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Anemia is associated with decreased local control of surgically treated squamous cell carcinomas of the glottic larynx
Int. J. Radiation Oncology Biol. Phys., Vol. 48, No. 5, pp. 1345–1350, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$–see front matter
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CLINICAL INVESTIGATION
Head and Neck
ANEMIA IS ASSOCIATED WITH DECREASED LOCAL CONTROL OF SURGICALLY TREATED SQUAMOUS CELL CARCINOMAS OF THE GLOTTIC LARYNX JOHANNES LUTTERBACH, M.D.
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ROLAND GUTTENBERGER, M.D.
*Abteilung Strahlenheilkunde, Radiologische Universita¨tsklinik, Hugstetterstrae, Freiburg, Germany Purpose: A strong association between hemoglobin levels and tumor control exists in head and neck cancer treated with radiotherapy. This retrospective study has been performed to determine whether or not this association can also be found in the surgical setting. Methods and Materials: Between January 1970 and December 1990, 258 patients with glottic SCC received conventional surgery only (T1/T2/T3/T4 n ⴝ 188/31/37/2, respectively). Locoregional control was calculated by the Kaplan–Meier method. The influence of hemoglobin, T stage, age, gender, performance/nutritional status, and grading was evaluated using a Cox model. Results: Five-year locoregional control for T1a/T1b/T2/T3/T4 tumors was 91%/85%/76%/62%/0%, respectively (log–rank test, p < 0.0001). Anemia (male < 13, female < 12 g/dL hemoglobin) was present in 27 patients. It was associated with significantly worse 5-year locoregional control, i.e., 60% vs. 85% (log–rank test, p ⴝ 0.003). In multivariate analysis stratified for T stage, two variables were of influence: positive margins (relative risk [RR], 3.8; 95% confidence interval [CI], 1.7– 8.4), anemia (RR, 3.0; 95% CI, 1.4 – 6.2). The largest subgroup consisted of 162 patients characterized by male gender, T1, and complete resection. In this subgroup, the significant variables were T stage (T1b vs. T1a; RR, 3.5; 95% CI, 0.96 –12.4) and hemoglobin with a RR of 1.4 (95% CI, 1.0 –2.1) per g/dL less analyzed as a continuous variable. Conclusion: Anemia is associated with a high risk of treatment failure in surgically treated glottic cancer. Hemoglobin levels might be predictive even within the normal range as indicated by subgroup analysis. © 2000 Elsevier Science Inc. Glottic cancer, Hemoglobin, Surgery, Local control, Prognosis.
Anemia is a frequent finding in cancer patients. A number of studies including our own data (1) found anemia to be an independent predictor of poor disease-free and/or overall survival in cancer of various sites, e.g., head and neck (2–11), lung (12, 13), uterine cervix (14, 15), and bladder (16). Bentzen et al. (8) analyzed pretreatment hemoglobin (Hb) as a continuous variable and found a steep dose– response relationship with best tumor control in patients with Hb levels in the upper normal range. It is not yet understood how Hb and outcome of radiotherapy are linked. However, for low Hb levels an increased fraction of hypoxic and hence radioresistant tumor cells has been postulated (2, 4 –11). According to van Acht et al. (2), early-stage head and neck tumors are of interest when studying the influence of Hb on tumor control. The tumor
volume is relatively small, which makes blood loss unlikely. Distant metastases are rare. Therefore, low Hb levels should not be a surrogate marker of advanced disease. In a recently published series, T1–T2 glottic carcinomas patients with high Hb levels had significantly lower local recurrence rates than those with low Hb at admission (4, 5, 11). In all of these studies, treatment consisted of radiotherapy alone. Little or nothing is known of whether or not the association of Hb with tumor control is unique to radiation oncology. Therefore, we retrospectively collected the data from the Department of Otorhinolaryngology, University Hospital Freiburg, to analyze specifically the influence of Hb on locoregional tumor control of surgically treated patients taking other potential prognostic factors into account. Here we report the results for all patients with glottic carcinoma treated with conventional surgery alone.
Reprint requests to: Dr. Johannes Lutterbach, Abteilung Strahlentherapie, Radiologische Universita¨tsklinik, Hugstetterstrae 55, 79106 Freiburg i. Br., Germany. E-mail: [email protected] Presented at the 41st Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology, October 31– November 4, 1999, San Antonio, TX (USA). Acknowledgment—Dedicated to our teacher, Prof. Joachim Sla-
nina, in honor of his 65th birthday. The authors would like to thank Dr. Chlodwig Beck, emeritus director of the Department of Otorhinolaryngology, University Hospital Freiburg, for his generous support in all questions concerning laryngeal surgery. We wish to thank Margit Guttenberger for proofreading this manuscript. Accepted for publication 27 April 2000.
