Renata Duchnowska

Oncology Clinic, Military Institute of the Health Services, Warsaw

Pseudoprogression during immunotherapy of cancers

ABSTRACT

Pseudoprogression denotes apparent, early progression of disease followed by long-lasting regression. This phenomenon is observed during the treatment of different cancers and in approximately 10% of patients receiving immunotherapy. The appearance of pseudoprogression could make difficult the assessment of treatment response based on Response Evaluation Criteria in Solid Tumours (RECIST). In this report, the scope of pseudoprogression was discussed as well as currently proposed alternative methods of treatment response assessment according to Immune-related Response Criteria (irRC).

Key words: pseudoprogression, immunotherapy, cancer, irRC

Oncol Clin Pract 2017; 13, 2: 57–60

Introduction

Pseudoprogression in cancer patients includes a preceding sub-acute reaction to the treatment, with signs of disease progression in imaging examinations, and also with clinical deterioration in a small portion of patients. Pseudoprogression was described for the first time as “bone scan flare phenomenon” in breast cancer and prostate cancer patients receiving hormone therapy or bisphosphonates [1–6]. In this case, it was based on the results of the first follow-up bone scintigraphy, showing increased radiotracer uptake in “hot spots” or even increasing their numbers. A similar phenomenon is not uncommon in magnetic resonance imaging in patients with malignant glioma undergoing radiochemotherapy [7–9].

The mechanism of pseudoprogression is not clear. It is assumed that it is connected with local tissue reaction for developing tumour, extensive inflammatory infiltration, increased vascular permeability, and oedema; as regards bones, engagement of osteoblasts in regenerative processes can play a role and “healing” of micrometastases, not visible in baseline imaging [5, 6, 9]. It could be that increased vascular permeability results from intensified uptake of contrast medium used in imaging examinations.

Pseudoprogression during immunotherapy

For the first time pseudoprogression during immunotherapy was observed in patients with disseminated skin melanoma, receiving ipilimumab, human monoclonal antibody directed against cytotoxic T lymphocyte antigen-4 (CTLA-4) [10]. Of note, despite disease progression during the initial phase of treatment with ipilimumab, some patients subsequently achieved robust clinical benefit [10]. Pseudoprogression in melanoma patients was also reported during treatment with monoclonal antibodies being immune-checkpoint inhibitors (anti-PD), like nivolumab or pembrolizumab [11, 12]. Similar changes were observed when PD inhibitors were used in non-small cell lung cancer (NSCLC) and breast cancer patients [13–18]. It is estimated that early pseudoprogression in imaging examinations occurs in approximately 10% of patients receiving immunotherapy [19]. In these circumstances, it seems that pseudoprogression is connected with infiltrations of active T-cells and other immune cells within metastases [19, 20]. This unusual response could contribute to overall survival (OS) benefits, but without progression-free survival (PFS) benefits in clinical trials with immunotherapy in NSCLC and renal-cell cancer (RCC) patients (Table 1) [13, 14, 21].

Table 1. The clinical trials with immunotherapy in NSCLC and renal-cell cancer patients

NSCLC — non-small cell lung cancer; RCC — renal-cell cancer; PFS — progression-free survival; OS — overall survival

Considering pseudoprogression, Wolchok et al. [19] proposed four types of response to treatment in melanoma patients receiving ipilimumab. The first two: regression of baseline lesions during first 12 weeks of therapy and disease stabilisation with possible subsequent slow shrinkage, were included into traditional criteria of response evaluation. On the other hand, the remaining two: disease regression after initial enlargement or regression during or after transitional occurrence of new lesions, are considered the phenomenon of pseudoprogression.

Assessment of treatment response in cancer patients receiving immunotherapy

Appropriate assessment of treatment response plays a crucial role in clinical decision-making processes. In 1981 the World Health Organisation (WHO) tried for the first time to standardise response criteria [22]. For majority of cancers, computed tomography (CT) is currently considered as the best method, both as regards to response evaluation and reproducibility. At present Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1) are used while interpreting CT images. These criteria were developed based on database including more than 6500 patients participating in prospective clinical trials, mainly with chemotherapy [23]. As regards immunotherapy, characterised by kinetics other than chemotherapy, RECIST or WHO criteria do not always reflect the actual treatment effect. Consequently, in patients with pseudoprogression it could lead to abandonment of potentially effective treatment. So, in 2009 some modifications of standard criteria of response assessment were proposed for patients receiving immunotherapy in prospective clinical studies, e.g. immune-related response criteria (irRC), encompassing occurrence of pseudoprogression during the initial phase [19]. According to these criteria, in the case of suspected disease progression it is required to confirm this during the next examination, and occurrence of the new lesion or lesions does not automatically mean a progression but is included into the total tumour burden (TTB), which is a sum of the products of the two largest perpendicular diameters (SPD) and a SPD of new, measurable lesions. SPD assessment includes maximally up to five lesions in one organ, up to 10 visceral and five skin lesions, and minimal magnitude of new measurable lesion must be 5 mm. During subsequent measurements, TTB changes should be taken into account. Table 2 presents a comparison of WHO, RECIST, and irRC criteria of treatment response assessment. In the meantime, these new response criteria are proposed for use in patients with solid tumours receiving immunotherapy; however, they need to be validated in prospective clinical studies.

Table 2. The comparison of WHO, RECIST, and irRC criteria of treatment response assessment

WHO — World Health Organisation; RECIST — Response Evaluation Criteria in Solid Tumours; irRC — Immune-related Response Criteria

Summary

Response to immunotherapy in patients with solid tumours frequently occurs later than after chemotherapy and not uncommonly is preceded with pseudoprogression in imaging examinations. Considering this phenomenon as actual, progression and premature treatment discontinuation could blight the possible chance for clinical benefit. This misinterpretation could be avoided by using new irRC response criteria, which take into account the possibility of images only resembling disease progression. However, these criteria need to be validated in prospective clinical trials.

