The impact of anaemia on treatment outcome in patients with squamous cell carcinoma of anal canal and anal margin

Open access

Background

Radiochemotherapy is the main treatment for patients with squamous cell carcinoma of the anal canal. Anaemia is reported to have adverse effect on survival in cancer patients. The aim of the study was to evaluate the influence of anaemia on radiochemotherapy treatment outcome in patients with squamous cell carcinoma of the anal canal.

Patients and methods

One hundred consecutive patients with histologically confirmed squamous cell carcinoma of the anal canal were treated radically with 3-dimensional conformal or intensity-modulated radiation therapy followed by brachytherapy or external beam radiotherapy boost and with concurrent mitomycin C and 5-fluorouracil. The influence on survival of pre-treatment, mean on-treatment and end-of-treatment haemoglobin (Hb) concentrations was studied.

Results

The 5-year locoregional control, disease free survival, disease specific survival and overall survival rates for all patients were 72%, 71%, 77% and 62%, respectively. In univariate analysis, patients with pre-treatment and end-of-treatment Hb > 120 g/L survived statistically significantly better compared to patients with Hb ≤ 120 g/L. Patients with mean on-treatment Hb > 120 g/L only had statistically significant better locoregional control and overall survival than patients with Hb ≤ 120 g/L. In multivariate analysis, independent prognostic factors were pre-treatment Hb (> 120 g/L vs. ≤ 120 g/L) for overall survival (hazard ratio [HR] = 0.419, 95% confidence interval [CI] = 0.190–0.927, p = 0.032) and stage (I & II vs. III) for disease specific (HR = 3.523, 95% CI = 1.375–9.026, p = 0.009) and overall survival (HR = 2.230, 95% CI = 1.167–4.264, p = 0.015).

Conclusions

The pre-treatment, mean on-treatment and end-of-treatment Hb concentration > 120 g/L carried better prognosis for patients for with squamous cell carcinoma of the anal canal treated with radiochemotherapy. The pre-treatment Hb > 120 g/L was an independent prognostic factor for overall survival of patients with anal canal cancer.

Abstract

Background

Radiochemotherapy is the main treatment for patients with squamous cell carcinoma of the anal canal. Anaemia is reported to have adverse effect on survival in cancer patients. The aim of the study was to evaluate the influence of anaemia on radiochemotherapy treatment outcome in patients with squamous cell carcinoma of the anal canal.

Patients and methods

One hundred consecutive patients with histologically confirmed squamous cell carcinoma of the anal canal were treated radically with 3-dimensional conformal or intensity-modulated radiation therapy followed by brachytherapy or external beam radiotherapy boost and with concurrent mitomycin C and 5-fluorouracil. The influence on survival of pre-treatment, mean on-treatment and end-of-treatment haemoglobin (Hb) concentrations was studied.

Results

The 5-year locoregional control, disease free survival, disease specific survival and overall survival rates for all patients were 72%, 71%, 77% and 62%, respectively. In univariate analysis, patients with pre-treatment and end-of-treatment Hb > 120 g/L survived statistically significantly better compared to patients with Hb ≤ 120 g/L. Patients with mean on-treatment Hb > 120 g/L only had statistically significant better locoregional control and overall survival than patients with Hb ≤ 120 g/L. In multivariate analysis, independent prognostic factors were pre-treatment Hb (> 120 g/L vs. ≤ 120 g/L) for overall survival (hazard ratio [HR] = 0.419, 95% confidence interval [CI] = 0.190–0.927, p = 0.032) and stage (I & II vs. III) for disease specific (HR = 3.523, 95% CI = 1.375–9.026, p = 0.009) and overall survival (HR = 2.230, 95% CI = 1.167–4.264, p = 0.015).

Conclusions

The pre-treatment, mean on-treatment and end-of-treatment Hb concentration > 120 g/L carried better prognosis for patients for with squamous cell carcinoma of the anal canal treated with radiochemotherapy. The pre-treatment Hb > 120 g/L was an independent prognostic factor for overall survival of patients with anal canal cancer.

Introduction

Squamous cell anal cancer is a rare tumour which represents 1.5% of gastrointestinal cancers, but in Slovenia only 0.5%.15 Despite its infrequent occurrence its incidence is increasing.4 Women are more commonly affected than men.36 Causal factors in the anal canal cancer are usually associated with human papilloma virus (HPV) infection (being the most important risk factor), human immuno-deficiency virus (HIV) infection, anal intercourse, higher lifetime number of sexual partners, genital warts and cigarette smoking.3,68

Anal canal cancer is predominantly a loco-regional disease, because it metastasizes in less than 10% of patients, mainly to lungs and liver.6

The management of anal canal cancer has undergone an interesting transformation over the course of the past three decades. With the report by Nigro et al. in 1974 it shifted from abdominoperineal resection with or without inguinal lymph node dissection to radical radiochemotherapy.9,10 Radiochemotherapy with 5-fluorouracil and mitomycin C, nowadays being the main treatment, results in complete tumour response in 70–90% and has a 5-year survival rate of 60–70%, leaving surgery only as a salvage treatment for tumours that do not respond to radiochemotherapy or recur.4,7 Anal margin cancers are classified as skin tumours and small tumours can be treated by surgery, while tumours T2 or larger should be treated with definitive radiochemotherapy.11