INTRODUCTION
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METHODS AND MATERIALS Patients Between January 1970 and December 1990, a total of 258 patients with newly diagnosed, histologically confirmed squamous cell carcinoma of the glottic larynx were treated by conventional surgery alone at the University Hospital Freiburg. 242 patients were male and 16 female. Median age was 64 years (range, 15–94 years; 25% percentile, 54 years; 75% percentile, 72 years). Preoperatively, all patients were seen in the department of internal medicine where the majority was judged to have a World Health Organization performance status of 0 or 1 (n ⫽ 196). Nutritional status was normal in 249 patients, indicated by a body–mass index (BMI) of at least 18.5 kg/m2 (17). Hb levels were determined at admission. The normal Hb range in our hospital was 13.0 –18.0 g/dL for males and 12.0 –16.0 g/dL for females; 231 patients had normal Hb levels, 27 were anemic. Median pretreatment Hb was 14.5 g/dL (range, 9.3– 18.1 g/dL; 25% percentile, 13.5 g/dL; 75% percentile, 15.5 g/dL). Tumors The primary tumor site was assessed by direct laryngoscopy and biopsy. All cases were uniformly restaged according to the UICC classification of 1997 (18). One hundred eighty-eight patients had T1 tumors (T1a ⫽ tumor limited to one vocal cord, n ⫽ 92; or T1b ⫽ tumor involving both vocal cords, n ⫽ 96). T2 tumors were found in 31 patients (T2 ⫽ tumor with supra- and/or subglottic extension and/or impaired vocal cord mobility). T3 carcinomas were diagnosed in 37 cases (T3 ⫽ tumor confined to the larynx with vocal cord fixation). Two patients presented with T4 lesions (T4 ⫽ tumor invading through the thyroid cartilage and/or extending beyond the larynx). All patients had negative neck nodes (cN0 or pN0) and were free of distant metastases (M0). Tumor differentiation was good in 29, moderate in 164, and poor in 65 cases. Treatment Laryngofissure and cordectomy was the treatment of choice for T1a tumors. In cases with very anteriorly located carcinomas, frontolateral/anterior laryngectomies were carried out to obtain clean margins. Resection of T1b tumors was done by frontolateral or frontoanterior laryngectomy. Most of the patients with more advanced lesions had total laryngectomy. In 21 cases (8%), resection remained microscopically incomplete. Further therapy had been either declined by the patient or judged not to be indicated due to age or comorbidity. The only patients excluded from this study were those receiving primary treatment other than conventional surgery alone. Laser surgery was introduced in our head and neck clinic in 1987, when only selected cases were treated, and became standard in the last decade. Postoperative radiotherapy was reserved for selected T3 tumors, all T4 tumors
Fig. 1. Kaplan–Meier plots of locoregional control after conventional surgery for glottic cancer in 258 patients show significant (p ⫽ 0.003) impact of pretreatment anemia.
(with two exceptions) and for patients with positive neck nodes. Locoregional control at 5 years was estimated by the product limit method of Kaplan and Meier. The log–rank test was employed to test for statistically significant differences. For multivariate analysis, we used a Cox model (proportional hazards). Significant variables were chosen by forward and by backward selection (19, 20).
RESULTS For event-free patients (n ⫽ 215), median follow-up was 71 months with a range of 7–282 months. Locoregional relapse was observed in 43 patients (local n ⫽ 29; local and regional n ⫽ 8; regional n ⫽ 6). Median time interval from primary treatment to locoregional failure was 10 months (range, 3–57 months). Actuarial 5-year locoregional control was 82%. Stratification for T stage yielded 91% for T1a, 85% for T1b, 76% for T2, 62% for T3, and 0% for T4 tumors, respectively. Normal Hb values rendered 5-year control rates of 85% compared to 60% for anemia (p ⫽ 0.003, see Fig. 1). Patients were also stratified according to Hb percentiles (25th, 50th, 75th). Sixty patients had Hb values less than 13.5 g/dL. Sixteen of them experienced locoregional failure, as did 9 of 68 patients with Hb between 13.5 and 14.4 g/dL. Tumor recurrence occurred in 9 of 63 patients with Hb levels from 14.5 to 15.4 g/dL and in 9 of 67 patients with Hb levels of at least 15.5 g/dL. Actuarial locoregional control at 5 years was 72%, 85%, 85%, and 86% for the aforementioned Hb classes, respectively. In multivariate analysis stratified for T stage we evaluated the influence of anemia, resection margins, grading, age, gender, and performance/nutritional status using a proportional hazards model (Table 1). Two variables were significant: positive margins carried a 3.8-fold risk (95% confidence interval [CI], 1.7– 8.4; p ⫽ 0.001), anemia a 3.0-fold risk (95% CI, 1.4 – 6.2; p ⫽ 0.004). Of the other variables tested, body mass index, analyzed as a continuous variable, was the only to show
Anemia predicts recurrence of glottic cancer
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Table 1. Results of univariate and multivariate analysis using a Cox model Analysis Multivariate Variable Anemia yes vs. no Positive margins yes vs. no Age continuous Performance status WHO 0/1 vs. WHO 2 Nutritional condition BMI continuous Grading 1/2 vs. 3 Gender female vs. male
Frequency
Univariate p
p
RR
CI (95%)
231/27 21/237
0.005 0.001
0.004 0.001
3.0 3.8
1.4–6.2 1.7–8.4
0.62 0.86 0.30 0.68 0.57
(0.34) (0.65) (0.1) (0.80) (0.54)
(1.0) (0.9) (1.1) (1.1) (1.6)
196/62 193/65 16/242
final model
full model
The proportional hazards models used were stratified for T stage. Numbers in parentheses were generated in a “full model” containing all listed variables. Anemia carries a relative risk (RR) of 3.0 for locoregional relapse obtained from analyzing all 258 patients. The only other significant variable was “positive margins.” The final model contained these two variables independent of the kind of selection procedure used (forward or backward). Abbreviations: WHO ⫽ World Health Organization; BMI ⫽ body-mass index; RR ⫽ relative ratio; CI ⫽ confidence interval.
