Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-76dd75c94c-5fx6p Total loading time: 0 Render date: 2024-04-30T08:24:03.453Z Has data issue: false hasContentIssue false

Chap 38 - MEDICAL ONCOLOGY OF SOFT TISSUE SARCOMAS

Published online by Cambridge University Press:  01 March 2011

By
Robert G. Maki
Edited by
Markku Miettinen
Markku Miettinen
Affiliation:
Armed Forces Institute of Pathology, Washington DC
Get access

Summary

Chemotherapy, that is, systemic agents whether classic cytotoxic agents or more specifically targeted agents, is used widely in the metastatic setting for patients with soft tissue sarcomas. Conversely, the use of chemotherapy in the adjuvant setting remains controversial, because the benefit for most sarcomas is small. Exceptions to this rule include rhabdomyosarcoma and Ewing sarcoma of soft tissue, in which adjuvant or neoadjuvant chemotherapy is a critical component of treatment in most patients. It is increasingly appreciated that systemic therapy must be tailored to the specific type of sarcoma being treated. In this respect, a working relationship with an expert sarcoma pathologist is paramount to the optimal treatment of the patients with primary or metastatic sarcoma. If chemotherapy is to have the same impact as radiation therapy and surgery in the management of sarcomas, effective drugs must be identified that help to improve the cure rate for patients with primary tumors and unseen microscopic metastatic disease for each specific sarcoma subtype. This section reviews the treatment of gastrointestinal stromal tumor (GIST), which has set a new paradigm for the treatment of solid tumors. Also discussed are the use of systemic chemotherapy in the adjuvant and metastatic settings for non-GIST sarcomas. Finally, a brief discussion of simultaneous chemotherapy and radiotherapy is included in this chapter.

GASTROINTESTINAL STROMAL TUMORS: A NEW MODEL FOR SOLID TUMOR CANCER THERAPY

GIST, if it can be considered a sarcoma at all, is the most common sarcoma subtype, and it can vary in size and clinical outcome from an incidental finding at operation to life-threatening metastatic disease.

Type
Chapter
Information
Modern Soft Tissue Pathology
Tumors and Non-Neoplastic Conditions
 , pp. 1070 - 1082
Publisher: Cambridge University Press
Print publication year: 2010

