Skip to main content
SpringerLink
Log in

Tumor Hypoxia Detected by Positron Emission Tomography with 60Cu-ATSM as a Predictor of Response and Survival in Patients Undergoing Neoadjuvant Chemoradiotherapy for Rectal Carcinoma: A Pilot Study

  • Original Contribution
  • Published:
Diseases of the Colon & Rectum

Abstract

PURPOSE

The response of rectal cancers to neoadjuvant chemoradiotherapy is variable. Tumor hypoxia reduces the effectiveness of both radiation therapy and chemotherapy and is a well-known risk factor for tumor radioresistence. We hypothesized that imaging with the novel hypoxia-detecting agent, 60Cu-diacetyl-bis (N4-methylthiosemicarbazone) (60Cu-ATSM), previously validated in cervical and lung cancers, would predict the response of rectal cancers to neoadjuvant chemoradiotherapy and prognosis.

METHODS

Patients with locally invasive (T2–4) primary or node-positive rectal cancer located <12 cm from the anal verge were recruited for this pilot study. Pretreatment tumor size and stage were determined by endorectal ultrasonography, CT, and magnetic resonance imaging. Eleven patients also underwent clinical positron emission tomography with 18F-fluorodeoxyglucose at the discretion of the treating clinician. The primary tumor was imaged by positron emission tomography with 60Cu-ATSM, and accumulation of the tracer was measured semiquantitatively by determining the tumor-to-muscle activity ratio. Neoadjuvant chemoradiotherapy was then administered (within 2 weeks of 60Cu-ATSM-positron emission tomography) and consisted of 45 Gy given in 25 fractions to the pelvis with continuous intravenous infusion of 5-fluorouracil (225 mg/m2/day). Proctectomy was performed six to eight weeks after neoadjuvant chemoradiotherapy and the tumor submitted to pathology for size measurement and staging. Tumor-to-muscle activity ratios were compared with tumor 18F-fluorodeoxyglucose uptake, tumor response to neoadjuvant chemoradiotherapy, and with patient survival.

RESULTS

Nineteen patients were enrolled in the study, two of whom were excluded from final analysis (1 death during neoadjuvant chemoradiotherapy and 1 tumor perforation during neoadjuvant chemoradiotherapy requiring emergent surgery). Of the 17 remaining patients, 14 had a reduction in tumor size and 13 were downstaged. The median tumor-to-muscle activity ratio of 2.6 discriminated those with worse prognosis from those with better prognosis. Both overall and progression-free survivals were worse with hypoxic tumors (tumor-to-muscle activity ratio >2.6) than with nonhypoxic tumors (tumor-to-muscle activity ratio ≤2.6; both P < 0.05). In addition, 2 of the 3 tumors with no change in size had tumor-to-muscle activity ratios >2.6 (positive predictive value 66 percent), whereas 6 of 14 with decreased size had tumor-to-muscle activity ratios >2.6 (negative predictive value 57 percent). Three of the 4 tumors not downstaged had tumor-to-muscle activity ratios >2.6 (positive predictive value 75 percent), whereas 5 of 13 downstaged tumors had tumor-to-muscle activity ratios >2.6 (negative predictive value 62 percent). The mean tumor-to-muscle activity ratio for downstaged tumors (2.2) was significantly lower than that of nondownstaged tumors (3.3) (P = 0.03). The difference in mean tumor-to-muscle activity ratio between downsized (2.3) and nondownsized (2.9) tumors did not reach statistical significance (P = 0.36). Tumor 18F-fluorodeoxyglucose uptake (n = 11) did not correlate with 60Cu-ATSM uptake (r = 0.4; P = 0.9) and there was no significant difference in mean tumor 18F-fluorodeoxyglucose uptake between patients with hypoxic tumors and those with normoxic tumors (P = 0.3).

CONCLUSIONS

The results of this small pilot study suggest that 60Cu-ATSM-PET may be predictive of survival and, possibly, tumor response to neoadjuvant chemoradiotherapy in patients with rectal cancer. A larger Phase II study is warranted to validate these results.

