Advertisement

Systematic review of the CUP trials characteristics and perspectives for next-generation studies

      Highlights

      • Over the last five years, CUP research involved primarily retrospective studies.
      • Prospective studies and clinical trials constituted a small proportion of CUP research.
      • The main topics were diagnostics (genomics) and treatment (empiric therapy).
      • Ongoing trials focus on multiple tumour types and are primarily phase II single-arm trials.
      • Two clinical trial designs are suggested to improve the quality of CUP research.

      Abstract

      Background

      Research on therapeutic strategies for patients with unknown primary cancer (CUP) has been underwhelming. This paper summarized and evaluated the CUP therapeutic research over the previous five years. Based on this evaluation, recommendations for clinical trial designs are made to improve the impact of CUP research on patients.

      Methods

      Published and ongoing research were evaluated. PubMed was searched from January 1, 2015, to November 1, 2021. The start date of 2015 was chosen to identify research published after ESMO issued new diagnostic and therapeutic guidelines. The US National Library of Medicine indexed ongoing clinical trials.

      Findings

      Of the 244 CUP studies indexed in PubMed, 11.9% were prospective studies, and 4.9% were clinical trials. The review protocol deemed 65 publications eligible for full-text review. Eleven studies evaluating therapeutic regimens were retained. The two prospective studies and non-randomized trials showed promising outcomes for site-specific treatments. Randomized clinical trials were less promising; however, the trials had recruitment challenges resulting in biased accrual and the inability to keep pace with advancing diagnostics and therapeutics. Most of the 35 ongoing studies were phase II single-arm trials assessing immune checkpoint inhibitors (ICI) or site-specific therapies among CUP patients with suspected favorable prognoses.

      Conclusion

      Our evaluation suggests two prospective clinical trial designs that addressed recent study design and recruitment challenges. A visionary approach uses a multi-arm, multistage randomized trial to address rapid advancements in diagnosis and therapy. A pragmatic approach utilizes a single-arm trial with historical controls to overcome comparison group and recruitment challenges.

      Keywords

      To read this article in full you will need to make a payment
      ESMO Member Login
      Login with your ESMO username and password.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Pavlidis N.
        • Pentheroudakis G.
        Cancer of unknown primary site.
        The Lancet. 2012; 379: 1428-1435
        • Hemminki K.
        • Pavlidis N.
        • Tsilidis K.K.
        • Sundquist K.
        • Ji J.
        Age-Dependent Metastatic Spread and Survival: Cancer of Unknown Primary as a Model.
        Sci Rep. 2016; 6: 23725
        • Pavlidis N.
        • Rassy E.
        • Smith‐Gagen J.
        Cancer of unknown primary: Incidence rates, risk factors and survival among adolescents and young adults.
        Int J Cancer. 2020; 146: 1490-1498
        • Bochtler T.
        • Krämer A.
        Does Cancer of Unknown Primary (CUP) Truly Exist as a Distinct Cancer Entity?.
        Front Oncol. 2019; 9: 402
        • Rassy E.
        • Pavlidis N.
        The diagnostic challenges of patients with carcinoma of unknown primary.
        Expert Rev Anticancer Ther. 2020; 20: 775-783
        • Pavlidis N.
        • Fizazi K.
        Carcinoma of unknown primary (CUP).
        Crit Rev Oncol Hematol. March 2009; 69: 271-278
        • Pavlidis N.
        • Briasoulis E.
        • Hainsworth J.
        • Greco F.A.
        Diagnostic and therapeutic management of cancer of an unknown primary.
        Eur J Cancer Oxf Engl 1990. September 2003; 39: 1990-2005
      1. Rassy E, Parent P, Lefort F, Boussios S, Baciarello G, Pavlidis N. New rising entities in cancer of unknown primary: Is there a real therapeutic benefit? Crit Rev Oncol Hematol 2020;147:102882.

