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© 2002 American Society for Clinical Oncology Tumor Hypoxia Has Independent Predictor Impact Only in Patients With Node-Negative Cervix CancerByFrom the Departments of Radiation Oncology, Medicine, Biostatistics, Clinical Informatics, and Experimental Therapeutics, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network and University of Toronto, Toronto, Canada. Address reprint requests to Anthony Fyles, MD, Department of Radiation Oncology, Rm 5-984, Princess Margaret Hospital, 610 University Ave, Toronto, Ontario, Canada M5G 2M9; email: anthony.fyles{at}rmp.uhn.on.ca
PURPOSE: This prospective clinical study was begun in 1994 to validate the independent prognostic impact of tumor hypoxia in patients with cervix cancer treated with definitive radiation therapy. PATIENTS AND METHODS: Between May 1994 and January 1999, 106 eligible patients with epithelial cervix cancer had tumor oxygen pressure (PO2) measured using the Eppendorf probe. Oxygenation data are presented as the hypoxic proportion, defined as the percentage of PO2 readings less than 5 mm/Hg (abbreviated as HP5) and the median PO2. RESULTS: The median HP5 in individual patients was 48%, and the median PO2 was HP5. Progression-free survival (PFS) for patients with hypoxic tumors (HP5 > 50%) was 37% at 3 years versus 67% in those patients with better oxygenated tumors (P = .004). In multivariate analysis, only tumor size (risk ratio [RR], 1.33; P = .0003) and evidence of pelvic nodal metastases on imaging studies (RR, 2.52; P = .0065) were predictive of PFS. However, an interaction between nodal status and oxygenation was observed (P = .006), and further analysis indicated that HP5 was an independent predictor of outcome in patients with negative nodes on imaging (P = .007). There was a significant increase in the 3-year cumulative incidence of distant metastases in the hypoxic group (41% v 15% in those with HP5 < 50%; P = .0023), but not in pelvic relapse (37% v 27%; P = .12). CONCLUSION: Tumor hypoxia is an independent predictor of poor PFS only in patients with node-negative cervix cancer, in addition to tumor size. Its impact appears to be related to an increased risk of distant metastases rather than to an effect on pelvic control.
THERE IS INCREASING interest in biomarkers for the prediction of treatment outcome in oncology, in part related to our greater understanding of the molecular and genetic factors involved in tumor progression. Tumor hypoxia is a microenvironmental factor related to poor response to radiation and chemotherapy, genetic instability, selection for resistance to apoptosis, and increased risk of invasion and metastasis.1-5 In patients with cervix cancer, it has been associated with an increased risk of relapse and death.6-8 Hypoxia has also been shown to have a prognostic impact in patients with head and neck tumors and soft tissue sarcomas.9,10 However, clinicopathologic features, such as tumor stage and size, are related to prognosis, and previous clinical studies of hypoxia have not always evaluated these in sufficient detail. Thus, the independent effect of hypoxia remains unclear. The analysis presented here describes the results of a prospective program that evaluated hypoxia in patients with cervix cancer treated by definitive radiation therapy alone at the Princess Margaret Hospital (PMH). This program was developed to validate the hypothesis that tumor hypoxia has a prognostic impact that accounts for the known effects of clinical and pathologic features. Our intention was to perform and analyze this clinical study in a rigorous manner, using strict methodology and statistical criteria for confirmatory prognostic factor studies.11 This was done to assess the independent value of hypoxia in predicting progression-free survival (PFS) (the primary objective), and as a marker of treatment response (pelvic and distant control as secondary objectives), as well as its role in clinical decision making in relation to standard prognostic factors.
This was a single-institution prospective study. An inception cohort of eligible subjects was defined that included newly diagnosed women with grossly evident, biopsy-proven carcinoma of the cervix for whom definitive radiation therapy alone was the planned treatment. Patients with clinically occult tumors or a prior malignancy were ineligible, and those who were subsequently treated surgically or who received chemotherapy as part of initial management were excluded from analysis of outcome. This study was approved by the Clinical Trials Committee of the PMH, and the Human Subjects Review Committee of the Office of Research Services at the University of Toronto. Written informed consent was obtained from each participant before study entry.
Investigation and Treatment External-beam radiotherapy was delivered to the pelvis or pelvis and para-aortic region (depending on the results of staging and lymphangiography), using a planned dose of 45 to 50 Gy in 1.8-to-2-Gy daily fractions with 18-to-25-MV photons. A four-field box technique was used to treat the pelvis, whereas anterior-posterior parallel opposed fields were used for the pelvis and para-aortic nodes. External radiation was followed by a single intracavitary brachytherapy application using an intrauterine line source. A planned dose of 35 to 40 Gy was prescribed 2 cm lateral to the midpoint of the sources (equivalent to Point A) using either low-dose rate or pulsed-dose rate equipment. Adjuvant or neoadjuvant chemotherapy was not used, and neither was concurrent chemoradiation.
