|Year : 2018 | Volume
| Issue : 1 | Page : 19-24
The impact of pretreatment anemia on response to neoadjuvant concurrent chemoradiotherapy in locally advanced carcinoma rectum: a single-institute prospective study
Neelam Sharma1, Puneet Takkar1, Abhishek Purakaystha2, Sonia Badwal1
1 Army Hospital R&R, Delhi, India
2 Command Hospital, Pune, India
|Date of Submission||23-Jul-2017|
|Date of Acceptance||02-Oct-2017|
|Date of Web Publication||3-Aug-2018|
Deparment of Radiotherapy, Army Hospital R&R, New Delhi, 110010
Source of Support: None, Conflict of Interest: None
Background Rectal cancer is one of the most frequent human malignant neoplasms and the second most common cancer in the large intestine. Neoadjuvant concurrent chemoradiotherapy along with surgery has been strongly recommended for locally advanced cancers located in the middle or the distal rectum. Anemia is reported to have adverse effects on survival in cancer patients. The aim of this study was to evaluate the influence of anemia on radiochemotherapy treatment outcome in these patients.
Patients and methods A total of 50 consecutive patients with histologically confirmed adenocarcinoma of the rectum were treated radically with three-dimensional conformal radiation therapy with concurrent 5-fluorouracil or 5-fluorouracil derivatives-based concurrent chemotherapy. The influence on the pathological response of hemoglobin concentrations at presentation before neoadjuvant concurrent chemoradiotherapy was studied.
Results Out of 50 patients 22 were anemic at presentation. There was a statistically significant difference, P value of 0.001, in anemic and nonanemic groups for tumor downstaging, whereas nodal downstaging did not reach statistical significance (P=0.201). In the multivariate analysis, the circumferential resection margin was found to be the most important risk feature, with a local control rate of 95.7% in patients with a negative margin and a 25% local control rate in the patients with a positive margin, with a significant P value of 0.002.
Conclusion Pretreatment anemia had negative effects on pathological response and local control among patients who underwent neoadjuvant chemoradiotherapy and surgery for rectal cancer. Strategies maintaining hemoglobin levels within the normal range could potentially be used to improve local control in rectal cancer patients.
Keywords: anemia, concurrent chemoradiotherapy, neoadjuvant therapy, rectal cancer
|How to cite this article:|
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;43:19-24
|How to cite this URL:|
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 [serial online] 2018 [cited 2021 Sep 21];43:19-24. Available from: http://www.ehj.eg.net/text.asp?2018/43/1/19/238539
| Introduction|| |
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. The distribution of CRC varies widely, with more than two-third of all cases and about 60% of all deaths occurring in countries with a high or a very high human development index . Environmental and dietary factors have been established as contributing toward CRC. Factors shown to increase the risk of developing this disease include increasing age, male sex, a family history of CRC, increasing height, increasing BMI, processed meat intake, excessive alcohol intake, and low folate consumption. Of these risk factors, only increasing age, male sex, and excessive alcohol use have been found to be associated with rectal cancer . The management of rectal cancer has undergone an interesting transformation over the course of the past 30 decades.
Rectal cancer treatment has advanced in nearly 300 years from a hopeless, morbid outcome to potentially curative treatments with a constant improvement in the quality of life. The earliest procedures were mostly palliative, with the first proposed resections for rectal cancer appearing in the eighteenth century. Extirpative procedures utilizing the perineal, vaginal, and sacral approaches were predominantly used until Miles’ abdominoperineal resection in 1908 revolutionized the principles for a correct oncological resection. In time, the focus of interest shifted toward less radical procedures centered on the restoration of intestinal continuity. Later on, sphincter preservation procedures and pouch surgery emerged in an attempt to achieve better functional outcomes. Heald’s total mesorectal excision proposed in the 1980s represented another milestone in the treatment of rectal cancer by significantly reducing local recurrence rates. Over recent years, combined multimodality therapy including radiation, surgery, and chemotherapy, and the development of laparoscopic surgery have led to major advancements in the field .
Refinements in management have, however, led to a decrease in locoregional rectal cancer recurrence rates from 25–40% to 4–8% only . Since 20–50% of these patients develop local recurrence in the absence of distant metastasis, it is intuitive that local disease management with neoadjuvant concurrent chemoradiotherapy (NACCRT) and surgery represents a viable treatment option .
