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Erschienen in: Journal of Gastroenterology 1/2012

01.01.2012 | Original Article—Liver, Pancreas, and Biliary Tract

Evaluation of molecular targeted cancer drug by changes in tumor marker doubling times

verfasst von: Kenichiro Enooku, Ryosuke Tateishi, Fumihiko Kanai, Yuji Kondo, Ryota Masuzaki, Tadashi Goto, Shuichiro Shiina, Haruhiko Yoshida, Masao Omata, Kazuhiko Koike

Erschienen in: Journal of Gastroenterology | Ausgabe 1/2012

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Abstract

Background

We evaluated the usefulness of tumor marker doubling time (DT) as an efficacy indicator of a molecular targeted anticancer agent.

Methods

Twenty-five patients with advanced hepatocellular carcinoma (HCC) received TSU-68, a multiple tyrosine kinase inhibitor. Exponential increase in HCC-specific tumor marker levels (alpha-fetoprotein or des-gamma-carboxyprothrombin) was seen in 15 of them prior to TSU-68 administration. The relationship between tumor marker DT and tumor volume DT was evaluated. Next, tumor marker DT in the first 8 weeks of TSU-68 administration was compared with tumor marker DT before treatment. Efficacy evaluation based on changes in tumor marker DT was compared with Response Evaluation Criteria In Solid Tumors (RECIST).

Results

Tumor marker DT and tumor volume DT were almost identical (r 2 = 0.94, P < 0.001) in each patient before TSU-68 administration. Efficacy evaluation based on changes in tumor marker DT on TSU-68 administration was in accordance with RECIST in 12/15 cases. Discordance was observed in three cases, for which RECIST indicated disease progression in spite of elongated tumor marker DT. Those cases showed substantial tumor necrosis without volume shrinkage or appearance of new lesions in spite of apparent effects on target lesions.