Oxygen Electrode Measurements Follow-up clinical visits after completing radiotherapy were performed by the responsible physician every 3 months for the first 2 years and every 4 to 6 months during the third to fifth years. A general physical examination and pelvic examination were performed at each visit, as well as a pelvic MRI at 3 to 6 months after treatment. MRIs and other diagnostic tests were performed thereafter only as indicated clinically.
Data Analysis The study was designed to enter 150 patients, which would result in approximately 60 events at 2 years of follow-up, with an 84% power to detect a two-fold increase in the hazard ratio for hypoxic versus oxic tumors, assuming a 2-year PFS of 70%. However, because of a change in treatment policy with the addition of concurrent cisplatin chemotherapy in the second quarter of 1999, it was not possible to accrue further patients treated with radiation alone, and the study was closed prematurely, with 106 eligible patients entered. Nevertheless, the study power was maintained because accrual took 5 years rather than the anticipated 3 years, a minimum of 1 year of follow-up was added, the PFS at 2 years was lower than anticipated (56%), and HP5 was evaluated as a continuous rather than a dichotomous variable. Assuming that the effect of hypoxia evaluated as a continuous variable is best represented by the difference between the first and third quartiles, this results in 87% power to detect an increase in the hazard ratio of 1.018 for each unit of increase in HP5.
Between May 1994 and January 1999, 116 patients with cervix cancer were entered onto the study and completed measurements of tumor oxygenation. Ten patients were excluded, eight had locally advanced or metastatic disease at subsequent radiologic evaluation that was treated with chemotherapy or palliative radiation, one patient chose to have surgery, and one had cervix sarcoma on pathology review. Characteristics of the remaining 106 patients are shown in Table 1. The maximum tumor diameter ranged from 2 to 10 cm, with a median size of 5 cm. Positive pelvic lymph nodes were identified using imaging in 22 patients, and positive para-aortic lymph nodes were seen in two patients (both also had pelvic lymphadenopathy).
The majority of patients received the planned treatment, with a median external pelvic radiation dose of 50 Gy (range, 40 to 52 Gy) in 25 fractions (range, 20 to 28 fractions). Two patients received less than the planned pelvic dose (both were treated to 40 Gy). Ninety-nine patients received intrauterine brachytherapy to a median dose of 40 Gy (range, 20.2 to 40 Gy) to Point A at a median dose rate of 0.68 Gy/h. Four of these patients received less than the planned intracavitary dose of 35 Gy (range, 20.2 to 30.8 Gy). Seven patients did not receive intracavitary brachytherapy, typically as a result of unfavorable tumor anatomy. Six of these patients received an additional external radiation small-field boost of between 5 and 20 Gy, and only one patient did not complete treatment, receiving external pelvic radiation alone without a boost. The median treatment duration was 41 days (range, 32 to 83 days), with 98 patients treated in 8 weeks or less. A median of five needle tracks (range, one to seven tracks) were made in each tumor before treatment, with four or more tracks in 82% of patients. A median of 128 oxygen measurements (range, 25 to 185 measurements) was made in each tumor. No complications were noted as a result of the procedure. The HP5 in individual patients ranged between 0% and 99%, with a mean and median of 47% and 48%, respectively. The median PO2 in individual tumors ranged from 0 to 94 mm/Hg, with a group mean and median of 14 and 5 mm/Hg, respectively. There was a strong correlation between these two measures of hypoxia (r = -.91) and, as mentioned, HP5 has been selected as the primary measure of hypoxia for analysis. The correlation between tumor size and HP5 or median PO2 was weak (r = .24 and r = -.23, respectively). There was no correlation observed between oxygenation and pretreatment hemoglobin level (r = -.13 for HP5 and r = .10 for median PO2) nor with stage, age, histologic grade, or smoking status.