Radiotherapy as well as chemotherapy is known to be more efficacious in the presence of oxygen than in hypoxic conditions.1215 Tumours are more hypoxic than the surrounding normal tissue.13 Anaemia, present in 75% of cancer patients, could increase the proportion of hypoxic tumour cells.13 Hypoxia is widely recognized as a major factor leading to the resistance of tumour cells to radiotherapy, but several mechanisms may also cause cells in the hypoxic region to be resistant to anticancer drugs.16 The influence of anaemia on the outcome of treatment was first recognized in 1940s in cervical cancer patients and later in patients with other tumours such as head and neck squamous cell carcinoma, carcinoma of the lungs, bladder, prostate and anus.7,17,18 The purpose of present study was to evaluate the influence of anaemia on radiochemotherapy treatment outcome in patients with squamous cell carcinoma of the anal canal.

Patients and methods

One hundred consecutive patients (60 females and 40 males) with histologically confirmed squamous cell carcinoma of the anal canal were included in the retrospective study. They were treated at the Institute of Oncology Ljubljana from January 2003 till June 2013.

For performance status (PS) the scoring system of the World Health Organization (WHO) was used19, and for TNM staging the criteria of the Union for International Cancer Control (UICC).20

Pre-treatment evaluation

Pre-treatment evaluation consisted of physical and digital rectal examination, rectoscopy with biopsy and fine needle aspiration biopsy of enlarged inguinal lymph nodes, also ultrasound-guided, like in other cancer patients.21 Imaging included chest X-ray or computer tomography (CT) of chest, abdominal ultrasound (US) or CT and magnetic resonance imaging (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 the treatment for each patient.

Radiotherapy

Clinical target volume (CTV) consisted of the tumour volume with a safety margin of 2–2.5 cm and the regional lymph node areas. An additional margin of 1 cm was applied to the CTV for the planning target volume (PTV). Initial tumour borders were marked with tattoo. Positron emission tomography with computed tomography (PETCT) was used as an aid in treatment planning. The treatment schedule for external beam radiotherapy (EBRT) consisted of 3-dimensional (3-D) conformal photon beam radiotherapy or intensity modulated radiotherapy (IMRT) with individual field arrangement. The total dose was 45 Gy in 25 fractions, 5-times weekly with 15 MV photon beam linear accelerator, plus a boost 10–15 Gy with interstitial pulsed-dose rate brachytherapy if tumour size was less than 5 cm. Metal needles were homogeneously implanted through a perineal template according to the rules of the Paris system. In tumours larger than 5 cm or in N2–3 disease, the boost was delivered with EBRT. CTV (brachytherapy/EBRT) of the boost corresponded to the initial gross tumour extension. In cases with positive inguinal lymph nodes, inguinal areas were boosted with electrons to a total dose of 59.4 Gy. When IMRT technique was used, inguinal lymph nodes were involved in CTV and PTV and irradiated to the same total dose of 59.4 Gy. If the tumour involved or crossed the external anal sphincter, this area was covered with a 1 cm thick gelatinous bolus to raise the dose at the surface to at least 95% of the planned dose.

Chemotherapy

Chemotherapy protocol consisted of 2 cycles of 96-hour continuous infusion of 5-fluorouracil with a daily dose of 1000 mg/m2 of body surface in the first and fifth week of radiotherapy. On day 1 the patients also received a bolus of mitomycin C in a dose of 10 mg/m2. Since 2006, we administered peroral cytostatic capecitabine in a dose of 825 mg/m2, twice daily, to cooperative patients with good performance status and without important comorbidities. First dose of capecitabine was administered one hour before the irradiation and the second dose 12 hours after. In cases of severe treatment toxicity according to common toxicity criteria22 radiotherapy and/or chemotherapy was modified according to the patient’s general condition and laboratory findings or was even temporarily interrupted.

Follow-up

During treatment, the patients were examined weekly to assess acute toxicity and compliance with radiochemotherapy, and complete blood count and serum biochemistry were performed as well.

The first post treatment examination was performed six weeks after the completion of radiochemotherapy, and then every 2–3 months for the first 2 years and every 6 months in the following 3 years.

When tumour response was incomplete, patients were examined every 6 weeks over a period of 4 months after the end of the treatment. In this period we performed all necessary investigations to prove tumour viability or its progression and in such cases surgery (abdomino-perineal resection) was recommended.

Tumour response was evaluated according to the WHO criteria.19

Statistical analysis

The survival estimates were carried out by using the Kaplan-Meier method23 and a log rank test24 was used to test the differences in survival between subgroups.

The end points of survival analysis were defined as follows: loco-regional control (LRC) as the time interval from the beginning of the treatment to the appearance of local and/or regional progression; disease-free survival (DFS) as the time interval from the beginning of the treatment to the appearance of local and/or regional progression and/or appearance of distant metastases; disease-specific survival (DSS) as the time interval from the beginning of the treatment to the death because of cancer; and overall survival (OS) as the time interval from the beginning of the treatment to the death due to any cause.

