1. bookVolume 50 (2016): Issue 1 (March 2016)
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1581-3207
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Open Access

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

Published Online: 16 Feb 2016
Volume & Issue: Volume 50 (2016) - Issue 1 (March 2016)
Page range: 113 - 120
Received: 26 Nov 2014
Accepted: 22 Dec 2014
Journal Details
License
Format
Journal
eISSN
1581-3207
First Published
30 Apr 2007
Publication timeframe
4 times per year
Languages
English
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.

Patients’ and tumours’ characteristics

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

WHO = World Health Organization

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

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

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

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

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.

Acute treatment toxicities

ToxicityGrade
01234Total
Stomatitis68121091100
Nausea, vomiting799930100
Diarrhoea571712131100
Hand-foot syndrome

Only in patients treated with capecitabine

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.

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

Acute treatment toxicities

ToxicityGrade
01234Total
Stomatitis68121091100
Nausea, vomiting799930100
Diarrhoea571712131100
Hand-foot syndrome

Only in patients treated with capecitabine

22012025
Radiodermatitis101213641100
Infection51142393100
Leucocyte count373120102100
Haemoglobin level43441120100
Platelet count5836330100

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

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

Patients’ and tumours’ characteristics

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

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.Lopez GuerraJLLozanoAJPeraJGutierrezCCambrayMFerrerFTwenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy>Clin Transl Oncol201113472910.1007/s12094-011-0684-zSearch in Google Scholar

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.RoldanGBChanAKBucknerMMaglioccoAMDollCMThe prognostic value of hemoglobin in patients with anal cancer treated with chemoradiotherapyDis Colon Rectum20105311273410.1007/DCR.0b013e3181d964c1Search in Google Scholar

Martin FT, Kavanagh D, Waldron R. Squamous cell carcinoma of the anal canal. Surgeon 2009; 7: 232–7.MartinFTKavanaghDWaldronRSquamous cell carcinoma of the anal canalSurgeon20097232710.1016/S1479-666X(09)80091-7Search in Google Scholar

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.JohnsonLGMadeleineMMNewcomerLMSchwartzSMDalingJRAnal cancer incidence and survival: the surveillance, epidemiology, and end results experience,1973-2000Cancer2004101281810.1002/cncr.20364Search in Google Scholar

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.Institute of Oncology Ljubljana, Cancer Registry of Republic of SloveniaCancer in Slovenia 2010Primic ZakeljMBrackoMHocevarMJarmKPompe-KirnVStrojanPeditors. Ljubljana: Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Cancer Registry of Republic of Slovenia2013Search in Google Scholar

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.AbbasAYangGFakihMManagement of anal cancer in 2010. Part 1: Overview, screening, and diagnosisOncology (Williston Park)2010243649Search in Google Scholar

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.OblakIPetricPAnderluhFVelenikVFrasPALong term outcome after combined modality treatment for anal cancerRadiol Oncol2012461455210.2478/v10019-012-0022-2Search in Google Scholar

Aggarwal A, Duke S, Glynne-Jones R. Anal cancer: are we making progress? Curr Oncol Rep 2013; 15: 170–81.AggarwalADukeSGlynne-JonesRAnal cancer: are we making progress?Curr Oncol Rep2013151708110.1007/s11912-013-0296-6Search in Google Scholar

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.NigroNDVaitkeviciusVKConsidineBJr.Combined therapy for cancer of the anal canal: a preliminary reportDis Colon Rectum197417354610.1007/BF02586980Search in Google Scholar

Harunobu S, Koh PK, Bartolo DCC. Management of anal canal cancer. Dis Colon Rectum 2005; 48: 1301–15.HarunobuSKohPKBartolo DCC. Management of anal canal cancerDis Colon Rectum20054813011510.1007/s10350-004-0934-zSearch in Google Scholar

Ko S. Anal cancer. In: Abraham J, Gulley JL, Allegra CJ, editors. Clinical oncology. Philadelphia: Woltes Kluwer; 2014. p. 129–42.KoSAnal cancerAbrahamJGulleyJLAllegraCJeditorsClinical oncologyPhiladelphiaWoltes Kluwer201412942Search in Google Scholar

Kumar P. Tumor hypoxia and anemia: impact of efficacy of radiation therapy. Semin Hematol 2000; 37: 4–8.KumarPTumor hypoxia and anemia: impact of efficacy of radiation therapySemin Hematol2000374810.1016/S0037-1963(00)90061-1Search in Google Scholar

Khan FA, Shukla AN, Joshi SC. Anaemia and cancer treatment: a conceptual change. Singapore Med J 2008; 49: 759–64.KhanFAShuklaANJoshiSCAnaemia and cancer treatment: a conceptual changeSingapore Med J20084975964Search in Google Scholar