a weak association with higher values indicating a higher risk. However, this was not significant (p ⫽ 0.1). To analyze Hb as a continuous variable, female patients were omitted because of their gender specific lower Hb values. This left 242 male patients on which the above analysis was repeated. The results did not differ markedly (Table 2). Each g/dL Hb less yielded a relative risk of 1.4 for tumor recurrence (95% CI, 1.1–1.8; p ⫽ 0.005). In a further attempt to avoid confounding factors, T2–T4 tumors and incompletely resected tumors were excluded. This resulted in a very homogeneous population of 162 patients (median age: 65 years; BMI ⱖ 18.5 kg/m2, n ⫽ 156; Grade 1/2/3: n ⫽ 22/111/29 cases, respectively). Median Hb was 14.7 g/dL (range, 10.9 –18.1 g/dL; 25% percentile, 13.6 g/dL; 75% percentile, 15.5 g/dL). Eighteen patients had Hb values below 13.0 g/dL. Tumor recurrence was observed in 14 patients (local n ⫽ 12; local and regional n ⫽ 1; regional n ⫽ 1). Median time interval from primary treatment to locoregional failure was 15 months (range, 7–58 months). Actuarial 5-year locoregional control
was 91%. Stratification for T stage yielded 96% for T1a and 86% for T1b (p ⫽ 0.05). Five-year locoregional control was 92% in patients with Hb of at least 13.0 g/dL compared to 80% in the anemic group (p ⫽ 0.05). 34 patients had Hb values less than 13.5 g/dL. 5 of them experienced locoregional failure. So did 5 of 45 patients with Hb between 13.5 and 14.4 g/dL. Tumor recurrence occurred in 3 of 40 patients with Hb levels from 14.5 to 15.4 g/dL and in 1 of 43 patients with Hb levels of at least 15.5 g/dL. Locoregional control was 84%, 88%, 92%, and 97% for the aforementioned Hb classes, respectively (p ⫽ 0.23). Anemia, age, performance/nutritional status, and grading were evaluated in a proportional hazards model stratified for T stage (T1a/T1b). Although we saw a trend for lower tumor control in anemic patients in this setting as well, no variable turned out to be significant. Analyzed as a continuous variable, each g/dL Hb less yielded a relative risk of 1.4 for tumor recurrence (see Table 3).
Table 2. Results of subgroup analysis (male patients only) Analysis Multivariate Variable
Frequency
Univariate p
Hemoglobin [g/dL] continuously decreasing Positive margins yes vs. no
20/222
0.01 0.001
Age continuous Performance status WHO 0/1 vs. WHO 2 Nutritional condition BMI continuous Grading 1/2 vs. 3
187/55 182/60
0.33 0.67 0.41 0.95
p
RR
CI (95%)
0.005 0.0004
1.4 4.4
1.1–1.8 1.9–10
(0.24) (0.72) (0.18) (0.70)
(1.0) (0.9) (1.1) (1.2)
final model
full model
Same analysis as in Table 1. By omitting the 16 female patients, anemia could be replaced by hemoglobin as a continuous variable. Each g/dl hemoglobin less carries a relative risk (RR) of 1.4 for locoregional relapse obtained from analyzing all 242 male patients. Abbreviations: WHO ⫽ World Health Organization; BMI ⫽ body-mass index; RR ⫽ relative ratio; CI ⫽ confidence interval.
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Table 3. Results of subgroup analysis (male patients with complete resection of T1 tumor) Analysis Multivariate Variable
Frequency
Univariate p
Hemoglobin [g/dL] continuously decreasing Tumor stage T1b vs. T1a
85/77
0.05 0.05
0.05 0.06
1.4 3.5
0.80 0.37 0.73 0.78
(0.37) (0.69) (0.32) (0.50)
(1.0) (0.75) (1.1) (0.6)
Age (continuous) Performance status WHO 0/1 vs. WHO 2 Nutritional condition BMI continuous Grading 1/2 vs. 3
130/32 133/29
p
RR
CI (95%) 1.0–2.1 1.0–12
final model
full model
Same analysis as in Table 2 but stratification could be dropped by omitting patients with T2-T4 or positive margins. Again, each g/dl hemoglobin less carries an RR of 1.4 for locoregional relapse obtained from analyzing this very homogenous group of 162 male patients. This confirms the results from the models stratified for T stage given in Tables 1 and 2. Abbreviations: WHO ⫽ World Health Organization; BMI ⫽ body-mass index; RR ⫽ relative ratio; CI ⫽ confidence interval.
