Skip to main content Accessibility help
×
Hostname: page-component-76fb5796d-vfjqv Total loading time: 0 Render date: 2024-04-29T23:45:32.846Z Has data issue: false hasContentIssue false

2 - Pathophysiology of malignant bone pain

from SECTION I - MECHANISMS AND EPIDEMIOLOGY

Published online by Cambridge University Press:  06 July 2010

JUAN MIGUEL JIMENEZ-ANDRADE
Affiliation:
University of Arizona
MONICA HERRERA
Affiliation:
University of Arizona
PATRICK MANTYH
Affiliation:
University of Arizona
Eduardo D. Bruera
Affiliation:
University of Texas, Houston
Russell K. Portenoy
Affiliation:
Albert Einstein College of Medicine, New York
Get access

Summary

Introduction

Currently, more than 10 million people are diagnosed with cancer every year, and by 2020, it is estimated that 20 million new cases will be diagnosed each year. In 2005, cancer caused 7.6 million deaths worldwide. In the United States, cancer is a major health problem, being the second leading cause of death. Currently, 25% of U.S. deaths are cancer related.

Cancer-associated pain may be present at any time during the course of the disease, but the frequency and intensity of cancer pain tend to increase with advancing stages of cancer. In patients with advanced cancer, 62%–86% experience significant pain, which is described as moderate to severe in approximately 40%–50% and as very severe in 25%–30%. Bone cancer pain is the most common pain in patients with advanced cancer; two thirds of patients with metastatic bone disease experience severe pain. Most common tumors, including those of the breast, prostate, thyroid, kidney, and lung, have a remarkable affinity to metastasize to bone.

Currently, the factors that drive bone cancer pain are poorly understood; however, several recently introduced models of bone cancer pain not only are providing insight into the mechanisms that drive bone cancer pain, but are guiding the development of novel mechanism-based therapies to treat the pain and skeletal remodeling that accompany metastatic bone cancer. As analgesics can also influence disease progression, findings from these studies may lead to therapies that have the potential to improve the quality of life and survival of patients with skeletal malignancies.

