Skip to main content
SpringerLink
Log in

Adenocarcinoma of unknown primary: retrospective analysis of chemosensitivity of 313 freshly explanted tumors in a tumor cloning system

  • Preclinical Studies
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Abstract

Cancer of unknown primary origin is the eighth most common form of malignancy and accounts for up to 10% of all neoplasms diagnosed. It is a set of heterogenous tumors with widely varying sensitivity to systemic chemotherapy. Over the past years progress has been made in identifying subsets of patients that can be effectively treated with chemotherapy and may achieve long-term survival even with metastatic disease. However, the large majority of cancers of unknown origin still is resistant to chemotherapy. In an attempt to identify conventional and investigational new agents with possible activity against cancers of unknown primary, we have retrospectively analyzed the results of chemosensitivity testing in a soft agar cloning systemin vitro and have compared these data with published clinical trials. Between 1978 and 1993, a total of 19584 tumor specimens were studied using a variety of investigational or established antitumor agents. Of these, 615 (3.1%) were tumors of unknown origin and confirmed on pathology review. The largest histologic subgroup was adenocarcinoma (332, 54%). Sufficient numbers of cells forin vitro testing were obtained from 313 tumor specimens (94.3%). Of 278 agents tested in adenocarcinoma of unknown origin, borderline activity (<20%in vitro response) was noted for 5-FU, doxorubicin, bleomycin, mitoxantrone, mitomycin-C, cisplatin, and etoposide.In vitro response rates of ≥20% were observed for actinomycin-D, BCNU, melphalan, methotrexate, taxol, and vinblastine. In addition, several investigational agents including fludarabine, methotrexate, taxol, and vinblastine. In addition, tiazofurin, LY104208 (vinzolidine), intoplicine, and topotecan had activity. We conclude that clinical inactivity of frequently used conventional antitumor compounds is reflected in the results of soft agar colony formation. However, several concentional and investigational agents have been identified that may hold some clinical promise, and further development of these agents with Phase II trials for patients with adenocarcinoma of unknown origin is warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Greco FA, Hainsworth JD: Tumors of unknown origin. Ca: A Cancer Journal For Clinicians 42:96–115, 1992

    CAS  Google Scholar 

  2. Altman E, Cadman E: An analysis of 1539 patients with cancer of unknown primary site. Cancer 57:120–124, 1986

    Article  PubMed  CAS  Google Scholar 

  3. Hainsworth JD, Greco FA: Poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary tumor site. Semin Oncol 20:279–286, 1993

    PubMed  CAS  Google Scholar 

  4. Ilson DH, Motzer Rj, Rodriguez E, Chaganti RS, Bosl GJ: Genetic analysis in the diagnosis of neoplasms of unknown primary tumor site. Semin Oncol 20:229–237, 1993

    PubMed  CAS  Google Scholar 

  5. Garrow GC, Greco FA, Hainsworth JD: Poorly differentiated neuroendocrine carcinoma of unknown primary tumor site. Semin Oncol 30:287–291, 1993

    Google Scholar 

  6. Hainsworth JD, Greco FA: Neoplasms of unknown primary site. In: Holland JF, Frei III E, Bast RC, Kufe DW, Morton DL, Weichselbaum RR (eds) Cancer Medicine. 3rd ed. Lea & Fiebiger, Philadelphia, 1993, pp 2121–2131.

    Google Scholar 

  7. Hainsworth JD, Johnson DH, Greco FA: Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol 10:912–922, 1992

    PubMed  CAS  Google Scholar 

  8. Hainsworth JD, Greco FA: Treatment of patients with cancer of unknown primary site. Important Adv Oncol 173–190, 1991

  9. Hainsworth JD, Greco FA: Treatment of patients with cancer of an unknown primary site. N Engl Med 329:257–263, 1993

    Article  CAS  Google Scholar 

  10. Alberts DS, Chen HS: Tabular summary of pharmacokinetic parameters relevant toin vitro drug assay. Prog Clin Biol Res 48:351–359, 1980

    PubMed  CAS  Google Scholar 

  11. Hamburger AW, Salmon SE: Primary bioassay of human tumor stem cells. Science 197:461–463, 1977

    Article  PubMed  CAS  Google Scholar 

  12. Hanauske A-R, Hanauske U, Von Hoff DD: The human tumor cloning assay in cancer research and therapy. Curr Probl Cancer 9:1–50, 1985

    Article  PubMed  CAS  Google Scholar 

  13. Hanauske U, Hanauske A-R, Marshall MH, Muggia VA, Von Hoff DD: Biphasic effects of vanadium salts onin vitro tumor colony growth. Int J Cell Cloning 5:170–178, 1987

    Article  PubMed  CAS  Google Scholar 

  14. Clark GM, Von Hoff DD: Statistical considerations forin vitro/in vivo correlations using a cloning system. In: Dendy P, Hill BT (eds) Human Tumor Drug Sensitivity testingin vitro. Academic press, New York, 1983, pp 225–233.