Radiotherapy as well as chemotherapy is known to be more efficacious in the presence of oxygen than under hypoxic conditions ,,,. Tumors are more hypoxic than the surrounding normal tissue. Anemia, present in 75% of cancer patients, could increase the proportion of hypoxic tumor cells . Hypoxia is widely recognized as a major factor leading to the resistance of tumor cells to radiotherapy, but several mechanisms may also cause cells in the hypoxic region to be resistant to anticancer drugs . 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 ,,. The aim of the present study was to evaluate the influence of anemia on radiochemotherapy treatment outcome in patients with adenocarcinoma of the rectum.
| Patients and methods|| |
A total of 50 consecutive patients (40 men and 10 women) with histologically confirmed adenocarcinoma of locally advanced (T3+ and N+) carcinoma rectum were included in the study. They were treated at the Army Hospital Research and Referral, Delhi, from March 2014 to March 2017.
For performance status, the scoring system of the WHO was used ; patients with performance status-2 were excluded and for tumor node metastasis staging, the criteria of the Union for International Cancer Control were used . Hemoglobin (Hb) levels as described by WHO to define anemia were used (Hb<12 g/dl in women, Hb<13 g/dl in men) . All these patients were Radiotherapy (RT) naive.
Pretreatment evaluation consisted of a physical and digital rectal examination and colonoscopy with biopsy. Imaging included chest radiography or contrast-enhanced computer tomography of the chest, abdominal ultrasound and contrast-enhanced computer tomography, or MRI of the pelvis. Laboratory tests included serum chemistry and complete blood count in all patients, and testing for HIV infection in high-risk patients. A multidisciplinary team consisting of a surgeon, a radiation oncologist, and a medical oncologist decided on the treatment for each patient.
With respect to the administration of RT, multiple RT fields were used to include the tumor or tumor bed with a 2 cm or 5 cm margin, presacral nodes, and the internal iliac nodes. The external iliac nodes were included for T4 tumors involving anterior structures; inclusion of the inguinal nodes for tumors invading the distal anal canal was also considered. In long-course RT, recommended doses of RT of typically 45–50 Gy in 25–28 fractions to the pelvis were used using 3 or 4 fields by three-dimensional conformal technique. Any boost clinical target volumes extended to the entire mesorectum and the presacral region at the involved levels, including 2 cm cephalad and caudad in the mesorectum and 2 cm on a gross tumor within the anorectum. Positioning and other techniques to minimize radiation to the small bowel were encouraged .
Either 5-fluorouracil (425 mg/m2) or leucovorin (25 mg/m2) was administered during the first 4 days in the first week and then restarted for 3 days during the fifth week of the treatment or capecitabine (CA) was administered concomitantly with RT at a dose of 825 mg/m2 twice daily (bid) during the entire period of RT (days 1–33) without weekend breaks. CA doses were administered every 12 h, with one of the doses administered 2 h before irradiation. If RT was interrupted, chemotherapy was not administered. Out of 50 patients, 48 received oral CA along with a dose of 850 mg/m2 twice daily, whereas only two patients received chemotherapy in the form of 5-fluorouracil.
After chemoradiation at 8–10 weeks, patients were assessed by per-rectal examination and pelvic imaging and surgery was planned if deemed resectable. All the eligible patients underwent laparoscopy-assisted complete total mesorectal excision with either low anterior resection or abdominoperineal resection with permanent colostomy.
Pathological speciman analysis and adjuvant chemotherapy
The postoperative specimen was analyzed in detail for tumor size, nodal stage, pathological response, margin status including circumferential resection margin (CRM), and tumor regression grade score using Mendard’s scoring. Every attempt was made by the pathologist to retrieve maximum nodes possible. All patients were planned for adjuvant chemotherapy. If all the nodes were negative in the resected specimen, they were planned for six cycles of adjuvant chemotherapy of CA alone, and for node-positive disease, six cycles of CAPOX (CA 1000 mg/m2 and injection oxaliplatin) were advised.