        • Rassy E.
        • Nicolai P.
        • Pavlidis N.
        Comprehensive management of HPV-related squamous cell carcinoma of the head and neck of unknown primary.
        Head Neck. October 2019; 41: 3700-3711
        • El Rassy E.
        • Kattan J.
        • Pavlidis N.
        A new entity of abdominal squamous cell carcinoma of unknown primary.
        Eur J Clin Invest. 2019; 49: e13111
        • Alvi M.A.
        • Wilson R.H.
        • Salto-Tellez M.
        Rare cancers: the greatest inequality in cancer research and oncology treatment.
        Br J Cancer. October 2017; 117: 1255-1257
        • Hayashi H.
        • Kurata T.
        • Takiguchi Y.
        • Arai M.
        • Takeda K.
        • Akiyoshi K.
        • et al.
        Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site.
        J Clin Oncol Off J Am Soc Clin Oncol. 2019; 37: 570-579
        • Mikhail S.
        • Lustberg M.B.
        • Ruppert A.S.
        • Mortazavi A.
        • Monk P.
        • Kleiber B.
        • et al.
        Biomodulation of capecitabine by paclitaxel and carboplatin in advanced solid tumors and adenocarcinoma of unknown primary.
        Cancer Chemother Pharmacol. November 2015; 76: 1005-1012
        • Hainsworth J.D.
        • Daugaard G.
        • Lesimple T.
        • Hübner G.
        • Greco F.A.
        • Stahl M.J.
        • et al.
        Paclitaxel/carboplatin with or without belinostat as empiric first-line treatment for patients with carcinoma of unknown primary site: A randomized, phase 2 trial.
        Cancer. 2015; 121: 1654-1661
        • Sakamoto S.
        • Yutani S.
        • Shichijo S.
        • Morita M.
        • Yamada A.
        • Itoh K.
        • et al.
        Immunological evaluation of personalized peptide vaccination for patients with histologically unfavorable carcinoma of unknown primary site.
        Cancer Immunol Immunother CII. October 2016; 65: 1223-1231
        • Yoon H.H.
        • Foster N.R.
        • Meyers J.P.
        • Steen P.D.
        • Visscher D.W.
        • Pillai R.
        • et al.
        Gene expression profiling identifies responsive patients with cancer of unknown primary treated with carboplatin, paclitaxel, and everolimus: NCCTG N0871 (alliance).
        Ann Oncol Off J Eur Soc Med Oncol. February 2016; 27: 339-344
        • Richards T.M.
        • Bhide S.A.
        • Miah A.B.
        • Del Rosario L.
        • Bodla S.
        • Thway K.
        • et al.
        Total Mucosal Irradiation with Intensity-modulated Radiotherapy in Patients with Head and Neck Carcinoma of Unknown Primary: A Pooled Analysis of Two Prospective Studies.
        Clin Oncol R Coll Radiol G B. 2016; 28: e77-e84
        • Shin D.-Y.
        • Choi Y.H.
        • Lee H.-R.
        • Na I.I.
        • Yuh Y.J.
        • Kim B.-S.
        • et al.
        A phase II trial of modified FOLFOX6 as first-line therapy for adenocarcinoma of an unknown primary site.
        Cancer Chemother Pharmacol. January 2016; 77: 163-168
        • Du C.
        • Ying H.
        • Zhang Y.
        • Huang Y.
        • Zhai R.
        • Hu C.
        Treatment for retropharyngeal metastatic undifferentiated squamous cell carcinoma from an unknown primary site: results of a prospective study with irradiation to nasopharyngeal mucosa plus bilateral neck.
        Oncotarget. 2017; 8: 42372-42381
        • Singh S.
        • Carnaghi C.
        • Buzzoni R.
        • Pommier R.F.
        • Raderer M.
        • Tomasek J.
        • et al.
        Everolimus in Neuroendocrine Tumors of the Gastrointestinal Tract and Unknown Primary.
        Neuroendocrinology. 2018; 106: 211-220
        • Dou S.
        • Li R.
        • Zhang L.
        • Wang Z.
        • Xie L.
        • Zhang C.
        • et al.
        Long-term results of elective mucosal irradiation for head and neck cancer of unknown primary in Chinese population: The EMICUP study.
        Cancer Med. March 2020; 9: 1712-1720
        • Folprecht G.
        • Trautmann K.
        • Stein A.
        • Huebner G.
        • Stahl M.
        • Kasper S.
        • et al.
        Adding cetuximab to paclitaxel and carboplatin for first-line treatment of carcinoma of unknown primary (CUP): results of the Phase 2 AIO trial PACET-CUP.
        Br J Cancer. February 2021; 124: 721-727
        • Hainsworth J.D.
        • Rubin M.S.
        • Spigel D.R.
        • Boccia R.V.
        • Raby S.
        • Quinn R.
        • et al.
        Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute.
        J Clin Oncol Off J Am Soc Clin Oncol. 2013; 31: 217-223
        • Moran S.
        • Martínez-Cardús A.
        • Sayols S.
        • Musulén E.
        • Balañá C.
        • Estival-Gonzalez A.
        • et al.
        Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis.
        Lancet Oncol. October 2016; 17: 1386-1395
        • Fizazi K.
        • Maillard A.
        • Penel N.
        • Baciarello G.
        • Allouache D.
        • Daugaard G.
        • et al.
        A phase III trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04).
        Ann Oncol. 2019; 30: v851https://doi.org/10.1093/annonc/mdz394
        • Rassy E.
        • Bakouny Z.
        • Choueiri T.K.
        • Allen E.M.V.
        • Fizazi K.
        • Greco F.A.
        • et al.
        The role of site-specific therapy for cancers of unknown of primary: A meta-analysis.
        Eur J Cancer. 2020; 127: 118-122
        • Hayashi H.
        • Takiguchi Y.
        • Minami H.
        • Akiyoshi K.
        • Segawa Y.
        • Ueda H.
        • et al.
        Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial.
        JAMA Oncol. 2020; 6: 1931-1938
        • Pauli C.
        • Bochtler T.
        • Mileshkin L.
        • Baciarello G.
        • Losa F.
        • Ross J.S.
        • et al.
        A Challenging Task: Identifying Patients with Cancer of Unknown Primary (CUP) According to ESMO Guidelines: The CUPISCO Trial Experience.
        Oncologist. 2021; 26: e769-e779
        • Kato S.
        • Alsafar A.
        • Walavalkar V.
        • Hainsworth J.
        • Kurzrock R.
        Cancer of Unknown Primary in the Molecular Era.
        Trends Cancer. 2021; 7: 465-477
      2. Lu MY, Chen TY, Williamson DFK, Zhao M, Shady M, Lipkova J, et al. AI-based pathology predicts origins for cancers of unknown primary. Nature 2021;1–5.