Type
Chapter
Information
Cancer Pain
Assessment and Management
, pp. 23 - 34
Publisher: Cambridge University Press
Print publication year: 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Stewart, BW, Kleihues, P. World Cancer Report. 2003. International Agency for Research on Cancer Press. Lyon, France. pp 11–19.Google Scholar
Brennan, F, Carr, DB, Cousins, M. Pain management: a fundamental human right. Anesth Analg 105:205–21, 2007.CrossRefGoogle ScholarPubMed
World Health Organization. Cancer. Web Page: http://www.who.int./cancer. Accessed on March, 9, 2009.
Jemal, A, Siegel, R, Ward, E, et al. Cancer statistics, 2007. CA Cancer J Clin 57:43–66, 2007.CrossRefGoogle ScholarPubMed
Beuken-van Everdingen, M, Rijke, J, Kessels, A, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 18:1437–49, 2007.CrossRefGoogle ScholarPubMed
Mercadante, S, Fulfaro, F. Management of painful bone metastases. Curr Opin Oncol 19:308–14, 2007.CrossRefGoogle ScholarPubMed
Coleman, RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 12:6243s–6249s, 2006.CrossRefGoogle ScholarPubMed
Coleman, RE. Skeletal complications of malignancy. Cancer 80:1588–94, 1997.3.0.CO;2-G>CrossRefGoogle Scholar
Mercadante, S.Malignant bone pain: pathophysiology and treatment. Pain 69:1–18, 1997.CrossRefGoogle ScholarPubMed
Mercadante, S, Arcuri, E. Breakthrough pain in cancer patients: pathophysiology and treatment. Cancer Treat Rev 24:425–32, 1998.CrossRefGoogle ScholarPubMed
Cherny, N.New strategies in opioid therapy for cancer pain. J Oncol Manag 9:8–15, 2000.Google ScholarPubMed
Hanks, GW, Conno, F, Cherny, N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 84:587–93, 2001.CrossRefGoogle ScholarPubMed
Portenoy, RK, Lesage, P. Management of cancer pain. Lancet 353:1695–700, 1999.CrossRefGoogle ScholarPubMed
Foley, KM. Misconceptions and controversies regarding the use of opioids in cancer pain. Anticancer drugs 6:4–13, 1995.CrossRefGoogle ScholarPubMed
Weber, M, Huber, C. Documentation of severe pain, opioid doses, and opioid-related side effects in outpatients with cancer: a retrospective study. J Pain Symptom Manage 17:49–54, 1999.CrossRefGoogle ScholarPubMed
Storey, JA, Torti, FM. Bone metastases in prostate cancer: a targeted approach. Curr Opin Oncol 19:254–8, 2007.CrossRefGoogle ScholarPubMed
Jemal, A, Murray, T, Ward, E, et al. Cancer statistics, 2005. CA Cancer J Clin 55:10–30, 2005.CrossRefGoogle ScholarPubMed
Guise, TA. Parathyroid hormone-related protein and bone metastases. Cancer 80:1572–80, 1997.3.0.CO;2-M>CrossRefGoogle ScholarPubMed
Halvorson, KG, Kubota, K, Sevcik, MA, et al. A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone. Cancer Res 65:9426–35, 2005.CrossRefGoogle ScholarPubMed
Honore, P, Rogers, SD, Schwei, MJ, et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 98:585–98, 2000.CrossRefGoogle ScholarPubMed
Sabino, MA, Ghilardi, JR, Jongen, JL, et al. Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2. Cancer Res 62:7343–9, 2002.Google ScholarPubMed
Schwei, MJ, Honore, P, Rogers, SD, et al. Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci 19:10886–97, 1999.CrossRefGoogle Scholar
Body, JJ. Metastatic bone disease: clinical and therapeutic aspects. Bone 13:S57–62, 1992.CrossRefGoogle ScholarPubMed
Peters, CM, Ghilardi, JR, Keyser, CP, et al. Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. Exp Neurol 193:85–100, 2005.CrossRefGoogle ScholarPubMed
Boyce, BF, Yoneda, T, Guise, TA. Factors regulating the growth of metastatic cancer in bone. Endocr Relat Cancer 6:333–47, 1999.CrossRefGoogle Scholar
Asmus, SE, Parsons, S, Landis, SC. Developmental changes in the transmitter properties of sympathetic neurons that innervate the periosteum. J Neurosci 20:1495–504, 2000.CrossRefGoogle ScholarPubMed
Bjurholm, A.Neuroendocrine peptides in bone. Int Orthop 15:325–9, 1991.CrossRefGoogle ScholarPubMed