For multivariate analysis, Cox proportional hazard model (with “Enter method”) was used.25

All statistical tests were two-sided and a P-value of p ≤ 0.05 was considered statistically significant. Statistical analyses were performed by using SPSS version 22 (Chicago, IL).

Ethical consideration

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, of the Republic of Slovenia.

Results

The study was closed on February 15, 2014. Median follow-up time of all patients was 52 months (range: 1–129 months) and 72 months (range: 6–129 months ) for the survivors. On the day of analysis, 59 patients were alive, 22 patients died of anal canal cancer, 15 patients died of other causes and in 4 patients the cause of death was unknown.

Characteristics of patients and tumours are shown in Table 1.

Table 1.

Patients’ and tumours’ characteristics

WHO = World Health Organization

CharacteristicsNo. of patients
Gender
 female60
 male40
Mean age (range)63 (34–87)
Performance status (WHO)
 076
 120
 23
 31
Tumour type
 Carcinoma of the anal canal72
 Carcinoma of the anal margin28
Tumour histology
Basaloid12
Squamous88
TNMN0N1N2N3
 T19010
 T236610
 T3191031
 T41175
Tumour stage
 I9
 II55
 IIIA17
 IIIB19

Characteristics of Hb values in subgroup of patients are shown in Table 2.

Table 2.

Haemoglobin (Hb) values in subgroups of patients

Hb (g/L)No. of patientsMedian Hb (g/L)Hb range (g/L)
Pre-treatment Hb12886–169
  > 120 g/L69136122–169
  ≤ 120 g/L3110786–120
Mean on-treatment Hb12796–157
  >120 g/L67134121–157
  ≤ 120 g/L3311396–119
End-of-treatment Hb12177–159
  > 120 g/L46134121–159
  ≤ 120 g/L5411477–120

Ninety-two patients (92%) completed their treatment according to the protocol. In 8 patients the treatment was modified: three did not receive chemotherapy due to significant comorbidities (ischemic heart disease or significant hepatopathy); in 1 patient chemotherapy was terminated due to acute side effects (chest pain due to a suspected ischemic event) and in 1 patient due to febrile neutropenia. One patient refused further treatment after 45 Gy and 1 patient refused chemotherapy. One patient received concurrent chemotherapy with cisplatin due to simultaneous treatment of the synchronous oropharyngeal cancer.

Median duration of radiochemotherapy was 1.9 months (range: 1–3.7 months). Fifty-six patients received brachytherapy boost with medial dose of 18.5 Gy (range: 10–25 Gy) or EBRT boost with medial dose of 14.4 Gy (range: 9–14.4 Gy). Capecitabine was used instead of 5-fluorouracil in 25 patients.

Tumour response to treatment

Complete clinical remission of the disease was achieved in 80 patients. The tumour disappeared within six weeks after the treatment completion in 73 patients, and within 4 months in 7 patients. One of them was operated on because of presumed persistent disease, yet the pathologist did not find disease residues. Of the remaining 20 patients, in 1 patient the disease progressed during treatment, 9 patients had APR performed and 2 patients had inguinal lymphadenectomy due to recurrence in inguinal lymph nodes; 8 patients had inoperable residual disease.

Survival

The 5-year LRC, DFS, DSS and OS rates for all patients were 72%, 71%, 77% and 62%, respectively.

Univariate analysis for survival according to the Hb level and other parameters is shown in Table 3.

Table 3.

Univariate analysis of survival of patients at 5 years by Hb level, tumour-, patients-, and treatment characteristics

DFS = disease-free survival; DSS = disease-specific survival; Hb = haemoglobin; LRC = loco-regional control; N = number of patients; OS = overall survival

CharacteristicsnLRCDFSDSSOS
Pre-treatment Hb
79%77%85%73%
 > 120 g/L69
57%57%56%39%
 ≤ 120 g/L31
P = 0.011P = 0.017P = 0.003P = 0.000
Mean on-treatment Hb
78%76%82%68%
 > 120 g/L67
60%60%67%50%
 ≤ 120 g/L33
P = 0.037P = 0.054P = 0.081P = 0.007
End-of-treatment Hb
82%80%89%75%
 > 120 g/L46
63%63%65%49%
 ≤ 120 g/L54
P = 0.022P = 0.037P = 0.011P = 0.003
Performance status
73%73%80%72%
  PS 076
69%64%66%34%
  PS 1–324
P = 0.480P = 0.283P = 0.231P = 0.000
Tumour stage
75%75%84%68%
T1–386
50%44%38%25%
T414
P = 0.054P = 0.015P = 0.000P = 0.001
Lymph node involvement
no6579%79%87%70%
yes3559%56%60%48%
P = 0.032P = 0.017P = 0.000P = 0.000
Overall disease stage
79%79%87%70%
I / II
64
IIIA / IIIB59%57%61%49%
36
P = 0.044P = 0.025P = 0.000P = 0.000
Histologic tumour type
basaloid12100%100%100%100%
squamous8868%67%74%57%
P = 0.030P = 0.026P = 0.051P = 0.016
Tumour site
69%68%78%62%
anal canal72
81%81%73%61%
anal margin28
P = 0.250P = 0.212P = 0.994P = 0.738
Blood transfusion
no72%71%78%64%
91
yes0%0%0%0%
9
P = 0.993P = 0.950P = 0.333P = 0.044
Overall radiation time
89%89%93%83%
≤ 1,08 months29
64%63%69%51%
> 1,08 months71
P = 0.015P = 0.011P = 0.012P = 0.012
Operation
no7389%88%88%69%
yes2729%29%52%45%
P = 0.000P < 0.000P = 0.001P = 0.018