Conclusions

Serum tumor marker DT can be used to evaluate viable tumor burden irrespective of the presence of tumor necrosis which can compromise radiographic evaluation. This approach may be applicable to the evaluation of responses to chemotherapy, particularly to cytostatic agents (ClinicalTrials.gov number, NCT00784290).
Literatur
1.
Zurück zum Zitat Cannistra SA. Phase II trials in Journal of Clinical Oncology. J Clin Oncol. 2009;27:3073–6.PubMedCrossRef Cannistra SA. Phase II trials in Journal of Clinical Oncology. J Clin Oncol. 2009;27:3073–6.PubMedCrossRef
2.
Zurück zum Zitat Paesmans M, Sculier JP, Libert P, Bureau G, Dabouis G, Thiriaux J, et al. Response to chemotherapy has predictive value for further survival of patients with advanced non-small cell lung cancer: 10 years experience of the European Lung Cancer Working Party. Eur J Cancer. 1997;33:2326–32.PubMedCrossRef Paesmans M, Sculier JP, Libert P, Bureau G, Dabouis G, Thiriaux J, et al. Response to chemotherapy has predictive value for further survival of patients with advanced non-small cell lung cancer: 10 years experience of the European Lung Cancer Working Party. Eur J Cancer. 1997;33:2326–32.PubMedCrossRef
3.
Zurück zum Zitat Buyse M, Thirion P, Carlson RW, Burzykowski T, Molenberghs G, Piedbois P. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet. 2000;356:373–8.PubMedCrossRef Buyse M, Thirion P, Carlson RW, Burzykowski T, Molenberghs G, Piedbois P. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet. 2000;356:373–8.PubMedCrossRef
4.
Zurück zum Zitat Goffin J, Baral S, Tu D, Nomikos D, Seymour L. Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval. Clin Cancer Res. 2005;11:5928–34.PubMedCrossRef Goffin J, Baral S, Tu D, Nomikos D, Seymour L. Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval. Clin Cancer Res. 2005;11:5928–34.PubMedCrossRef
5.
Zurück zum Zitat Keppke AL, Salem R, Reddy D, Huang J, Jin J, Larson AC, et al. Imaging of hepatocellular carcinoma after treatment with yttrium-90 microspheres. AJR Am J Roentgenol. 2007;188:768–75.PubMedCrossRef Keppke AL, Salem R, Reddy D, Huang J, Jin J, Larson AC, et al. Imaging of hepatocellular carcinoma after treatment with yttrium-90 microspheres. AJR Am J Roentgenol. 2007;188:768–75.PubMedCrossRef
6.
Zurück zum Zitat Miller FH, Keppke AL, Reddy D, Huang J, Jin J, Mulcahy MF, et al. Response of liver metastases after treatment with yttrium-90 microspheres: role of size, necrosis, and PET. AJR Am J Roentgenol. 2007;188:776–83.PubMedCrossRef Miller FH, Keppke AL, Reddy D, Huang J, Jin J, Mulcahy MF, et al. Response of liver metastases after treatment with yttrium-90 microspheres: role of size, necrosis, and PET. AJR Am J Roentgenol. 2007;188:776–83.PubMedCrossRef
7.
Zurück zum Zitat Burton A. REGIST: right time to renovate? Eur J Cancer. 2007;43:1642.PubMed Burton A. REGIST: right time to renovate? Eur J Cancer. 2007;43:1642.PubMed
8.
Zurück zum Zitat Therasse P, Eisenhauer EA, Buyse M. Update in methodology and conduct of cancer clinical trials. Eur J Cancer. 2006;42:1322–30.PubMedCrossRef Therasse P, Eisenhauer EA, Buyse M. Update in methodology and conduct of cancer clinical trials. Eur J Cancer. 2006;42:1322–30.PubMedCrossRef
9.
Zurück zum Zitat Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: a review of validation studies on tumour assessment. Eur J Cancer. 2006;42:1031–9.PubMedCrossRef Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: a review of validation studies on tumour assessment. Eur J Cancer. 2006;42:1031–9.PubMedCrossRef
10.
Zurück zum Zitat Stroobants S, Goeminne J, Seegers M, Dimitrijevic S, Dupont P, Nuyts J, et al. 18FDG-positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer. 2003;39:2012–20.PubMedCrossRef Stroobants S, Goeminne J, Seegers M, Dimitrijevic S, Dupont P, Nuyts J, et al. 18FDG-positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer. 2003;39:2012–20.PubMedCrossRef
11.
Zurück zum Zitat Antoch G, Kanja J, Bauer S, Kuehl H, Renzing-Koehler K, Schuette J, et al. Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med. 2004;45:357–65.PubMed Antoch G, Kanja J, Bauer S, Kuehl H, Renzing-Koehler K, Schuette J, et al. Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med. 2004;45:357–65.PubMed
12.
Zurück zum Zitat D’Amico AV, Desjardin A, Chen MH, Paik S, Schultz D, Renshaw AA, et al. Analyzing outcome-based staging for clinically localized adenocarcinoma of the prostate. Cancer. 1998;83:2172–80.PubMedCrossRef D’Amico AV, Desjardin A, Chen MH, Paik S, Schultz D, Renshaw AA, et al. Analyzing outcome-based staging for clinically localized adenocarcinoma of the prostate. Cancer. 1998;83:2172–80.PubMedCrossRef
13.
