Abstract
Combining concurrent radiation with platinum compounds has been the subject of both preclinical and clinical cancer research for over two decades. The property of platinum to enhance the effect of radiation on a variety of tumors has been successfully translated to the treatment of head and neck, non-small cell lung (NSCLC), and cervical cancer.
Several molecular pathways accounting for the mechanisms of radiation potentia-tion and sensitization have been described. Platinums create DNA adducts causing cross links which eventually lead to double strand DNA breaks. Such damage to the DNA triggers the cellular mismatch repair (MMR) apparatus, leading to cell cycle arrest and apoptosis. This pathway can be harnessed to enhance radiotherapy by targeting the subset of hypoxic tumor cells, resistant to the traditional effects of radiation.
Noticeably, in tumors with either a genetic defect or a gene rendered nonfunctional due to promoter hyper-methylation in the MMR pathway, resistance to both chemotherapies and ionizing radiation occurs. Concurrent administration of both modalities though, has shown to overcome this form of resistance. The mechanism underlying the combined effects includes platinum interference with repair mechanisms of sub lethal radiation damage to DNA and radiation potentiation of the effects of platinum by enhancing uptake and binding to DNA.
Experience from the clinic suggests that many variables govern the success of the combination. Specifically, the kind of platinum compound chosen and its dosing and scheduling during radiotherapy varies among tumor sites. The more manageable toxicity profile of carboplatin makes it a particularly attractive candidate for combined modality treatments. In a phase III CALBG and ECOG study, 283 patients with unresectable stage III NSCLC received radiosensitization with carboplatin. Complete Response (CR) rate was 18% in the chemo-radiation arm vs. 10% in the radiation-only arm, without significant difference detected in the 4-year survival rates (13% vs. 10%). Conversely, in cervical cancer the combination of carboplatin and radiotherapy resulted in a survival improvement compared to other chemoradiation regimes.
A better insight of the genomics and biology of cancer will soon provide clinicians with the necessary rationale to devise multimodality protocols that target individual tumor pathways of resistance. Combinations of platinum agents with ionizing radiation could then be selectively offered to carriers of cancers with genetic and pheno-typic characteristics that make them more likely to be vulnerable to this approach.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Sharp SY, Rogers PM, Kelland LR. Transport of cisplatin and bis-acetato-ammine-dichlorocyclohexylamine Platinum(IV) (JM216) in human ovarian carcinoma cell lines: identification of a plasma membrane protein associated with cisplatin resistance. Clin Cancer Res 1995;1:981–9.
Shen DW, Goldenberg S, Pastan I, Gottesman MM. Decreased accumulation of [14C]carbo-platin in human cisplatin-resistant cells results from reduced energy-dependent uptake. J Cell Physiol 2000;183:108–16.
Gately, DP, SB Howell. Cellular accumulation of the anticancer agent cisplatin: a review. Br J Cancer 1993;67:1171–6.
Kondo Y, Kuo SM, Watkins SC, Lazo JS. Metallothionein localization and cisplatin resistance in human hormone-independent prostatic tumor cell lines. Cancer Res 1995;55:474–7.
Perego P, Righetti SC, Supino R et al. Role of apoptosis and apoptosis-related proteins in the cisplatin-resistant phenotype of human tumor cell lines. Apoptosis 1997;2:540–8.
Pestell KE, Medlow CJ, Titley JC, Kelland LR, Walton MI. Effect of p53 status on sensitivity to platinum complexes in a human ovarian cancer cell line. Mol Pharmacol 2000;57:503–11.
Fink D, Nebel S, Aebi S, et al. The role of DNA mismatch repair in platinum drug resistance. Cancer Res 1996;56:4881–6.
Lage H, Dietel M. Involvement of the DNA mismatch repair system in antineoplastic drug resistance. J Cancer Res Clin Oncol 1999;125:156–65.
Perego P, Zunino F, Carenini N, et al. Sensitivity to cisplatin and platinum-containing compounds of Schizosaccharomyces pombe rad mutants. Mol Pharmacol 1998;54:213–9.
Richmond RC, Khokhar AR, Teicher BA, Douple EB. Toxic variability and radiation sensiti-zation by Pt(II) analogs in Salmonella typhimuriumcells. Radiat Res 1984;99:609–26.
Yang LX, Douple EB, Wang HJ. Irradiation enhances cellular uptake of carboplatin. Int J Radiat Oncol Biol Phys 1995;33:641–6.
Servidei T, Ferlini C, Riccardi A, et al. The novel trinuclear platinum complex BBR3464 induces a cellular response different from cisplatin. Eur J Cancer 2001;37:930–8.