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

FIGURE 1
FIGURE 2

Similar content being viewed by others

References

  1. Han N, Galandiuk S. Induction chemoradiation for rectal cancer. Arch Surg 2006;141:1246–53.

    Article  PubMed  Google Scholar 

  2. Matrai Z, Lovey J, Hitre E, et al. Histologic response after neoadjuvant therapy in rectal adenocarcinoma: own experience and review of the literature. Orv Hetil 2006;147:2011–20.

    PubMed  Google Scholar 

  3. Cervantes A, Chirivella I, Rodriguez-Braun E, Campos S, Navarro S, Garcia Granero E. A multimodality approach to localized rectal cancer. Ann Oncol 2006;17(Suppl 10):x129–34.

    Article  PubMed  Google Scholar 

  4. Hoogsteen IJ, Marres HA, van der Kogel AJ, Kaanders JH. The hypoxic tumour microenvironment, patient selection and hypoxia-modifying treatments. Clin Oncol (R Coll Radiol) 2007;19:385–96.

    CAS  Google Scholar 

  5. Brahimi-Horn MC, Chiche J, Pouyssegur J. Hypoxia signalling controls metabolic demand. Curr Opin Cell Biol 2007;19:223–9.

    Article  PubMed  CAS  Google Scholar 

  6. Milosevic M, Fyles A, Hedley D, Hill R. The human tumor microenvironment: invasive (needle) measurement of oxygen and interstitial fluid pressure. Semin Radiat Oncol 2004;14:249–58.

    Article  PubMed  Google Scholar 

  7. Padhani A. PET imaging of tumour hypoxia. Cancer Imaging 2006;6:S117–21.

    Article  PubMed  Google Scholar 

  8. Williams KJ, Parker CA, Stratford IJ. Exogenous and endogenous markers of tumour oxygenation status: definitive markers of tumour hypoxia? Adv Exp Med Biol 2005;566:285–94.

    Article  PubMed  CAS  Google Scholar 

  9. Hoskins WJ, Urban N, Trimble EC. Priorities of the Gynecologic Cancer Progress Review Group. National Institutes of Health. November 2001.

  10. Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H, Konishi J, Yokoyama A. Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med 1997;38:1155–60.

    PubMed  CAS  Google Scholar 

  11. Lewis JS, McCarthy DW, McCarthy TJ, Fujibayashi Y, Welch MJ. Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model. J Nucl Med 1999;40:177–83.

    PubMed  CAS  Google Scholar 

  12. Dehdashti F, Grigsby PW, Mintun MA, Lewis JS, Siegel BA, Welch MJ. Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response: a preliminary report. Int J Radiat Oncol Biol Phys 2003;55:1233–8.

    PubMed  Google Scholar 

  13. Dehdashti F, Mintun MA, Lewis JS, et al. In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur J Nucl Med Mol Imaging 2003;30:844–50.

    PubMed  CAS  Google Scholar 

  14. Ohtsuka T, Nomori H, Watanabe K, et al. Prognostic significance of [(18)F]fluorodeoxyglucose uptake on positron emission tomography in patients with pathologic stage I lung adenocarcinoma. Cancer 2006;107:2468–73.

    Article  PubMed  Google Scholar 

  15. Hatano E, Ikai I, Higashi T, et al. Preoperative positron emission tomography with fluorine-18-fluorodeoxyglucose is predictive of prognosis in patients with hepatocellular carcinoma after resection. World J Surg 2006;30:1736–41.

    Article  PubMed  Google Scholar 

  16. Bass LA, McCarthy DW, Jones LA, et al. High purity production and potential applications of copper-60 and copper-61. J Labeled Compd Radiopharm 1997;40:325–7.

    Google Scholar 

  17. McCarthy DW, Bass LA, Cutler PD, et al. High purity production and potential applications of copper-60 and copper-61. Nucl Med Biol 1999;26:351–8.

    Article  PubMed  CAS  Google Scholar 

  18. Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 1996;41:31–9.

