Ovarian Cancer Algorithm

The objective of the program is to help in the management of patients with abdominal masses, the differential diagnosis with benign gynecological pathology and the monitoring of patients with ovarian neoplasms. It has two complementary and related parts:

First:

First of all, the application of the criteria and experience in the differential diagnosis in women of the abdominal masses, and of the benign gynecological pathology of ovarian cancer. This malignant tumor is a silent neoplasm, with few symptoms and that is usually diagnosed in advanced stages, with a high mortality.

It is usually presented as an abdominal mass, frequent pathology. One in five women will have an abdominal mass throughout their lives. The 10% must go to surgery to perform a differential diagnosis with 15% of these malignancies. Due to its high mortality it is important to make an early diagnosis. Vaginal ultrasound is one of the main diagnostic methods, but it is not conclusive in more than 30% of cases.

In recent years, various methods have appeared to support the diagnosis of ovarian cancer. They mainly consist of tumor markers such as CA 125, HE4, alone or in an algorithm called ROMA (Risk of ovarian carcinoma).

This last algorithm has been criticized for subdividing patients in relation to functional ovarian status (premenopause or menopause) and not age. Recently another algorithm called Copenhagen has been published that takes into account age. The publications made have a great disparity of results, which makes difficult the correct evaluation of the results.

Second:

The second part of the program uses tumor markers in the therapeutic monitoring of ovarian cancer. Ovarian cancer is diagnosed late and is often treated by combining chemotherapy and surgery. It is a tumor that is sensitive to chemotherapy, so survival is linked to the response and rapid and efficient assessment of therapeutic results is fundamental. To give an ineffective treatment, only gets to increase the toxicity, with a high cost and time lost that could be used trying a second treatment could be applied, allowing the tumor to grow. The algorithm incorporates the monitoring of therapeutic response through the serial evaluation of markers and the study of criteria to assess the response in an early and cost-effective manner. These results will be perfectly validated in relation to the usual radiological evaluation criteria, RECIST v1.1: if there is response, progression or stabilization of the disease. 

The patients included in the study are preferably the clinical routine of the Hospital Clinic, obtained for more than 10 years, but there have been collaborations from other Spanish, European and Asian centers.

This collaboration with other centers, allows to avoid the possible bias of results from single-center studies. This information is of great importance since important differences have been described between serum concentrations of HE4 and CA 125 in women of Asian origin and in women of color , in relation to Caucasian women.

The variability between the results of the analytical results, the incorporation of the differences in the numerical concordance between them and their possible influence on the approach to the diagnosis through the study of tumor markers has also been evaluated.

BIBLIOGRAPHY

REFERENCES related to this topic from members of the team or collaborators.

 Parra Robert M,Molina V, Miro S, Filella X, AUge JM, Molina R. Relationship between CA 19.9 and the Lewis phenotype: Options to improve diagnostic efficiency. Anticancer Res. In press

Holdenrieder S, Molina R, Qiu L, Zhi X, Rutz S, Engel C, Kasper-Sauer P, Dayyani F, Korse CM. Technical and clinical performance of a new assay to detect squamous cell carcinoma antigen levels for the differential diagnosis of cervical, lung, and head and neck cancer.Tumour Biol. 2018 Apr;40(4):1010428318772202. doi: 10.1177/1010428318772202. PMID:29701125

Filippou PS, Ren AH, Korbakis D, Dimitrakopoulos L, Soosaipillai A, Barak V, Frenkel S, Pe’er J, Lotem M, Merims S, Molina R, Blasutig I, Bogdanos DP, Diamandis EP. Exploring the potential of mucin 13 (MUC13) as a biomarker for carcinomas and other diseases. Clin Chem Lab Med. 2018 May 16. pii: /j/cclm.ahead-of-print/cclm-2018-0139/cclm-2018-0139.xml. doi: 10.1515/cclm-2018-0139. [Epub ahead of print]. PMID:29768245

S Sölétormos G, Duffy MJ, Othman S, Verheijen RHM, Tholander B, Bast Jr RC, Gaarenstroom KN, Sturgeon CM, Bonfrer H, Hyltoft Petersen P, Troonen H, Torre GC, Kulpa J, Tuxen MK, Molina R Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer: Updated Guidelines from The European Group on Tumor Markers (EGTM). Int J Gynecol Cancer 2016;26: 43-51).