Hukkanen, M, Konttinen, YT, Rees, RG, et al. Innervation of bone from healthy and arthritic rats by substance P and calcitonin gene related peptide containing sensory fibers. J Rheumatol 19:1252–9, 1992.Google ScholarPubMed
Mach, DB, Rogers, SD, Sabino, MC, et al. Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience 113:155–66, 2002.CrossRefGoogle ScholarPubMed
Bjurholm, A, Kreicbergs, A, Brodin, E, et al. Substance P- and CGRP-immunoreactive nerves in bone. Peptides 9:165–71, 1988.CrossRefGoogle ScholarPubMed
Bjurholm, A, Kreicbergs, A, Terenius, L, et al. Neuropeptide Y-, tyrosine hydroxylase- and vasoactive intestinal polypeptide-immunoreactive nerves in bone and surrounding tissues. J Auton Nerv Syst 25:119–25, 1988.CrossRefGoogle ScholarPubMed
Tabarowski, Z, Gibson-Berry, K, Felten, SY. Noradrenergic and peptidergic innervation of the mouse femur bone marrow. Acta Histochem 98:453–7, 1996.CrossRefGoogle ScholarPubMed
Tsujino, H, Kondo, E, Fukuoka, T, et al. Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: a novel neuronal marker of nerve injury. Mol Cell Neurosci 15:170–82, 2000.CrossRefGoogle ScholarPubMed
Honore, P, Luger, N, Sabino, M, et al. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med 6: 521–8, 2000.Google ScholarPubMed
Sevcik, MA, Ghilardi, JR, Peters, CM, et al. Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization. Pain 115:128–41, 2005.CrossRefGoogle ScholarPubMed
Ghilardi, JR, Rohrich, H, Lindsay, TH, et al. Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain. J Neurosci 25:3126–31, 2005.CrossRefGoogle ScholarPubMed
Obata, K, Yamanaka, H, Fukuoka, T, et al. Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats. Pain 101:65–77, 2003.CrossRefGoogle ScholarPubMed
Luger, NM, Honore, P, Sabino, MA, et al. Osteoprotegerin diminishes advanced bone cancer pain. Cancer Res 61:4038–47, 2001.Google ScholarPubMed
Delaisse, JM, Vaes, G. Mechanism of mineral solubilization and matrix degradation in osteoclastic bone resorption. In: Rifkin, BR, Gay, CV, eds. Biology and physiology of the osteoclast. Ann Arbor: CRC, 1992, pp 289–314.Google Scholar
Clohisy, DR, Perkins, SL, Ramnaraine, ML. Review of cellular mechanisms of tumor osteolysis. Clin Orthop Rel Res 373:104–14, 2000.CrossRefGoogle Scholar
Berenson, JR, Rosen, LS, Howell, A, et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 91:1191–200, 2001.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
Fulfaro, F, Casuccio, A, Ticozzi, C, et al. The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials. Pain 78:157–69, 1998.CrossRefGoogle ScholarPubMed
Major, PP, Lipton, A, Berenson, J, et al. Oral bisphosphonates: a review of clinical use in patients with bone metastases. Cancer 88:6–14, 2000.3.0.CO;2-D>CrossRefGoogle ScholarPubMed
Horton, A, Nesbitt, S, Bennett, J, et al. Integrins and other cell surface attachment molecules of bone cells. In: Bilezikian, JP, Raisz, LG, Rodan, GA, eds. Principles of bone biology. New York: Academic Press, 2002, pp 265–86.CrossRefGoogle Scholar
Simonet, WS, Lacey, DL, Dunstan, CR, et al. Osteoprotegerin – a novel secreted protein involved in the regulation of bone density. Cell 89:309–19, 1997.CrossRefGoogle ScholarPubMed
Anderson, DM, Maraskovsky, E, Billingsley, WL, et al. A homologue of the Tnf receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390:175–9, 1997.CrossRefGoogle ScholarPubMed
Yasuda, H, Shima, N, Nakagawa, N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 95:3597–602, 1998.CrossRefGoogle ScholarPubMed
Rodan, GA, Martin, TJ. Therapeutic approaches to bone diseases. Science 289:1508–14, 2000.CrossRefGoogle ScholarPubMed
Sutherland, S, Cook, S, McCleskey, EW. Chemical mediators of pain due to tissue damage and ischemia. Prog Brain Res 129:21–38, 2000.CrossRefGoogle ScholarPubMed
Woolf, CJ, American College of Physicians, American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 140:441–51, 2004.CrossRefGoogle ScholarPubMed
Olson, TH, Riedl, MS, Vulchanova, L, et al. An acid sensing ion channel (ASIC) localizes to small primary afferent neurons in rats. Neuroreport 9:1109–13, 1998.CrossRefGoogle ScholarPubMed