Moreland NJ, Illand M, Kim YT, Paul J, Brown R. Modulation of drug resistance mediated by loss of mismatch repair by the DNA polymerase inhibitor aphidicolin. Cancer Res 1999;59:2102–6.
Steel GG, Peckham MJ. Exploitable mechanisms in combined radiotherapy-chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys 1979;5:85–91.
Overgaard J, Khan AR. Selective enhancement of radiation response in a C3H mammary carcinoma by cisplatin. Cancer Treat Rep 1981;65:501–3.
Wodinsky I, Swiniarski J, Kensler CJ, Venditti JM.Combination radiotherapy and chemotherapy for P388 lymphocytic leukemia in vivo. Cancer Chemother Rep 2 1974;4:73–97.
Richmond RC, Zimbrick JD, Hykes DL. Radiation-induced DNA damage and lethality in E. colias modified by the antitumor agent cis-dichlorodiammineplatinum (II). Radiat Res 1977;71:447–60.
Richmond RC, Powers EL. Radiation sensitization of bacterial spores by cis-dichloro-diammineplatinum(II). Radiat Res 1976;68:251–7.
Dritschilo A, Piro AJ, Kelman AD. The effect of cis-platinum on the repair of radiation damage in plateau phase Chinese hamster (V-79) cells. Int J Radiat Oncol Biol Phys 1979;5:1345–9.
Stratford IJ, Williamson C, Adams GE. Combination studies with misonidazole and a cis-platinum complex: cytotoxicity and radiosensitization in vitro. Br J Cancer 1980;41:517–22.
Dewit L. Combined treatment of radiation and cisdiamminedichloroplatinum (II): a review of experimental and clinical data. Int J Radiat Oncol Biol Phys 1987;13:403–26.
Szumiel I, Nias AH. The effect of combined treatment with a platinum complex and ionizing radiation on chinese hamster ovary cells in vitro. Br J Cancer 1976; 33:450–8.
Douple EB, Richmond RC. Enhancement of the potentiation of radiotherapy by platinum drugs in a mouse tumor. Int J Radiat Oncol Biol Phys 1982;8:501–3.
Muggia FM, Rozencweig M, Louie AE. Role of chemotherapy in head and neck cancer: systemic use of single agents and combinations in advanced disease. Head Neck Surg 1980;2: 196–205.
Wittes R, Heller K, Randolph V, et al. Cis-Dichlorodiammineplatinum(II)-based chemotherapy as initial treatment of advanced head and neck cancer. Cancer Treat Rep 1979;63:1533–8.
Eisenberger M, Hornedo J, Silva H, Donehower R, Spaulding M, Van Echo D. Carboplatin (NSC-241–240): an active platinum analog for the treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol 1986;4:1506–9.
Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355:949–55.
Amrein PC, Weitzman SA. Treatment of squamous-cell carcinoma of the head and neck with cisplatin and 5-fluorouracil. J Clin Oncol 1985;3:1632–9.
Kish JA, Weaver A, Jacobs J, Cummings G, Al-Sarraf M. Cisplatin and 5-fluorouracil infusion in patients with recurrent and disseminated epidermoid cancer of the head and neck. Cancer 1984;53:1819–24.
Wendt TG, Hartenstein RC, Wustrow TP, Lissner J. Cisplatin, fluorouracil with leucovorin calcium enhancement, and synchronous accelerated radiotherapy in the management of locally advanced head and neck cancer: a phase II study. J Clin Oncol 1989;7:471–6.
Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999;91:2081–6.
Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluor-ouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest oncology group study. J Clin Oncol 1992;10: 1245–51.
Jacobs C, Lyman G, Velez-GarcÃa E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992;10:257–63.
Schrijvers D, Vermorken JB. Taxanes in the treatment of head and neck cancer. Curr Opin Oncol 2005;17:218–24.
Clark JI, Hofmeister C, Choudhury A, et al. Phase II evaluation of paclitaxel in combination with carboplatin in advanced head and neck carcinoma. Cancer 2001;92:2334–40.
Basaran M, Bavbek SE, Güllü I, et al. A phase II study of paclitaxel and cisplatin combination chemotherapy in recurrent or metastatic head and neck cancer. J Chemother 2002;14:207–13.
Cmelak AJ, Murphy BA, Burkey B, Douglas S, Shyr Y, Netterville J. Taxane-based chem-oirradiation for organ preservation with locally advanced head and neck cancer: results of a phase II multi-institutional trial. Head Neck 2007;29:315–24.