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.HorsmanMRWoutersBGJoinerMCOvergaardJThe oxygen effect and fractionated radiotherapyJoinerMvan der KogelAeditorsBasic clinical radiobiology4th editionLondonHodder Arnold20092071610.1201/b13224-16Search in Google Scholar

Varlotto J, Stevenson MA. Anemia, tumor hypoxemia, and the cancer patient. int J Radiat Oncol Biol Phys 2005; 63: 25–36.VarlottoJStevensonMAAnemia, tumor hypoxemia, and the cancer patientint J Radiat Oncol Biol Phys200563253610.1016/j.ijrobp.2005.04.049Search in Google Scholar

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.ColeSPCTannockIFDrug resistanceTannockIHillRBristowRHarringtonLeditorsThe basic science of oncologyNew York1McGraw-Hill Education201344367Search in Google Scholar

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.HarrisonLBChadhaMHillRJHuKShashaDImpact of tumor hypoxia and anemia on radiation therapy outcomesOncologist2002749250810.1634/theoncologist.7-6-492Search in Google Scholar

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.OblakIStrojanPZakotnikBBudihnaMSmidLHemoglobin as a factor influencing the outcome in inoperable oropharyngeal carcinoma treated by concomitant radiochemotherapyNeoplasma200350452810.1016/S1359-6349(03)90188-1Search in Google Scholar

World Health Organization. WHO handbook for reporting results of cancer treatment. WHO Offset Publication No. 48. Geneva: World Health Organization; 1979.World Health OrganizationWHO handbook for reporting results of cancer treatment. WHO Offset Publication No. 48.GenevaWorld Health Organization1979Search in Google Scholar

UICC International Union Against Cancer. TNM classification of malignant tumours. Sobin L, Gospodarowicz M, Wittekind C, editors. 7th edition. New York: Wiley-Liss; 2009.UICC International Union Against CancerTNM classification of malignant tumoursSobinLGospodarowiczMWittekindCeditors7th editionNew YorkWiley-Liss2009Search in Google Scholar

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.SolivettiFMEliaFSantaguidaMGGuerrisiAViscaPCercatoMCThe role of ultrasound and ultrasound-guided fine needle aspiration biopsy of lymph nodes in patients with skin tumoursRadiol Oncol201448293410.2478/raon-2013-0084Search in Google Scholar

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

Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81.KaplanELMeierPNonparametric estimation from incomplete observationsJ Am Stat Assoc1958534578110.1007/978-1-4612-4380-9_25Search in Google Scholar

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.PetoRPikeMCArmitagePBreslowNECoxDRHowardSVDesign and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examplesBr J Cancer1977313910.1038/bjc.1977.1Search in Google Scholar

Cox DR. Regression models and life tables. J R Stat Soc 1972; 34: 187–220.CoxDRRegression models and life tablesJ R Stat Soc19723418722010.1007/978-1-4612-4380-9_37Search in Google Scholar

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.AbbasAYangGFakihMManagement of anal cancer in 2010. Part 2: current treatment standards and future directionsOncology (Williston Park)20102441724Search in Google Scholar

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.MitchellSEMendenhallWMZloteckiRACarrollRRSquamous cell carcinoma of the anal canalInt J Radiat Oncol Biol Phys20014910071310.1016/S0360-3016(00)01518-2Search in Google Scholar

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.ChapetOGerardJPRicheBAlessioAMornexFRomestaingPPrognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancerInt J Radiat Oncol Biol Phys20056313162410.1016/j.ijrobp.2005.05.04716169674Search in Google Scholar

Marshall DT, Thomas CR Jr. Carcinoma of the anal canal. Oncol Rev 2009; 3: 27–40.MarshallDTThomasCRJr.Carcinoma of the anal canalOncol Rev20093274010.1007/s12156-009-0006-7Search in Google Scholar

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.ProsnitzRGYaoBFarrellCLCloughRBrizelDMPretreatment anemia is correlated with the reduced effectiveness of radiation and concurrent chemotherapy in advanced head and neck cancerInt J Radiat Oncol Biol Phys20056110879510.1016/j.ijrobp.2004.07.710Search in Google Scholar

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.van de PolSMDoornaertPAde BreeRLeemansCRSlotmanBJLangendijkJAThe significance of anemia in squamous cell head and neck cancer treated with surgery and postoperative radiotherapyOral Oncol200642131810.1016/j.oraloncology.2005.06.021Search in Google Scholar

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.BhideSAAhmedMRengarajanVPowellCMiahANewboldKAnemia during sequential induction chemotherapy and chemoradiation for head and neck cancer: the impact of blood transfusion on treatment outcomeInt J Radiat Oncol Biol Phys200973391810.1016/j.ijrobp.2008.04.052Search in Google Scholar

