Main

Biopsy for pharmacodynamic (PD) and biomarker analysis is increasingly common in early-phase cancer trials (Twelves, 2006; Goulart et al, 2007). In principle, PD end points can provide evidence of target effects for a drug, and support decision making for subsequent trials (Workman, 2003; Sarker et al, 2007; Sarker and Workman, 2007; Tan et al, 2009). However, many PD studies require invasive procedures like tumour biopsy.

Studies find that many patients are willing to undergo research biopsy (Seah et al, 2013) and that ethics review committees and oncologists may overestimate patient anxiety associated with biopsies (Agulnik et al, 2006). In one study, overall and major complication rates for tumour biopsies were 5.2% and 0.8%, respectively (Overman et al, 2012). However, the majority of patients describe their biopsies as being painful (Agulnik et al, 2006) and other studies indicate that 10% of patients receiving one common procedure – breast tumour biopsy – report moderate-to-severe pain (a more extended discussion of tumour biopsy risk and burden is available at Brown et al (2008); Hemmer et al (2008); Kimmelman et al (2012)). As biopsies often have no value for subjects in terms of clinical management, their ethical justification rests on an expectation that their performance will be redeemed by the value of the knowledge accrued (Olson et al, 2011).

Given that the burdens of such procedures are well understood, debates concerning their application revolve around conflicting views about the scientific utility of PD evidence. Some commentators question whether research biopsies return sufficient knowledge to justify their risks (Dowlati et al, 2001; Parulekar and Eisenhauer, 2004;

Change history

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Acknowledgements

This work was funded by the Canadian Institutes of Health Research (EOG 102824).

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Authors and Affiliations

  1. Division of Experimental Medicine, Department of Medicine, Biomedical Ethics Unit, McGill University, Montreal, Qubec, Canada

    G A Freeman

  2. Department of Social Studies of Medicine, Biomedical Ethics Unit, McGill University, 3647 Peel Street, Montreal, H3A 1X1, Qubec, Canada

    J Kimmelman

  3. Department of Oncology, NCIC Clinical Trials Group, Clinical Translational Research, Queen’s University, Kingston, Ontario, Canada

    J Dancey

  4. Cancer Clinical Trials Division, NCIC Clinical Trials Group, Cancer Research Institute, Queen’s University, Kingston, Ontario, Canada

    J G Monzon

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  1. G A Freeman
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Correspondence to J Kimmelman.

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Appendices

Appendix 1

Appendix 2

Inventory of studies included in sample

Adjei AA, RB Cohen, WFranklin, CMorris, DWilson, JRMolina, LJHanson, L Gore, L Chow, S Leong, L Maloney, G Gordon, H Simmons, A Marlow, K Litwiler, S Brown, G Poch, K Kane, J Haney, SG Eckhardt (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor Azd6244 (Arry-142886) in patients with advanced cancers. J Clin Oncol 26(13): 2139–2146.

Agulnik M, EW Cohen, RB Cohen, EX Chen, EE Vokes, SJ Hotte, EWinquist, S Laurie, DN Hayes, JE Dancey, S Brown, GR Pond, I Lorimer, M Daneshmand, J Ho, MS Tsao, LL Siu (2007) Phase Ii study of lapatinib in recurrent or metastatic epidermal growth factor receptor and/or Erbb2 expressing adenoid cystic carcinoma and non adenoid cystic carcinoma malignant tumors of the salivary glands. J Clin Oncol 25(25): 3978–3984.

Agulnik M, G da Cunha Santos, D Hedley, T Nicklee, PP Dos Reis, J Ho, GR Pond, H Chen, S Chen, Y Shyr, E Winquist, D Soulieres, EX Chen, JA Squire, P Marrano, S Kamel-Reid, J Dancey, LL Siu, MS Tsao (2007) Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib. J Clin Oncol 25(16): 2184–2190.

Albanell J, F Rojo, S Averbuch, A Feyereislova, JM Mascaro, R Herbst, P LoRusso, D Rischin, S Sauleda, J Gee, RI Nicholson, J Baselga (2002) Pharmacodynamic studies of the epidermal growth factor receptor inhibitor zd1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20(1): 110–124.

Annunziata CM, AJ Walker, L Minasian, M Yu, H Kotz, BJ Wood, K Calvo, P Choyke, D Kimm, SM Steinberg, EC Kohn (2010) Vandetanib, designed to inhibit Vegfr2 and Egfr signaling, had no clinical activity as monotherapy for recurrent ovarian cancer and no detectable modulation of Vegfr2. Clin Cancer Res 16(2): 664–672.

