Annals of Oncology Advance Access originally published online on February 16, 2007
Annals of Oncology 2007 18(4):722-729; doi:10.1093/annonc/mdl491
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© 2007 European Society for Medical Oncology
gynecologic tumors |
Hemoglobin variation and blood transfusion rates in patients affected by locally advanced cervical cancer undergoing neo-adjuvant chemotherapy followed by radical surgery: the role of erythropoietic growth factors
1 Department of Gynecology, Obstetrics and Perinatology, University of Rome ‘La Sapienza’
2 Department of Gynecology and Obstetrics, University of Rome ‘Campus BioMedico’, Rome, Italy
* Correspondence to: Dr P. Benedeth Panici, Department of Gynecology and Obstetrics, University of Rome ‘La Sapienza’, V.le Regina Elena 324, 00161 Rome, Italy. Tel: +39-3394774328; Fax +39-06-49972615; E-mail: pierluigi.benedettipanici{at}uniroma1.it
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: The objectives of the present study were to evaluate hemoglobin levels and consequent clinical behaviors related to anemia developed in patients affected by locally advanced cervical cancer treated with neo-adjuvant chemotherapy in the last decade and to evaluate the impact that the introduction of erythropoietic growth factors had in the clinical practice.
Patients and methods: Blood chemistries, prospectively recorded from 98 cervical cancer patients, treated with neo-adjuvant chemotherapy and, if necessary, erythropoietic growth factors, were compared with matched historical controls before the introduction of growth factors in clinical practice.
Results: Hemoglobin level in the study group did not differ significantly during chemotherapy. At the third cycle of chemotherapy and at the end of chemotherapy, hemoglobin level was significantly higher in the study group compared with the control group. Transfusion rates in the study group were significantly lower. The analysis within the study group revealed that hemoglobin level in patients who suffer at diagnosis from anemia tends to increase whereas hemoglobin level in nonanemic patients tends to decrease.
Conclusions: Erythropoietic growth factors increase hemoglobin level and reduce blood transfusions in cervical cancer patients undergoing neo-adjuvant chemotherapy followed by radical surgery. An appropriate autologous blood donation program can noticeably reduce homologous blood transfusions.
Key words: blood transfusions, erythropoietic growth factors, locally advanced cervical cancer, neo-adjuvant chemotherapy
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Cervical cancer remains the second most common malignancy in women worldwide with estimated 493 000 new cases and 274 000 deaths in the year 2002 [1]. The introduction of screening programs has noticeably reduced the incidence of cervical cancer in developed countries but most patients affected by invasive disease are still diagnosed with advanced tumors. Women with locally advanced disease require combined treatments such as concurrent chemoradiotherapy [2] or, as recently suggested by several authors, neo-adjuvant chemotherapy followed by radical surgery [3]. These treatments, although effective, are associated with several side-effects such as anemia.
The prevalence of anemia ranges from 67% to 82% [4–6] of patients affected by cervical cancer. This condition is associated with a decrease in quality of life [7–11], an increase in transfusion rates [12] and possibly a decrease in survival [13–16].
In the last decade, several authors have advocated the use of erythropoietic growth factors to reduce the incidence of anemia and reduce blood transfusion rates. The objective of the present trial was to evaluate the effect that the introduction of erythropoietic growth factors in the routine clinical practice had in the management of anemia and blood transfusions in patients treated with neo-adjuvant chemotherapy.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The objectives of the present analysis were to evaluate hemoglobin levels and consequent clinical behaviors related to anemia developed in patients affected by locally advanced cervical cancer treated with neo-adjuvant chemotherapy in the last decade and to evaluate the impact that the introduction of erythropoietic growth factors had in the clinical practice.
treatment behavior during the study period
Since the end of the 1980s, cervical cancer International Federation of Gynecology and Obstetrics (FIGO) stage Ib2–IIIb patients are being treated at our institutions with three cycles of cisplatin-based neo-adjuvant chemotherapy followed by radical hysterectomy. Drug regimens usually include cisplatin 75–100 mg/mq administered every 3 weeks.
