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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 2  |  Page : 41-45

The importance of hemoglobin levels before and during chemoradiotherapy in locally advanced carcinoma cervix


Department of Radiation Oncology, Father Muller Medical College, Mangalore, Karnataka, India

Date of Submission30-Nov-2020
Date of Acceptance03-Dec-2020
Date of Web Publication03-Jun-2021

Correspondence Address:
Dr. Sharaschandra Shankar
Department of Radiation Oncology, Father Muller Medical College, Mangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_66_20

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  Abstract 


Purpose: Carcinoma cervix forms a major burden among malignancies in women in India. Anemia is very common among Indian women and a high proportion of carcinoma cervix patients present with anemia. Previous studies show that hemoglobin level may be considered as a prognostic factor in carcinoma cervix. It has been observed that anemia is associated with diminished radiocurability in patients with carcinoma of the cervix. However, the therapeutic benefit of the measures to correct anemia remains debatable. The objective of this study was to evaluate the association of hemoglobin concentrations and its correction by blood transfusions before and during treatment and the response to chemoradiation. Materials and Methods: Fifty patients with histologically proven squamous cell carcinoma of the cervix (Stage II to IV) from December 2018 to May 2020 were taken up for this study. Patients received definitive chemoradiation of 50 Gy in 25 fractions, 2 Gy/fraction, 5 fractions per week, along with-weekly injection cisplatin/carboplatin, followed by brachytherapy. All patients had their pretreatment hemoglobin levels measured at the first consultation. The effects of hemoglobin concentrations at presentation and during therapy on the clinical response to radiotherapy were studied. Blood transfusions and the time point when transfusions were given were recorded. Results: Eighteen patients received packed red blood cell transfusion before the start of radiation therapy and 9 patients received packed cell transfusion during radiation therapy. Out of the 18 patients who received transfusion before RT, 3 patients had complete response. Out of the 9 patients who received transfusion during radiation, 4 had complete response. The presence of anemia had a significant impact on the response rate. Pretreatment anemia was associated with poor response and local control among patients who underwent chemoradiotherapy for cervical cancer. Conclusion: Pretreatment hemoglobin and hemoglobin levels during radiation therapy were prognostic factors for local control, in addition to stage and histology, which might have independently predicted the outcome.

Keywords: Anemia, hypoxia, transfusion


How to cite this article:
Sequeira LJ, Fernandes D, Shankar S, Athiyamaan M S, Rao SB, Vidyasagar M S, Mohsina V, Santhmayer S. The importance of hemoglobin levels before and during chemoradiotherapy in locally advanced carcinoma cervix. J Radiat Cancer Res 2021;12:41-5

How to cite this URL:
Sequeira LJ, Fernandes D, Shankar S, Athiyamaan M S, Rao SB, Vidyasagar M S, Mohsina V, Santhmayer S. The importance of hemoglobin levels before and during chemoradiotherapy in locally advanced carcinoma cervix. J Radiat Cancer Res [serial online] 2021 [cited 2021 Jul 28];12:41-5. Available from: https://www.journalrcr.org/text.asp?2021/12/2/41/317718




  Introduction Top


Cervical cancer ranks 4th in women worldwide and 9th overall globally with an estimated 569,847 new cases in 2018.[1] Carcinoma cervix is the 2nd most common malignancy among Indian women. The common etiology for the development of carcinoma cervix includes HPV infection, early onset of sexual activity, early childbirth, multiparity, contraceptive use, low socioeconomic status, immune suppression, and poor genital hygiene. The most common presentations are postcoital bleeding, intermenstrual bleeding, postmenopausal bleeding, discharge per vaginum, and urinary symptoms. Majority of the cases of carcinoma cervix present as locally advanced disease in India. EBRT with concurrent chemotherapy followed by brachytherapy forms the standard of care for advanced cervical cancer. The prognosis of carcinoma cervix depends on factors such as stage, tumor volume, lymph node involvement, histology, and hemoglobin levels. In developing countries, most of the patients are anemic. Anemia is one of the predisposing factors to poor patient outcomes in cancer treatment.[2] The influence of anemia on the outcome of treatment was first recognized in the 1940s in cervical cancer patients and later in patients with other tumors such as head and neck squamous cell carcinoma, carcinoma of the lungs, bladder, prostate, and anus.[3] Hemoglobin levels during radiation therapy are considered to be a very important prognostic factor, apparently second only to stage in importance.[4]