Chougule PB, Akhtar MS, Rathore R, et al. Concurrent chemoradiotherapy with weekly paclitaxel and carboplatin for locally advanced head and neck cancer: long-term follow-up of a brown university oncology group phase II study (HN-53). Head Neck 2008;30:289–96.
El-Sharouni S Y, Kal HB, Battermann JJ, Schramel FM. Sequential versus concurrent chemo-radiotherapy in inoperable stage III non-small cell lung cancer. Anticancer Res 2006;26:495–505.
Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cispla-tin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a gynecologic oncology group and Southwest oncology group study. J Clin Oncol 1999;17:1339–48.
Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137–43.
Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–53.
Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–61.
Peters WA III, Liu PY, Barrett RJ II, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606–13.
Pearcey R, Brundage M, Drouin P, et al. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 2002;20:966–72.
McGuire WP III, Arseneau J, Blessing JA, et al. A randomized comparative trial of carbo-platin and iproplatin in advanced squamous carcinoma of the uterine cervix: a gynecologic oncology group study. J Clin Oncol 1989;7:1462–8.
Weiss GR, Green S, Hannigan EV, et al. A phase II trial of carboplatin for recurrent or meta-static squamous carcinoma of the uterine cervix: a Southwest oncology group study. Gynecol Oncol 1990;39:332–6.
Micheletti E, La Face B, Bianchi E, et al. Continuous infusion of carboplatin during conventional radiotherapy treatment in advanced squamous carcinoma of the cervix uteri IIB-IIIB (UICC). A phase I/II and pharmacokinetic study. Am J Clin Oncol 1997;20:613–20.
Corn BW, Hernandez E, Anderson L, Fein DA, Dunton CJ, Heller P. Phase I/II study of concomitant irradiation and carboplatin for locally advanced carcinoma of the uterine cervix: an interim report. Am J Clin Oncol 1996;19:317–21.
Higgins RV, Naumann WR, Hall JB, Haake M. Concurrent carboplatin with pelvic radiation therapy in the primary treatment of cervix cancer. Gynecol Oncol 2003;89:499–503.
Muderspach LI, Curtin JP, Roman LD, et al. Carboplatin as a radiation sensitizer in locally advanced cervical cancer: a pilot study. Gynecol Oncol 1997;65:336–42.
Dubay RA, Rose PG, O'Malley DM, Shalodi AD, Ludin A, Selim MA. Evaluation of concurrent and adjuvant carboplatin with radiation therapy for locally advanced cervical cancer. Gynecol Oncol 2004;94:121–4.
de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxali-platin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–47.
André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343–51.
Magné N, Fischel JL, Formento P, et al. Oxaliplatin-5-fluorouracil and ionizing radiation. Importance of the sequence and influence of p53 status. Oncology 2003;64:280–7.
Folkvord S, Flatmark K, Seierstad T, Røe K, Rasmussen H, Ree AH. Inhibitory effects of oxaliplatin in experimental radiation treatment of colorectal carcinoma: does oxaliplatin improve 5-fluorouracil-dependent radiosensitivity? Radiother Oncol 2008;86:428–34.
Turitto G, Panelli G, Frattolillo A, et al. Phase II study of neoadjuvant concurrent chemio-radiotherapy with oxaliplatin-containing regimen in locally advanced rectal cancer. Front Biosci 2006;11:1275–9.
Valentini V, Coco C, Minsky BD, et al. Randomized, Multicenter, Phase IIB study of preoperative chemoradiotherapy in T3 mid-distal rectal cancer: raltitrexed + oxaliplatin + radiotherapy Versus cisplatin + 5-Fluorouracil + radiotherapy. Int J Radiat Oncol Biol Phys 2008;70:403–12.
Hospers GA, Punt CJ, Tesselaar ME, et al. Preoperative chemoradiotherapy with capecitabine and oxaliplatin in locally advanced rectal cancer. A phase I-II multicenter study of the Dutch colorectal cancer group. Ann Surg Oncol 2007;14:2773–9.
Gambacorta MA, Valentini V, Coco C, et al. Chemoradiation with raltitrexed and oxaliplatin in preoperative treatment of stage II-III resectable rectal cancer: phase I and II studies. Int J Radiat Oncol Biol Phys 2004;60:139–48.
Rödel C, Grabenbauer GG, Papadopoulos T, Hohenberger W, Schmoll HJ, Sauer R. Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 2003;21:3098–104.
Benson AB III. New approaches to assessing and treating early-stage colon and rectal cancers: cooperative group strategies for assessing optimal approaches in early-stage disease. Clin Cancer Res 2007;13:6913s–20s.