    Google Scholar 

  15. Greenberg BR, Salmon SE: Human tumor clonogenic assay in patients with unknown primary carcinoma. J Clin Oncol 2:46–50, 1984

    PubMed  CAS  Google Scholar 

  16. Grosh W, Von Hoff DD: The human tumor clonogenic assay and other cell culture techniques: Potential applications to the study of undifferentiated neoplasms or cancers of unknown origin. In: Fer MF, Greco FA, Oldham RK (eds) Poorly Differentiated Neoplasms and Tumors of Unknown Origin. Grune & Stratton, Orlando, 1986, pp 451–477

    Google Scholar 

  17. Greco FA, Hainsworth JD: The management of patients with adenocarcinoma and poorly differentiated carcinoma of unknown primary site. Semin Oncol 16:116–122, 1989

    PubMed  CAS  Google Scholar 

  18. Von Hoff DD: He’s not going to talk aboutin vitro predictive assays again, is he? J Natl Cancer Inst 82:96–101, 1990

    Article  Google Scholar 

  19. Shildt RA, Kennedy PS, Chen TT, Athens JW, O’Bryan RM, Balcerzak SP: Management of patients with metastic adenocarcinoma of unknown origin: a Southwest Oncology Group study. Cancer Treat Rep 67:77–79

  20. Johnson RO, Castro R, Asfield FJ: Response of primary unknown cancers of treatment with 5-fluorouracil. Cancer Chemother Rep 38:63–64, 1964

    PubMed  CAS  Google Scholar 

  21. Moertel CG, Reitemeier RJ, Schutt AJ, Hahn RG: Treatment of the patient with adenocarcinoma of unknown origin. Cancer 30:1469–1472, 1972

    Article  PubMed  CAS  Google Scholar 

  22. van der Gaast A, Henzen-Logmans SC, Planting AST, Stoter G, Verweij J: Phase II study of oral administration of etoposide for patients with well- and moderately-differentiated adenocarcinoma of unknown primary site. Ann Oncol 4:789–790, 1993

    PubMed  Google Scholar 

  23. Goldberg RM, Smith FP, Ueno W, Ahlgren JD, Schein PS. 5-fluorouracil, adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary. J Clin Oncol 4:395–399, 1986

    PubMed  CAS  Google Scholar 

  24. Sporn JR, Greenberg BR: Empirical chemotherapy for adenocarcinoma of unknown primary tumor site. Semin Oncol 20:261–267, 1993

    PubMed  CAS  Google Scholar 

  25. Sporn JR, Greenberg BR: Empiric chemotherapy in patients with carcinoma of unknown primary site. Amer J Med 88:49–55, 1990

    Article  PubMed  CAS  Google Scholar 

  26. Kambhu SA, Kelsen DP, Fiore J, Niedzwiecki D, Chapman D, Vinciguerra V, Rosenbluth R: Metastatic adenocarcinomas of unknown primary site. Prognostic variables and treatment results. Amer J Clin Oncol 13:55–60, 1990

    Article  CAS  Google Scholar 

  27. Fiore JJ, Kelsen DP, Gralla RJ, Casper ES, Magill G, Cheng E, Ochoa M, Jr.: Adenocarcinoma of unknown primary origin: treatment with vindesine and doxurubicin. Cancer Treat Rep 69:591–594, 1985

    PubMed  CAS  Google Scholar 

  28. Treat J, Falchuk SC, Tremblay C, Spielman M, Woolley PV, Rouesse J, Sevin D, Le Chevalier T: Phase II trial of methotrexate-FAM (m-FAM) in adenocarcinoma of unknown primary. Eur J Cancer Clin Oncol 25:1053–1055, 1989

    Article  PubMed  CAS  Google Scholar 

  29. Milliken ST, Tattersall MH, Woods RL, Coates AS, Levi JA, Fox RM, Raghavan D: Metastatic adenocarcinoma of unknown primary site. A randomized study of two combination chemotherapy regimens. Eur J Cancer Clin Oncol 23:1645–1648, 1987

    Article  PubMed  CAS  Google Scholar 

  30. van der Gaast A, Verweij J, Planting AS, Stoter G: 5-Fluorouracil, doxorubicin and mitomycin C (FAM) combination chemotherapy for metastatic adenocarcinoma of unknown primary. Eur J Cancer Clin Oncol 24:765–768, 1988