Although no formal institutional guidelines were approved throughout the study period, physicians within the departments were advised to adopt erythropoietic growth factors in all patients in chemotherapy with hemoglobin level <11 g/dl until an internal lecture discussing the American Society of Clinical Oncology and the American Society of Hematology current guidelines [17] was carried out in 2002. After this lecture, physicians were asked to comply with these clinical guidelines. Physicians advised patients to keep them informed on the weekly results of their blood chemistries and to apply to the center in the need for any medical subscription necessary. All attempts were made to collaborate as closely as possible with general practitioners throughout the territory although mainly due to geographical reasons, this was not always possible.
acquisition of the prospective data (study group)
From 1998 to 2004, a prospective database with the objective of analyzing hemoglobin alterations and blood transfusion rates in patients affected by locally advanced cervical cancer planned to undergo neo-adjuvant chemotherapy followed by radical surgery, was started.
The database included: patient's demographic characteristics, tumor characteristics, treatment and toxicity data [18] and hemoglobin levels. In particular, hemoglobin levels were defined as follows:
Hemoglobin levels throughout treatment:
- Hemoglobin level on the day of hospital admission.
- Hemoglobin level at first, second and third chemotherapy cycle was the result obtained from blood chemistries on the day of chemotherapy.
- Preoperative hemoglobin level was the result obtained from blood chemistries carried out after chemotherapy the day before surgery. This term was also adopted to describe the hemoglobin level at the end of chemotherapy also in patients who were not amenable to surgery.
- Postoperative hemoglobin level was the blood chemistry value obtained the morning of the first postoperative day.
Blood transfusions throughout treatment were recorded. Perioperative blood transfusions were defined as homologous transfusions carried out during surgery, or within 2 weeks of surgery, or before hospital discharge.
acquisition of the retrospective data (control group)
Each patient identified in the database was sequentially matched to patients treated before 1997, period in which erythropoietic agents were not used in our routine clinical practice. Matching was carried out for hemoglobin level at diagnosis (±1 g/dl). Inclusion criteria were tumor stage Ib2–IIIb treated with three cycles of neo-adjuvant chemotherapy with cisplatin dose intensity (>25 mg/week). A standard sheet was used to collect the data of the control group. Information regarding demographic data, tumor characteristics, chemotherapy regimen, surgical and transfusion data and blood chemistries were retrospectively collected from patients' charts.
objective 1.
In order to analyze the trends of hemoglobin level, blood transfusion rates and use of erythropoietic growth factors throughout treatment, data were retrieved from the patients included in the prospective database. A comparison was carried out between patients with and without anemia at diagnosis. Analyses were carried out only on patients treated with three cycles of chemotherapy in order to be able to have patients in treatment (chemotherapy and surgery, when feasible) for a relatively standardized length of time.
objective 2.
In order to assess the influence that erythropoietic growth factors had on the clinical practice, comparisons were made between hemoglobin levels, proportion of patients being transfused and number of units transfused, during the study period and a matched control group treated before the introduction of the routine use in the clinical practice of erythropoietic growth factors.
statistical analysis
Parametric tests were used after having evaluated the normal distribution of the data to be analyzed. The student's two-tailed t-test for paired and unpaired data and Mann–Whitney U-test were used for the comparison of parametric and nonparametric numerical data, respectively, whereas the Fisher's exact test and the Chi-square test were used for categorical data where appropriate. Multiple comparisons were evaluated by analysis of variance and any significant difference was identified using the Bonferroni correction for multiple comparisons. Correlations between hemoglobin levels and hemoglobin change were evaluated by Pearson correlation coefficients. A P value <0.05 was considered significant.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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objective 1: overall study group population
patients' selection.