Zhang L, Zhao C, Peng PJ, et al. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 2005;23:8461–8.
Amorino GP, Mohr PJ, Hercules SK, Pyo H, Choy H. Combined effects of the orally active cisplatin analog, JM216, and radiation in antitumor therapy. Cancer Chemother Pharmacol 2000;46:423–6.
van de Vaart PJ, Klaren HM, Hofland I, Begg AC. Oral platinum analogue JM216, a radio-sensitizer in oxic murine cells. Int J Radiat Biol 1997;72:675–83.
Wosikowski K, Lamphere L, Unteregger G, et al. Preclinical antitumor activity of the oral platinum analog satraplatin. Cancer Chemother Pharmacol 2007;60:589–600.
McKeage MJ, Raynaud F, Ward J, et al., Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer. J Clin Oncol 1997;15:2691–700.
George CM, Haraf DJ, Mauer AM, et al. A phase I trial of the oral platinum analogue JM216 with concomitant radiotherapy in advanced malignancies of the chest. Invest New Drugs 2001;19:303–10.
Sugiyama T, Kumagai S, Nishida T, et al. Experimental and clinical evaluation of cisplatin-containing microspheres as intraperitoneal chemotherapy for ovarian cancer. Anticancer Res 1998;18:2837–42.
Meerum Terwogt JM, Groenewegen G, Pluim D, et al. Phase I and pharmacokinetic study of SPI-77, a liposomal encapsulated dosage form of cisplatin. Cancer Chemother Pharmacol 2002;49:201–10.
Lana SE, Dernell WS, Lafferty MH, Withrow SJ, LaRue SM. Use of radiation and a slow-release cisplatin formulation for treatment of canine nasal tumors. Vet Radiol Ultrasound 2004;45:577–81.
Lilenbaum RC. The evolving role of cetuximab in non-small cell lung cancer. Clin Cancer Res 2006;12:4432s–5s.
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–78.
Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006;24:1072–8.
Shirai K, O'Brien PE. Molecular targets in squamous cell carcinoma of the head and neck. Curr Treat Opt Oncol 2007;8:239–51.
Teicher BA, Holden SA, Ara G, et al. Influence of an anti-angiogenic treatment on 9L gliosar-coma: oxygenation and response to cytotoxic therapy. Int J Cancer 1995;61:732–7.
Lee CG, Heijn M, di Tomaso E, et al. Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000;60:5565–70.
Griffin RJ, Williams BW, Wild R, Cherrington JM, Park H, Song CW. Simultaneous inhibition of the receptor kinase activity of vascular endothelial, fibroblast, and platelet-derived growth factors suppresses tumor growth and enhances tumor radiation response. Cancer Res 2002;62:1702–6.
Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 2004;64:3731–6.
Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci USA 1996;93:14765–70.
Dings RP, Loren M, Heun H, et al. Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clin Cancer Res 2007;13:3395–402.
Citrin D, Menard C, Camphausen K. Combining radiotherapy and angiogenesis inhibitors: clinical trial design. Int J Radiat Oncol Biol Phys 2006;64:15–25.
Lymberis SC, Parhar PK, Katsoulakis E, Formenti SC. Pharmacogenomics and breast cancer. Pharmacogenomics 2004;5:31–55.
Olopade OI, Wei M. FANCF methylation contributes to chemoselectivity in ovarian cancer. Cancer Cell 2003;3:417–20.
Rottenberg S, Nygren AO, Pajic M, et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc Natl Acad Sci USA 2007;104:12117–22.
Liu X, Holstege H, van der Gulden H, et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci USA 2007;104:12111–6.
Swisher EM, Sakai W, Karlan BY, Wurz K, Urban N, Taniguchi T. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res 2008;68:2581–6.
Sakai W, Swisher EM, Karlan BY, et al., Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 2008;451:1116–20.
Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434:913–7.
Smith LM, Willmore E, Austin CA, Curtin NJ. The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Clin Cancer Res 2005;11:8449–57.
Lewis C, Low JA. Clinical poly(ADP-ribose) polymerase inhibitors for the treatment of cancer. Curr Opin Investig Drugs 2007;8:1051–6.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Baer, L., Muggia, F.M., Formenti, S.C. (2009). Platinum Compounds and Radiation. In: Bonetti, A., Leone, R., Muggia, F.M., Howell, S.B. (eds) Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-459-3_26
Download citation
DOI: https://doi.org/10.1007/978-1-60327-459-3_26
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-60327-458-6
Online ISBN: 978-1-60327-459-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)