DISCUSSION Hemoglobin in surgical oncology Our data shows a detrimental effect of moderate anemia before therapy on locoregional control in conventionally operated patients with glottic cancer. We found that higher levels of Hb were associated with better local control, even in the normal range. This was particularly true for a very homogeneous subgroup of male patients with completely resected T1 tumors. To the best of our knowledge, this is the first publication dealing with this subject in head and neck cancer patients. Vigario et al. (21) grouped patients with Stage I or II uterine cervix cancer according to initial Hb levels of 10.0 or less, 11.0 –13.0 and ⬎ 13.0 g/dL. Five-year cause-specific survival was 60%, 73%, 83% for radical resection (n ⫽ 258) and 59%, 69%, 76% for definite radiotherapy (n ⫽ 398), respectively. His results can be criticized because the surgical group included patients who had planned postoperative radiotherapy and no separate analysis was presented for the 181 patients with radical resection only. In a multivariate analysis recently presented by Obermair et al. (22), the relative risk of death was significantly associated with decreasing hemoglobin levels in patients with ovarian cancer. Other than age, no patient related variable was examined. Three different histologic subtypes were included. Residual tumor was present in 91 patients; 146 had chemotherapy, 35 underwent radiotherapy, 6 were put on hormone therapy, and 2 patients did not receive any adjuvant therapy. Intraoperative or postoperative transfusions were given to 32 patients, and 16 patients received erythropoietin postoperatively. Both inhomogeneities with regard to tumor- and treatment-related variables and the omission of factors, such as performance status, do not allow any conclusions concerning the role of hemoglobin in this study. Hemoglobin in radiation oncology In contrast to the sparse surgical data, the effect of anemia on outcome in head and neck cancer patients has been the
topic of several radiotherapy studies. Taskinen (23) examined laryngeal carcinomas treated with definite radiotherapy. Five-year survival differed significantly in patients with T1 tumors and Hb of at least 11.5 g/dL or less than 11.5 g/dL: 74% (107/145) vs. 47% (14/30). Subgroups with Hb values of less than 10.0, 10.0 –11.4, 11.5–13.4, and 13.5 or greater had 5-year survival rates of 20%, 33%, 51%, and 55%, respectively. Taskinen concluded that a low Hb value at the beginning of treatment implied a poorer prognosis than a high Hb value. Van Acht et al. (2) described that in laryngeal carcinoma patients with Hb levels below normal at the start of radiotherapy, disease-free survival was worse, although not significantly different from the nonanemic patients (p ⫽ 0.08). Fein et al. (4) studied 109 T1/T2 glottic carcinomas treated with definite radiotherapy. Actuarial 2-year local control was 95% for patients with Hb ⬎ 13.0 g/dL compared to 66% for patients with Hb of 13.0 g/dL or less (p ⫽ 0.0018). Warde et al. (5) published a study with 735 patients undergoing radiotherapy for T1–T2 glottic cancer. In this work, rising Hb levels were associated with higher local control probabilities: A patient with a Hb value of 12.0 g/dL was 1.8 times more likely to develop a local relapse compared to a patient with a Hb value of 15.0 g/dL (95% CI, 1.2–2.5). In a very homogeneous population of 235 patients with T1N0 M0 glottic cancer Skladowski et al. (11) found that a drop of Hb level of 1 g/dL (from 13.8 to 12.8 g/dL) gave a 6% decrease of local control.
Tumor stage and surgical margins It is well known that tumor stage and complete resection are prognostic factors of great importance. The present Freiburg results do not differ from other surgical series (24, 25). However, to reduce the number of variables in our analyses, T stage was mainly used for stratification. Nevertheless, it is worth noting a 9% difference in local control— T1a, 96% vs. T1b, 87%—reflecting the more advanced character of T1b lesions.
Anemia predicts recurrence of glottic cancer
Performance/nutritional status In previously published reports, patient characteristics had an impact on prognosis. In multivariate analysis of 496 head and neck tumor patients by Van den Bogaert et al. (26), a good Karnofsky performance status was significantly related to higher locoregional control and survival. Due to alcohol and tobacco abuse, performance status is frequently low in head and neck cancer patients. With regard to the literature, this is not necessarily true for laryngeal cancer: In the study of Kokoska et al. (27), comorbidity was present in only 14% of 193 patients. In the study group of van Acht et al. (2), 98% of 233 patients had a Karnofsky performance status of 90 –100%. In accordance with these findings, performance status and nutritional status at admission were normal in the majority of our patients (76% and 97%, respectively) and were not associated with prognosis (see Tables 1–3). Anemia was not a surrogate marker of a worse perfomance/nutritional status in our patients. In the series of Canaday et al. with 139 T1 glottic carcinomas pretreatment, Hb was not a significant predictor of local control when assessed as a continuous variable nor as a dichotomous variable (28). However, overall survival was significantly better for patients with pretreatment Hb ⬎ 13 g/dL (78%) compared to patients with Hb of 13 g/dL or less (68%, p ⫽ 0.004). According to the authors this suggests that patients with lower pretreatment Hb may have confounding medical problems that detract from their overall survival. This hypothesis is not substantiated in the article as the prognostic impact of comorbidity is not analyzed. Our data confirm that anemia is a prognostic factor for overall survival. The Kaplan–Meier estimates of 5-year survival were 77% vs. 65% for nonanemic vs. anemic patients (p ⫽ 0.04). However, in multivariate analysis stratified for T stage, the only significant variables were local recurrence and age (data not shown). As anemia is significantly associated with local recurrence, this could explain its impact on survival in univariate analysis. Future perspectives There appears to be a consensus among radiation oncologists that anemia is related to hypoxic conditions within the
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tumor. Recently, Becker et al. confirmed that tumor oxygenation is significantly worse in patients with head and neck squamous cell carcinomas and pretreatment Hb ⬍ 11 g/dL compared to patients with higher Hb level (p ⬍ 0.0001) (29). In experimental radiotherapy, hypoxia has long been known to reduce the effect of radiation on tumor cells (30). Recent data reveal that this holds for the clinic (31, 32). Aside from radiobiologic considerations, there is now evidence that exposure of tumor cells to hypoxic stress causes a broad variety of molecular and genetic changes, even in neoplasms microscopic in size (33, 34). This leads to the hypothesis that the poor prognosis of anemic patients in our surgical series could be due to hypoxia-induced tumor cell migration beyond the resection margins. It is interesting to note that the increased risk of locoregional recurrence associated with low hemoglobin levels is unchanged when analysis is limited to patients with microscopically clean margins. Thus, there could be two independent mechanisms leading to increased recurrence rates: radiobiologic hypoxia and tumor cell migration. The latter would result in a higher number of tumor cells to be sterilized by postoperative irradiation. However, hemoglobin elevating agents could, nevertheless, improve the outcome of radiotherapy by reducing radiobiologic hypoxia. Low hemoglobin levels can be safely and quickly corrected with erythropoietin (35). Randomized studies have been initiated for patients undergoing radiotherapy to examine whether or not correction of anemia yields better tumor control, but, hitherto, results are not yet available.