In multivariate analysis, pre-treatment Hb (> 120 g/L vs. ≤ 120 g/L) was an independent prognostic factor only for OS (hazard ratio [HR]= 0.419, 95% confidence interval [CI] = 0.190−0.927, p = 0.032) and stage (I & II vs. III) for DSS (HR = 3.523, 95% CI = 1.375−9.026, p = 0.009) and OS (HR = 2.230, 95% CI = 1.167−4.264, p = 0.015).

Patients’ age, gender, tumour site, type of radiotherapy boost (tele- or brachytherapy) and type of chemotherapy (5-fluorouracil or capecitabine) did not have an influence on survival.

Haemoglobin concentration during treatment

In the group of patients with Hb > 120 g/L the mean Hb concentration during the treatment slightly but not significantly decreased (mean pre-treatment Hb = 139 g/L, mean end-of-treatment Hb = 125 g/L). However in the group of patients with Hb ≤ 120 g/L it slightly increased (mean pre-treatment Hb = 106 g/L, mean end-of-treatment Hb = 113 g/L). One third of patients had low iron levels and received iron preparations. Nine patients received blood transfusion due to a drop in their Hb concentration below 100 g/L.

Acute side effects

None of the patients died because of acute side effects. Most grade 3 side effects were caused by radiodermatitis. Serious, life-threatening infections were observed in 3 patients: 2 patients experienced severe pneumonia that requested transfer to the intensive care unit and 1 patient developed febrile neutropenia which required termination of radiochemotherapy. One patient developed severe stomatitis and needed parenteral nutrition. In 1 patient, serious diarrhoea developed, which required hospitalization. Frequency and intensity of acute side effects are shown in Table 4.

Table 4.

Acute treatment toxicities

ToxicityGrade
01234Total
Stomatitis68121091100
Nausea, vomiting799930100
Diarrhoea571712131100
Hand-foot syndrome*22012025
Radiodermatitis101213641100
Infection51142393100
Leucocyte count373120102100
Haemoglobin level43441120100
Platelet count5836330100

Discussion

Survival rates of our patients and the profile and frequency of acute side effects are similar to the results of other researchers.2,7,2629 There was no difference in survival of anal canal and anal margin cancer patients. The survival rate of patients with higher pre-treatment and end-of treatment Hb concentrations was generally better, compared to those patients with lower Hb concentrations, yet only pre-treatment Hb concentration was an independent prognostic factor for OS. Patients with mean on-treatment Hb > 120 g/L only had statistically significant better LRC and OS than patients with Hb ≤ 120 g/L. Many authors found that anaemic patients respond worse to radiotherapy and/or chemotherapy and have worse survival rates.2,8,12,13,1518,3041 There is convincing evidence of a correlation between Hb concentration and tumour oxygenation in various kinds of tumours.42 Nordsmark’s et al. comparison of pre-treatment Hb with pre-treatment tumour pO2 measurements in head and neck cancer showed a quadratic regression correlation between Hb concentration and median pO2.43 Tumours of anaemic patients are consequently more hypoxic and more resistant to radiotherapy (and chemotherapy).16 The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of blood transfusion in symptomatic patients with Hb concentration < 100 g/L to improve oxygen delivery to the tumour.44 Nine patients in our study received blood transfusion. They had statistically significant worse OS than other patients. The conclusions about beneficial effect of transfusion in our study cannot be made because the patients who received transfusion were few. The contribution to low survival of other unfavourable factors, which are often combined with anaemia, was not possible to assess.

The reports in the literature of the influence of transfusions on the outcome are not consistent. Some authors found favourable effect45, some found none46,47 and some found unfavourable effect.2,32 It is possible that a better oxygen delivery is not sufficient to improve oxygenation of a tumour with high oxygen consumption.30,35 Moreover, anaemic patients are assumed to have a more aggressive disease from the start.35,46 Immune suppression in patients could also play a part (7, 35).7,35

The use of erythropoetin is controversial due to the possible effect on tumour growth14,33,48, however, only in the subpopulation of patients whose tumours expressed erythropoetin receptors.49 Another potential mechanism by which erythropoetin therapy may result in negative outcomes in cancer patients is through promotion of thrombovascular events.50 Therefore, it was not used in our patients. De Los Santos et al. believe the connection between anaemia and hypoxia is complex; therefore, it is not clear whether transfusion or erythropoetin do patients any favour.51

The Hb concentration during treatment progressively decreased, which is in agreement with other reports.2,7,17,18,3033,46 At the beginning of treatment, 31% of our patients were anaemic, and at the end 54%. That should cause more hypoxia in the tumour. It is possible that a decreased delivery of oxygen to the tumour due to of Hb drop during the treatment is partially counterbalanced by the reoxygenation due to shrinkage of the tumour and does not influence very much the outcome. In some patients with Hb ≤ 120 g/L it was possible to raise the mean Hb level by the blood transfusion or by iron preparations.