From 1998 to 2004, 126 patients were entered in the prospective database. Twenty-eight patients were excluded from the present analysis for one or more of the following reasons: one patient affected by FIGO stage IIIb tumor deceased shortly after the first cycle of chemotherapy, eight patients were not treated with cisplatin, three patients were scheduled with a cisplatin dose <25 mg/mq/week, eleven patients scheduled to receive three cycles were actually treated with a different number of chemotherapy cycles and eight patients received chemotherapy or radiotherapy for cervical cancer before being addressed to the center. The present analysis has been carried out in the remaining 98 patients.
patients' characteristics.
Patients' characteristics are reported in Table 1. Median age at diagnosis was 51 years (range 29–78). Median performance status was zero (0–4). FIGO stage was I, II and III in 18, 44 and 36 of patients, respectively. The most frequent histotype was squamous carcinoma. Mean tumor size as diagnosed by computed tomography/magnetic resonance imaging was 5.8 (+1.4) cm. Eighty-one patients achieved a complete or partial clinical response, whereas the remaining 17 suffered from steady or progressive disease. Eighty-three patients underwent radical surgery, whereas five, six and four patients were treated with radiotherapy alone, chemotherapy alone or concomitant chemoradiotherapy.
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Radical surgery was radical hysterectomy in 72 patients, radical hysterectomy with partial cystectomy or partial ureterectomy in five patients and pelvic anterior exenteration in the remaining six patients. All patients underwent systemic pelvic lymphadenectomy. Thirty-nine patients were subjected to aortic lymphadenectomy. Median number of pelvic nodes removed was 39 (13–82). Median number of aortic lymph nodes removed was 6 (1–33).
anemia and hemoglobin level.
At diagnosis, 56 patients were anemic although only 16 patients were affected by grade 2–4 anemia. Mean hemoglobin level did not change significantly throughout treatment being 11.4 (±1.5) g/dl at diagnosis and 11.5 (±1.1) g/dl at the preoperative control (Figure 1). Similar results were obtained in patients who had not been subjected to blood transfusions or autologous blood donation programs. Mean preoperative hemoglobin level was 11.5 (+1.1) g/dl, whereas mean postoperative hemoglobin was 8.9 (+1.3) g/dl. Hemoglobin variation during chemotherapy was 0.1 (+1.5) g/dl. There was a direct significant correlation between hemoglobin level at diagnosis and hemoglobin level preoperatively (r = 0.43, P < 0.0001). There was a significant inverse correlation between hemoglobin level at diagnosis and hemoglobin change (r = –0.71, P < 0.0001) during chemotherapy. During surgery, mean hemoglobin drop was 2.6 (+1.43) g/dl. There was a mild significant correlation between preoperative hemoglobin and postoperative hemoglobin level (r = 0.28, P < 0.01). Interestingly, there was a significant correlation between preoperative hemoglobin level and surgical hemoglobin drop (r = –0.46, P < 0.0001). Similar results were confirmed after the exclusion of patients subjected to blood transfusions.
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erythropoietin.
During chemotherapy, 72 patients received erythropoietic growth factors. Forty-four patients started growth factors after the first cycle of chemotherapy, 17 patients after the second cycle and 11 additional patients after the third cycle. Median hemoglobin value to begin erythropoietic growth factors was 10.6 g/dl. Median number of units administered was 120 000 IU (range 0 IU–390 000 IU). Overall, 1 238 000 IU were administered during the study period.
blood transfusions.
Two patients were transfused at diagnosis, five patients were transfused after the first cycle, two patients were transfused after the second cycle and three patients were transfused after the third cycle of chemotherapy. Figure 2 shows the cumulative number of patients who have received a blood transfusion during the different phases of chemotherapy (Figure 2). Overall, 10 patients received blood transfusion during chemotherapy. Twenty patients received homologous blood during or immediately after surgery, three of whom had previously been transfused. Median number of blood units transfused throughout curative treatment was 0 (range 0–6). Sixteen patients were addressed to a preoperative autologous blood donation program and all 16 patients received at least one of the autologous blood units donated. Five out of seven patients (71%) who had donated a single unit received, in addition to an autologous blood transfusion, at least one homologous blood unit, whereas none of the nine patients who had donated two units received homologous blood (P < 0.005).