Zurück zum Zitat Sheu JC, Sung JL, Chen DS, Yang PM, Lai MY, Lee CS, et al. Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications. Gastroenterology. 1985;89:259–66.PubMed Sheu JC, Sung JL, Chen DS, Yang PM, Lai MY, Lee CS, et al. Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications. Gastroenterology. 1985;89:259–66.PubMed
14.
Zurück zum Zitat Tian F, Appert HE, Myles J, Howard JM. Prognostic value of serum CA 19-9 levels in pancreatic adenocarcinoma. Ann Surg. 1992;215:350–5.PubMedCrossRef Tian F, Appert HE, Myles J, Howard JM. Prognostic value of serum CA 19-9 levels in pancreatic adenocarcinoma. Ann Surg. 1992;215:350–5.PubMedCrossRef
15.
Zurück zum Zitat Tanaka K, Noura S, Ohue M, Seki Y, Yamada T, Miyashiro I, et al. Doubling time of carcinoembryonic antigen is a significant prognostic factor after the surgical resection of locally recurrent rectal cancer. Dig Surg. 2008;25:319–24.PubMedCrossRef Tanaka K, Noura S, Ohue M, Seki Y, Yamada T, Miyashiro I, et al. Doubling time of carcinoembryonic antigen is a significant prognostic factor after the surgical resection of locally recurrent rectal cancer. Dig Surg. 2008;25:319–24.PubMedCrossRef
16.
Zurück zum Zitat Stamey TA, Kabalin JN, Ferrari M. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. III. Radiation treated patients. J Urol. 1989;141:1084–7.PubMed Stamey TA, Kabalin JN, Ferrari M. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. III. Radiation treated patients. J Urol. 1989;141:1084–7.PubMed
17.
Zurück zum Zitat Stamey TA, Kabalin JN, Ferrari M, Yang N. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. IV. Anti-androgen treated patients. J Urol. 1989;141:1088–90.PubMed Stamey TA, Kabalin JN, Ferrari M, Yang N. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. IV. Anti-androgen treated patients. J Urol. 1989;141:1088–90.PubMed
18.
Zurück zum Zitat Stamey TA, Kabalin JN, McNeal JE, Johnstone IM, Freiha F, Redwine EA, et al. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol. 1989;141:1076–83.PubMed Stamey TA, Kabalin JN, McNeal JE, Johnstone IM, Freiha F, Redwine EA, et al. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol. 1989;141:1076–83.PubMed
19.
Zurück zum Zitat Fabbro D, Manley PW. Su-6668. SUGEN. Curr Opin Investig Drugs. 2001;2:1142–8.PubMed Fabbro D, Manley PW. Su-6668. SUGEN. Curr Opin Investig Drugs. 2001;2:1142–8.PubMed
20.
Zurück zum Zitat Pang RW, Poon RT. From molecular biology to targeted therapies for hepatocellular carcinoma: the future is now. Oncology. 2007;72(Suppl 1):30–44.PubMedCrossRef Pang RW, Poon RT. From molecular biology to targeted therapies for hepatocellular carcinoma: the future is now. Oncology. 2007;72(Suppl 1):30–44.PubMedCrossRef
21.
Zurück zum Zitat Kanai F, Yoshida H, Tateishi R, Sato S, Kawabe T, Obi S, et al. A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2011;67:315–24.PubMedCrossRef Kanai F, Yoshida H, Tateishi R, Sato S, Kawabe T, Obi S, et al. A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2011;67:315–24.PubMedCrossRef
22.
Zurück zum Zitat Eisenhauer EA. Phase I and II trials of novel anti-cancer agents: endpoints, efficacy and existentialism. The Michel Clavel Lecture, held at the 10th NCI-EORTC Conference on New Drugs in Cancer Therapy, Amsterdam, 16–19 June 1998. Ann Oncol. 1998;9:1047–52.PubMedCrossRef Eisenhauer EA. Phase I and II trials of novel anti-cancer agents: endpoints, efficacy and existentialism. The Michel Clavel Lecture, held at the 10th NCI-EORTC Conference on New Drugs in Cancer Therapy, Amsterdam, 16–19 June 1998. Ann Oncol. 1998;9:1047–52.PubMedCrossRef
23.
Zurück zum Zitat Eisenhauer EA. Response evaluation: beyond RECIST. Ann Oncol. 2007;18 Suppl 9:ix29–32. Eisenhauer EA. Response evaluation: beyond RECIST. Ann Oncol. 2007;18 Suppl 9:ix29–32.
24.
Zurück zum Zitat Gelmon KA, Eisenhauer EA, Harris AL, Ratain MJ, Workman P. Anticancer agents targeting signaling molecules and cancer cell environment: challenges for drug development? J Natl Cancer Inst. 1999;91:1281–7.PubMedCrossRef Gelmon KA, Eisenhauer EA, Harris AL, Ratain MJ, Workman P. Anticancer agents targeting signaling molecules and cancer cell environment: challenges for drug development? J Natl Cancer Inst. 1999;91:1281–7.PubMedCrossRef
25.
Zurück zum Zitat Korn EL, Arbuck SG, Pluda JM, Simon R, Kaplan RS, Christian MC. Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol. 2001;19:265–72.PubMed Korn EL, Arbuck SG, Pluda JM, Simon R, Kaplan RS, Christian MC. Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol. 2001;19:265–72.PubMed
26.