Leung, Felix; et al. 2016. Validation of a Novel Biomarker Panel for the Detection of Ovarian Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION. AMER ASSOC CANCER RESEARCH. 25-9, pp.1333-1340. ISSN 1538-7755

Duffy MJ, Sturgeon CM, Sölétormos G, Barak V, Molina R, Hayes DF, Diamandis EP, Bossuyt PM. Validation of new cancer biomarkers: a position statement from the European group on tumor markers.Clin Chem. 2015 Jun;61(6):809-20. doi: 10.1373/clinchem.2015.239863. Epub 2015 Apr 16. Review

Trapé J, Gurt G, Franquesa J, Montesinos J, Arnau A, Sala M, Sant F, Casado E, Ordeig JM, Bergos C, Vida F, Sort P, Isava Á, González M, Molina R. Diagnostic Accuracy of Tumor Markers CYFRA21-1 and CA125 in the Differential Diagnosis of Ascites.Anticancer Res. 2015 Oct;35(10):5655-60.

Duffy, Michael J.; Esteva, Francisco J.; Harbeck, Nadia; Hayes, Daniel F.; Molina, Rafael. Tumor Markers in ovarian cancer. ACTA BIOQUIMICA CLINICA LATINOAMERICANA.2014: 48 - 1, pp. 88 - 106. ISSN 0325-2957, ISSN 1851-6114

R. Molina, J.M. Augé, J.M. Escudero, X. Filella.Tumor markers (TM) Applications in clinical practice. ©2014 Roche-Roche Diagnostics International Ltd CH-6343 Rotkreuz Switzerland www.roche.com. 

Rafael Molina, Xavier Filella, J. M. Augé, J. M. Escudero. Clinical value of tumor markers Current status and future prospects III. Roche Diagnostics International Ltd CH-6343 Rotkreuz Switzerland www.cobas.com. 2013

Trapé J, Molina R, Sant F, Montesinos J, Arnau A, Franquesa J, Blavia R, Martín E, Marquilles E, Perich D, Pérez C, Roca JM, Doménech M, López J, Badal JM. Diagnostic accuracy of tumour markers in serous effusions: a validation study. Tumour Biol. 2012 Oct;33(5):1661-8.PMID: 22678976 [PubMed - indexed for MEDLINE] 

Molina R, Bosch X, Augé JM, Filella X, Escudero JM, Molina V, Solé M, López-Soto A. Utility of serum tumor markers as an aid in the differential diagnosis of patients w ith clinical suspicion of cancer and in patients w ith cancer of unknown primary site. Tumour Biol. 2012 Apr;33(2):463-74.PMID: 22161237 [PubMed - indexed for MEDLINE].

Escudero JM,  Auge JM, Filella X, Torne A,, Pahisa J, Molina R The utility of serum Human Epididymis protein (HE4) in patients with malignant and non malignant diseases: comparison with CA 125. Clin Chem 2011 Nov;57(11):1534-44.

Molina R, Escudero JM,  Auge JM, Filella X, Foj L,  Torne A,  Lejarcegui,L, Pahisa J, HE-4 a novel tumor marker for ovarian cancer: comparison with CA 125 in patients with gynecological diseases. Tumor Biol 2011 Dec;32(6):1087-95.