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objective 1: subgroup analysis of anemic and nonanemic patients at diagnosis
At diagnosis 56 patients were affected by anemia, whereas 42 patients had hemoglobin level
12 g/dl. Demographic characteristics of the patients are reported in Table 2. No significant difference in terms of age, tumor stage, tumor histotype and grade at diagnosis was present. A greater proportion of nonanemic patients was subjected to radical surgery although this difference was not significant (P = 0.09). A significantly higher proportion of nonanemic patients benefited from complete (no clinical evidence of disease) or partial (reduction >50%) response to chemotherapy (39 of 42 versus 42 of 56, P < 0.05) when compared with initially anemic patients. There was no significant correlation between chemotherapy response and preoperative hemoglobin levels.
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Mean hemoglobin in initially anemic patients progressively increased as follows: 10.4 ± 1.3; 10.6 ± 1.3; 10.8 ± 1.3; 11. 2 ± 1.2; 11.3 ± 1.2 at diagnosis, first, second, third and end of third cycle, respectively. Mean hemoglobin in nonanemic patients progressively decreased as follows: 12.7 ± 0.6; 12.7 ± 0.6; 12.2 ± 1.0; 11.9 ± 1.2; 11.8 ± 1.1 at diagnosis, first, second, third and end of third cycle (Figure 3). There was a significant difference between hemoglobin levels between the two groups until preoperative control (at the end of the third cycle). In this latter hemoglobin control, nonanemic patients had higher hemoglobin levels although this did not reach statistical significance (P = 0.051). At the end of chemotherapy, a similar proportion of patients suffered from anemia in the two groups [37 of 56 versus 26 of 42, P = not significant (NS) for initially anemic and nonanemic patients, respectively]. As expected, initially anemic patients had a significant higher probability of being treated with erythropoietin (52 of 56 versus 20 of 42, P < 0.0001).
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During neo-adjuvant chemotherapy the risk of receiving blood transfusion was similar in initially anemic and nonanemic patients. During surgery no significant difference in transfusion rate was present between initially anemic and nonanemic patients. No difference in the proportion of patients transfused overall (at diagnosis, during chemotherapy and during surgery) was present between the two groups.
objective 2: comparison with the control group
general characteristics.
Patients' characteristics of the study group and the control group have previously been described in Table 1. Hemoglobin level at diagnosis were nonsignificantly different. This analysis was carried out to check the matching process. Patients' median age was similar in the two groups (51 years old versus 50.5 years old in the study and the control group, respectively, P = NS). Tumor size, histotype, grading and response to chemotherapy were all not significantly different. Surgical aggressiveness, using the number of pelvic lymph nodes removed as a surrogate marker was similar in the two groups (median number 39, range 13–82; median number 40, range 12–72 for the experimental and control group, respectively; P = NS). Postoperative stay was significantly longer in the control group compared with the experimental group [median number 7 (range 4–38) versus 12 (range 5–30) for the experimental and control group, respectively, P < 0.0001].
hemoglobin levels throughout treatment.
Hemoglobin levels are shown in Figure 1. Briefly, no significant difference was present between the two groups at diagnosis, on the day of first and second chemotherapy cycles. A significant difference in favor of the study group was present on the day of the third chemotherapy cycle and preoperatively. Proportion of patients suffering from different grading of anemia are shown in Figure 4. Surprisingly, no difference was identified between the two groups after surgery.
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blood transfusions.