Zurück zum Zitat Ratain MJ, Eckhardt SG. Phase II studies of modern drugs directed against new targets: if you are fazed, too, then resist RECIST. J Clin Oncol. 2004;22:4442–5.PubMedCrossRef Ratain MJ, Eckhardt SG. Phase II studies of modern drugs directed against new targets: if you are fazed, too, then resist RECIST. J Clin Oncol. 2004;22:4442–5.PubMedCrossRef
27.
Zurück zum Zitat Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.PubMedCrossRef Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.PubMedCrossRef
28.
Zurück zum Zitat Dachman AH, MacEneaney PM, Adedipe A, Carlin M, Schumm LP. Tumor size on computed tomography scans: is one measurement enough? Cancer. 2001;91:555–60.PubMedCrossRef Dachman AH, MacEneaney PM, Adedipe A, Carlin M, Schumm LP. Tumor size on computed tomography scans: is one measurement enough? Cancer. 2001;91:555–60.PubMedCrossRef
29.
30.
Zurück zum Zitat Chan SL, Mo FK, Johnson PJ, Hui EP, Ma BB, Ho WM, et al. New utility of an old marker: serial alpha-fetoprotein measurement in predicting radiologic response and survival of patients with hepatocellular carcinoma undergoing systemic chemotherapy. J Clin Oncol. 2009;27:446–52.PubMedCrossRef Chan SL, Mo FK, Johnson PJ, Hui EP, Ma BB, Ho WM, et al. New utility of an old marker: serial alpha-fetoprotein measurement in predicting radiologic response and survival of patients with hepatocellular carcinoma undergoing systemic chemotherapy. J Clin Oncol. 2009;27:446–52.PubMedCrossRef
31.
Zurück zum Zitat Riaz A, Ryu RK, Kulik LM, Mulcahy MF, Lewandowski RJ, Minocha J, et al. Alpha-fetoprotein response after locoregional therapy for hepatocellular carcinoma: oncologic marker of radiologic response, progression, and survival. J Clin Oncol. 2009;27:5734–42.PubMedCrossRef Riaz A, Ryu RK, Kulik LM, Mulcahy MF, Lewandowski RJ, Minocha J, et al. Alpha-fetoprotein response after locoregional therapy for hepatocellular carcinoma: oncologic marker of radiologic response, progression, and survival. J Clin Oncol. 2009;27:5734–42.PubMedCrossRef
32.
Zurück zum Zitat Shao YY, Lin ZZ, Hsu C, Shen YC, Hsu CH, Cheng AL. Early alpha-fetoprotein response predicts treatment efficacy of antiangiogenic systemic therapy in patients with advanced hepatocellular carcinoma. Cancer. 2010;116:4590–6.PubMedCrossRef Shao YY, Lin ZZ, Hsu C, Shen YC, Hsu CH, Cheng AL. Early alpha-fetoprotein response predicts treatment efficacy of antiangiogenic systemic therapy in patients with advanced hepatocellular carcinoma. Cancer. 2010;116:4590–6.PubMedCrossRef
33.
Zurück zum Zitat Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.PubMedCrossRef Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.PubMedCrossRef
34.
Zurück zum Zitat Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.PubMedCrossRef Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.PubMedCrossRef
35.
Zurück zum Zitat Bourhis J, Wilson G, Wibault P, Janot F, Bosq J, Armand JP, et al. Rapid tumor cell proliferation after induction chemotherapy in oropharyngeal cancer. Laryngoscope. 1994;104:468–72.PubMedCrossRef Bourhis J, Wilson G, Wibault P, Janot F, Bosq J, Armand JP, et al. Rapid tumor cell proliferation after induction chemotherapy in oropharyngeal cancer. Laryngoscope. 1994;104:468–72.PubMedCrossRef
36.
Zurück zum Zitat Davis AJ, Tannock JF. Repopulation of tumour cells between cycles of chemotherapy: a neglected factor. Lancet Oncol. 2000;1:86–93.PubMedCrossRef Davis AJ, Tannock JF. Repopulation of tumour cells between cycles of chemotherapy: a neglected factor. Lancet Oncol. 2000;1:86–93.PubMedCrossRef
37.
Zurück zum Zitat Kim JJ, Tannock IF. Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer. 2005;5:516–25.PubMedCrossRef Kim JJ, Tannock IF. Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer. 2005;5:516–25.PubMedCrossRef
38.
Zurück zum Zitat Okazaki N, Yoshino M, Yoshida T, Suzuki M, Moriyama N, Takayasu K, et al. Evaluation of the prognosis for small hepatocellular carcinoma based on tumor volume doubling time. A preliminary report. Cancer. 1989;63:2207–10.PubMedCrossRef Okazaki N, Yoshino M, Yoshida T, Suzuki M, Moriyama N, Takayasu K, et al. Evaluation of the prognosis for small hepatocellular carcinoma based on tumor volume doubling time. A preliminary report. Cancer. 1989;63:2207–10.PubMedCrossRef
Metadaten
Titel
Evaluation of molecular targeted cancer drug by changes in tumor marker doubling times
verfasst von
Kenichiro Enooku
Ryosuke Tateishi
Fumihiko Kanai
Yuji Kondo
Ryota Masuzaki
Tadashi Goto
Shuichiro Shiina
Haruhiko Yoshida
Masao Omata
Kazuhiko Koike
Publikationsdatum
01.01.2012
Verlag
Springer Japan
Erschienen in
Journal of Gastroenterology / Ausgabe 1/2012
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-011-0462-2

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