    PubMed  CAS  Google Scholar 

  19. Schwarzbach MH, Hinz U, Dimitrakopoulou-Strauss A, et al. Prognostic significance of preoperative [18-F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in patients with resectable soft tissue sarcomas. Ann Surg 2005;241:286–94.

    Article  PubMed  Google Scholar 

  20. Young H, Carnochan P, Zweit J, Babich J, Cherry S, Ott R. Evaluation of copper(II)-pyruvaldehyde bis (N-4-methylthiosemicarbazone) for tissue blood flow measurement using a trapped tracer model. Eur J Nucl Med 1994;21:336–41.

    Article  PubMed  CAS  Google Scholar 

  21. Pillot G, Siegel BA, Govindan R. Prognostic value of fluorodeoxyglucose positron emission tomography in non-small cell lung cancer: a review. J Thorac Oncol 2006;1:152–9.

    Article  PubMed  Google Scholar 

  22. Adam LE, Zaers J, Ostertag H, et al. Performance evaluation of the whole-body PET scanner ECAT EXAT HR+following the IEC standard. IEEE Trans Nucl Sci 1997;44:1172–9.

    Article  Google Scholar 

  23. Overgaard J, Horsman MR. Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol 1996;6:10–21.

    Article  PubMed  Google Scholar 

  24. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66.

    PubMed  Google Scholar 

  25. Ceelen W, Pattyn P, Boterberg T, Peeters M. Pre-operative combined modality therapy in the management of locally advanced rectal cancer. Eur J Surg Oncol 2006;32:259–68.

    Article  PubMed  CAS  Google Scholar 

  26. Saw RP, Morgan M, Koorey D, et al. p53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy. Dis Colon Rectum 2003;46:192–202.

    Article  PubMed  Google Scholar 

  27. Chang HJ, Jung KH, Kim DY, et al. Bax, a predictive marker for therapeutic response to preoperative chemoradiotherapy in patients with rectal carcinoma. Human pathology 2005;36:364–71.

    Article  PubMed  CAS  Google Scholar 

  28. Ghadimi BM, Grade M, Difilippantonio MJ, et al. Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 2005;23:1826–38.

    Article  PubMed  CAS  Google Scholar 

  29. Glynne-Jones R, Mawdsley S, Pearce T, Buyse M. Alternative clinical end points in rectal cancer–are we getting closer? Ann Oncol 2006;17:1239–48.

    Article  PubMed  CAS  Google Scholar 

  30. Brizel DM, Scully SP, Harrelson JM, et al. Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas. Cancer Res 1996;56:5347–50.

    PubMed  CAS  Google Scholar 

  31. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996;56:4509–15.

    PubMed  CAS  Google Scholar 

  32. Goethals L, Debucquoy A, Perneel C, et al. Hypoxia in human colorectal adenocarcinoma: comparison between extrinsic and potential intrinsic hypoxia markers. Int J Radiat Oncol Biol Phys 2006;65:246–54.

    PubMed  CAS  Google Scholar 

  33. Lu XG, Xing CG, Feng YZ, Chen J, Deng C. Clinical significance of immunohistochemical expression of hypoxia-inducible factor-1alpha as a prognostic marker in rectal adenocarcinoma. Clin Colorectal Cancer 2006;5:350–3.

    Article  PubMed  CAS  Google Scholar 

  34. Isa AY, Ward TH, West CM, Slevin NJ, Homer JJ. Hypoxia in head and neck cancer. Br J Radiol 2006;79:791–8.

    Article  PubMed  CAS  Google Scholar 

  35. Box B, Lindsey I, Wheeler JM, et al. Neoadjuvant therapy for rectal cancer: improved tumor response, local recurrence, and overall survival in nonanemic patients. Dis Colon Rectum 2005;48:1153–60.

    Article  PubMed  Google Scholar 

  36. Higashi K, Ueda Y, Arisaka Y, et al. 18F-FDG uptake as a biologic prognostic factor for recurrence in patients with surgically resected non-small cell lung cancer. J Nucl Med 2002;43:39–45.