Badros A, AM Burger, S Philip, R Niesvizky, SS Kolla, O Goloubeva, C Harris, J Zwiebel, JJ Wright, I Espinoza-Delgado, MR Baer, JL Holleran, MJ Egorin, S Grant (2009) Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 15(16): 5250–5257.

Baselga J, J Albanell, A Ruiz, A Lluch, P Gascon, V Guillem, S Gonzalez, S Sauleda, I Marimon, JM Tabernero, MT Koehler, F Rojo (2005) Phase Ii and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 23(23): 5323–5333.

Baselga J, D Rischin, M Ranson, H Calvert, E Raymond, DG Kieback, SB Kaye, L Gianni, A Harris, T Bjork, SD Averbuch, A Feyereislova, H Swaisland, F Rojo, J Albanell (2002) Phase I safety, pharmacokinetic, and pharmacodynamic trial of zd1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20(21): 4292–4302.

Baselga J, V Semiglazov, P van Dam, A Manikhas, M Bellet, J Mayordomo, M Campone, E Kubista, R Greil, G Bianchi, J Steinseifer, B Molloy, E Tokaji, H Gardner, P Phillips, M Stumm, HA Lane, JM Dixon, W Jonat, HS Rugo (2009) Phase Ii randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27(16): 2630–2637.

Borghaei H, K Alpaugh, G Hedlund, G Forsberg, C Langer, A Rogatko, R Hawkins, S Dueland, U Lassen, RB Cohen (2009) Phase I dose escalation, pharmacokinetic and pharmacodynamic study of naptumomab estafenatox alone in patients with advanced cancer and with docetaxel in patients with advanced non-small-cell lung cancer. J Clin Oncol 27(25): 4116–4123.

Boss DS, GK Schwartz, MR Middleton, DD Amakye, H Swaisland, RS Midgley, M Ranson, S Danson, H Calvert, R Plummer, C Morris, RD Carvajal, LR Chirieac, JH Schellens, GI Shapiro (2010) Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor azd5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours. Ann Oncol 21(4): 884–894.

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Dowlati A, K Robertson, T Radivoyevitch, J Waas, NP Ziats, P Hartman, FW Abdul-Karim, JK Wasman, J Jesberger, J Lewin, K McCrae, P Ivy, SC Remick (2005) Novel phase i dose de-escalation design trial to determine the biological modulatory dose of the antiangiogenic agent Su5416. Clin Cancer Res 11(21): 7938–7944.

Duran I, J Kortmansky, D Singh, H Hirte, W Kocha, G Goss, L Le, A Oza, T Nicklee, J Ho, D Birle, GR Pond, D Arboine, J Dancey, S Aviel-Ronen, MS Tsao, D Hedley, LL Siu (2006) A phase Ii clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95(9): 1148–1154.

Dy GK, JP Thomas, G Wilding, L Bruzek, S Mandrekar, C Erlichman, D Alberti, K Binger, HC Pitot, SR Alberts, LJ Hanson, R Marnocha, K Tutsch, SH Kaufmann, AA Adjei (2005) A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, Ps-341 (Bortezomib, Velcade), in patients with advanced cancer. Clin Cancer Res 11(9): 3410–3416.

Eder JP, GI Shapiro, LJ Appleman, AX Zhu, D Miles, H Keer, B Cancilla, F Chu, S Hitchcock-Bryan, L Sherman, S McCallum, EI Heath, SA Boerner, PM LoRusso (2010) A phase I study of foretinib, a multi-targeted inhibitor of C-Met and vascular endothelial growth factor receptor 2. Clin Cancer Res 16(13): 3507–3516.

Fakih MG, L Pendyala, G Fetterly, K Toth, JA Zwiebel, I Espinoza-Delgado, A Litwin, YM Rustum, ME Ross, JL Holleran, MJ Egorin (2009) A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combination with 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer. Clin Cancer Res 15(9): 3189–3195.

Fakih MG, A Rajput, GY Yang, L Pendyala, K Toth, JL Smith, DD Lawrence, YM Rustum (2006) A phase I study of weekly intravenous oxaliplatin in combination with oral daily capecitabine and radiation therapy in the neoadjuvant treatment of rectal adenocarcinoma. Int J Radiat Oncol Biol Phys 65(5): 1462–1470.

Felip E, F Rojo, M Reck, A Heller, B Klughammer, G Sala, S Cedres, S Peralta, H Maacke, D Foernzler, M Parera, J Mocks, C Saura, U Gatzemeier, J Baselga (2008) A phase Ii pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy. Clin Cancer Res 14(12): 3867–3874.