At diagnosis, a significant higher proportion of patients in the control group received a homologous blood transfusion compared with the experimental group (10 of 98 versus two of 98, respectively, P < 0.05). Homologous blood transfusion rate was similar after the first and second chemotherapy cycle. The number of patients receiving homologous blood was significantly higher in the control group after the third cycle of chemotherapy (35 of 98 versus 12 of 98, respectively, P < 0.005). Homologous blood transfusions were also significantly higher during surgery in the control group compared with the experimental arm (35/86 versus 20/83, respectively, P < 0.05). Overall, a significantly smaller proportion of patients in the study group received homologous blood transfusions throughout treatment (odds ratio for patients in the study group was 0.216, 95% confidence interval 0.087–0.472) (Figure 2).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Anemia represents one of the most frequent problems encountered by gynecologic oncologists [19] in their clinical practice ranging in cervical cancer patients from 67% to 82% of patients [6]. Anemia in cancer patients has been associated with an increase in postoperative morbidity and mortality [20], a decrease in quality of life, an increase in transfusion rates and a decrease in survival rates [21]. The traditional treatment of anemia is blood transfusions although in the last decades erythropoietic growth factors have acquired increasing consensus.
The first objective of the present analysis was to evaluate hemoglobin levels and consequent clinical behavior developed in patients affected by locally advanced cervical cancer treated with neo-adjuvant chemotherapy after the clinical introduction of erythropoietic growth factors. In order to do this, a prospective database was started. The analysis of the overall data did not show any significant difference in mean hemoglobin level throughout treatment, although a significant correlation between hemoglobin level at diagnosis and at the end of medical treatment (preoperative control) was present (r = 0.43, P < 0.0001). It is worth of notice that there was a strong inverse correlation between hemoglobin level at diagnosis and hemoglobin variation during treatment (r = –0.71, P < 0.0001). This probably reflects the earlier initiation of erythropoietin in anemic patients. A more careful analysis demonstrates how anemic patients will tend to increase their level of hemoglobin, whereas nonanemic patients will behave in an opposite way and in the end suffer from mild anemia (Figure 3). This trend is particularly clear if we consider that mean preoperative hemoglobin level in initially anemic and nonanemic patients was, as expected, significantly different at diagnosis, but, by the end of treatment, this statistical significance was lost (P = 0.051). In addition, these data appear even more relevant if one considers that no difference in blood transfusion rates was present between these two groups. The present results show how most blood transfusions are carried out during the perioperative period and therefore efforts on blood conservation strategies should be concentrated in this therapeutic moment. It is of particular interest that in this series, there appears to be an inverse correlation between preoperative hemoglobin and hemoglobin drop. We are unable to justify this result but can speculate that anemic patients suffer from a chronic vessel constriction that reduces intraoperative blood loss or that due to the lower hemodilution, similar volumes of blood loss result in smaller hemoglobin concentration drop. Larger series, with the aim of confirming this data, are warranted. Autologous blood donations appeared to reduce homologous blood transfusions only when at least two units of autologous blood were obtained preoperatively. In fact, most patients with a single donated blood unit were also subjected to homologous blood. During chemotherapy, most patients received erythropoietic growth factors but the analysis of the mean haemoglobin level at which treatment with erythropoietic growth factors commenced and final haemoglobin level show that this therapy was started late. This is demonstrated by the fact that most patients arrive at surgery with a mild anemia and that noninitially anemic patients develop anemia during treatment.
The second end point was to evaluate the effect of erythropoietin on clinical behavior towards anemia and transfusion rate. In order to do so, we decided to compare the results from the database with a historical control group. This analysis obviously carries several inherited biases. In order to minimize the possible bias, a matched process for hemoglobin levels was carried out. In addition, in the attempt to minimize the difference due to different chemotherapy regimens, a minimum platinum dose intensity was set. Finally, in order to evaluate possible differences in the surgical techniques, an analysis on the number of lymph nodes removed was carried out and failed to identify any significant difference between groups. Hemoglobin level in the control group significantly decreased during treatment becoming significantly lower compared with the study group at the third chemotherapy cycle (10.9 g/dl versus 11.5 g/dl for the control and experimental group, respectively, P < 0.001). This difference was present despite the significantly greater proportion of patients receiving blood transfusion in the primer group. This indicates that erythropoietic growth factors are effective in avoiding anemia during chemotherapy.
