and Radiation Oncology (RO) has technologically progressed and it has a key role in cancer treatment. Postoperative radiation therapy (PORT) has been shown to be significantly useful to prevent local recurrence and/or to improve survival in high risk patients with all type of cancer. But in lung cancer (LC) a few doubts remain about his exact role.

6 2. Evolution of (PORT) trails in LC ( ) (I) Attempts to define benefit of PORT have been reported: Paterson (1967), Bangma (1971), EORTC (1979), Van Houte (1980), LCSG (1986), Debevec (1996), Lafitte (1996) and MRC (1996). These studies suggest benefit for subgroups of patients but survival benefit has been not corroborated by any randomized study. And studies have substantial design flaws: a) To include patients not stratify according to level of risk. b) These trials took place with important technical limitations (X rays, Cobalt, not CT planning, spinal cord blocks, hypofractionation regimens = > TOXICITY). c) The majority of trials included a small number of patients with no statistical hope of demonstrating even a moderated sized difference in outcome.

7 2. Evolution of (PORT) trails in LC ( ) (II) However, several aspects were point out: a) A non significant trend toward lower survival rate in irradiated patients related to treatment toxicity [3]. b) For pn2 patients radiotherapy led to improve rate of local recurrence (but p=0,18). c) And also for pn2 patients, radiotherapy led to improve survival (but p= 0.07) [4]. A well done phase III trial continued been mandatory [3] Van Houtte P et al. Postoperative radiation therapy in lung cancer: a controlled trial after resection of curative design. Int J Radiat Oncol Biol Phys 1980; 6: [4] Stephens RJ et al. The role of postoperative radiotherapy in non-small-cell lung cancer: a multicenter randomised trial in patients with pathologically staged T1-2, N1-2, M 0 disease. Br J Cancer 1996; 74:

8 3. PORT Meta-analysis (1998) This trial found that PORT techniques previous 80s, had a significant adverse effect on survival, with a hazard ratio of 1.21 (95% CI ) [5], and a 7% decrease in absolute survival concentrated in the pn0-pn1 patients. In pn2 a statistically insignificant trend toward better survival with PORT was observed (hazard ratio=0,96). LC PORT MA was in the same way the MA of PORT for breast cancer [6]. But a well-designed randomized trial have demonstrated a survival benefit when breast cancer patients were well selected and treated with modern techniques [7]. [5] Port.Postoperative radiotherapy in NSCLC: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet 1998; 352: [6] Cuzik J, et al. Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 1987; 71: [7] Ragaz J, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Eng J Med 1997; 337:

9 4. PORT techniques after 80s, ( )(I) Two single institution phase III trials, not included in the first PORT meta-analysis, using smaller and conformal fields, have suggested a favourable ratio for PORT [8-9]. And prospective and well-designed trials demonstrated that risk of death from intercurent disease (DID) is not excessively increased by modern PORT for high-risk resected NSCLC [10]. [8] Mayer R et al. Postoperative radiotherapy in radically resected non-small cell lung cancer. Chest 1997; 112: [9] Trodella L, et al. Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: Definitive results of a phase III randomized trail. Radiother Oncol 2002; 62: [10] Machtay M et al. Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma. J Clin Oncol 2001; 19:

10 4. PORT techniques after 80s, ( ) (II) Another phase III trial which compared PORT versus chemoport [11] was published without increase of DID. A nonrandomized analysis of a SEER database (26% of the United States population) shown a survival benefit of modern PORT [12], in pn2 patients. A mathematical model was made to describe the tumor stage and field size-dependent risks/benefits of PORT and smaller RDT fields, tailored to treat the areas most at risk for recurrence, providing the highest therapeutic ratio [13]. [11] Wakelee HA et al.postoperative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA NSCLC does not increase the expected risk of death from intercurent disease. ECOG trial E3590. Lung Cancer 2005; 48: [12] Lally Be, et al. Postoperative radiotherapy for stage III for non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 2006; 24: [13] Miles EF, et al. Estimating the magnitude and field size dependence of radiotherapy-induced mortality and tumor control after PORT for NSCLC: calculations from clinical trials. Int J Radiat Oncol Biol Phys 2007; 8:

11 4. PORT techniques after 80s, ( ) (III) With all this evidence a multinational European group of Radiation oncologists shown the need for a definitive and well-designed phase III trial of PORT in LC [14]. And finally a sub analysis of ANITA Randomized trial point out the benefit of PORT on survival in patients resected for LC [15]. [14] Le Péchoux C et al. Need for new trial to evaluate adjuvant postoperative radiotherapy in nonsmall-cell lung cancer patients with N2 mediastinal involvement. J Clin Oncol 2007; 25; e10-e11. [15] Douillard JY, Rosell R et al. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA NSCLC treated with adjuvant chemotherapy: The adjuvant Navelbine International Trialist Association (ANITA) randomized trial. Int J Radiat Oncol Biol Phys 2008;72:

12 5.LUNG-ART trial: a well designed phase III trial of PORT (I) In January of 2008 was approved a phase III study comparing PORT to no PORT in patients with completely resected NSCLC and pn2 involvement. The main objective was improvement of DFS by conformal thoracic radiotherapy (ctrt) compared to no ctrt, and the secondary: a) Impact of ctrt on cardiac and pulmonary toxicity (identification of plasmatic predictive factors of toxicity). b) Local control. c) Patterns of recurrence. d) Overall survival (OS). e) Second cancers. f) Prognostic and predictive factors of treatment effect on DFS and OS. g) Cost of each year of life without recurrence gained (in French centres)

13 5. LUNG-ART trial: a well designed phase III trial of PORT (II) Timing of randomization/surgery and chemotherapy (if any): a) In case of no post-operative CT, randomisation will be performed as soon as possible after histological results of complete surgery. Randomisation should take place within 6 weeks after surgery. b) In case of post-operative CT, randomisation should be performed as soon as possible after the end of the last cycle of CT (within 3 weeks) and no later than 6 months after surgery.

14 5. LUNG-ART trial: a well designed phase III trial of PORT (III) Timing of radiotherapy: In patients allocated to RT arm, ctrt should start: a) In case of no post-operative CT, no sooner than 4 weeks and no later than 8 weeks after surgery. b) In case of post-operative CT, no sooner than 2 weeks after the last day of CT (and no later than 6 weeks after the last day of chemotherapy) and, at the latest, within 3 weeks after randomisation.

15 5. LUNG-ART trial: a well designed phase III trial of PORT (IV) Statistical considerations: Sample size of 700 patients will allow show a 10% difference in terms of 3-year disease-free survival stratified on the factors used for randomisation. Inclusion period: 3 to 5 years. Post-treatment period: up to 10 years.

16 6. And previously to get definitive Lung Art Trial results? Common sense and no dogmatic interpretation of scientific literature. Strong collaboration between thoracic surgeons and clinical oncologists with a tailored adjuvant treatment for each patient. A possible use to nomograms for predicting the survival benefit of PORT in patients with NSCLC [16]. [15] Wang SJ, et al. A nomogram for predicting the survival benefit of Post-operative radiotherapy for patients with non-small- cell lung cancer. Proceedings of ASTRO 2008; S447: 2621

17 7. What about the answers to other open and burning questions? Timing of CT-RT in pn2 patients with positive margins: concurrent versus sequential, or full dose versus weekly doses of CT? pn1 in limited mediastinal lymph node exploration in resected high risk patients: PORT or not PORT? And so on Another time common sense and strong scientific collaboration between specialists