Molina R, Alvarez E, Aniel Quiroga A, Borque M, Candas B, Leon A, Poyatos RM, Gelabert M. Evaluation of chromogranin A determined by three different procedures in patients with benign diseases, neuroendocrine tumors and other malignancies. Tumor Biol 2011; 32:13-22

van Dalen A, Favier J, Hallensleben E, Burges A, Stieber P, de Bruijn HW, Fink D, Ferrero A, McGing P, Harlozinska A, Kainz Ch, Markowska J, Molina R, Sturgeon C, Bowman A, Einarsson R, Goike H. Significance of serum CA125 and TPS antigen levels for determination of overall survival after three chemotherapy courses in ovarian cancer patients during long-term follow-up. Eur J Gynaecol Oncol.2009;30(6):609-15. PubMed PMID: 20099488.

Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brünner N, Chan DW, Babaian R, Bast RC Jr, Dowell B, Esteva FJ, Haglund C, Harbeck N, Hayes DF, Holten-Andersen  M, Klee GG, Lamerz R, Looijenga LH, Molina R, Nielsen HJ, Rittenhouse H, Semjonow A, Shih IeM, Sibley P, Sölétormos G, Stephan C, Sokoll L, Hoffman BR, Diamandis EP; National Academy of Clinical Biochemistry. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in  testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008 Dec;54(12):e11-79. PubMed PMID: 19042984.

Sturgeon CM, Hoffman BR, Chan DW, Ch'ng SL, Hammond E, Hayes DF, Liotta LA, Petricoin EF, Schmitt M, Semmes OJ, Söletormos G, van der Merwe E, Diamandis EP; National Academy of Clinical Biochemistry. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in  clinical practice: quality requirements. Clin Chem. 2008 Aug;54(8):e1-e10. Epub 2008 Jul 7. PubMed PMID: 18606634.

Molina R, Filella X, Auge JM, Bosch E, Torne A, Pahisa J, Lejarcegui JA, Rovirosa A, Mellado B, Ordi J, Biete A. CYFRA 21.1 in patients with cervical cancer: comparison with SCC and CEA.Anticancer Res. 2005 May-Jun;25(3A):1765-71. PMID: 16033097 [PubMed - indexed for MEDLINE]

Molina R, Auge JM, Alicarte J, Filella X, Vinolas N, Ballesta AM. Pro-gastrin-releasing peptide in patients with benign and malignant diseases.

Tumour Biol. 2004 Jan-Apr;25(1-2):56-61. PMID: 15192313 [PubMed - indexed for MEDLINE]

Trape J, Molina R, Sant F. Clinical evaluation of the simultaneous determination of tumor markers in fluid and serum and their ratio in the differential diagnosis of serous effusions.Tumour Biol. 2004 Sep-Dec;25(5-6):276-81. PMID: 15627892 [PubMed - indexed for MEDLINE]

Molina R, Filella X, Lejarcegui JA, Pahisa J, Torne A, Rovirosa A, Mellado B, Ordi J, Puig-Tintore LM, Alicarte J, Biete A, Iglesias J. Prospective evaluation of squamous cell carcinoma and carcinoembryonic antigenas prognostic factors in patients with cervical cancer.Tumour Biol. 2003 May-Jun;24(3):156-64. PMID: 14610320 [PubMed - indexed for MEDLINE]

Van Dalen A, Favier J, Baumgartner L, Hasholzner U, De Bruijn H, Dobbler D, Dombi VH, Fink D, Giai M, McGing P, Harlozinska A, Kainz C, Markowska J, Molina R, Sturgeon C, Bowman A, Einarsson R. Serum levels of CA 125 and TPS during treatment of ovarian cancer.Anticancer Res. 2000 Nov-Dec;20(6D):5107-8. PMID: 11326677 [PubMed - indexed for MEDLINE]

Van Dalen A, Favier J, Burges A, Hasholzner U, de Bruijn HW, Dobler-Girdziunaite D, Dombi VH, Fink D, Giai M, McGing P, Harlozinska A, Kainz C, Markowska J, Molina R, Sturgeon C, Bowman A, Einarsson R. Prognostic significance of CA 125 and TPS levels after 3 chemotherapy courses in ovarian cancer patients.Gynecol Oncol. 2000 Dec;79(3):444-50. PMID: 11104617 [PubMed - indexed for MEDLINE]

Tumour markers in gynaecological cancers--EGTM recommendations. European Group on Tumor Markers. Anticancer Res. 1999 Jul-Aug;19(4A):2807-10. Review. PubMed PMID: 10470246.