Most data in literature regarding the relationship between hemoglobin level, quality of life and blood transfusions were obtained during trials regarding erythropoietic agents administered during chemotherapy. Although the heterogeneity of the scales adopted in the different trials renders data interpretations difficult [22], most authors agree on a direct correlation between hemoglobin level and quality of life [8, 9, 23]. In addition, there is clear data that demonstrates that, in patients undergoing long chemotherapy regimens the use of erythropoietin decreases blood transfusion rates [8, 9, 22, 23].
Data regarding hemoglobin level throughout the perioperative period are scarcer. There is some evidence in nongynecologic tumors that anemia is a risk factor for receiving blood transfusion [12, 20] and that the use of erythropoietic growth factors in the fortnight preceding surgery can reduce transfusion rates [24].
The prognostic influence of anemia and blood transfusions in patients affected by cervical cancer treated with surgery remains a matter of debate. Recently, the detrimental prognostic influence of anemia in the subgroup of patients treated with neo-adjuvant chemotherapy followed by radical surgery has been reported [16]. The effect of blood transfusions remains unclear. Although crude data show a worse prognosis for transfused patients, multivariate analysis are unable to confirm these observations [25–27]. Although predetermined end points of this analysis were different from the correlation of anemia with tumor response or survival, the significantly higher response rate obtained in nonanemic patients appears indirectly to confirm the correlation between anemia and poor prognosis. A hypothesis to justify this association is that hypoxic cell fraction of the tumor increases as a consequence of anemia and this confers chemoresistance to cellular clones'. If future trials will demonstrate the independent prognostic importance of appropriate hemoglobin level for optimal treatment efficacy during chemotherapy, as for radiotherapy [28], erythropoietic growth factors will become an integral part of treatment.
Recently, the results of two large randomized trials comparing erythropoietic alfa [29] and beta [30] against placebo have questioned the beneficial effect on survival of erythropoietic growth factors. In addition, a third trial [31] carried on lung cancer patients showed a nonsignificant divergence in survival curves after 12 months favoring the placebo group. All these studies differed from previous ones since nonanemic patients were also enrolled or because the objective was to achieve high hemoglobin levels. Two possible explanations can justify these discouraging results: a direct effect of erythropoietic growth factors on cancer cells or an increase in the risk of thrombovascular events. The primer hypothesis is sustained by in vitro studies that demonstrate how erythropoietin activates antiapoptotic pathways [32] and that it is used by tumor cells for growth and angiogenesis [33, 34]. The second hypothesis is sustained by the observation that these discouraging results were obtained only in trials in which the goal was to achieve particularly high hemoglobin levels and not trials in which erythropoietin doses or dose intensities were particularly high [29, 35]. In addition, in favor of the absence of the clinical harmful effect of erythropoietic growth factors are the results reported by the Cochrane group [22] that state ‘Based on the data available, there is suggestive but inconclusive evidence for a positive effect of erythropoietin on overall survival’.
In conclusion, the results from the present report indicate that erythropoietin is able to increase hemoglobin level and reduce blood transfusions in cervical cancer patients undergoing neo-adjuvant chemotherapy. In addition, it indicates that a possible strategy to further reduce transfusion rates especially during surgery could be the application of autologous blood donation programs for the storage of at least two blood units. This appears a feasible and safe goal especially if the program is commenced early during chemotherapy in patients who are not initially anemic. Further randomized trials on gynecologic and nongynecologic cancer patients undergoing neo-adjuvant chemotherapy before surgery in order to evaluate this possible treatment strategy are strongly warranted.
Received for publication June 15, 2006. Revision received December 7, 2006. Accepted for publication December 11, 2006.
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