There were 47 events (relapses or deaths), with a median follow-up time in alive patients of 2.5 years (range, 0.5 to 5.5 years; three patients were lost to follow-up at 0.9, 1.1, and 1.8 years). Overall survival estimated at 3 years was 65%, and the PFS rate was 53%. For patients with an HP5 of
Multivariate Analysis In the first Cox model, where the clinical factors FIGO stage, tumor size, imaging nodal status, and pretreatment hemoglobin were considered, only tumor diameter (P = .0004; risk ratio [RR], 1.32) and nodal status (P = .0068; RR, 2.51) were significant independent predictors of PFS (Table 3). When HP5 was added to the clinical model, it failed to provide additional prognostic information (P = .11; RR, 1.01). However, an interaction between nodal status and HP5 was noted (P = .006), such that the effect of HP5 differed between node-negative and node-positive groups. Therefore HP5 was tested separately in the node-negative and node-positive subgroups (Table 4). In the node-negative group (n = 84), both tumor size (P = .0012; RR, 1.41) and HP5 (P = .007; RR, 1.02) independently predicted outcome, whereas in the node-positive group (n = 22), neither tumor size (P = .16; RR, 1.18) nor HP5 (P = .18; RR, 0.99) were significant. PFS of node-negative patients stratified by median tumor size and HP5 is shown in Fig 2.
Sites of Relapse An exploratory analysis of the effect of hypoxia on pelvic and distant relapse was performed. The cumulative incidence of pelvic relapse at 3 years was 37% in the hypoxic group and 27% in those with HP5 less than 50% (P = .12) (Fig 3). In contrast, there was a significant increase in distant metastases in the hypoxic group (cumulative incidence of 41% v 15%; P = .0023) (Fig 4). Multivariate analysis revealed that tumor size (P = .0018) and HP5 (P = .032) were independently predictive of distant failure (Table 5). In the multivariate analysis of pelvic relapse, only tumor size was significant (P = .0008) (Table 6).
Prognostic Model On the basis of the analysis of these three significant covariates for PFS, and by examining the RRs for relapse, we defined three patient risk groups as follows: good risk (n = 35), consisting of patients with small (  5 cm), imaging node-negative, well-oxygenated tumors (HP5 50%); intermediate risk (n = 31), consisting of patients with node-negative, small hypoxic (HP5 > 50%) and large oxygenated tumors; and high risk (n = 40), consisting of those with node-positive or large hypoxic node-negative tumors. PFS curves are shown in Fig 5 and demonstrate highly significant differences in prognosis between the three groups (P < .00001). The high-risk group of patients (38% of the total population) had only a 23% probability of PFS at 3 years. Conversely, the low-risk group of patients had a PFS of 79% at 3 years after treatment with radiation therapy alone, and intermediate-risk patients had a PFS of 59%.
Although this prospective study does not confirm the global hypothesis that hypoxia has independent prognostic impact for PFS in patients with hypoxic cervix tumors, it does demonstrate that hypoxia has substantial impact in a large subgroup of patients with clinically negative lymph nodes. Because this subgroup was identified on the basis of a significant observed interaction between hypoxic status and nodal involvement, it is likely to represent a valid relationship between hypoxic and outcome in node-negative patients. Similarly, although the number of patients entered was less than predicted, power was maintained because the event rate was sufficient because of longer accrual and follow-up and lower than predicted PFS. Simon and Altman11 have defined a rigorous set of guidelines for confirmatory prognostic factor studies, based on prespecified hypotheses and end points in a prospectively collected and therapeutically homogeneous group of patients to determine reliably the impact of new biomarkers. We have adhered to these guidelines as much as possible in performing and analyzing this trial. The effect of hypoxia in patients with positive nodes appears to be lost as a result of the known strong association between hypoxia and nodal metastases,24,25 although these conclusions are limited by the small numbers of node-positive patients in the study. Furthermore, the limitation that imaging was used to define nodal status may have led to false-positive and false-negative nodal staging compared with surgical dissection. This is a limitation of any imaging study; indeed, 21 of the patients in this trial had equivocal evidence for nodal involvement, typically multiple small nodes not meeting the size criteria for involvement. Because their outcome was similar to node-negative patients, they were grouped together for analysis. However, when separated by hypoxic status, patients with equivocal nodes and oxic tumors (n = 11) had a PFS at 3 years of 72% versus 30% for those with equivocal nodes and hypoxic tumors (n = 10; P = .08). These results are similar to those for node-negative and node-positive patients, which suggests that hypoxic status of the tumor may contribute to the assessment of nodal involvement on imaging studies, although larger numbers of patients will be required to assess the additional contribution of tumor size. Tumor hypoxia was associated with distant metastatic relapse but not with relapse in the irradiated pelvis. The lack of a relationship between hypoxia and pelvic failure in our analysis suggests that tumor hypoxia may not be associated with radiation resistance, perhaps because reoxygenation during treatment is sufficient to overcome the effects of hypoxia in patients treated with both external radiation and brachytherapy. However, the analyses of