The significance of mean on-treatment Hb concentration and end-of-treatment Hb concentration is less clear. Some authors found a positive effect of higher mean on-treatment Hb concentration on treatment outcome2,15,18,32,33,35 and some found a positive effect of higher end-of-treatment Hb concentration on treatment outcome35,36, while others found no influence on outcome of either mean- or end- of-treatment Hb level.31 In our patients, the mean- or end- of treatment Hb levels had less influence on survival compared to the pre-treatment values of Hb concentration.

Our study showed that pre-treatment Hb was an important independent prognostic factor for overall survival in patients with squamous cell carcinoma of the anal canal and anal margin treated with radiochemotherapy, which is in agreement with findings of most other authors. Mean on-treatment Hb and end-of-treatment Hb do not seem to have much influence on survival.

Because of a small number of patients who needed blood transfusion its influence on survival could not be assessed in our study.

References

  • 1

    Lopez Guerra JL, Lozano AJ, Pera J, Gutierrez C, Cambray M, Ferrer F, et al. Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy. Clin Transl Oncol 2011; 13: 472–9.

  • 2

    Roldan GB, Chan AK, Buckner M, Magliocco AM, Doll CM. The prognostic value of hemoglobin in patients with anal cancer treated with chemoradiotherapy. Dis Colon Rectum 2010; 53: 1127–34.

  • 3

    Martin FT, Kavanagh D, Waldron R. Squamous cell carcinoma of the anal canal. Surgeon 2009; 7: 232–7.

  • 4

    Johnson LG, Madeleine MM, Newcomer LM, Schwartz SM, Daling JR. Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973–2000. Cancer 2004; 101: 281–8.

  • 5

    Institute of Oncology Ljubljana, Cancer Registry of Republic of Slovenia. Cancer in Slovenia 2010. Primic Zakelj M, Bracko M, Hocevar M, Jarm K, Pompe-Kirn V, Strojan P, et al., editors. Ljubljana: Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Cancer Registry of Republic of Slovenia; 2013.

  • 6

    Abbas A, Yang G, Fakih M. Management of anal cancer in 2010. Part 1: Overview, screening, and diagnosis. Oncology (Williston Park) 2010; 24: 364–9.

  • 7

    Oblak I, Petric P, Anderluh F, Velenik V, Fras PA. Long term outcome after combined modality treatment for anal cancer. Radiol Oncol 2012; 46: 145–52.

  • 8

    Aggarwal A, Duke S, Glynne-Jones R. Anal cancer: are we making progress? Curr Oncol Rep 2013; 15: 170–81.

  • 9

    Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974; 17: 354–6.

  • 10

    Harunobu S, Koh PK, Bartolo DCC. Management of anal canal cancer. Dis Colon Rectum 2005; 48: 1301–15.

  • 11

    Ko S. Anal cancer. In: Abraham J, Gulley JL, Allegra CJ, editors. Clinical oncology. Philadelphia: Woltes Kluwer; 2014. p. 129–42.

  • 12

    Kumar P. Tumor hypoxia and anemia: impact of efficacy of radiation therapy. Semin Hematol 2000; 37: 4–8.

  • 13

    Khan FA, Shukla AN, Joshi SC. Anaemia and cancer treatment: a conceptual change. Singapore Med J 2008; 49: 759–64.

  • 14

    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 edition. London: Hodder Arnold; 2009. p. 207–16.

  • 15

    Varlotto J, Stevenson MA. Anemia, tumor hypoxemia, and the cancer patient. int J Radiat Oncol Biol Phys 2005; 63: 25–36.

  • 16

    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. p. 443–67.

  • 17

    Harrison LB, Chadha M, Hill RJ, Hu K, Shasha D. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist 2002; 7: 492–508.

  • 18

    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 2003; 50: 452–8.

  • 19

    World Health Organization. WHO handbook for reporting results of cancer treatment. WHO Offset Publication No. 48. Geneva: World Health Organization; 1979.

  • 20

    UICC International Union Against Cancer. TNM classification of malignant tumours. Sobin L, Gospodarowicz M, Wittekind C, editors. 7th edition. New York: Wiley-Liss; 2009.

  • 21

    Solivetti FM, Elia F, Santaguida MG, Guerrisi A, Visca P, Cercato MC, et al. The role of ultrasound and ultrasound-guided fine needle aspiration biopsy of lymph nodes in patients with skin tumours. Radiol Oncol 2014; 48: 29–34.