Cervix cancers frequently bleed and this can result in profound anemia, whereas in patients with head and neck tumors, poor nutritional status may contribute to the mild anemia sometimes seen. Many patients with malignancy have low levels of erythropoietin, consistent with an anemia of chronic disease.[5] The pathophysiology of cancer-related anemia is found to be multifactorial. Anemia occurs as a consequence of direct inhibitory effects of inflammatory cytokines, blood loss, nutritional deficiency, renal insufficiency, and sociocultural and religious factors. Treatment-associated factors may also increase the incidence of anemia and these may compromise patient's tolerance of treatment.[6]

While several mechanisms have been proposed to explain this relationship, tumor hypoxia is clearly one of the major factors. Although well-documented causal relationship between hemoglobin concentration level, tumor oxygenation, and response to radiotherapy and chemotherapy has not been shown, it is nevertheless likely that such a relationship does exist and there is a rationale for investigating the possibility of improving the treatment outcome in cancer patients undergoing chemo-radiotherapy.[7]

Many studies have shown that tumors are more hypoxic than the surrounding normal tissue. Tumor oxygenation is mainly affected by the rate of blood flow, microcirculation, and hemoglobin concentration; therefore, correcting the hemoglobin level could improve the tumor oxygenation.[8] Tumor hypoxia is a major contributor for the nonresponsiveness to radiation therapy. Furthermore, tumor hypoxia can lead to increased tendency for rapid progression and distant metastases.[9]

The aim of the present study was to evaluate the effects of anemia on radiochemotherapy treatment outcomes in patients with carcinoma cervix.


  Materials and Methods Top


Source of data

This study was conducted in the Department of Radiation Oncology, between December 2018 and May 2020 after obtaining approval from the institutional ethics committee.

Patient selection

Fifty patients with squamous cell carcinoma of the cervix were taken up for the study. Patients received definitive chemoradiation with a total dose of 50 Gy in 25 fractions, 2 Gy/fractions, 5 fractions per week, by three-dimensional conformal radiotherapy/intensity-modulated radiation therapy technique through a 6Mv photon linear accelerator, along with-weekly injection cisplatin (35 mg/m2)/carboplatin (AUC 2), followed by intracavitory (7.5 Gy in 3 sessions) or interstitial (4 Gy in 4 sessions) high-dose rate brachytherapy. Pretreatment hemoglobin levels at presentation and during concurrent chemoradiotherapy were studied. Blood transfusions and the time point when transfusions were given were recorded. Hemoglobin level of 10 g/dL was taken as an arbitrary value by us in this study based on the mean hemoglobin levels of female patients at our oncology center. Patients with hemoglobin <10 g/dL were transfused. The first follow-up was done after 4 weeks. A complete gynecological examination was performed and subsequent follow-up was done every month. Complete response was taken as an absence of cervical lesion on gynecological examination. Patients who had persistent tumor on completion of radiation therapy were subjected to a biopsy and biopsy confirmed patients were considered to have a partial response

Statistical analysis

Data were analyzed for frequency, percentage, mean, and standard deviation. Chi-square test was used to determine the statistical significance. The level of significance for all tests was P < 0.05. SPSS version 23.0 was used to analyze the data.


  Results Top


Twenty patients (40%) had hemoglobin levels more than 12 g/dL, 5 patients (10%) had hemoglobin levels <12 g/dL, 7 patients (14%) had hemoglobin <11 g/dL, and 18 patients (36%) had hemoglobin <10 g/dL. In our study, 36% (18 patients) were diagnosed with anemia before the start of radiation therapy, 18% (9 patients) developed anemia during radiation therapy. All 18 patients with pretreatment anemia were transfused with PRBC before RT and 9 patients were transfused duringRadiation therapy (RT). Twenty-five (50%) patients had a complete response [Table 1]. The mean baseline hemoglobin in our study in Stage IIB, IIIA, IIIB, and IV A was 11.5, 10.33, 11.13, and 10 respectively [Table 2]. Complete response was seen in 50%, 83%, 50%, and 50% of patients in Stage IIB, IIIA, IIIB, and IIIC, respectively [Table 3].
Table 1: Patient characteristics

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Table 2: Correlation of stage and hemoglobin

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Table 3: Correlation between stage and response

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In patients who did not receive any transfusion, complete response was seen in 82.6%. Of the patients who received 1 pint transfusion, 26.3% had a complete response. In patients where 2 pints were transfused, 14.3% had a complete response [Table 4].
Table 4: Comparison between transfusion and response

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About 4% of our patients with well-differentiated squamous cell carcinoma (WDSCC) had pretreatment anemia and 18% of patients with moderately differentiated SCC (MDSCC) had pretreatment anemia. About 69.6% of patients with WDSCC and 45% of patients with MDSCC had a complete response [Table 5].
Table 5: Comparison between pathology and response