        • Rassy E.
        • Assi T.
        • Pavlidis N.
        Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?.
        Br J Cancer. 2020; 122: 1124-1132
        • Rassy E.
        • Boussios S.
        • Chebly A.
        • Farra C.
        • Kattan J.
        • Pavlidis N.
        Comparative genomic characterization of melanoma of known and unknown primary.
        Clin Transl Oncol. 2021; 23: 2302-2308
        • Rassy E.
        • Boussios S.
        • Pavlidis N.
        Genomic correlates of response and resistance to immune checkpoint inhibitors in carcinomas of unknown primary.
        Eur J Clin Invest. 2021; 51: e13583
        • Tanizaki J.
        • Yonemori K.
        • Akiyoshi K.
        • Minami H.
        • Ueda H.
        • Takiguchi Y.
        • et al.
        Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary.
        Ann Oncol. 2022; 33: 216-226
        • Zheng M.
        Tumor mutation burden for predicting immune checkpoint blockade response: the more, the better.
        J Immunother Cancer. 2022; 10: e003087
        • Kandoth C.
        • McLellan M.D.
        • Vandin F.
        • Ye K.
        • Niu B.
        • Lu C.
        • et al.
        Mutational landscape and significance across 12 major cancer types.
        Nature. October 2013; 502: 333-339
        • Scher H.I.
        Observed Advantages of the STAMPEDE Study Design.
        Eur Urol. 2015; 67: 1039-1041