Julius, D, Basbaum, AI. Molecular mechanisms of nociception. Nature 413:203–10, 2001.CrossRefGoogle ScholarPubMed
Caterina, MJ, Schumacher, MA, Tominaga, M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–24, 1997.Google ScholarPubMed
Tominaga, M, Caterina, MJ, Malmberg, AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–43, 1998.CrossRefGoogle ScholarPubMed
Bassilana, F, Champigny, G, Waldmann, R, et al. The acid-sensitive ionic channel subunit ASIC and the mammalian degenerin MDEG form a heteromultimeric H+-gated Na+ channel with novel properties. J Biol Chem 272:28819–22, 1997.CrossRefGoogle Scholar
Griffiths, R.Are cancer cells acidic?Br J Cancer 64:425–7, 1991.CrossRefGoogle ScholarPubMed
Deigner, HP, Kinscherf, R. Modulating apoptosis: current applications and prospects for future drug development. Curr Med Chem 6:399–414, 1999.Google ScholarPubMed
Niiyama, Y, Kawamata, T, Yamamoto, J, et al. Bone cancer increases transient receptor potential vanilloid subfamily 1 expression within distinct subpopulations of dorsal root ganglion neurons. Neuroscience 148:560–72, 2007.CrossRefGoogle ScholarPubMed
Galasko, CS. Diagnosis of skeletal metastases and assessment of response to treatment. Clin Orthop Rel Res (312):64–75, 1995.Google Scholar
Nielsen, OS, Munro, AJ, Tannock, IF. Bone metastases: pathophysiology and management policy. J Clin Oncol 9:509–24, 1991.CrossRefGoogle ScholarPubMed
DeLeo, JA, Yezierski, RP. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 90:1–6, 2001.CrossRefGoogle ScholarPubMed
Watkins, LR, Maier, SF, Goehler, . Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain 63:289–302, 1995.CrossRefGoogle ScholarPubMed
Watkins, LR, Maier, SF. Implications of immune-to-brain communication for sickness and pain. Proc Natl Acad Sci U S A 96:7710–13, 1999.CrossRefGoogle ScholarPubMed
Nadler, RB, Koch, AE, Calhoun, EA, et al. IL-1beta and TNF-alpha in prostatic secretions are indicators in the evaluation of men with chronic prostatitis. J Urol 164:214–18, 2000.CrossRefGoogle ScholarPubMed
, Davar G.Endothelin-1 and metastatic cancer pain. Pain Med 2:24–7, 2001.CrossRefGoogle Scholar
Nelson, JB, Carducci, MA. The role of endothelin-1 and endothelin receptor antagonists in prostate cancer. BJU Int 85:45–8, 2000.CrossRefGoogle ScholarPubMed
Opree, A, Kress, M. Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heat-evoked calcitonin gene-related peptide release from rat skin. J Neurosci 20:6289–93, 2000.CrossRefGoogle Scholar
Watkins, LR, Goehler, , Relton, J, et al. Mechanisms of tumor necrosis factor-alpha (Tnf-alpha) hyperalgesia. Brain Res 692:244–50, 1995.CrossRefGoogle ScholarPubMed
Stoscheck, CM, King, Jr. Role of epidermal growth factor in carcinogenesis. Cancer Res 46:1030–7, 1986.Google ScholarPubMed
Poon, RT, Fan, ST, Wong, J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19:1207–25, 2001.CrossRefGoogle ScholarPubMed
Roman, C, Saha, D, Beauchamp, R. TGF-beta and colorectal carcinogenesis. Microsc Res Tech 52:450–7, 2001.3.0.CO;2-O>CrossRefGoogle ScholarPubMed
Silver, BJ. Platelet-derived growth factor in human malignancy. Biofactors 3:217–27, 1992.Google ScholarPubMed
Daughaday, WH, Deuel, TF. Tumor secretion of growth factors. Endocrinol Metab Clin North Am 20:539–63, 1991.Google ScholarPubMed
Radinsky, R.Growth factors and their receptors in metastasis. Semin Cancer Biol 2:169–77, 1991.Google Scholar
Shappell, SB, Manning, S, Boeglin, WE, et al. Alterations in lipoxygenase and cyclooxygenase-2 catalytic activity and mRNA expression in prostate carcinoma. Neoplasia 3:287–303, 2001.CrossRefGoogle ScholarPubMed
Kundu, N, Yang, QY, Dorsey, R, et al. Increased cyclooxygenase-2 (cox-2) expression and activity in a murine model of metastatic breast cancer. International J Cancer 93:681–6, 2001.CrossRefGoogle Scholar
Ohno, R, Yoshinaga, K, Fujita, T, et al. Depth of invasion parallels increased cyclooxygenase-2 levels in patients with gastric carcinoma. Cancer 91:1876–81, 2001.3.0.CO;2-H>CrossRefGoogle ScholarPubMed