Van Dalen A, Favier J, Baumgartner L, Hasholzner U, de Bruijn H, Dobbler D, Dombi VH, Fink D, Giai M, McGing P, Harlozinska A, Kainz C, Markowska J, Molina R, Sturgeon C, Einarsson R. Prognostic significance of CA 125 and TPS levels after chemotherapy in ovarian cancer patients.Anticancer Res. 1999 Jul-Aug;19(4A):2523-6. PMID: 10470187 [PubMed - indexed for MEDLINE]

Borras G, Molina R, Xercavins J, Ballesta A, Iglesias J. Tumor antigens CA 19.9, CA 125, and CEA in carcinoma of the uterine cervix.Gynecol Oncol. 1995 May;57(2):205-11. PMID: 7729735 [PubMed - indexed for MEDLINE]

Ballesta AM, Molina R, Filella X, Jo J, Gimenez N. Carcinoembryonic antigen in staging and follow-up of patients with solid tumors. Tumour Biol. 1995;16(1):32-41. Review. PMID: 7863220 [PubMed - indexed for MEDLINE]

Molina R, Agusti C, Filella X, Jo J, Joseph J, Gimenez N, Ballesta AM. Study of a new tumor marker, CYFRA 21-1, in malignant and nonmalignant diseases. Tumour Biol. 1994;15(6):318-25. PMID: 7997803 [PubMed - indexed for MEDLINE]

 Ballesta AM, Molina R. Tumor markers. Definition and clasification. Ballesta A.M, Torre G.C, Bombardieri E, Gion M, Molina R (eds). Up dating on tumor markers in tissues and in biological fluids. Minerva Medica, 1993: 75-88.

Borras G, Molina R, Xercavins J, Ballesta A, Iglesias X. Squamous cell carcinoma antigen in cervical cancer.Eur J Gynaecol Oncol. 1992;13(5):414-8. PMID: 1486921 [PubMed - indexed for MEDLINE]

Molina R, Ojeda B, Filella X, Borras G, Jo J, Mas E, Lopez JJ, Ballesta A. A prospective study of tumor markers CA 125 and CA 19.9 in patients with epithelial ovarian carcinomas.Tumour Biol. 1992;13(5-6):278-86. PMID: 1290025 [PubMed - indexed for MEDLINE]

Molina R, Filella X, Bruix J, Mengual P, Bosch J, Calvet X, Jo J, Ballesta AM. Cancer antigen 125 in serum and ascitic fluid of patients with liver diseases. Clin Chem. 1991 Aug;37(8):1379-83. PMID: 1868598 [PubMed - indexed for MEDLINE]

Molina R, Filella X, Torres MD, Ballesta AM, Mengual P, Cases A, Balague A. SCC antigen measured in malignant and nonmalignant diseases. Clin Chem. 1990 Feb;36(2):251-4. PMID: 2302769 [PubMed - indexed for MEDLINE]

A.M. Ballesta, R. Molina, X. Filella, J.L. Bedini, A. Balagué. I biomarcatori tumorali nel carcinoma ovarico: Gli antigeni CA 125 e CA 19.9. In: Rosso G, Torre GC, Verri PG, Pecchio F eds.  La diagnosi delle neoplasie ginecologiche. Confronto delle tecniche attuali. Tipolitografia Toso, Torino, Italy, 1989: 175-184.

A.M. Ballesta, R. Molina, J.L. Marín, J. Caballería, E. Montserrat, J. Bosch, M. Nolla, E. Casals, J. Rodés, A. Balagué. Patologia epatica e CA 12.5 In: Coli AC, Torre GC, Vecchione A., Zacutti Jr A. eds. I markers tumorali in ginecologia. CIC edizioni internazionali. 1986, Roma: 161-172.