CONCLUSION In this retrospective study, we found in 258 patients with surgically treated glottic cancer that had moderate anemia before therapy had a negative influence on locoregional tumor control. Pretreatment hemoglobin had predictive power even within the normal Hb range.
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CLINICAL INVESTIGATION
Head and Neck
ANEMIA IS ASSOCIATED WITH DECREASED LOCAL CONTROL OF SURGICALLY TREATED SQUAMOUS CELL CARCINOMAS OF THE GLOTTIC LARYNX JOHANNES LUTTERBACH, M.D.
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ROLAND GUTTENBERGER, M.D.
*Abteilung Strahlenheilkunde, Radiologische Universita¨tsklinik, Hugstetterstrae, Freiburg, Germany Purpose: A strong association between hemoglobin levels and tumor control exists in head and neck cancer treated with radiotherapy. This retrospective study has been performed to determine whether or not this association can also be found in the surgical setting. Methods and Materials: Between January 1970 and December 1990, 258 patients with glottic SCC received conventional surgery only (T1/T2/T3/T4 n ⴝ 188/31/37/2, respectively). Locoregional control was calculated by the Kaplan–Meier method. The influence of hemoglobin, T stage, age, gender, performance/nutritional status, and grading was evaluated using a Cox model. Results: Five-year locoregional control for T1a/T1b/T2/T3/T4 tumors was 91%/85%/76%/62%/0%, respectively (log–rank test, p < 0.0001). Anemia (male < 13, female < 12 g/dL hemoglobin) was present in 27 patients. It was associated with significantly worse 5-year locoregional control, i.e., 60% vs. 85% (log–rank test, p ⴝ 0.003). In multivariate analysis stratified for T stage, two variables were of influence: positive margins (relative risk [RR], 3.8; 95% confidence interval [CI], 1.7– 8.4), anemia (RR, 3.0; 95% CI, 1.4 – 6.2). The largest subgroup consisted of 162 patients characterized by male gender, T1, and complete resection. In this subgroup, the significant variables were T stage (T1b vs. T1a; RR, 3.5; 95% CI, 0.96 –12.4) and hemoglobin with a RR of 1.4 (95% CI, 1.0 –2.1) per g/dL less analyzed as a continuous variable. Conclusion: Anemia is associated with a high risk of treatment failure in surgically treated glottic cancer. Hemoglobin levels might be predictive even within the normal range as indicated by subgroup analysis. © 2000 Elsevier Science Inc. Glottic cancer, Hemoglobin, Surgery, Local control, Prognosis.
Anemia is a frequent finding in cancer patients. A number of studies including our own data (1) found anemia to be an independent predictor of poor disease-free and/or overall survival in cancer of various sites, e.g., head and neck (2–11), lung (12, 13), uterine cervix (14, 15), and bladder (16). Bentzen et al. (8) analyzed pretreatment hemoglobin (Hb) as a continuous variable and found a steep dose– response relationship with best tumor control in patients with Hb levels in the upper normal range. It is not yet understood how Hb and outcome of radiotherapy are linked. However, for low Hb levels an increased fraction of hypoxic and hence radioresistant tumor cells has been postulated (2, 4 –11). According to van Acht et al. (2), early-stage head and neck tumors are of interest when studying the influence of Hb on tumor control. The tumor
volume is relatively small, which makes blood loss unlikely. Distant metastases are rare. Therefore, low Hb levels should not be a surrogate marker of advanced disease. In a recently published series, T1–T2 glottic carcinomas patients with high Hb levels had significantly lower local recurrence rates than those with low Hb at admission (4, 5, 11). In all of these studies, treatment consisted of radiotherapy alone. Little or nothing is known of whether or not the association of Hb with tumor control is unique to radiation oncology. Therefore, we retrospectively collected the data from the Department of Otorhinolaryngology, University Hospital Freiburg, to analyze specifically the influence of Hb on locoregional tumor control of surgically treated patients taking other potential prognostic factors into account. Here we report the results for all patients with glottic carcinoma treated with conventional surgery alone.
Reprint requests to: Dr. Johannes Lutterbach, Abteilung Strahlentherapie, Radiologische Universita¨tsklinik, Hugstetterstrae 55, 79106 Freiburg i. Br., Germany. E-mail: [email protected] Presented at the 41st Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology, October 31– November 4, 1999, San Antonio, TX (USA). Acknowledgment—Dedicated to our teacher, Prof. Joachim Sla-
nina, in honor of his 65th birthday. The authors would like to thank Dr. Chlodwig Beck, emeritus director of the Department of Otorhinolaryngology, University Hospital Freiburg, for his generous support in all questions concerning laryngeal surgery. We wish to thank Margit Guttenberger for proofreading this manuscript. Accepted for publication 27 April 2000.