Molina, MA, Sitja-Arnau, M, Lemoine, MG, et al. Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res 59:4356–62, 1999.Google ScholarPubMed
Dubois, RN, Radhika, A, Reddy, BS, et al. Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors. Gastroenterology 110:1259–62, 1996.CrossRefGoogle ScholarPubMed
Vasko, MR. Prostaglandin-induced neuropeptide release from spinal cord. Prog Brain Res 104:367–80, 1995.CrossRefGoogle ScholarPubMed
Sonoshita, M, Takaku, K, Sasaki, N, et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice. Nat Med 7:1048–51, 2001.CrossRefGoogle ScholarPubMed
Sheng, H, Shao, J, Kirkland, SC, et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest 99:2254–9, 1997.CrossRefGoogle ScholarPubMed
Williams, CS, Tsujii, M, Reese, J, et al. Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 105:1589–94, 2000.CrossRefGoogle ScholarPubMed
Masferrer, JL, Leahy, KM, Koki, AT, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–11, 2000.Google ScholarPubMed
Harris, RE, Alshafie, GA, Abou-Issa, H, et al. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res 60:2101–3, 2000.Google ScholarPubMed
Reddy, BS, Hirose, Y, Lubet, R, et al. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res 60:293–7, 2000.Google ScholarPubMed
Lal, G, Ash, C, Hay, K, et al. Suppression of intestinal polyps in Msh2-deficient and non-Msh2-deficient multiple intestinal neoplasia mice by a specific cyclooxygenase-2 inhibitor and by a dual cyclooxygenase-1/2 inhibitor. Cancer Res 61:6131–6, 2001.Google ScholarPubMed
Nelson, JB, Hedican, SP, George, DJ, et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nature Med 1:944–9, 1995.CrossRefGoogle ScholarPubMed
Pomonis, JD, Rogers, SD, Peters, CM, et al. Expression and localization of endothelin receptors: implication for the involvement of peripheral glia in nociception. J Neurosci 21:999–1006, 2001.CrossRefGoogle Scholar
Davar, G, Hans, G, Fareed, MU, et al. Behavioral signs of acute pain produced by application of endothelin-1 to rat sciatic nerve. Neuroreport 9:2279–83, 1998.CrossRefGoogle ScholarPubMed
Dawas, K, Laizidou, M, Shankar, A, et al. Angiogenesis in cancer: the role of endothelin-1. Ann R Coll Surg Engl 81:306–10, 1999.Google ScholarPubMed
Asham, EH, Loizidou, M, Taylor, I. Endothelin-1 and tumour development. Eur J Surg Oncol 24:57–60, 1998.CrossRefGoogle ScholarPubMed
Peters, CM, Lindsay, TH, Pomonis, JD, et al. Endothelin and the tumorigenic component of bone cancer pain. Neuroscience 126:1043–52, 2004.CrossRefGoogle ScholarPubMed
Couture, R, Harrisson, M, Vianna, RM, et al. Kinin receptors in pain and inflammation. Eur J Pharmacol 429:161–76, 2001.CrossRefGoogle ScholarPubMed
Fox, A, Wotherspoon, G, McNair, K, et al. Regulation and function of spinal and peripheral neuronal B1 bradykinin receptors in inflammatory mechanical hyperalgesia. Pain 104:683–91, 2003.CrossRefGoogle ScholarPubMed
Sevcik, MA, Ghilardi, JR, Halvorson, KG, et al. Analgesic efficacy of bradykinin B1 antagonists in a murine bone cancer pain model. J Pain 6:771–5, 2005.CrossRefGoogle Scholar
Hefti, FF, Rosenthal, A, Walicke, PA, et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci 27:85–91, 2006.CrossRefGoogle ScholarPubMed
Pezet, S, McMahon, SB. Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci 29:507–38, 2006.CrossRefGoogle Scholar
Gould, HJ 3rd, Gould, TN, England, JD, et al. A possible role for nerve growth factor in the augmentation of sodium channels in models of chronic pain. Brain Res 854:19–29, 2000.CrossRefGoogle ScholarPubMed
Ji, RR, Samad, TA, Jin, SX, et al. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36:57–68, 2002.CrossRefGoogle ScholarPubMed
Heumann, R, Korsching, S, Bandtlow, C, et al. Changes of nerve growth factor synthesis in nonneuronal cells in response to sciatic nerve transection. J Cell Biol 104:1623–31, 1987.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×