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

Gold, J., Zwan, et al S.. (2007). Outcome of Metastatic GIST in the Era beforeTyrosine Kinase Inhibitors. Ann Surg Oncol 14(1): 134–142.CrossRefGoogle ScholarPubMed
Verweij, J., Casali, et al P. G.. (2004). Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364(9440): 1127–1134.CrossRefGoogle ScholarPubMed
Demetri, G. D., Oosterom, et al A. T.. (2006). Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368(9544): 1329–1338.CrossRefGoogle ScholarPubMed
Heinrich, M. C., Corless, et al C. L.. (2003). Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21(23): 4342–4349.CrossRefGoogle ScholarPubMed
Eilber, F. C., Rosen, et al G.. (1999). Surgical resection and intraperitoneal chemotherapy for recurrent abdominal sarcomas. Ann Surg Oncol 6(7): 645–650.CrossRefGoogle ScholarPubMed
Corless, C. L., Schroeder, et al A.. (2005). PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23(23): 5357–5364.CrossRefGoogle ScholarPubMed
Shankar, S., vanSonnenberg, et al E.. (2005). Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. Radiology 235(3): 892–898.CrossRefGoogle ScholarPubMed
Antonescu, C. R., Besmer, et al P.. (2005). Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11(11): 4182–4190.CrossRefGoogle ScholarPubMed
Heinrich, M. C., Maki, et al R. G.. (2006). Sunitinib (SU) response in imatinib-resistant (IM-R) GIST correlates with KIT and PDGFRA mutation status. J Clin Oncol 24(18S): 9502.Google Scholar
Casali, P. G., Garrett, et al C. R.. (2006). Updated results from a phase III trial of sunitinib in GIST patients (pts) for whom imatinib (IM) therapy has failed due to resistance or intolerance. J Clin Oncol 24(18S): 9513.Google Scholar
Blay, J. Y., Bonvalot, et al S.. (2005). Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20–21 March 2004, under the auspices of ESMO. Ann Oncol 16(4): 566–578.CrossRefGoogle ScholarPubMed
Wardelmann, E., Merkelbach-Bruse, et al S.. (2006). Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12(6): 1743–1749.CrossRefGoogle ScholarPubMed
Wardelmann, E., Thomas, et al N.. (2005). Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations. Lancet Oncol 6(4): 249–51.CrossRefGoogle ScholarPubMed
DeMatteo, R. P., Maki, et al R. G.. (2007). Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor. Ann Surg 245(3): 347–352.CrossRefGoogle ScholarPubMed
DeMatteo, R., Owzar, et al K.. (2007). Adjuvant imatinib mesylate increases recurrence-free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup Phase III trial ACOSOG Z9001. J. Clin Oncol 25(18S): 10079.Google Scholar
DeMatteo, R. P., Antonescu, et al C. R.. (2005). Adjuvant imatinib mesylate in patients with primary high-risk gastrointestinal stromal tumor (GIST) following complete resection: Safety results from the U.S. Intergroup Phase II trial ACOSOG Z9000. J Clin Oncol 23(16S): 9009.CrossRefGoogle Scholar
,American College of Surgeons. (2006). Z9001 Synopsis. Retrieved September 1, 2006, from https://www.acosog.org/studies/synopses/Z9001_Synopsis.pdf.
Oosterom, A. T., Dumez, et al H.. (2004). Combination signal transduction inhibition: A phase I/II trial of the oral mTOR-inhibitor everolimus (E, RAD001) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM. J Clin Oncol 22(14S): 3002.CrossRefGoogle Scholar
Talpaz, M., Shah, et al N. P.. (2006). Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354(24): 2531–2541.CrossRefGoogle ScholarPubMed
Nakatani, H., Kobayashi, et al M.. (2005). STI571 (Glivec) inhibits the interaction between c-KIT and heat shock protein 90 of the gastrointestinal stromal tumor cell line, GIST-T1. Cancer Sci 96(2): 116–119.CrossRefGoogle ScholarPubMed
Brennan, M. F. (1996). The surgeon as a leader in cancer care: lessons learned from the study of soft tissue sarcoma. J Am Coll Surg 182(6): 520–529.Google Scholar
Rosenberg, S. A., Tepper, et al J.. (1982). The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 196(3): 305–315.CrossRefGoogle ScholarPubMed
,Sarcoma Meta-Analysis Collaboration. (1997). Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 350(9092): 1647–1654.CrossRefGoogle Scholar
Fisher, B., Gunduz, et al N.. (1983). Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res 43(4): 1488–1492.Google ScholarPubMed
Alvegard, T. A., Sigurdsson, et al H.. (1989). Adjuvant chemotherapy with doxorubicin in high-grade soft tissue sarcoma: a randomized trial of the Scandinavian Sarcoma Group. J Clin Oncol 7(10): 1504–1513.CrossRefGoogle ScholarPubMed
Bramwell, V., Rouesse, et al J.. (1994). Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma–reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 12(6): 1137–1149.CrossRefGoogle ScholarPubMed
Frustaci, S., Gherlinzoni, et al F.. (2001). Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol 19(5): 1238–1247.CrossRefGoogle ScholarPubMed
Frustaci, S., Paoli, et al A.. (2003). Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology 65 Suppl 2: 80–84.CrossRefGoogle Scholar