secondary end points should be considered hypothesis-generating rather than definitive, and this trial is somewhat restricted in its ability to detect small differences in pelvic control because of the limited number of relapses experienced. Nevertheless, the strength of the relationship between hypoxia and distant relapse is consistent with other studies, such as those recently reported from the Norwegian Radium Hospital.26 In a group of 32 patients, they found a significant effect of hypoxic fraction on survival (P = .056) but not pelvic control (P = .22) and an effect of tumor volume on both end points (P = .0001 and P = 0.02, respectively, in univariate analysis). They also multiplied the two to generate the hypoxic subvolume, a concept originated by Stadler et al.27 Not surprisingly, the hypoxic subvolume had prognostic impact; however, in our patients, it did not add additional information to that provided by tumor size and HP5 individually. Other studies that have assessed the effect of tumor hypoxia on pelvic control have found conflicting results. Knocke et al8 found a borderline-significant relationship between hypoxia and pelvic relapse on univariate analysis (P = .053) in 51 patients treated with radiation, although the independent effect of hypoxia, including other prognostic factors such as tumor size, was not assessed.22 Hockel et al3 noted a greater risk of pelvic relapse in cervix cancer patients with hypoxic tumors treated surgically as well as with radiation; however, again, a multivariate assessment of pelvic control was not performed. The increased risk of nodal and distant metastases in hypoxic tumors may be related to upregulation of hypoxia-responsive genes associated with angiogenesis, invasion, and metastasis, as has been demonstrated in experimental systems.28-30 In addition, hypoxia selects for tumor cells that are genetically unstable4 and resistant to apoptosis,1 both of which may result in increased risk of disease progression to a more malignant and treatment-resistant phenotype. As part of our prospective program, we have also been measuring tumor interstitial fluid pressure (IFP) in these patients. In a recent analysis,16 we found that elevated IFP is also an independent predictor of outcome, in addition to hypoxia. Furthermore, the prognostic effect of IFP is not affected by nodal status. Elevated IFP is related to abnormalities of the tumor vasculature and may reflect differences in angiogenesis mediated by hypoxia-responsive proteins, such as vascular endothelial growth factor. The combined effect of tumor size, imaging nodal status, and hypoxic fraction defines groups with significantly different risks of recurrence or death. High-risk patients have only a 23% PFS rate at 3 years when treated with radiation alone and are appropriate candidates for novel therapies in clinical trials. Intermediate-risk patients may benefit from the addition of chemotherapy to radiation, as demonstrated in several randomized studies.31-34 Low-risk patients have a 79% PFS rate after radiation alone, and the small benefits of chemotherapy must be weighed against the potential increased toxicity. The addition of oxygenation status to the clinical prognostic model on the basis of tumor size and nodal status alone resulted in reclassification of 36 patients (18 small node-negative with a PFS rate of 59% misclassified as low-risk and 18 node-negative large hypoxic with a PFS rate of 32% misclassified as intermediate-risk) and greater separation of the PFS curves. We, therefore, believe we can now recommend that tumor oxygenation studies be part of routine pretreatment assessment at our center, especially for patients with negative nodes on imaging studies. Use of the Eppendorf probe as a measure of tumor hypoxia is somewhat cumbersome and expensive; however, assays that are more user-friendly are in development and will allow the probe’s wider use as a prognostic factor and in multicenter clinical trials.35-37 The therapeutic implications of these findings suggest that treatment approaches using radiation sensitizers and carbogen breathing may not be effective because hypoxia in the primary tumor may be reduced by reoxygenation during treatment. Rather, hypoxia should be exploited as a therapeutic target in studies of novel drugs and hypoxia-targeted gene therapy.29 Tirapazamine is a promising compound that is both toxic to hypoxic cells38 and potentiates cisplatin cytotoxicity,39 an ideal combination in the treatment of cervix cancer. In the next phase of our prospective study, we will evaluate the impact of oxygenation in a cohort of patients who have been treated with chemoradiation using weekly cisplatin and will validate the performance of the prognostic model in these patients. In summary, tumor hypoxia is an independent predictor of poor PFS in patients with node-negative cervix cancer, in addition to tumor size. Its impact appears to be related to an increased risk of distant metastases rather than an effect on pelvic control. Hypoxia measurements may also be used as part of a prognostic index to provide an improved estimation of outcome in individual patients. Tumor hypoxia thus appears to be a clinically relevant feature of the tumor microenvironment that provides novel information about the biologic behavior of cervix cancer and its outcome after radiation treatment.
Supported by a grant from the National Cancer Institute of Canada and the Terry Fox Run, Toronto, Canada. We thank Ami Syed and Shelley Sprague for clinical trials support and Alex Sun, Raimond Wong, James Wylie, Katrien De Jaeger, and Graham Pitson, who were clinical fellows in the program.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