    Article  PubMed  Google Scholar 

  31. Walach N, Horn Y: Combination chemotherapy in the treatment of adenocarcinoma of unknown primary origin. Cancer Treat Rep 71:605–607, 1987

    PubMed  CAS  Google Scholar 

  32. Kelsen D, Martin DS, Colofiore J, Sawyer R, Coit D: A phase II trial of biochemical modulation using N-phosphonacetyl-L-aspartate, high-dose methotrexate, high-dose 5-fluorouracil, and leucovorin in patients with adenocarcinoma of unknown primary site. Cancer 70:1988–1992, 1992

    Article  PubMed  CAS  Google Scholar 

  33. Worzalla JE, Kaiman BD, Johnson BM, Ramirez G, Bryan GT: Metabolism of hexamethylmelamine-ring-14C in rats and man. Cancer Res 34:2669–2674, 1974

    PubMed  CAS  Google Scholar 

  34. Von Hoff DD, Burris HA, 3rd, Eckardt J, Rothenberg M, Fields SM, Chen SF, Kuhn JG: Preclinical and phase I trials of topoisomerase I inhibitors. Cancer Chemother Pharmacol 34 Suppl:S41–5, 1994

    Article  Google Scholar 

  35. Riou JF, Fosse P, Nguyen CH, Larsen AK, Bissery MC, Grondard L, Saucier JM, Bisagni E, Lavelle F: Intoplicine (RP 60475) and its derivatives, a new class of antitumor agents inhibiting both topoisomerase I and II activities. Cancer Res 53:5987–5993, 1993

    PubMed  CAS  Google Scholar 

  36. Poddevin B, Riou JF, Lavelle F, Pommier Y: Dual topoisomerase I and II inhibition by intoplicine (RP-60475), a new antitumor agent in early clinical trials. Mol Pharmacol 44:767–774, 1993

    PubMed  CAS  Google Scholar 

  37. Melink TJ, Sarosy G, Hanauske A-R, Phillips JL, Bayne JH, Grever MR, Jayaram HN, Von Hoff DD: Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule. Sel Cancer Therapeutics 6:51–61, 1990

    CAS  Google Scholar 

  38. Batist G, Klecker RW, Jayaram HN, Jenkins JF, Grygiel J, Ihde DC, Eddy JL, Kerr IG, Collins JM: Phase I and pharmacokinetics study of Tiazofurin (TCAR, NSC 286193) administered by continuous infusion. Invest New Drugs 3:349–357, 1985

    Article  PubMed  CAS  Google Scholar 

  39. Melink TJ, Von Hoff DD, Kuhn JG, Hersh MR, Sternson LA, Patton TF, Siegler R, Boldt DH, Clark GM: Phase I evaluation and pharmacokinetics of Tiazofurin (2-B-D-ribofuranosylthiazole-4-carboxamide, NSC 286193). Cancer Res 45:2859–2865, 1985

    PubMed  CAS  Google Scholar 

  40. Lillie JW, O’Keefe M, Valinski H, Hamlin HA, Jr., Varban ML, Kaddurah Daouk R: Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) inhibits growth of a broad spectrum of cancer cells derived from solid tumors. Cancer Res 53:3172–3178, 1993

    PubMed  CAS  Google Scholar 

  41. Martin KJ, Chen SF, Clark GM, Degen D, Wajima M, Von Hoff DD, Kaddurath Daouk R: Evaluation of creatine analogues as a new class of anticancer agents using freshly explanted human tumor cells. J Natl Cancer Inst 86:608–613, 1994

    Article  PubMed  CAS  Google Scholar 

  42. Kreis W, Budman DR, Schulman P, Freeman J, Greist A, Nelson RL, Marks M, Kevill L: Clinical pharmacology of vinzolidine. Cancer Chemother Pharmacol 16:70–74, 1986

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, I. Department of Medicine, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Str. 22, D-81675, München, FRG

    Axel -R. Hanauske

  2. Division of Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl, Dr, 78284, San Antonio, TX, USA

    Gary M. Clark & Daniel D. Von Hoff

Authors
  1. Axel -R. Hanauske
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gary M. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel D. Von Hoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hanauske, A.R., Clark, G.M. & Von Hoff, D.D. Adenocarcinoma of unknown primary: retrospective analysis of chemosensitivity of 313 freshly explanted tumors in a tumor cloning system. Invest New Drugs 13, 43–49 (1995). https://doi.org/10.1007/BF02614219

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02614219

Key words

Search

Navigation