Petrioli, R., Coratti, et al A.. (2002). Adjuvant epirubicin with or without ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol 25(5): 468–473.CrossRefGoogle ScholarPubMed
Gortzak, E., Azzarelli, et al A.. (2001). A randomised phase II study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer 37(9): 1096–1103.CrossRefGoogle ScholarPubMed
Brodowicz, T., Schwameis, et al E.. (2000). Intensified adjuvant IFADIC chemotherapy for adult soft tissue sarcoma: A prospective randomized feasibility trial. Sarcoma 4: 151–160.CrossRefGoogle ScholarPubMed
Woll, P. J., Glabbeke, et al M.. (2007). Adjuvant chemotherapy with doxorubicin and ifosfamide in resected soft tissue sarcoma: interim analysis of a randomised phase III trial. J. Clin Oncol 25(18S): 10008 (abstract)Google Scholar
Kattan, M. W., Leung, et al D. H.. (2002). Postoperative nomogram for 12-year sarcoma-specific death. J Clin Oncol 20(3): 791–796.CrossRefGoogle ScholarPubMed
Eggermont, A. M., ten Hagen, T. L.. (2003). Tumor necrosis factor-based isolated limb perfusion for soft tissue sarcoma and melanoma: ten years of successful antivascular therapy. Curr Oncol Rep 5(2): 79–80.CrossRefGoogle ScholarPubMed
Bonvalot, S., Laplanche, et al A.. (2005). Limb salvage with isolated perfusion for soft tissue sarcoma: could less TNF-alpha be better?Ann Oncol 16(7): 1061–1068.CrossRefGoogle ScholarPubMed
Westermann, A. M., Wiedemann, et al G. J.. (2003). A Systemic Hyperthermia Oncologic Working Group trial. Ifosfamide, carboplatin, and etoposide combined with 41.8 degrees C whole-body hyperthermia for metastatic soft tissue sarcoma. Oncology 64(4): 312–321.CrossRefGoogle Scholar
DeLaney, T. F., Spiro, et al I. J.. (2003). Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 56(4): 1117–1127.CrossRefGoogle ScholarPubMed
O'Sullivan, B., Davis, et al A. M.. (2002). Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 359(9325): 2235–2241.CrossRefGoogle ScholarPubMed
Kraybill, W. G., Harris, et al J.. (2006). Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol 24(4): 619–625.CrossRefGoogle ScholarPubMed
O'Bryan, R. M., Luce, et al J. K.. (1973). Phase II evaluation of adriamycin in human neoplasia. Cancer 32(1): 1–8.3.0.CO;2-X>CrossRefGoogle ScholarPubMed
Lorigan, P., Verweij, et al J.. (2007). Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 25(21): 3144–3150.CrossRefGoogle ScholarPubMed
Judson, I., Radford, et al J. A.. (2001). Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 37(7): 870–877.CrossRefGoogle ScholarPubMed
Nielsen, O. S., Judson, et al I.. (2000). Effect of high-dose ifosfamide in advanced soft tissue sarcomas. A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 36(1): 61–67.CrossRefGoogle ScholarPubMed
Talbot, S. M., Keohan, et al M. L.. (2003). A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma. Cancer 98(9): 1942–1946.CrossRefGoogle ScholarPubMed
Patel, S. R., Gandhi, et al V.. (2001). Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 19(15): 3483–3489.CrossRefGoogle ScholarPubMed
Fayette, J., Coquard, et al I. R.. (2006). ET-743: a novel agent with activity in soft-tissue sarcomas. Curr Opin Oncol 18(4): 347–353.CrossRefGoogle ScholarPubMed
Grosso, F., Jones, et al R. L.. (2007). Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol 8(7): 595–602.CrossRefGoogle ScholarPubMed
Lanza, L. A., Putnam, Jr., et al J. B.. (1991). Response to chemotherapy does not predict survival after resection of sarcomatous pulmonary metastases. Ann Thorac Surg 51(2): 219–224.CrossRefGoogle Scholar
Elias, A., Ryan, et al L.. (1989). Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 7(9): 1208–1216.CrossRefGoogle ScholarPubMed
Antman, K., Crowley, et al J.. (1993). An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 11(7): 1276–1285.CrossRefGoogle ScholarPubMed
Hensley, M. L., Maki, et al R.. (2002). Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 20(12): 2824–2831.CrossRefGoogle ScholarPubMed
Leu, K. M., Ostruszka, et al L. J.. (2004). Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol 22(9): 1706–1712.CrossRefGoogle ScholarPubMed
Bay, J. O., Ray-Coquard, et al I.. (2006). Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis. Int J Cancer 119(3): 706–711.CrossRefGoogle ScholarPubMed
Maki, R. G., Wathen, et al J. K.. (2007). Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas. J Clin Oncol 25(19): 2755–2763.CrossRefGoogle ScholarPubMed
Seynaeve, C., Verweij, J.. (1999). High-dose chemotherapy in adult sarcomas: no standard yet. Semin Oncol 26(1): 119–133.Google ScholarPubMed
Deyrup, A. T., Weiss, S. W.. (2006). Grading of soft tissue sarcomas: the challenge of providing precise information in an imprecise world. Histopathology 48(1): 42–50.CrossRefGoogle Scholar
Fong, Y., Coit, et al D. G.. (1993). Lymph node metastasis from soft tissue sarcoma in adults. Analysis of data from a prospective database of 1772 sarcoma patients. Ann Surg 217(1): 72–77.CrossRefGoogle ScholarPubMed