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  Discussion Top


Anemia is associated with reduced local tumor control and an impaired quality of life in patients with various types of solid tumors. Besides the negative impact on the response to radiotherapy, anemia is also an important factor that should be considered during treatments. In most clinical settings, anemia is treated with red blood cell transfusions, but mild-to-moderate anemia has usually been neglected. Anemia has been one of the most powerful prognostic factors in patients with cancer of the cervix. The incidence of anemia at the time of diagnosis is 25%–40% and is higher in more advanced stage diseases.[10] In most studies, multivariate analyses have shown that only tumor stage is more predictive of treatment outcome. Anemia is also correlated with advancing tumor stage but appears to have independent prognostic power despite this interaction.[5] Recent human trials showed that only 50% of patients with cervix cancer demonstrated an increase in tumor oxygenation following transfusion. This means that it is not only hemoglobin levels but also a combination of factors like tumor microvasculature and necrosis which may be responsible for hypoxia. Studies have shown that hemoglobin concentrations of <10 g/dL are associated with hypoxia, but transfusing patients with hypoxic tumors and normal hemoglobin are unlikely to increase tumor oxygenation or improve outcomes. Transfusion of the most profoundly anemic patients may improve oxygen delivery, but does not necessarily improve treatment results as anemia is associated with tumor size, which has an adverse prognosis, independent of oxygenation, due to greater clonogen number, suboptimal brachytherapy dose delivery, and greater risk of metastatic disease. Large tumor size is also associated with a poor response to therapy with persistent bleeding during treatment and resulting anemia, iron deficiency, and requirement for transfusion. Poorly responding tumors will have lower hemoglobin during treatment, therefore, anemia during therapy may be a surrogate marker of response;[5] as a result will be poor responders to radiation therapy.

In this study, 66% of patients presented with locally advanced carcinoma cervix – 24% of the patients belonged to Stage IIB, 12% belonged to Stage IIIA, 32% belonged to Stage IIIB, 18% in stage IIIC, and 10% in Stage IVA [Table 1]. It shows that a high proportion of patients (66%) had a locally advanced disease which is reflective of the Indian scenario. Nearly half of these patients had a stage III B disease further suggestive of a delayed presentation of our patients at the time of diagnosis. About 46% of the patients had well-differentiated SCC, 40% had moderately differentiated SCC as the histology. In the study conducted by Grogan et al.,[4] tumors with squamous cell histology were seen in 498 patients (82%), adenocarcinoma in 96 patients (16%), and other histologies in 36 patients (2%). Our study had a much smaller sample size and all patients turned out to be of squamous histology which is not surprising as it is the dominant histology.

As observed in this study, 36% (18 patients) were diagnosed with anemia before the start of radiation therapy, 18% (9 patients) developed anemia during radiation therapy. Among the 18 patients with pretreatment anemia, 3 patients were from Stage IIB, 2 patients from Stage IIIA, 5 patients from Stage IIIB, 5 patients from Stage III C, and 3 patients from Stage IV.

All 18 patients with pretreatment anemia were transfused with PRBC before RT and 9 patients were transfused during RT. Twenty-five (50%) patients had a complete response. Complete response was seen in 50%, 83%, 50%, and 50% of patients in Stage IIB, IIIA, IIIB, and IIIC, respectively [Table 3]. Again the complete responses do not seem to correlate with the responses expected according to the stage of the disease. The discrepancy of patient numbers between stages may have lead to such an observation. In patients who did not receive any transfusion, complete response was seen in 82.6%. Of the patients who received 1 pint transfusion, 26.3% had a complete response and in patients where 2 pints were transfused, 14.3% had a complete response [Table 4]. Our study simply demonstrates an inverse correlation between requirement and number of blood transfusions with a complete response to treatment. We observed in this study group that blood transfusions to correct anemia were not necessarily improving the clinical outcome in anemic patients.

In the study by Grogan et al.[4] one hundred fifty-two patients (25%) received a blood transfusion, 88 of 152 patients (58%) received a single blood transfusion, and 64 of 152 patients (42%) received more than one blood transfusion. Patients who had a low hemoglobin level at the presentation that remained low during radiation had a 5-year survival rate of 51%, patients who had a low hemoglobin level at presentation and whose hemoglobin level was raised to a high level during radiation had a 5-year survival rate of 70%, which was not significantly different from those who started off with a high level that remained high during treatment. In our study, the duration of the study was not sufficient to make any conclusion on survival statistics which would be possible only by keeping the study group on further follow-up.