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METHODS AND MATERIALS Patients Between January 1970 and December 1990, a total of 258 patients with newly diagnosed, histologically confirmed squamous cell carcinoma of the glottic larynx were treated by conventional surgery alone at the University Hospital Freiburg. 242 patients were male and 16 female. Median age was 64 years (range, 15–94 years; 25% percentile, 54 years; 75% percentile, 72 years). Preoperatively, all patients were seen in the department of internal medicine where the majority was judged to have a World Health Organization performance status of 0 or 1 (n ⫽ 196). Nutritional status was normal in 249 patients, indicated by a body–mass index (BMI) of at least 18.5 kg/m2 (17). Hb levels were determined at admission. The normal Hb range in our hospital was 13.0 –18.0 g/dL for males and 12.0 –16.0 g/dL for females; 231 patients had normal Hb levels, 27 were anemic. Median pretreatment Hb was 14.5 g/dL (range, 9.3– 18.1 g/dL; 25% percentile, 13.5 g/dL; 75% percentile, 15.5 g/dL). Tumors The primary tumor site was assessed by direct laryngoscopy and biopsy. All cases were uniformly restaged according to the UICC classification of 1997 (18). One hundred eighty-eight patients had T1 tumors (T1a ⫽ tumor limited to one vocal cord, n ⫽ 92; or T1b ⫽ tumor involving both vocal cords, n ⫽ 96). T2 tumors were found in 31 patients (T2 ⫽ tumor with supra- and/or subglottic extension and/or impaired vocal cord mobility). T3 carcinomas were diagnosed in 37 cases (T3 ⫽ tumor confined to the larynx with vocal cord fixation). Two patients presented with T4 lesions (T4 ⫽ tumor invading through the thyroid cartilage and/or extending beyond the larynx). All patients had negative neck nodes (cN0 or pN0) and were free of distant metastases (M0). Tumor differentiation was good in 29, moderate in 164, and poor in 65 cases. Treatment Laryngofissure and cordectomy was the treatment of choice for T1a tumors. In cases with very anteriorly located carcinomas, frontolateral/anterior laryngectomies were carried out to obtain clean margins. Resection of T1b tumors was done by frontolateral or frontoanterior laryngectomy. Most of the patients with more advanced lesions had total laryngectomy. In 21 cases (8%), resection remained microscopically incomplete. Further therapy had been either declined by the patient or judged not to be indicated due to age or comorbidity. The only patients excluded from this study were those receiving primary treatment other than conventional surgery alone. Laser surgery was introduced in our head and neck clinic in 1987, when only selected cases were treated, and became standard in the last decade. Postoperative radiotherapy was reserved for selected T3 tumors, all T4 tumors
Fig. 1. Kaplan–Meier plots of locoregional control after conventional surgery for glottic cancer in 258 patients show significant (p ⫽ 0.003) impact of pretreatment anemia.
(with two exceptions) and for patients with positive neck nodes. Locoregional control at 5 years was estimated by the product limit method of Kaplan and Meier. The log–rank test was employed to test for statistically significant differences. For multivariate analysis, we used a Cox model (proportional hazards). Significant variables were chosen by forward and by backward selection (19, 20).
RESULTS For event-free patients (n ⫽ 215), median follow-up was 71 months with a range of 7–282 months. Locoregional relapse was observed in 43 patients (local n ⫽ 29; local and regional n ⫽ 8; regional n ⫽ 6). Median time interval from primary treatment to locoregional failure was 10 months (range, 3–57 months). Actuarial 5-year locoregional control was 82%. Stratification for T stage yielded 91% for T1a, 85% for T1b, 76% for T2, 62% for T3, and 0% for T4 tumors, respectively. Normal Hb values rendered 5-year control rates of 85% compared to 60% for anemia (p ⫽ 0.003, see Fig. 1). Patients were also stratified according to Hb percentiles (25th, 50th, 75th). Sixty patients had Hb values less than 13.5 g/dL. Sixteen of them experienced locoregional failure, as did 9 of 68 patients with Hb between 13.5 and 14.4 g/dL. Tumor recurrence occurred in 9 of 63 patients with Hb levels from 14.5 to 15.4 g/dL and in 9 of 67 patients with Hb levels of at least 15.5 g/dL. Actuarial locoregional control at 5 years was 72%, 85%, 85%, and 86% for the aforementioned Hb classes, respectively. In multivariate analysis stratified for T stage we evaluated the influence of anemia, resection margins, grading, age, gender, and performance/nutritional status using a proportional hazards model (Table 1). Two variables were significant: positive margins carried a 3.8-fold risk (95% confidence interval [CI], 1.7– 8.4; p ⫽ 0.001), anemia a 3.0-fold risk (95% CI, 1.4 – 6.2; p ⫽ 0.004). Of the other variables tested, body mass index, analyzed as a continuous variable, was the only to show
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Table 1. Results of univariate and multivariate analysis using a Cox model Analysis Multivariate Variable Anemia yes vs. no Positive margins yes vs. no Age continuous Performance status WHO 0/1 vs. WHO 2 Nutritional condition BMI continuous Grading 1/2 vs. 3 Gender female vs. male
Frequency
Univariate p
p
RR
CI (95%)
231/27 21/237
0.005 0.001
0.004 0.001
3.0 3.8
1.4–6.2 1.7–8.4
0.62 0.86 0.30 0.68 0.57
(0.34) (0.65) (0.1) (0.80) (0.54)
(1.0) (0.9) (1.1) (1.1) (1.6)
196/62 193/65 16/242
final model
full model
The proportional hazards models used were stratified for T stage. Numbers in parentheses were generated in a “full model” containing all listed variables. Anemia carries a relative risk (RR) of 3.0 for locoregional relapse obtained from analyzing all 258 patients. The only other significant variable was “positive margins.” The final model contained these two variables independent of the kind of selection procedure used (forward or backward). Abbreviations: WHO ⫽ World Health Organization; BMI ⫽ body-mass index; RR ⫽ relative ratio; CI ⫽ confidence interval.