All patients were reviewed weekly during chemoradiotherapy for treatment compliance, toxicities, and need for symptomatic management. The toxicities were recorded on the basis of common terminology criteria for adverse events (CTCAE) version 3 criteria. Weekly blood counts were performed to monitor hematological parameters. After surgery and adjuvant chemotherapy, further follow-up was scheduled 3 monthly for the first 2 years and then 6 monthly. Complete blood count liver function tests and renal function tests with carcinoembryonic antigen (CEA) were performed at each follow-up. Colono videoscope examinations were performed at 1 year postoperatively and then once every 3 years. Recurrence was diagnosed pathologically by surgical resection, biopsy or cytology, and/or radiological findings showing an increase in tumor size over time.
All analyses were carried out using SPSS 17.0 version by IBM Inc. (SPSS Statistics for Windows,Version 17.0, Chicago; SPSS Inc.). The χ2-test was used to determine associations among different variables and anemia. The odds ratio was calculated for univariate analysis, whereas logistic regression was used for multivariate analysis.
The study was carried out according to the Helsinki Declaration (1964, with later amendments) and according to the European Council Convention on Protection of Human Rights in Bio-Medicine (Oviedo, 1997). It was approved by the Institutional Review Board Committee and by the National Committee for Medical Ethics, Ministry of Health, the Republic of Slovenia.
| Results|| |
Patient and tumor characteristics at baseline are listed in [Table 1]. In the younger age group, 23/42 patients were anemic, whereas in the older age group, 8/8 patients were anemic, with a significant P value of 0.016. In this study, the majority of patients were men, 40/50, whereas only 10/50 patients were women. Although female patients had a very high incidence of anemia, 8/10, the difference did not reach a statistically significant P value of 0.190 compared with their male counterparts. Distance from the anal verge, initial CEA levels, type of chemotherapy, clinical T-stage (primary tumor), and N-stage (nodal stage) at presentation and type of surgery did not reach statistical significance between the anemic and the nonanemic groups. However, a statistically significant difference was noted between the two groups in the post-NACCRT pathological downgrading of the T-stage (P=0.021) and the N-stage (P=0.004), respectively.
[Table 2] shows the tumor and nodal downstaging between the anemic and the nonanemic groups, respectively. In the non-anemic patients, 14/19 patients showed tumor downstaging, whereas in the anemic group, only 8/31 patients showed tumor downstaging, with a significant (P=0.001). Nodal downstaging was observed in 6/19 patients in the nonanemic group, whereas only 5/31 patients had a nodal response in the anemic group after NACCRT; however, this did not reach statistical significance (P=0.201) ([Figure 1]).
|Figure 1 Shows the tumour and nodal downstaging between anaemic and non- anaemic groups.|
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The local control rate at 3 years was 100% in patients who did not have anemia before NACCRT versus 83.9% in patients with anemia at presentation ([Figure 2]). A stepwise forward conditional multivariate analysis also showed that only CRM was significantly associated with local control, with an odds ratio 0.015 (95% CI: 0.001–0.219) and P value of 0.002 ([Table 3]).
|Figure 2 Showing relation between local control rates at 3 years and various factors.|
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|Table 3 Univariate and multivariate survival analyses of clinicopathologic variables associated with local control|
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| Discussion|| |
Anemia is a major health problem in India. In the 2005–2006 National Family Health Survey (NFHS-3), a household survey aimed at obtaining national and state representative data on population health and nutrition, the prevalence of anemia was 70% in children aged 6–59 months, 55% in females aged 15–49 years, and 24% in males aged 15–49 years .
Anemia is associated with reduced local tumor control and impaired quality of life in patients with several types of solid tumors. The prevalence of anemia in patients who present at radiation oncology departments has not been well documented, and the impact of anemia on the outcome of radiation therapy is not widely appreciated in the radiation oncology setting. In a study by Harrison et al. , they reported that at presentation, about 41% of all patients were anemic (Hb<12 g/dl); by the end of radiation therapy, this percentage increased to 54%. The most common tumor types were prostate (16%), breast (14%), head and neck (12%), colorectal (11%), lung/bronchus (11%), and uterine-cervix (9%) .