Fracasso PM, H Burris 3rd, MA Arquette, R Govindan, F Gao, LP Wright, SA Goodner, FA Greco, SF Jones, N Willcut, C Chodkiewicz, A Pathak, GM Springett, GR Simon, DM Sullivan, R Marcelpoil, SD Mayfield, D Mauro, CR Garrett (2007) A phase 1 escalating single-dose and weekly fixed-dose study of cetuximab: pharmacokinetic and pharmacodynamic rationale for dosing. Clin Cancer Res 13(3): 986–993.

Goss G, H Hirte, WH Miller Jr, IA Lorimer, D Stewart, G Batist, DA Parolin, P Hanna, S Stafford, J Friedmann, W Walsh, S Mathews, L Douglas, LK Seymour (2005) A phase I study of oral Zd 1839 given daily in patients with solid tumors: Ind.122, a study of the investigational new drug program of the national cancer institute of canada clinical trials group.’ Invest New Drugs 23(2): 147–155.

Haddad RI, LJ Weinstein, TJ Wieczorek, N Bhattacharya, H Raftopoulos, MW Oster, X Zhang, VM Latham Jr, R Costello, J Faucher, C DeRosa, M Yule, LP Miller, M Loda, MR Posner, GI Shapiro (2004) A phase Ii clinical and pharmacodynamic study of E7070 in patients with metastatic, recurrent, or refractory squamous cell carcinoma of the head and neck: modulation of retinoblastoma protein phosphorylation by a novel chloroindolyl sulfonamide cell cycle inhibitor. Clin Cancer Res 10(14): 4680–4687.

Herbst RS, AM Davies, RB Natale, TP Dang, JH Schiller, LL Garland, VA Miller, D Mendelson, AD Van den Abbeele, Y Melenevsky, DJ De Vries, DA Eberhard, B Lyons, SG Lutzker, BE Johnson (2007) Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non small cell lung cancer. Clin Cancer Res 13(20): 6175–6181.

Jansen B, V Wacheck, E Heere-Ress, H Schlagbauer-Wadl, C Hoeller, T Lucas, M Hoermann, U Hollenstein, K Wolff, H Pehamberger (2000) Chemosensitisation of malignant melanoma by Bcl2 antisense therapy. Lancet 356(9243): 1728–1733.

Jatoi A, VJ Suman, P Schaefer, M Block, C Loprinzi, P Roche, S Garneau, R Morton, PJ Stella, SR Alberts, M Pittelkow, J Sloan, R Pagano (2003) A phase Ii study of topical ceramides for cutaneous breast cancer. Breast Cancer Res Treat 80(1): 99–104.

Joensuu G, T Joensuu, P Nokisalmi, C Reddy, J Isola, M Ruutu, M Kouri, PA Kupelian, J Collan, S Pesonen, A Hemminki (2010) A phase I/Ii trial of gefitinib given concurrently with radiotherapy in patients with nonmetastatic prostate cancer. Int J Radiat Oncol Biol Phys 78(1): 42–49.

Koon HB, GJ Bubley, L Pantanowitz, D Masiello, B Smith, K Crosby, J Proper, W Weeden, TE Miller, P Chatis, MJ Egorin, SR Tahan, BJ Dezube (2005) Imatinib-induced regression of AIDS-related kaposi’s sarcoma. J Clin Oncol 23(5): 982–989.

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Lin J, J Gilbert, MA Rudek, JA Zwiebel, S Gore, A Jiemjit, M Zhao, SD Baker, RF Ambinder, JG Herman, RC Donehower, MA Carducci (2009) A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors. Clin Cancer Res 15(19): 6241–6249.

LoRusso PM, SS Krishnamurthi, JJ Rinehart, LM Nabell, L Malburg, PB Chapman, SE DePrimo, S Bentivegna, KD Wilner, W Tan, AD Ricart (2010) Phase I pharmacokinetic and pharmacodynamic study of the oral Mapk/Erk kinase inhibitor Pd-0325901 in patients with advanced cancers. Clin Cancer Res 16(6): 1924–1937.

Mackay H, D Hedley, P Major, C Townsley, M Mackenzie, M Vincent, P Degendorfer, MS Tsao, T Nicklee, D Birle, J Wright, L Siu, M Moore, A Oza (2005) A phase Ii trial with pharmacodynamic endpoints of the proteasome inhibitor bortezomib in patients with metastatic colorectal cancer. Clin Cancer Res 11(15): 5526–5533.

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Freeman, G., Kimmelman, J., Dancey, J. et al. Reporting practices of pharmacodynamic studies involving invasive research procedures in cancer trials. Br J Cancer 109, 897–908 (2013). https://doi.org/10.1038/bjc.2013.417

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