  • 22

    U.S. department of health and human services. Common terminology criteria for adverse events (CTCAE): Version 4.03 [internet]. 2010 June 14. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_8.5x11.pdf. Accessed 14 Jan 2015.

  • 23

    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81.

  • 24

    Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 1977; 3: 1–39.

  • 25

    Cox DR. Regression models and life tables. J R Stat Soc 1972; 34: 187–220.

  • 26

    Abbas A, Yang G, Fakih M. Management of anal cancer in 2010. Part 2: current treatment standards and future directions. Oncology (Williston Park) 2010; 24: 417–24.

  • 27

    Mitchell SE, Mendenhall WM, Zlotecki RA, Carroll RR. Squamous cell carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2001; 49: 1007–13.

  • 28

    Chapet O, Gerard JP, Riche B, Alessio A, Mornex F, Romestaing P. Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer. Int J Radiat Oncol Biol Phys 2005; 63: 1316–24.

  • 29

    Marshall DT, Thomas CR Jr. Carcinoma of the anal canal. Oncol Rev 2009; 3: 27–40.

  • 30

    Prosnitz RG, Yao B, Farrell CL, Clough R Brizel DM. Pretreatment anemia is correlated with the reduced effectiveness of radiation and concurrent chemotherapy in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 2005; 61: 1087–95.

  • 31

    van de Pol SM, Doornaert PA, de Bree R, Leemans CR, Slotman BJ, Langendijk JA. The significance of anemia in squamous cell head and neck cancer treated with surgery and postoperative radiotherapy. Oral Oncol 2006; 42: 131–8.

  • 32

    Bhide SA, Ahmed M, Rengarajan V, Powell C, Miah A, Newbold K, et al. Anemia during sequential induction chemotherapy and chemoradiation for head and neck cancer: the impact of blood transfusion on treatment outcome. Int J Radiat Oncol Biol Phys 2009; 73: 391–8.

  • 33

    Walter CJ, Bell LT, Parsons SR, Jackson C, Borley NR, Wheeler JM. Prevalence and significance of anaemia in patients receiving long-course neoadjuvant chemoradiotherapy for rectal carcinoma. Colorectal Dis 2013; 15: 52–6.

  • 34

    Hoff CM, Hansen HS, Overgaard M, Grau C, Johansen J, Bentzen J, et al. The importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy – Results from the randomized DAHANCA 5 study. Radiother Oncol 2011; 98: 28–33.

  • 35

    Lee SD, Park JW, Park KS, Lim SB, Chang HJ, Kim DY, et al. Influence of anemia on tumor response to preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Colorectal Dis 2009; 24: 1451–8.

  • 36

    Hoff CM. Importance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapy. Acta Oncol 2012; 51: 419–32.

  • 37

    van Acht MJ, Hermans J, Boks DE, Leer JW. The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal carcinoma. Radiother Oncol 1992; 23: 229–35.

  • 38

    Constantinou EC, Daly W, Fung CY, Willett CG, Kaufman DS, DeLaney TF. Time-dose considerations in the treatment of anal cancer. Int J Radiat Oncol Biol Phys 1997; 39: 651–7.

  • 39

    Schäfer U, Micke O, Müller SB, Schüller P, Willich N. Hemoglobin as an independent prognostic factor in the radiotherapy of head and neck tumors. Strahlenther Onkol 2003; 179: 527–34.

  • 40

    Valencia Julve J, Alonso Orduna V, Esco Baron R, Lopez-Mata M, Mendez Villamon A. Influence of hemoglobin levels on survival after radical treatment of esophageal carcinoma with radiotherapy. Clin Transl Oncol 2006; 8: 22–30.

  • 41

    Glynne-Jones R, Sebag-Montefiore D, Adams R, Gollins S, Harrison M, Meadows HM, Jitlal M; United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial Working Party. Prognostic factors for recurrence and survival in anal cancer: generating hypotheses from the mature outcomes of the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I). Cancer 2013; 119: 748–55.

  • 42

    Dietz DW, Dehdashti F, Grigsby PW, Malyapa RS, Myerson RJ, Picus J, et al. Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study. Dis Colon Rectum 2008; 51: 1641–8.

  • 43

    Vaupel P, Mayer A, Hockel M. Impact of hemoglobin levels on tumor oxygenation: The higher, the better? Strahlenther Onkol 2006; 182: 63–71.

  • 44

    Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 2005; 77: 18–24.

  • 45

    NCCN National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Cancer- and chemotherapy- induced anemia. Version 2.2014 [internet]. Fort Washington: National Comprehensive Cancer Network; 2013 Jul 24. Available at: http://www.oncomap.org/ download_zhinan/%E6%8C%87%E5%8D%97/anemia.pdf. Accessed 17 Feb 2014.

  • 46

    Kader AS, Lim JT, Berthelet E, Petersen R, Ludgate D, Truong PT. Prognostic significance of blood transfusions in patients with esophageal cancer treated with combined chemoradiotherapy. Am J Clin Oncol 2007; 30: 492–7.

  • 47

    Strauss HG, Haensgen G, Dunst J, Hayward CR, Burger HU, Scherhag A, et al. Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer. Int J Gynecol Cancer 2008; 18: 515–24.