a weak association with higher values indicating a higher risk. However, this was not significant (p ⫽ 0.1). To analyze Hb as a continuous variable, female patients were omitted because of their gender specific lower Hb values. This left 242 male patients on which the above analysis was repeated. The results did not differ markedly (Table 2). Each g/dL Hb less yielded a relative risk of 1.4 for tumor recurrence (95% CI, 1.1–1.8; p ⫽ 0.005). In a further attempt to avoid confounding factors, T2–T4 tumors and incompletely resected tumors were excluded. This resulted in a very homogeneous population of 162 patients (median age: 65 years; BMI ⱖ 18.5 kg/m2, n ⫽ 156; Grade 1/2/3: n ⫽ 22/111/29 cases, respectively). Median Hb was 14.7 g/dL (range, 10.9 –18.1 g/dL; 25% percentile, 13.6 g/dL; 75% percentile, 15.5 g/dL). Eighteen patients had Hb values below 13.0 g/dL. Tumor recurrence was observed in 14 patients (local n ⫽ 12; local and regional n ⫽ 1; regional n ⫽ 1). Median time interval from primary treatment to locoregional failure was 15 months (range, 7–58 months). Actuarial 5-year locoregional control
was 91%. Stratification for T stage yielded 96% for T1a and 86% for T1b (p ⫽ 0.05). Five-year locoregional control was 92% in patients with Hb of at least 13.0 g/dL compared to 80% in the anemic group (p ⫽ 0.05). 34 patients had Hb values less than 13.5 g/dL. 5 of them experienced locoregional failure. So did 5 of 45 patients with Hb between 13.5 and 14.4 g/dL. Tumor recurrence occurred in 3 of 40 patients with Hb levels from 14.5 to 15.4 g/dL and in 1 of 43 patients with Hb levels of at least 15.5 g/dL. Locoregional control was 84%, 88%, 92%, and 97% for the aforementioned Hb classes, respectively (p ⫽ 0.23). Anemia, age, performance/nutritional status, and grading were evaluated in a proportional hazards model stratified for T stage (T1a/T1b). Although we saw a trend for lower tumor control in anemic patients in this setting as well, no variable turned out to be significant. Analyzed as a continuous variable, each g/dL Hb less yielded a relative risk of 1.4 for tumor recurrence (see Table 3).
Table 2. Results of subgroup analysis (male patients only) Analysis Multivariate Variable
Frequency
Univariate p
Hemoglobin [g/dL] continuously decreasing Positive margins yes vs. no
20/222
0.01 0.001
Age continuous Performance status WHO 0/1 vs. WHO 2 Nutritional condition BMI continuous Grading 1/2 vs. 3
187/55 182/60
0.33 0.67 0.41 0.95
p
RR
CI (95%)
0.005 0.0004
1.4 4.4
1.1–1.8 1.9–10
(0.24) (0.72) (0.18) (0.70)
(1.0) (0.9) (1.1) (1.2)
final model
full model
Same analysis as in Table 1. By omitting the 16 female patients, anemia could be replaced by hemoglobin as a continuous variable. Each g/dl hemoglobin less carries a relative risk (RR) of 1.4 for locoregional relapse obtained from analyzing all 242 male patients. Abbreviations: WHO ⫽ World Health Organization; BMI ⫽ body-mass index; RR ⫽ relative ratio; CI ⫽ confidence interval.
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Table 3. Results of subgroup analysis (male patients with complete resection of T1 tumor) Analysis Multivariate Variable
Frequency
Univariate p
Hemoglobin [g/dL] continuously decreasing Tumor stage T1b vs. T1a
85/77
0.05 0.05
0.05 0.06
1.4 3.5
0.80 0.37 0.73 0.78
(0.37) (0.69) (0.32) (0.50)
(1.0) (0.75) (1.1) (0.6)
Age (continuous) Performance status WHO 0/1 vs. WHO 2 Nutritional condition BMI continuous Grading 1/2 vs. 3
130/32 133/29
p
RR
CI (95%) 1.0–2.1 1.0–12
final model
full model
Same analysis as in Table 2 but stratification could be dropped by omitting patients with T2-T4 or positive margins. Again, each g/dl hemoglobin less carries an RR of 1.4 for locoregional relapse obtained from analyzing this very homogenous group of 162 male patients. This confirms the results from the models stratified for T stage given in Tables 1 and 2. Abbreviations: WHO ⫽ World Health Organization; BMI ⫽ body-mass index; RR ⫽ relative ratio; CI ⫽ confidence interval.
DISCUSSION Hemoglobin in surgical oncology Our data shows a detrimental effect of moderate anemia before therapy on locoregional control in conventionally operated patients with glottic cancer. We found that higher levels of Hb were associated with better local control, even in the normal range. This was particularly true for a very homogeneous subgroup of male patients with completely resected T1 tumors. To the best of our knowledge, this is the first publication dealing with this subject in head and neck cancer patients. Vigario et al. (21) grouped patients with Stage I or II uterine cervix cancer according to initial Hb levels of 10.0 or less, 11.0 –13.0 and ⬎ 13.0 g/dL. Five-year cause-specific survival was 60%, 73%, 83% for radical resection (n ⫽ 258) and 59%, 69%, 76% for definite radiotherapy (n ⫽ 398), respectively. His results can be criticized because the surgical group included patients who had planned postoperative radiotherapy and no separate analysis was presented for the 181 patients with radical resection only. In a multivariate analysis recently presented by Obermair et al. (22), the relative risk of death was significantly associated with decreasing hemoglobin levels in patients with ovarian cancer. Other than age, no patient related variable was examined. Three different histologic subtypes were included. Residual tumor was present in 91 patients; 146 had chemotherapy, 35 underwent radiotherapy, 6 were put on hormone therapy, and 2 patients did not receive any adjuvant therapy. Intraoperative or postoperative transfusions were given to 32 patients, and 16 patients received erythropoietin postoperatively. Both inhomogeneities with regard to tumor- and treatment-related variables and the omission of factors, such as performance status, do not allow any conclusions concerning the role of hemoglobin in this study. Hemoglobin in radiation oncology In contrast to the sparse surgical data, the effect of anemia on outcome in head and neck cancer patients has been the
topic of several radiotherapy studies. Taskinen (23) examined laryngeal carcinomas treated with definite radiotherapy. Five-year survival differed significantly in patients with T1 tumors and Hb of at least 11.5 g/dL or less than 11.5 g/dL: 74% (107/145) vs. 47% (14/30). Subgroups with Hb values of less than 10.0, 10.0 –11.4, 11.5–13.4, and 13.5 or greater had 5-year survival rates of 20%, 33%, 51%, and 55%, respectively. Taskinen concluded that a low Hb value at the beginning of treatment implied a poorer prognosis than a high Hb value. Van Acht et al. (2) described that in laryngeal carcinoma patients with Hb levels below normal at the start of radiotherapy, disease-free survival was worse, although not significantly different from the nonanemic patients (p ⫽ 0.08). Fein et al. (4) studied 109 T1/T2 glottic carcinomas treated with definite radiotherapy. Actuarial 2-year local control was 95% for patients with Hb ⬎ 13.0 g/dL compared to 66% for patients with Hb of 13.0 g/dL or less (p ⫽ 0.0018). Warde et al. (5) published a study with 735 patients undergoing radiotherapy for T1–T2 glottic cancer. In this work, rising Hb levels were associated with higher local control probabilities: A patient with a Hb value of 12.0 g/dL was 1.8 times more likely to develop a local relapse compared to a patient with a Hb value of 15.0 g/dL (95% CI, 1.2–2.5). In a very homogeneous population of 235 patients with T1N0 M0 glottic cancer Skladowski et al. (11) found that a drop of Hb level of 1 g/dL (from 13.8 to 12.8 g/dL) gave a 6% decrease of local control.
