Breaking a paradigm in the concept of organ-driven intervention
James Fleck & Mariana Rodrigues: Anticancerweb 23(03), 2019
Exploring cancer is akin to having a glimpse of all the laws of physics in action just by looking at the sky. Studies in cancer molecular biology progressively reveal its genomic instability. Discovery of new mutation patterns amplifies interactions in the already known signal transduction pathways. Cancer Genome Atlas (TCGA) has continuously generated genomic and proteomic data increasing our knowledge on 33 organ-categorized types of cancer. Use of big data resources (machine learning and deep-learning) will shortly provide a cancer comprehensive molecular description identifying cellular clusters able to anticipate tumor biological behavior, regardless the location of the primary tumor.
The concept of oligometastatic disease is supported by tumor biological behavior, involving a limited number of dissemination sites. The concept shows a high polymorphism in tumor phenotypic expression, and can be observed in spite of tumor histology. It is a clinical finding that still lacks a unifying molecular support. Oligometastatic disease breaks a paradigm, extending curative interventions into a new metastatic scenario, characterized by a low tumor burden.
In August 2018, the International Journal of Radiation Oncology Biology and Physics published the Phase II multicenter study evaluating the use of Stereotactic Ablative Radiation Therapy (SABR) in oligometastatic disease. Using SABR, metastatic sites were treated with high doses of radiotherapy in a highly precise field, reducing undesirable toxicity to normal tissues. The definition of oligometastatic disease included different primary tumors, showing a number of 5 or less metastases, expressed in 3 or less organs and detected by PET-CT. In addition, the study included only patients with oligometastatic disease in a metachronous presentation. The most common primary tumors were lung cancer (21.8%), colorectal adenocarcinoma (21.1%), squamous cell carcinoma of the head and neck (10.9%), breast cancer (8.8%) and adenocarcinoma of the prostate (7.5%). SABR was used predominantly to one (70.7%) or two (19%) metastatic sites. The most frequent treated-sites were lung (52.3%), lymph nodes (14.7%) and bones (6.9%). After a median follow-up of 41.3 months, the patients achieved a median overall survival of 42.3 months and a 5-year overall survival of 43%. A multivariate analysis showed independent prognostic factors. Performance status and previous metastasectomy influenced overall survival. Resection of the primary tumor and less than 3 metastatic sites influenced local progression-free survival. There was also a significant difference in overall survival of different primary tumors (5-year overall survival was 100% and 56%, respectively, in the prostate and breast, and median overall survival was 54.4 months and 26.8 months, respectively, in colorectal and lung). SABR presented a low toxicity index and did not compromise quality of life in questionnaires answered by the patients. The authors concluded that SABR was safe and effective in the treatment of oligometastatic cancer, although the efficacy parameters (overall 5-year survival or median overall survival) were methodologically inadequate for a phase II study without a control arm.
Epidemiological data published in 2017 by the US Surveillance, Epidemiology and End Results (SEER) program indicated in metastatic nonhematologic cancer a 5-year overall survival ranging from 3 to 38%. The table shown below illustrates the 5-year overall survival published by SEER 2017, according to the location of the primary tumor. The outcome in metastatic tumors published by SEER 2017 compared with the one observed in the five predominant oligometastatic diseases included in the SABR study is different, both in the joint or individualized primary tumor analysis. It is clearly a selection bias whose best outcome could be attributed only to the indolent biological behavior, regardless the intervention. The study validates the safety of SABR in the scenario of the oligometastatic disease, but does not allow to conclude its effectiveness.
In November 2018 the preliminary results of the SABR-COMET trial were presented at the American Society for Radiation Oncology (ASTRO) 60th Annual Meeting. Despite being a phase II study, patients with oligometastatic disease were distributed in a 1: 2 ratio for a control arm undergoing standard care treatment (SCT) or a test arm in which patients received SCT + SABR. In spite of the small number of patients (n = 99), the study was positive. The median overall survival was 41 months in the SABR arm versus 28 months in the control arm. A small n associated with a 1: 2 distribution limit the conclusions, but favors the design of phase III trial, which would increase statistical power.
Reference:
Philip Sutera,David A. Clump,Ronny Kalash, et al: Initial Results of a Multicenter Phase 2 Trial of Stereotactic Ablative Radiation Therapy for Oligometastatic Cancer,Int J Radiation Oncol Biol Phys103 (1):116 - 122, 2018
Rebecca L. Siegel, Kimberly D. Miller, Ahmedin Jemal:Cancer Statistics, Surveillance and Health Services Research, American Cancer Society, CA Cancer J Clin 67: 7 – 30, 2017
D.A. Palma, R.A. Olson, S. Harrow, et al: Stereotactic Ablative Radiation Therapy for the Comprehensive Treatment of Oligometastatic Tumors (SABR-COMET): Results of a Randomized Trial, Int J Radiation Oncol Biol Phys102 (3) S3-S4, 2018
As seen in the Alpha DaRT intratumoral ablation study, Stereotactic Ablative Radiotherapy is another good example of promising results in this therapeutic field. Although the SABR study has some important weaknesses (low n and likely selection bias), it is safe enough to have it's continuation approved and even reasonably supported, if we consider that its efficacy and effectiveness results are of some value.
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