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.WalterCJBellLTParsonsSRJacksonCBorleyNRWheelerJMPrevalence and significance of anaemia in patients receiving long-course neoadjuvant chemoradiotherapy for rectal carcinomaColorectal Dis20131552610.1111/j.1463-1318.2012.03112.xSearch in Google Scholar

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.HoffCMHansenHSOvergaardMGrauCJohansenJBentzenJThe importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy – Results from the randomized DAHANCA 5 studyRadiother Oncol201198283310.1016/j.radonc.2010.09.024Search in Google Scholar

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.LeeSDParkJWParkKSLimSBChangHJKimDYInfluence of anemia on tumor response to preoperative chemoradiotherapy for locally advanced rectal cancerInt J Colorectal Dis2009241451810.1007/s00384-009-0762-7Search in Google Scholar

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.HoffCMImportance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapyActa Oncol2012514193210.3109/0284186X.2011.653438Search in Google Scholar

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.van AchtMJHermansJBoksDELeerJWThe prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal carcinomaRadiother Oncol1992232293510.1016/S0167-8140(92)80126-4Search in Google Scholar

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.ConstantinouECDalyWFungCYWillettCGKaufmanDSDeLaneyTFTime-dose considerations in the treatment of anal cancerInt J Radiat Oncol Biol Phys199739651710.1016/S0360-3016(97)00329-5Search in Google Scholar

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.SchäferUMickeOMüllerSBSchüllerPWillichNHemoglobin as an independent prognostic factor in the radiotherapy of head and neck tumorsStrahlenther Onkol20031795273410.1007/s00066-003-1117-x14509951Search in Google Scholar

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.Valencia JulveJAlonso OrdunaVEsco BaronRLopez-MataMMendez VillamonAInfluence of hemoglobin levels on survival after radical treatment of esophageal carcinoma with radiotherapyClin Transl Oncol20068223010.1007/s12094-006-0091-zSearch in Google Scholar

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.Glynne-JonesRSebag-MontefioreDAdamsRGollinsSHarrisonMMeadowsHMJitlalMUnited 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)Cancer20131197485510.1002/cncr.27825Search in Google Scholar

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.DietzDWDehdashtiFGrigsbyPWMalyapaRSMyersonRJPicusJTumor 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 studyDis Colon Rectum2008511641810.1007/s10350-008-9420-3Search in Google Scholar

Vaupel P, Mayer A, Hockel M. Impact of hemoglobin levels on tumor oxygenation: The higher, the better? Strahlenther Onkol 2006; 182: 63–71.VaupelPMayerAHockelMImpact of hemoglobin levels on tumor oxygenation: The higher, the better?Strahlenther Onkol2006182637110.1007/s00066-006-1543-7Search in Google Scholar

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.NordsmarkMBentzenSMRudatVBrizelDLartigauEStadlerPPrognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center studyRadiother Oncol200577182410.1016/j.radonc.2005.06.038Search in Google Scholar

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.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 athttp://www.oncomap.org/download_zhinan/%E6%8C%87%E5%8D%97/anemia.pdfAccessed 17 Feb 2014Search in Google Scholar

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.KaderASLimJTBertheletEPetersenRLudgateDTruongPTPrognostic significance of blood transfusions in patients with esophageal cancer treated with combined chemoradiotherapyAm J Clin Oncol200730492710.1097/01.coc.0000264177.66369.18Search in Google Scholar

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.StraussHGHaensgenGDunstJHaywardCRBurgerHUScherhagAEffects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancerInt J Gynecol Cancer2008185152410.1111/j.1525-1438.2007.01032.xSearch in Google Scholar

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.HenkeMLaszigRRübeCSchäferUHaaseKDSchilcherBErythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trialLancet2003362939212556010.1016/S0140-6736(03)14567-9Search in Google Scholar

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.HenkeMMatternDPepeMBézayCWeissenbergerCWernerMPajonkFDo erythropoietin receptors on cancer cells explain unexpected clinical findings?J Clin Oncol2006102447081310.1200/JCO.2006.06.273717028293Search in Google Scholar

Hadland BK, Longmore GD. Erythroid-stimulating agents in cancer therapy: potential dangers and biologic mechanisms. J Clin Oncol 2009; 27: 4217–26.HadlandBKLongmoreGDErythroid-stimulating agents in cancer therapy: potential dangers and biologic mechanismsJ Clin Oncol20092742172610.1200/JCO.2008.21.694519636005Search in Google Scholar

De Los Santos JF, Thomas GM. Anemia correction in malignancy management: threat or opportunity? Gynecol Oncol 2007; 105: 517–29.De Los SantosJFThomasGMAnemia correction in malignancy management: threat or opportunity?Gynecol Oncol20071055172910.1016/j.ygyno.2006.12.03717367848Search in Google Scholar

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