R. Molina, A.M. Ballesta, E. Casals, G. Borras, M. Elena, A. Balagué. Value of CA 12.5 antigen as tumor marker . Preliminary results. In Peetes H. ed. Protides of the biological fluids, 32, Pergamon Press, Oxford, 1985: 851-853.

A. van Dalen, V. Barak, A. Cremaschi, M. Gion, R. Molina, N. Namer, P. Stieber, C. Sturgeon, R. Einarsson. - Increasing marker levels in breast cancer patients with clinically complete remission, partial remission or stable disease. Results of a multicenter study.  En: Molina R, Ballesta AM (eds). Biology and clinicial usefulness of tumor markers, Grafiques Sant Quirze, Barcelona. 1999, 138-141.

R. Molina, MD. Torres, M. Moragas, X. Filella, J. Jo, M. Perez, AM. Ballesta. - Prognostic significance of SCC antigen in serum of patients with head and neck cancer.  En: Molina R, Ballesta AM (eds). Biology and clinicial usefulness of tumor markers, Grafiques Sant Quirze, Barcelona. 1999,197-205.

C. Escriche, R. Molina, X. Filella, J. Jo, AM. Ballesta. - The biologic variability of tumor markers in the monitorization of patients with breast and colon cancer with no-evidence of disease.  En: Molina R, Ballesta AM (eds). Biology and clinicial usefulness of tumor markers, Grafiques Sant Quirze, Barcelona. 1999,212-215.

A. van Dalen, L. Baumgartner, H. de Bruijn, VH. Dombi, D. Fink, M. Giai, P. McGing, U. Hasholzner, A. Harlozinska, Ch. Kainz, R. Molina, C. Sturgeon, R. Einarsson. - Prognostic significance of combined CA 125 and TPS levels after chemotherapy in ovarian cancer patients. Preliminary results of a multicenter study.  En: Molina R, Ballesta AM (eds). Biology and clinicial usefulness of tumor markers, Grafiques Sant Quirze, Barcelona. 1999,106-107.

  

Spanish

R. Molina, JM Auge, X. Filella, L Foj, J.M. Escudero. Marcadores tumorales (MT) séricos en neoplasias epiteliales ginecológicas En: Cursos Clinic de Formacion Continuada en Obstetricia y Ginecologia.. Ginecologica Oncologica. J Pahisa, A. Torne (eds).  2011: 315-330

R. Molina Porto, JM Auge Fradera, X. Filella Pla, L Foj Capell, J.M. Escudero Fernandez. Marcadores tumorales (MT) séricos en neoplasias epiteliales ginecológicas En: Cursos Clinic de Formacion Continuada en Obstetricia y Ginecologia.. Ginecologica Oncologica. J Pahisa Fabregas, A. Torne Blade (eds).  2014: 231-248

R. Molina Porto, X. Filella Pla y A. M. Ballesta Gimeno. Marcadores Tumorales en neoplasias del aparato genital femenino y de la mama. En: Gonzalez Merlo J, Gonzalez Bosquet J, y cols (eds). Ginecología Oncológica. Masson, 2002:437-453.

R. Molina, X. Filella, N. Gimenez. - Utilidad de los marcadores tumorales en neoplasias de origen desconocido.  En: Molina R, Ballesta AM (eds). Biology and clinicial usefulness of tumor markers, Grafiques Sant Quirze, Barcelona. 1999, 233-242.

S. Crespi, J. Vilimelis, M. Moragues, A. Mayol, R. Molina. - El diagnostico de malignidad en los derrames serosos mediante el uso de marcadores tumorales: utilidad de la determinación simultánea (liquido/suero) . En: Molina R, Ballesta AM (eds). Biology and clinicial usefulness of tumor markers, Grafiques Sant Quirze, Barcelona. 1999, 240-242.