Dr. med. Christina Schröder, Prof. Dr. med. Matthias Guckenberger Klinik für Radio-Onkologie, Universitätsspital Zürich
With the development of precise and locally highly effec-tive techniques, like stereotactic body radiation therapy (SBRT), radiation therapy is one of the main treatment modalities in this group of patients [7].
Nowadays, the concept of oligometastatic disease is more and more integrated into the clinical routine when treat-ing patients with only a few metastases and favourable prognosis though generally, there is limited evidence regarding both, the amount and the quality of existing publications. However, there is an increasing evidence for some tumor entities, including non-small cell lung cancer (NSCLC), prostate cancer and colorectal cancer.
One of the first groups of patients, in which the concept of oligometastatic disease and the radical local treatment of metastatic sites was described, were those with colorec-tal carcinoma suffering from liver metastases. In these pa-tients, resection of liver metastases led to a favorable disease
free survival. Giacchetti et al. for instance reported a 25%
5-year disease-free survival after resection for metastatic colorectal carcinoma [8]. Pitroda et al. classified patients with colorectal liver metastases according to molecular sub-types combined with a clinical risk score. They identified three subtypes (low, intermediate and high risk) with an excellent 10-year OS of up to 94% in the low risk group [9].
A randomized controlled approach was published by Ruers et al. (CLOCC trial) in 2012 and was updated in 2017. In this trial the overall-survival (OS) of 119 pa-tients without extrahepatic disease was evaluated after either systemic therapy alone or systemic treatment plus locally ablative treatment using radio-frequency ablation.
After a median follow-up time of 4.4 years a significantly improved progression-free survival (PFS) in the combina-tion arm (hazard ratio (HR) 0.63, p = 0.025) was shown, which did not yet translate into a significantly better overall-survival HR 0.74, p = 0.218) [10]. The long-term follow-up data published in 2017 now also shows a sta-tistically significant OS benefit (HR 0.58, P = 0.01) at almost 10 years follow-up for patients in the combina-tion arm. The OS-rate at eight years was 35.9% vs. 8.9%
for the combined therapy arm and the systemic treatment only arm, respectively [11].
The promising data of aggressive local treatment in oligo-metastatic patients with colorectal carcinoma is also re-flected in the ESMO guidelines featuring a passage on oligometastatic disease [12]. It is emphasized that in metastatic patients systemic therapy is still the standard of care and should be considered as the initial part of the treatment strategy, with the exception of patients with only a few liver or lung lesions. In these patients an ab-lative local treatment should be considered. They offer a toolbox of different ablative therapies, including stereo-tactic body radiotherapy (SBRT) if the preferred surgical resection is not possible.
Likewise, for non-small-cell lung cancer (NSCLC) the con-cept of oligometastatic disease was implemented into the 8th version of the TNM system and the NCCN guidelines as well as the ESMO guidelines. Stage IVa M1b is defined as a single extrathoracic metastasis, where local treatment with radiotherapy or surgical resection is recommended [13]. The recommendations in the ESMO guidelines are more cautious: it is stated that oligometastatic patients may experience a good disease-free survival following systemic therapy and radical local treatment but that due to the limited high-level evidence the inclusion in clinical trials is recommended. An exception are patients with brain metastases, for whom a radical local treatment with surgical resection and/or stereotactic radiotherapy is recom mended [14].
Currently, the published data of two prospective random-ized trials by Gomez et al. and Iyengar et al. are available.
Though there are differences in the design of the trials and small sample sizes, both trials showed a significantly better PFS in patients treated with a combination of local ablative radiotherapy and systemic therapy vs. systemic therapy alone [15, 16].
Prostate cancer patients constitute another group for which the concept of oligometastatic disease is commonly used. Though the general problem of low level evidence also applies here, there is data, mostly retrospective, but also some from prospective randomized trials supporting radical local treatment like prostatectomy or SBRT for pa-tients with metastatic disease.