Numerous studies have found anemia to be a predictor of poor local control and survival at various sites of malignancy including rectal cancer. Box et al.  reported that nonanemic patients achieved better tumor response and developed less local recurrence (7 vs. 38%, P=0.003) and improved OS (91 vs. 61%, P=0.021) than anemic patients. Berardi et al.  also showed that disease free survival (DFS) was worse in patients with Hb less than or equal to 12.0 g/dl compared with those with Hb more than 12.0 g/dl (P=0.018). Rades et al.  found that locally recurrent rectal cancer patients with Hb levels greater than or equal to 12.0 g/dl had significantly better local control than those with levels less than 12.0 g/dl (P<0.001). Hb levels greater than or equal to 12.0 g/dl were also associated with significantly better survival in their study (P=0.031).However, in our study, although the local control rate at 3 years was 100 and 83.9% in the nonanemic and the anemic groups, it did not reach statistical significance.
The most important prognostic factor affecting local control and survival is tumor extent, which is commonly evaluated on the basis of the tumor node metastasis staging system. In this study, we found a statistically significant difference between anemic and nonanemic patients in T and N-stage downgrading after NACCRT, with a P value of 0.021 and 0.004, respectively. In both the TME , and the CR07 trials , in patients with primary resectable rectal carcinomas, the HR values for local recurrence in CRM-positive patients are 3.8 and 2.3 (no neoadjuvant therapy, 95% CI: 3.3–5.6 and 1.9–3.0) veresus 10.0 and 5.3 (5×5 Gy, 95% CI: 6.7–25.0 and 3.6–10.0), which was significantly different. In this study, a stepwise forward conditional multivariate analysis showed that CRM is associated with local control with an odds ratio of 0.015, 95% CI: 0.001–0.219, and P=0.002.
Besides the negative impact on response to radiotherapy, anemia itself is also an important factor that should be considered during treatments. As anemia is a major cause of fatigue, and fatigue is the most common symptom in cancer patients resulting in decreased quality of life, identifying and correcting anemia is important for quality-of-life improvement in cancer patients ,,. In most clinical settings, severe anemia is treated with red blood cell transfusions, but mild-to-moderate anemia has usually been neglected. However, early correction of anemia up to an Hb level of 12.0–14.0 g/dl may improve both local control as well as quality of life.
There are numerous methods to correct anemia, including iron supplements, transfusion of packed red blood cells, and/or the administration of erythropoietin-stimulating agents (ESAs). ESAs were initially used to treat anemia in patients with chronic renal failure, including those on hemodialysis. Recent clinical trials have established that ESAs are also effective in increasing Hb levels, decreasing the need for transfusions, and subsequently improving quality of life in patients with cancer-related and chemotherapy-induced anemia ,,. Although there is general agreement that ESAs are not indicated in anemic cancer patients who are not receiving chemotherapy , the use of ESAs in patients receiving radiotherapy remains controversial. Although the effectiveness of ESAs on survival was not shown by a recent randomized clinical trial for head and neck cancer patients undergoing radiotherapy ,, our data suggest that similar trials might be needed for rectal cancer patients.
Our study showed that pretreatment Hb was an important independent prognostic factor for tumor control in patients with adenocarcinoma of the rectum treated with neoadjuvant radiochemotherapy, which is in agreement with the findings of most other authors. We can conclude that anemia and hypoxia possibly associated with anemia are obstacles to local tumor control and maintenance of quality of life; strategies to reverse anemia should receive greater attention.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Ferlay J, Soerjomataram I, Ervik M. LOBOCAN 2012 vl.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No 11
. Lyon: France International Agency for Research on Cancer; 2013.
Wei EK, Govannucci E, Wu K. Comparison of risk factors for colon and rectal cancer. Int J Cancer
Reguer JL, Longo WE. The evolving treatment of rectal cancer. In: Longo W, Reddy V, Audisio R, editors. Modern management of cancer of the rectum
. 2nd ed. London: Springer; 2015. 1–12.
Kapiteijn E, Marijnen CAM, Nagtegaal ID et al.
Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med
Bozzetti F, Bertario L, Rossetti C et al.