Address for correspondence:

Assoc. Prof. Renata Duchnowska MD, PhD

Wojskowy Instytut Medyczny,

Klinika Onkologii, Warszawa

e-mail: rdtt@wp.pl

References

1. 1. Rossleigh MA, Lovegrove FT, Reynolds PM, et al. The assessment of response to therapy of bone metastases in breast cancer. Aust N Z J Med. 1984; 14(1): 19–22, indexed in Pubmed: 6235799.
2. 2. Parbhoo SP. Usefulness of current techniques in detecting and monitoring bone metastases from breast cancer. J R Soc Med. 1985; 78 Suppl 9: 7–10, indexed in Pubmed: 3876441.
3. 3. Janicek MJ, Hayes DF, Kaplan WD. Healing flare in skeletal metastases from breast cancer. Radiology. 1994; 192(1): 201–204, doi: 10.1148/radiology.192.1.8208938, indexed in Pubmed: 8208938.
4. 4. Coleman RE, Mashiter G, Whitaker KB, et al. Bone scan flare predicts successful systemic therapy for bone metastases. J Nucl Med. 1988; 29(8): 1354–1359, indexed in Pubmed: 3261330.
5. 5. Vogel CL, Schoenfelder J, Shemano I, et al. Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer. J Clin Oncol. 1995; 13(5): 1123–1128, doi: 10.1200/JCO.1995.13.5.1123, indexed in Pubmed: 7537797.
6. 6. Scher HI, Halabi S, Tannock I, et al. Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008; 26(7): 1148–1159, doi: 10.1200/JCO.2007.12.4487, indexed in Pubmed: 18309951.
7. 7. Hygino da Cruz LC, Rodriguez I, Domingues RC, et al. Pseudoprogression and pseudoresponse: imaging challenges in the assessment of posttreatment glioma. AJNR Am J Neuroradiol. 2011; 32(11): 1978–1985, doi: 10.3174/ajnr.A2397, indexed in Pubmed: 21393407.
8. 8. Reimer C, Deike K, Graf M, et al. Differentiation of pseudoprogression and real progression in glioblastoma using ADC parametric response maps. PLoS One. 2017; 12(4): e0174620, doi: 10.1371/journal.pone.0174620, indexed in Pubmed: 28384170.
9. 9. Ellingson BM, Chung C, Pope WB, et al. Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape. J Neurooncol. 2017 [Epub ahead of print], doi: 10.1007/s11060-017-2375-2, indexed in Pubmed: 28382534.
10. 10. Saenger YM, Wolchok JD. The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Cancer Immun. 2008; 8: 1, indexed in Pubmed: 18198818.
11. 11. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014; 32(10): 1020–1030, doi: 10.1200/JCO.2013.53.0105, indexed in Pubmed: 24590637.
12. 12. Hodi FS, Ribas A, Daud A, et al. Evaluation of immune-related response criteria (irRC) in patients (pts) with advanced melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475. J Clin Oncol. 2014; 32(supl): 15s.
13. 13. Fehrenbacher L, Spira A, Ballinger M, et al. POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016; 387(10030): 1837–1846, doi: 10.1016/S0140-6736(16)00587-0, indexed in Pubmed: 26970723.
14. 14. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015; 373(17): 1627–1639, doi: 10.1056/NEJMoa1507643, indexed in Pubmed: 26412456.
15. 15. Nanda R, Chow LQM, Dees EC, et al. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016; 34(21): 2460–2467, doi: 10.1200/JCO.2015.64.8931, indexed in Pubmed: 27138582.
16. 16. Emens LA, Butterfield LH, Hodi FS, et al. Cancer immunotherapy trials: leading a paradigm shift in drug development. J Immunother Cancer. 2016; 4: 42, doi: 10.1186/s40425-016-0146-9, indexed in Pubmed: 27437105.
17. 17. Emens LA, Braiteh FS, Cassier PA, et al. Abstract 2859: Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Cancer Research. 2015; 75(15 Supplement): 2859–2859, doi: 10.1158/1538-7445.am2015-2859.
18. 18. Dirix LY, Takacs I, Nikolinakos P, et al. Abstract S1-04: Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. Cancer Research. 2016; 76(4 Supplement): S1-04-S1–04, doi: 10.1158/1538-7445.sabcs15-s1-04.
19. 19. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009; 15(23): 7412–7420, doi: 10.1158/1078-0432.CCR-09-1624, indexed in Pubmed: 19934295.
20. 20. Ribas A, Chmielowski B, Glaspy JA. Do we need a different set of response assessment criteria for tumor immunotherapy? Clin Cancer Res. 2009; 15(23): 7116–7118, doi: 10.1158/1078-0432.CCR-09-2376, indexed in Pubmed: 19934296.
21. 21. Motzer R, Escudier B, McDermott D, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New England Journal of Medicine. 2015; 373(19): 1803–1813, doi: 10.1056/nejmoa1510665.
22. 22. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer. 1981; 47(1): 207–214, doi: 10.1002/1097-0142(19810101)47:1<207::aid-cncr2820470134 >3.0.co;2-6, indexed in Pubmed: 7459811.
23. 23. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECI ST guideline (version 1.1). Eur J Cancer. 2009; 45(2): 228–247, doi: 10.1016/j.ejca.2008.10.026, indexed in Pubmed: 19097774.