Regarding cytoreductive prostatectomy in patients with metastatic disease, Heidenreich et al. and Gratzke et al.
found it to be feasible and observed a better OS than in patients without a local resection. Additionally, patients treated with a surgical resection experienced no cancer-related symptoms like those without a local treatment [17, 18].
O`Shaughnessy et al. described a small series of 20 pa-tients receiving multimodal therapy including Androgen Deprivation Therapy (ADT), radical prostatectomy and SBRT on bone metastases or primary site in oligometa-static setting. 95% of patients achieved an undetectable PSA of which 20% remained undetectable following tes-tosterone recovery for up to 46 months [19].
One of the best quality data regarding locally ablative therapy on metastases using SBRT in metastatic prostate cancer was published by Ost et al. In 2016, they pub-lished the results of a retrospective multicenter analysis including 119 patients with up to three N1 or M1a-c le-sions after primary locally ablative therapy for prostate cancer. They found it to be safe and observed prolonged progression free interval as well as a meaningful period without ADT [20]. Just recently in February of this year the authors elaborated on this in terms of a phase II pro-spective randomized trial including 62 patients with
≤ 3 metastases. Patients were randomly assigned to ei-ther surveillance or metastasis-directed ei-therapy (surgery or SBRT). The patients in the therapy group showed a better ADT-free survival, though the results were not sig-nificant. Generally, the treatment was well tolerated with-out any ≥ grade 2 toxicities. Although these results are promising, the authors emphasized the need for phase III trials in their conclusion, further re-enforcing the need for high-level evidence on the subject [21].
Up to this day both the definition of an oligometastastic disease and the selection of patients for a locally curative
SCHWERPUNKTTHEMA: RADIOONKOLOGIE
treatment remains challenging. In the initial publication from 1995, Hellmann and Weichselbaum already empha-sized the importance of the identification of the interme-diate tumor stage, the oligometastatic disease. 20 years later, Reyes and Pienta examined 20 clinical studies on oligometastatic lung cancer, found 17 different definitions of oligometastatic disease and each study performed a dif-ferent treatment protocol [22]. Still, up to this day the im-plementation of prospective trials with a sufficient num-ber of patients remains challenging. An opportunity to pool existing data regarding treatment schemes, outcome and toxicity profile lies in the implementation of register trials [23]. The accumulation of clinical data could en-able safe and beneficial standards of care. The clinic for radiation oncology of the University Hospital Zürich has a leading role in two of these trials, the TOaSTT (Toxicity and efficacy of combined stereotactic radiotherapy (SRT) and systemic targeted or immunotherapy) trial and joint Oligocare project of the EORTC and ESTRO. Both of these will hopefully help to further improve patient care on a daily clinical basis.
References
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2. Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol 8: 378-382, 2011.
3. Gadd MA, Casper ES, Woodruff JM, McCormack PM, Brennan MF. Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 218:
705-712, 1993.
4. Hughes KS, Simon R, Songhorabodi S, et al. Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence. Surgery 100: 278-284, 1986.
5. Kern KA, Pass HI, Roth JA. Surgical treatment of pulmonary metastases. In: Rosenberg SA, editor. Surgical Treatment of Meta-static Cancer. Philadelphia: Lippincot; p. 69-100, 1987.
6. Nordlinger B, Vaillant JC, Guiguet M, et al. Survival benefit of repeat liver resections for recurrent colorectal metastases: 143 cases. Association Francaise de Chirurgie. J Clin Oncol 12: 1491-1496, 1994.
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8. Giacchetti S, Itzhaki M, Gruia G, et al. Long-term survival of patients with unresectable colorectal cancer liver metastases fol-lowing infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10: 663-669, 1999.
9. Pitroda SP, Khodarev NN, Huang L, et al. Integrated molecu-lar subtyping defines a curable oligometastatic state in colorectal liver metastasis. Nat Commun 9: 1793, 2018.
10. Ruers T, Punt C, Van Coevorden F, et al. Radiofrequency abla-tion combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004).