    PubMed  Google Scholar 

  37. Pillot G, Siegel BA, Govindan R. Prognostic significance of fluorodeoxyglucose positron emission tomography in non-small cell lung cancer: a review. J Thorac Oncol 2006;1:152–9.

    Article  PubMed  Google Scholar 

  38. Gearhart SL, Frassica D, Rosen R, Choti M, Schulick R, Wahl R. Improved staging with pretreatment positron emission tomography/computed tomography in low rectal cancer. Ann Surg Oncol 2006;13:397–404.

    Article  PubMed  Google Scholar 

  39. Melton GB, Lavely WC, Jacene HA, et al. Efficacy of preoperative combined 18-fluorodeoxyglucose positron emission tomography and computed tomography for assessing primary rectal cancer response to neoadjuvant therapy. J Gastrointest Surg 2007;11:961–9.

    Article  PubMed  Google Scholar 

  40. Guillem JG, Puig-La Calle J Jr, Akhurst T, et al. Prospective assessment of primary rectal cancer response to preoperative radiation and chemotherapy using 18-fluorodeoxyglucose positron emission tomography. Dis Colon Rectum 2000;43:18–24.

    Article  PubMed  CAS  Google Scholar 

  41. Denecke T, Rau B, Hoffmann KT, et al. Comparison of CT, MRI and FDG-PET in response prediction of patients with locally advanced rectal cancer after multimodal preoperative therapy: is there a benefit in using functional imaging? Eur Radiol 2005;15:1658–66.

    Article  PubMed  CAS  Google Scholar 

  42. Tatum JL, Kelloff GJ, Gillies RJ, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol 2006;82:699–757.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Benjamin Tan, Division of Oncology, Department of Medicine, and Drs. Matthew Mutch, Elisa Birnbaum, Ira Kodner, and James Fleshman, Section of Colon and Rectal Surgery, Department of Surgery at Washington University School of Medicine for their help and support in recruiting patients.

Author information

Authors and Affiliations

  1. Department of Colorectal Surgery, Cleveland Clinic, 9500 Euclid Avenue, Desk A-30, Cleveland, Ohio, 44195, USA

    David W. Dietz M.D.

  2. Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology, St. Louis, Missouri, USA

    Farrokh Dehdashti M.D. & Barry A. Siegel M.D.

  3. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA

    Farrokh Dehdashti M.D., Perry W. Grigsby M.D., Robert S. Malyapa M.D., Robert J. Myerson M.D., Joel Picus M.D., Jason S. Lewis Ph.D., Michael J. Welch Ph.D. & Barry A. Siegel M.D.

  4. Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA

    Perry W. Grigsby M.D., Robert S. Malyapa M.D. & Robert J. Myerson M.D.

  5. Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Joel Picus M.D.

  6. Department of Pathology, Washington University School of Medicine, St. Louis, Missouri, USA

    Jon Ritter M.D.

  7. Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, St. Louis, Missouri, USA

    Jason S. Lewis Ph.D. & Michael J. Welch Ph.D.

Authors
  1. David W. Dietz M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Farrokh Dehdashti M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Perry W. Grigsby M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert S. Malyapa M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert J. Myerson M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joel Picus M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jon Ritter M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jason S. Lewis Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael J. Welch Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Barry A. Siegel M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David W. Dietz M.D..

Additional information

Supported by an American Cancer Society Institutional Research Grant (ACS-IRG #58–010–46).

About this article

Cite this article

Dietz, D.W., Dehdashti, F., Grigsby, P.W. et al. Tumor Hypoxia Detected by Positron Emission Tomography with 60Cu-ATSM as a Predictor of Response and Survival in Patients Undergoing Neoadjuvant Chemoradiotherapy for Rectal Carcinoma: A Pilot Study. Dis Colon Rectum 51, 1641–1648 (2008). https://doi.org/10.1007/s10350-008-9420-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10350-008-9420-3

KEY WORDS

Search

Navigation