Clinical investigation: cervix
Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: Relationship to therapeutic response—a preliminary report

https://doi.org/10.1016/S0360-3016(02)04477-2Get rights and content

Abstract

Purpose

Tumor hypoxia is associated with poor response to therapy. We have investigated whether pretreatment tumor hypoxia assessed by positron emission tomography (PET) with Cu-60 diacetyl-bis(N4-methylthiosemicarbazone) (60Cu-ATSM) predicts responsiveness to subsequent therapy in cervical cancer.

Methods and materials

Fourteen patients with biopsy-proved cervical cancer were studied by PET with 60Cu-ATSM before initiation of radiotherapy and chemotherapy. 60Cu-ATSM uptake was evaluated semiquantitatively by determining the tumor-to-muscle activity ratio (T/M) and peak slope index of tumor tracer uptake. All patients also underwent clinical PET with F-18 fluorodeoxyglucose (FDG) before institution of therapy. The PET results were correlated with follow-up evaluation (14–24 months).

Results

Tumor uptake of 60Cu-ATSM was inversely related to progression-free survival and overall survival (log–rank p = 0.0005 and p = 0.015, respectively). An arbitrarily selected T/M threshold of 3.5 discriminated those likely to develop recurrence; 6 of 9 patients with normoxic tumors (T/M < 3.5) are free of disease at last follow-up, whereas all of 5 patients with hypoxic tumors (T/M > 3.5) have already developed recurrence. Similar discrimination was achieved with the peak slope index. The frequency of locoregional nodal metastasis was greater in hypoxic tumors (p = 0.03). Tumor FDG uptake did not correlate with 60Cu-ATSM uptake (r = 0.04; p = 0.80), and there was no significant difference in tumor FDG uptake between patients with hypoxic tumors and those with normoxic tumors.

Conclusion

60Cu-ATSM-PET in patients with cervical cancer revealed clinically relevant information about tumor oxygenation that was predictive of tumor behavior and response to therapy in this small study.

Introduction

Tumor hypoxia in several solid cancers, notably those of lung, head and neck, and uterine cervix, has been recognized for many years to be important in determining response to radiotherapy, because tumor cells become radioresistant at low oxygen tensions 1, 2. In addition, tumor hypoxia is associated with resistance to chemotherapy and with increased tumor aggressiveness, manifested as a higher rate of recurrence and metastasis 3, 4, 5, 6, 7. Therefore, considerable effort has been focused on methods to improve the oxygen content of hypoxic tumors. However, trials of most therapeutic strategies known to improve tumor oxygenation have not demonstrated clear improvement in patient outcome. Accordingly, the clinical relevance of tumor hypoxia remains controversial.

Direct measurement of oxygen tension in human tumors can be performed with polarographic oxygen electrodes (Eppendorf GmbH, Hamburg, Germany). The pretreatment oxygen tension assessed with this method has been shown to predict response to radiation therapy and survival in patients with cervical cancer 4, 8, 9, 10. However, this method is invasive and technically demanding and thus has not been widely used in clinical practice. Accordingly, there has been substantial interest in the development of noninvasive imaging methods for assessing tumor hypoxia. The most widely studied method involves the use of positron emission tomography (PET) with the radiolabeled nitroimidazole derivative, 18F-fluoromisonidazole (FMISO) (11). This compound is reduced enzymatically and trapped within hypoxic cells. However, because of relatively low relative uptake of FMISO in hypoxic tissues, its clinical application has had limited success.

Recently, Fujibayashi and colleagues have developed copper-labeled diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM), which appears to be more optimal for imaging hypoxic tissues (12). Cu-ATSM, as with FMISO, is reduced and retained in hypoxic tissues, but its uptake occurs more rapidly and the hypoxic/normoxic tissue activity ratio is greater, likely reflecting the greater membrane permeability of Cu-ATSM and its more rapid blood clearance (13). We thus undertook a pilot study to determine whether there is a relationship between tumor uptake of 60Cu-ATSM assessed by PET and response to therapy in patients with locally advanced cervical cancer.

Section snippets

Patients

We prospectively studied 14 patients (ages 23–84 years) with biopsy-proved cervical cancer who underwent PET with 60Cu-ATSM before initiation of therapy. This investigation was approved by the Human Studies Committee and the Radioactive Drug Research Committee of Washington University School of Medicine. Each patient gave written informed consent before participating in the study.

All patients were initially evaluated before treatment with a history (smoking history was not recorded) and

Results

All patients had locally advanced cervical cancer with primary lesions >2.0 cm in diameter (FIGO clinical Stage IB1 in 1, Stage IB2 in 1, Stage IIB in 8, and Stage IIIB in 4). The tumor histology was squamous cell carcinoma in 13 and adenosquamous carcinoma in 1. A summary of the pertinent clinical data and study results for these patients is shown in Table 1.

The clinical FDG-PET studies demonstrated markedly increased FDG uptake in the primary cervical tumors of all 14 patients. The mean SUV

Discussion

Hypoxia is a common feature of solid tumors and has an important role in determining response to therapy and tumor progression (2). Therefore, several therapeutic strategies, including blood transfusions, hyperbaric oxygenation, split-course irradiation, neutron irradiation, and hypoxic cell sensitizers, have been used in attempts to overcome hypoxia in a variety of tumors. However, none of these therapeutic strategies currently has been proven to have an important impact on patient outcome (22)

References (33)

  • D.M. Brizel et al.

    Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas

    Cancer Res

    (1996)
  • M. Höckel et al.

    Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix

    Cancer Res

    (1996)
  • E.K. Rofstad et al.

    Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis

    Br J Cancer

    (2000)
  • D. Shweiki et al.

    Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis

    Nature

    (1992)
  • T.G. Graeber et al.

    Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumors

    Nature

    (1996)
  • M. Höckel et al.

    Tumor hypoxia in pelvic recurrences of cervical cancer

    Int J Cancer

    (1998)
  • Cited by (0)

    Supported by NIH Grant CA81525 and DOE Grant DE-FG02-87.

    View full text