  • 48

    Henke M, Laszig R, Rübe C, Schäfer U, Haase KD, Schilcher B, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362(9392): 1255–60.

  • 49

    Henke M, Mattern D, Pepe M, Bézay C, Weissenberger C, Werner M, Pajonk F. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol. 2006; 10; 24: 4708–13.

  • 50

    Hadland BK, Longmore GD. Erythroid-stimulating agents in cancer therapy: potential dangers and biologic mechanisms. J Clin Oncol 2009; 27: 4217–26.

  • 51

    De Los Santos JF, Thomas GM. Anemia correction in malignancy management: threat or opportunity? Gynecol Oncol 2007; 105: 517–29.

Footnotes

*

Only in patients treated with capecitabine

1

Lopez Guerra JL, Lozano AJ, Pera J, Gutierrez C, Cambray M, Ferrer F, et al. Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy. Clin Transl Oncol 2011; 13: 472–9.

2

Roldan GB, Chan AK, Buckner M, Magliocco AM, Doll CM. The prognostic value of hemoglobin in patients with anal cancer treated with chemoradiotherapy. Dis Colon Rectum 2010; 53: 1127–34.

3

Martin FT, Kavanagh D, Waldron R. Squamous cell carcinoma of the anal canal. Surgeon 2009; 7: 232–7.

4

Johnson LG, Madeleine MM, Newcomer LM, Schwartz SM, Daling JR. Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973–2000. Cancer 2004; 101: 281–8.

5

Institute of Oncology Ljubljana, Cancer Registry of Republic of Slovenia. Cancer in Slovenia 2010. Primic Zakelj M, Bracko M, Hocevar M, Jarm K, Pompe-Kirn V, Strojan P, et al., editors. Ljubljana: Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Cancer Registry of Republic of Slovenia; 2013.

6

Abbas A, Yang G, Fakih M. Management of anal cancer in 2010. Part 1: Overview, screening, and diagnosis. Oncology (Williston Park) 2010; 24: 364–9.

7

Oblak I, Petric P, Anderluh F, Velenik V, Fras PA. Long term outcome after combined modality treatment for anal cancer. Radiol Oncol 2012; 46: 145–52.

8

Aggarwal A, Duke S, Glynne-Jones R. Anal cancer: are we making progress? Curr Oncol Rep 2013; 15: 170–81.

9

Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974; 17: 354–6.

10

Harunobu S, Koh PK, Bartolo DCC. Management of anal canal cancer. Dis Colon Rectum 2005; 48: 1301–15.

11

Ko S. Anal cancer. In: Abraham J, Gulley JL, Allegra CJ, editors. Clinical oncology. Philadelphia: Woltes Kluwer; 2014. p. 129–42.

12

Kumar P. Tumor hypoxia and anemia: impact of efficacy of radiation therapy. Semin Hematol 2000; 37: 4–8.

13

Khan FA, Shukla AN, Joshi SC. Anaemia and cancer treatment: a conceptual change. Singapore Med J 2008; 49: 759–64.

14

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 edition. London: Hodder Arnold; 2009. p. 207–16.

15

Varlotto J, Stevenson MA. Anemia, tumor hypoxemia, and the cancer patient. int J Radiat Oncol Biol Phys 2005; 63: 25–36.

16

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. p. 443–67.

17

Harrison LB, Chadha M, Hill RJ, Hu K, Shasha D. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist 2002; 7: 492–508.

18

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 2003; 50: 452–8.

19

World Health Organization. WHO handbook for reporting results of cancer treatment. WHO Offset Publication No. 48. Geneva: World Health Organization; 1979.

20

UICC International Union Against Cancer. TNM classification of malignant tumours. Sobin L, Gospodarowicz M, Wittekind C, editors. 7th edition. New York: Wiley-Liss; 2009.

21

Solivetti FM, Elia F, Santaguida MG, Guerrisi A, Visca P, Cercato MC, et al. The role of ultrasound and ultrasound-guided fine needle aspiration biopsy of lymph nodes in patients with skin tumours. Radiol Oncol 2014; 48: 29–34.

22

U.S. department of health and human services. Common terminology criteria for adverse events (CTCAE): Version 4.03 [internet]. 2010 June 14. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_8.5x11.pdf. Accessed 14 Jan 2015.

23

Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81.

24

Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 1977; 3: 1–39.

25

Cox DR. Regression models and life tables. J R Stat Soc 1972; 34: 187–220.

26

Abbas A, Yang G, Fakih M. Management of anal cancer in 2010. Part 2: current treatment standards and future directions. Oncology (Williston Park) 2010; 24: 417–24.

27

Mitchell SE, Mendenhall WM, Zlotecki RA, Carroll RR. Squamous cell carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2001; 49: 1007–13.

28

Chapet O, Gerard JP, Riche B, Alessio A, Mornex F, Romestaing P. Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer. Int J Radiat Oncol Biol Phys 2005; 63: 1316–24.

29

Marshall DT, Thomas CR Jr. Carcinoma of the anal canal. Oncol Rev 2009; 3: 27–40.