Surgical treatment of locally recurrent rectal carcinoma. Dis Colon Rectum
Kumar P. Tumor hypoxia and anemia: impact of efficacy of radiation therapy. Semin Hematol
Khan FA, Shukla AN, Joshi SC. Anemia and cancer treatment: a conceptual change. Singapore Med J
Horsman MR, Wouters BG, Joiner MC, Overgaard J. The oxygen effect and fractionated radiotherapy. In: Joiner M, van der Kogel A, editors. Basic clinical radiobiology
. 4th ed. London: Hodder Arnold; 2009. 207–216.
Varlotto J, Stevenson MA. Anemia, tumor hypoxemia, and the cancer patient. Int J Radiat Oncol Biol Phys
Cole SPC, Tannock IF. Drug resistance. In: Tannock I, Hill R, Bristow R, Harrington L, editors. The basic science of oncology
. New York: McGraw-Hill Education; 2013. 443–467.
Oblak I, Petric P, Anderluh F, Velenik V, Fras PA. Long term outcome after combined modality treatment for anal cancer. Radiol Oncol
Harrison LB, Chadha M, Hill RJ, Hu K, Shasha D. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist
Oblak I, Strojan P, Zakotnik B, Budihna M, Smid L. Hemoglobin as a factor influencing the outcome in inoperable oropharyngeal carcinoma treated by concomitant radiochemotherapy. Neoplasma
World Health Organization. WHO handbook for reporting results of cancer treatment. WHO Offset Publication No. 48
. Geneva: World Health Organization; 1979.
UICC International Union Against Cancer. TNM classification of malignant tumors
. In: Sobin L, Gospodarowicz M, Wittekind C, editors. 7th ed. New York: Wiley-Liss; 2009.
Behera S, Bulliyya G. Magnitude of anemia and hematological predictors among children under 12 years in Odisha, India. Anemia
Gay HA, Barthold HJ, O’Meara E, Bosch WR, El Naqa I, Al-Lozi R et al.
Pelvic normal tissue contouring guidelines for radiation therapy: a Radiation Therapy Oncology Group consensus panel atlas. Int J Radiat Oncol Biol Phys
Harrison L, Shasha D, Shiaova L, White C, Ramdeen B, Portenoy R. Prevalence of anemia in cancer patients undergoing radiation therapy. Semin Oncol
Box B, Lindsey I, Wheeler JM et al.
Neoadjuvant therapy for rectal cancer: improved tumor response, local recurrence, and overall survival in nonanemic patients. Dis Colon Rectum
Berardi R, Braconi C, Mantello G et al.
Anemia may influence the outcome of patients undergoing neo-adjuvant treatment of rectal cancer. Ann Oncol
Rades D, Kuhn H, Schultze J et al.
Prognostic factors affecting locally recurrent rectal cancer and clinical significance of hemoglobin. Int J Radiat Oncol Biol Phys
Nagtegaal ID, Marijnen CAM, Klein Kranenbarg E et al.
Circumferential margin is still an important predictor of local recurrence in rectal carcinoma: not one millimeter but two millimeters is the limit. Am J Surg Pathol
Marijnen CAM, Nagtegaal ID, Kapiteijn E et al.
Radiotherapy does not compensate for positive resection margins in rectal cancer patients. Int J Radiat Oncol Biol Phys
Sebag-Montefiore D, Steele R, Quirke P et al.
Routine short course preoperative radiotherapy or selective postoperative chemoradiotherapy for resectable rectal cancer? Preliminary results of the MRC CR07 randomised trial. J Clin Oncol
Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B, Epoetin Alfa Study Group. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol
Vogelzang NJ, Breitbart W, Cella D et al.
Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol
Park HC, Janjan NA, Mendoza TR et al.
Temporal patterns of fatigue predict pathologic response in patients treated with preoperative chemoradiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys
Cella D, Bron D. The effect of Epoetin alfa on quality of life in anemic cancer patients. Cancer Pract
Rizzo JD, Brouwers M, Hurley P et al.
American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol
Henke M, Laszig R, Rube C et al.
Erythropoietin to treat head and neck cancer patients with anemia undergoing radiotherapy: randomized, double-blind, placebo-controlled trial. Lancet
Hoskin PJ, Robinson M, Slevin N, Morgan D, Harrington K, Gaffney C. Effect of epoetin alfa on survival and cancer treatment-related anemia and fatigue in patients receiving radical radiotherapy with curative intent for head and neck cancer. J Clin Oncol
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]