Tumor stage and surgical margins It is well known that tumor stage and complete resection are prognostic factors of great importance. The present Freiburg results do not differ from other surgical series (24, 25). However, to reduce the number of variables in our analyses, T stage was mainly used for stratification. Nevertheless, it is worth noting a 9% difference in local control— T1a, 96% vs. T1b, 87%—reflecting the more advanced character of T1b lesions.
Anemia predicts recurrence of glottic cancer
Performance/nutritional status In previously published reports, patient characteristics had an impact on prognosis. In multivariate analysis of 496 head and neck tumor patients by Van den Bogaert et al. (26), a good Karnofsky performance status was significantly related to higher locoregional control and survival. Due to alcohol and tobacco abuse, performance status is frequently low in head and neck cancer patients. With regard to the literature, this is not necessarily true for laryngeal cancer: In the study of Kokoska et al. (27), comorbidity was present in only 14% of 193 patients. In the study group of van Acht et al. (2), 98% of 233 patients had a Karnofsky performance status of 90 –100%. In accordance with these findings, performance status and nutritional status at admission were normal in the majority of our patients (76% and 97%, respectively) and were not associated with prognosis (see Tables 1–3). Anemia was not a surrogate marker of a worse perfomance/nutritional status in our patients. In the series of Canaday et al. with 139 T1 glottic carcinomas pretreatment, Hb was not a significant predictor of local control when assessed as a continuous variable nor as a dichotomous variable (28). However, overall survival was significantly better for patients with pretreatment Hb ⬎ 13 g/dL (78%) compared to patients with Hb of 13 g/dL or less (68%, p ⫽ 0.004). According to the authors this suggests that patients with lower pretreatment Hb may have confounding medical problems that detract from their overall survival. This hypothesis is not substantiated in the article as the prognostic impact of comorbidity is not analyzed. Our data confirm that anemia is a prognostic factor for overall survival. The Kaplan–Meier estimates of 5-year survival were 77% vs. 65% for nonanemic vs. anemic patients (p ⫽ 0.04). However, in multivariate analysis stratified for T stage, the only significant variables were local recurrence and age (data not shown). As anemia is significantly associated with local recurrence, this could explain its impact on survival in univariate analysis. Future perspectives There appears to be a consensus among radiation oncologists that anemia is related to hypoxic conditions within the
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tumor. Recently, Becker et al. confirmed that tumor oxygenation is significantly worse in patients with head and neck squamous cell carcinomas and pretreatment Hb ⬍ 11 g/dL compared to patients with higher Hb level (p ⬍ 0.0001) (29). In experimental radiotherapy, hypoxia has long been known to reduce the effect of radiation on tumor cells (30). Recent data reveal that this holds for the clinic (31, 32). Aside from radiobiologic considerations, there is now evidence that exposure of tumor cells to hypoxic stress causes a broad variety of molecular and genetic changes, even in neoplasms microscopic in size (33, 34). This leads to the hypothesis that the poor prognosis of anemic patients in our surgical series could be due to hypoxia-induced tumor cell migration beyond the resection margins. It is interesting to note that the increased risk of locoregional recurrence associated with low hemoglobin levels is unchanged when analysis is limited to patients with microscopically clean margins. Thus, there could be two independent mechanisms leading to increased recurrence rates: radiobiologic hypoxia and tumor cell migration. The latter would result in a higher number of tumor cells to be sterilized by postoperative irradiation. However, hemoglobin elevating agents could, nevertheless, improve the outcome of radiotherapy by reducing radiobiologic hypoxia. Low hemoglobin levels can be safely and quickly corrected with erythropoietin (35). Randomized studies have been initiated for patients undergoing radiotherapy to examine whether or not correction of anemia yields better tumor control, but, hitherto, results are not yet available.
CONCLUSION In this retrospective study, we found in 258 patients with surgically treated glottic cancer that had moderate anemia before therapy had a negative influence on locoregional tumor control. Pretreatment hemoglobin had predictive power even within the normal Hb range.
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