Ann Oncol 23: 2619-2626, 2012.
11. Ruers T, Van Coevorden F, Punt CJ, et al. Local Treatment of Un-resectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial. J Natl Cancer Inst 109, 2017. doi: 10.1093/jnci/
djx015
12. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consen-sus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 27: 1386-1422, 2016.
13. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 4.2018, April 26, 2018).
14. Novello S, Barlesi F, Califano R, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 27 (suppl 5): v1-v27, 2016.
15. Gomez DR, Blumenschein GR, Jr., Lee JJ, et al. Local consolida-tive therapy versus maintenance therapy or observation for pa-tients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, ran-domised, controlled, phase 2 study. Lancet Oncol 17: 1672-1682, 2016.
16. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiother-apy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol 4: e173501, 2018.
17. Gratzke C, Engel J, Stief CG. Role of radical prostatectomy in metastatic prostate cancer: data from the Munich Cancer Registry.
Eur Urol 66: 602-603, 2014.
18. Heidenreich A, Pfister D, Porres D. Cytoreductive radical prosta-tectomy in patients with prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study. J Urol 193: 832-838, 2015.
19. O’Shaughnessy MJ, McBride SM, Vargas HA, et al. A Pilot Study of a Multimodal Treatment Paradigm to Accelerate Drug Evalu-ations in Early-stage Metastatic Prostate Cancer. Urology 102:
164-172, 2017.
20. Ost P, Jereczek-Fossa BA, As NV, et al. Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institu-tional Analysis. Eur Urol 69: 9-12, 2016.
21. Ost P, Reynders D, Decaestecker K, et al. Surveillance or Metasta-sis-Directed Therapy for Oligometastatic Prostate Cancer Recur-rence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin Oncol 36: 446-453, 2018.
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SCHWERPUNKTTHEMA: RADIOONKOLOGIE
Correspondence:
Prof. Dr. med. Matthias Guckenberger Klinikdirektor
SCHWERPUNKTTHEMA: RADIOONKOLOGIE
Introduction
Over the past decade, immunotherapy (IMT) treatments that function by driving the immune system to fight can-cer, have emerged as a game changer in oncology. How-ever, while immune checkpoint blockade (ICB), for ex-ample, has shown remarkable clinical responses against a variety of tumors, the proportion of patients obtaining clinical benefit when used as single modality is relatively low, at only 15-20% [1, 2]. Thus, there is an urgent need to develop novel combinatorial regimens that increase re-sponse rates to IMT.
A prerequisite for response to ICB is the presence of tumor infiltrating lymphocytes (TILs) in the tumor microenvi-ronment (TME) [3-6]. In the context of infiltrated «hot»
tumors, ICB, such as antagonists of the program death 1/ligand 1 (PD1/PDL1) axis, reinvigorate the activity of pre-existing antitumor T cells [6, 7]. Tumors that lack im-mune infiltration, so-called «cold» tumors, are refractory to ICB. Radiation therapy (RT) is a widely used anticancer treatment, and has undergone significant technological improvements that can guarantee the precise delivery of x-rays with limited and manageable side effects [8]. In pre-clinical tumor models robust systemic immune responses have been observed when RT is combined with ICB. More-over, anecdotic cases of «abscopal effects», the disappear-ance of unirradiated tumor deposits when other metasta-ses are irradiated, have been described [9, 10]. Thus, RT has the potential to be broadly used as a powerful and safe approach to convert «cold» or T-cell «excluded» tumors into inflamed ones [11]. Here we review the main mecha-nisms by which RT can elicit tumor immunity [12], in situ vaccination and immune reprogramming, and we provide examples of pharmacological interventions that boost ab-scopal responses in current immuno-oncology practice.
Intratumoral in situ vaccination induced by radiation therapy
The damage caused to proliferating tumor cells follow-ing exposure to radiation initiates a variety of transcrip-tional responses that may alter cell-cycle progression, in-duce DNA repair, and/or trigger cell death. Single strand