Casper, E. S., Waltzman, et al R. J.. (1998). Phase II trial of paclitaxel in patients with soft-tissue sarcoma. Cancer Invest 16(7): 442–446.CrossRefGoogle ScholarPubMed
Fury, M. G., Antonescu, et al C. R.. (2005). A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy. Cancer J 11(3): 241–247.CrossRefGoogle ScholarPubMed
Weiss, S. W., Enzinger, F. M.. (1982). Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 50(5): 970–981.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
D'Adamo, D. R., Keohan, et al M.. (2007). Clinical results of a phase II study of sorafenib in patients (pts) with non-GIST sarcomas (CTEP study #7060). J Clin Oncol 25(18S): 10001.Google Scholar
Sutton, G., Brunetto, et al V. L.. (2000). A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol 79(2): 147–153.CrossRefGoogle ScholarPubMed
Wolfson, A. H., Brady, et al M. F.. (2006). Gynecologic Oncology Group randomized trial of whole abdominal irradiation vs cisplatin-ifosfamide+mesna in optimally debulked stage I-IV carcinosarcoma of the uterus. J Clin Oncol 24(18S): 5001.Google Scholar
Keen, C. E., Philip, G.. (1989). Progestogen-induced regression in low-grade endometrial stromal sarcoma. Case report and literature review. Br J Obstet Gynaecol 96(12): 1435–1439.CrossRefGoogle ScholarPubMed
Wade, K., Quinn, et al M. A.. (1990). Uterine sarcoma: steroid receptors and response to hormonal therapy. Gynecol Oncol 39(3): 364–367.CrossRefGoogle ScholarPubMed
Goorin, A. M., Schwartzentruber, et al D. J.. (2003). Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 21(8): 1574–1580.CrossRefGoogle ScholarPubMed
Grier, H. E., Krailo, et al M. D.. (2003). Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348(8): 694–701.CrossRefGoogle ScholarPubMed
Bane, B. L., Evans, et al H. L.. (1990). Extraskeletal osteosarcoma: A clinicopathologic review of 26 cases. Cancer 65(12): 2762–70.3.0.CO;2-K>CrossRefGoogle ScholarPubMed
Crist, W. M., Anderson, et al J. R.. (2001). Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19(12): 3091–3102.CrossRefGoogle ScholarPubMed
Spear, M. A., Jennings, et al L. C.. (1998). Individualizing management of aggressive fibromatoses. Int J Radiat Oncol Biol Phys 40(3): 637–645.CrossRefGoogle ScholarPubMed
Ballo, M. T., Zagars, et al G. K.. (1998). Radiation therapy in the management of desmoid tumors. Int J Radiat Oncol Biol Phys 42(5): 1007–1014.CrossRefGoogle ScholarPubMed
Lev, D., Kotilingam, et al D.. (2007). Optimizing treatment of desmoid tumors. J Clin Oncol 25(13): 1785–1791.CrossRefGoogle ScholarPubMed
Deyrup, A. T., Tretiakova, et al M.. (2006). Estrogen receptor-beta expression in extraabdominal fibromatoses: an analysis of 40 cases. Cancer 106(1): 208–213.CrossRefGoogle ScholarPubMed
Patel, S. R., Evans, et al H. L.. (1993). Combination chemotherapy in adult desmoid tumors. Cancer 72(11): 3244–3247.3.0.CO;2-D>CrossRefGoogle ScholarPubMed
Patel, S. R. and Benjamin, R. S. (2006). Desmoid tumors respond to chemotherapy: defying the dogma in oncology. J Clin Oncol 24(1): 11–12.CrossRefGoogle Scholar
Seiter, K., Kemeny, N.. (1993). Successful treatment of a desmoid tumor with doxorubicin. Cancer 71(7): 2242–2244.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
Weiss, A. J., Horowitz, et al S.. (1999). Therapy of desmoid tumors and fibromatosis using vinorelbine. Am J Clin Oncol 22(2): 193–195.CrossRefGoogle ScholarPubMed
Chugh, R., Maki, et al R. G.. (2006). A SARC phase II multicenter trial of imatinib mesylate (IM) in patients with aggressive fibromatosis. J Clin Oncol 24(18S): 9515.Google Scholar
Heinrich, M. C., McArthur, et al G. A.. (2006). Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). J Clin Oncol 24(7): 1195–1203.CrossRefGoogle Scholar
Bauer, S., Yu, et al L. K.. (2006). Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res 66(18): 9153–9161.CrossRefGoogle ScholarPubMed
Sambol, E. B., Ambrosini, et al G.. (2006). Flavopiridol targets c-KIT transcription and induces apoptosis in gastrointestinal stromal tumor cells. Cancer Res 66(11): 5858–5866.CrossRefGoogle ScholarPubMed
Hosoi, H., Dilling, et al M. B.. (1999). Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res 59(4): 886–894.Google ScholarPubMed
LeRoith, D., Helman, L. (2004). The new kid on the block(ade) of the IGF-1 receptor. Cancer Cell 5(3): 201–202.CrossRefGoogle ScholarPubMed
Wan, X., Harkavy, et al B.. (2007). Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26(13): 1932–1940.CrossRefGoogle ScholarPubMed
Gregory, R. I., Yan, et al K. P.. (2004). The microprocessor complex mediates the genesis of microRNAs. Nature 432(7014): 235–240.CrossRefGoogle ScholarPubMed
Welch, E. M., Barton, et al E. R.. (2007). PTC124 targets genetic disorders caused by nonsense mutations. Nature 447(7140): 87–91.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
×