In our study, twenty patients (40%) had hemoglobin levels more than 12 g/dL, 5 patients (10%) had hemoglobin levels <12 g/dL, 7 patients (14%) had hemoglobin <11 g/dL, and 18 patients (36%) had hemoglobin <10 g/dL. In the study by Grogan et al.,[4] 172 patients (34%) had a hemoglobin level less 12 g/dL, 93 patients (19%) had a hemoglobin level <11 g/dL, and 54 patients (11%) had a hemoglobin level <10 g/dL. It is evident here that in an Indian scenario, a hemoglobin level of <10 g/dL is quite a common finding. The mean baseline hemoglobin in our study in Stage IIB, IIIA, IIIB, and IV A was 11.5, 10.33, 11.13, and 10 respectively, whereas in the study by Grogan et al., the average hemoglobin level at presentation was 12.9 g/dl, 12.5 g/dl, and 11.6 g/dl for Stage IIA, IIB, and III. It is only logical that with an advance in the tumor stage, there ought to be a more severe level of anemia. This can be attributed to a large tumor size and possibly more bleeding from it. In contrast to the reference study Grogan et al., our study does not seem to demonstrate such a correlation most probably due to a much smaller sample size.

Four percent of our patients with WD SCC had pretreatment anemia and 18% of patients with MD SCC had pretreatment anemia. About 69.6% of patients with WDSCC and 45% of patients with MD SCC histology had a complete response. About 14% had PD SCC as histology and none of the patients had complete response [Table 5]. WD SCC patients had a very small proportion of anemic patients and also a good response to therapy even when all stages were accounted for. It may suggest that tumor hypoxia is less in well-differentiated tumors which may account for their better response to chemoradiation.

In comparison to the studies in literature, our study had a smaller sample size. But our study methodology was comparable to the studies in literature. It demonstrated that pretreatment hemoglobin was an important independent prognostic factor for tumor control in carcinoma cervix patients treated with chemoradiotherapy.


  Conclusion Top


We can conclude that anemia and hypoxia are possible obstacles to local tumor control. Strategies to prevent anemia by early diagnosis should receive greater attention. However, it is not clear if early correction of anemia improves local control and in turn quality of life in carcinoma cervix.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 2019;144:1941-53.  Back to cited text no. 1
    
2.
Vias P, Angural H, Seam RK, Gupta MK, Gupta M, Fotedar V, et al. A prospective study comparing hemoglobin levels and response in patients of locally advanced carcinoma cervix receiving accelerated chemoradiation versus conventional chemoradiation. J Radiat Cancer Res 2019;10:135.  Back to cited text no. 2
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Sharma N, Takkar P, Purakaystha A, Badwal S. The impact of pretreatment anemia on response to neoadjuvant concurrent chemoradiotherapy in locally advanced carcinoma rectum: A single-institute prospective study. Egypt J Haematol 2018;43:19.  Back to cited text no. 3
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4.
Grogan M, Thomas GM, Melamed I, Wong FL, Pearcey RG, Joseph PK, et al. The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 1999;86:1528-36.  Back to cited text no. 4
    
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Fyles AW, Milosevic M, Pintilie M, Syed A, Hill RP. Anemia, hypoxia and transfusion in patients with cervix cancer: A review. Radiother Oncol 2000;57:13-9.  Back to cited text no. 5
    
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Demetri GD. Anaemia and its functional consequences in cancer patients: Current challenges in management and prospects for improving therapy. Br J Cancer 2001;84 Suppl 1:31-7.  Back to cited text no. 6
    
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Aruah SC, Oyesegun R, Ogbe O. Anaemia in cancer patients undergoing radiotherapy and chemotherapy at the national hospital, Abuja J Neoplasm 2017;5:2.  Back to cited text no. 7
    
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Kelleher DK, Mattheinsen U, Thews O, Vaupel P. Blood flow, oxygenation, and bioenergetic status of tumors after erythropoietin treatment in normal and anemic rats. Cancer Res 1996;56:4728-34.  Back to cited text no. 8
    
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Vaupel P, Harrison L. Tumor hypoxia: Causative factors, compensatory mechanisms, and cellular response. Oncologist 2004;9 Suppl 5:4-9.  Back to cited text no. 9
    
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Lim MC, Kim JY, Kim TH, Park S, Kong SY, Yoon JH, et al. Allogeneic blood transfusion given before radiotherapy is associated with the poor clinical outcome in patients with cervical cancer. Yonsei Med J 2008;49:993-1003.  Back to cited text no. 10
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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