30

Prosnitz RG, Yao B, Farrell CL, Clough R Brizel DM. Pretreatment anemia is correlated with the reduced effectiveness of radiation and concurrent chemotherapy in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 2005; 61: 1087–95.

31

van de Pol SM, Doornaert PA, de Bree R, Leemans CR, Slotman BJ, Langendijk JA. The significance of anemia in squamous cell head and neck cancer treated with surgery and postoperative radiotherapy. Oral Oncol 2006; 42: 131–8.

32

Bhide SA, Ahmed M, Rengarajan V, Powell C, Miah A, Newbold K, et al. Anemia during sequential induction chemotherapy and chemoradiation for head and neck cancer: the impact of blood transfusion on treatment outcome. Int J Radiat Oncol Biol Phys 2009; 73: 391–8.

33

Walter CJ, Bell LT, Parsons SR, Jackson C, Borley NR, Wheeler JM. Prevalence and significance of anaemia in patients receiving long-course neoadjuvant chemoradiotherapy for rectal carcinoma. Colorectal Dis 2013; 15: 52–6.

34

Hoff CM, Hansen HS, Overgaard M, Grau C, Johansen J, Bentzen J, et al. The importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy – Results from the randomized DAHANCA 5 study. Radiother Oncol 2011; 98: 28–33.

35

Lee SD, Park JW, Park KS, Lim SB, Chang HJ, Kim DY, et al. Influence of anemia on tumor response to preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Colorectal Dis 2009; 24: 1451–8.

36

Hoff CM. Importance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapy. Acta Oncol 2012; 51: 419–32.

37

van Acht MJ, Hermans J, Boks DE, Leer JW. The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal carcinoma. Radiother Oncol 1992; 23: 229–35.

38

Constantinou EC, Daly W, Fung CY, Willett CG, Kaufman DS, DeLaney TF. Time-dose considerations in the treatment of anal cancer. Int J Radiat Oncol Biol Phys 1997; 39: 651–7.

39

Schäfer U, Micke O, Müller SB, Schüller P, Willich N. Hemoglobin as an independent prognostic factor in the radiotherapy of head and neck tumors. Strahlenther Onkol 2003; 179: 527–34.

40

Valencia Julve J, Alonso Orduna V, Esco Baron R, Lopez-Mata M, Mendez Villamon A. Influence of hemoglobin levels on survival after radical treatment of esophageal carcinoma with radiotherapy. Clin Transl Oncol 2006; 8: 22–30.

41

Glynne-Jones R, Sebag-Montefiore D, Adams R, Gollins S, Harrison M, Meadows HM, Jitlal M; United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial Working Party. Prognostic factors for recurrence and survival in anal cancer: generating hypotheses from the mature outcomes of the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I). Cancer 2013; 119: 748–55.

42

Dietz DW, Dehdashti F, Grigsby PW, Malyapa RS, Myerson RJ, Picus J, et al. Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study. Dis Colon Rectum 2008; 51: 1641–8.

43

Vaupel P, Mayer A, Hockel M. Impact of hemoglobin levels on tumor oxygenation: The higher, the better? Strahlenther Onkol 2006; 182: 63–71.

44

Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 2005; 77: 18–24.

45

NCCN National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Cancer- and chemotherapy- induced anemia. Version 2.2014 [internet]. Fort Washington: National Comprehensive Cancer Network; 2013 Jul 24. Available at: http://www.oncomap.org/ download_zhinan/%E6%8C%87%E5%8D%97/anemia.pdf. Accessed 17 Feb 2014.

46

Kader AS, Lim JT, Berthelet E, Petersen R, Ludgate D, Truong PT. Prognostic significance of blood transfusions in patients with esophageal cancer treated with combined chemoradiotherapy. Am J Clin Oncol 2007; 30: 492–7.

47

Strauss HG, Haensgen G, Dunst J, Hayward CR, Burger HU, Scherhag A, et al. Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer. Int J Gynecol Cancer 2008; 18: 515–24.

48

Henke M, Laszig R, Rübe C, Schäfer U, Haase KD, Schilcher B, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362(9392): 1255–60.

49

Henke M, Mattern D, Pepe M, Bézay C, Weissenberger C, Werner M, Pajonk F. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol. 2006; 10; 24: 4708–13.

50

Hadland BK, Longmore GD. Erythroid-stimulating agents in cancer therapy: potential dangers and biologic mechanisms. J Clin Oncol 2009; 27: 4217–26.

51

De Los Santos JF, Thomas GM. Anemia correction in malignancy management: threat or opportunity? Gynecol Oncol 2007; 105: 517–29.

Radiology and Oncology

The Journal of Association of Radiology and Oncology

Journal Information


IMPACT FACTOR 2017: 1.722
5-year IMPACT FACTOR: 1.729

CiteScore 2017: 1.84

SCImago Journal Rank (SJR) 2017: 0.574
Source Normalized Impact per Paper (SNIP) 2017: 0.814


Cited By

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 360 360 50
PDF Downloads 51 51 2