|Ahead of print
Lower pretreatment hemoglobin status and treatment breaks in locally advanced head and neck squamous cell carcinoma during concurrent chemoradiation
Rajesh Kar Narayanasamy1, RM Muthusekar2, Sathiamoorthy Pattanam Nagalingam1, Sendil Thyagarajan1, Balasubramaniam Ramakrishnan3, Karthikeyan Perumal1
1 Consultant Oncologist, Dr. Rai - Comprehensive Blood and Cancer Center Oncology Services, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu, India
2 Department of Oral and Maxillofacial Surgery, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu, India
3 Consultant Bio-Statistician, Dr. Rai - Comprehensive Blood and Cancer Center Oncology Services, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu, India
|Date of Submission||08-Oct-2018|
|Date of Decision||30-Jun-2019|
|Date of Acceptance||12-Jul-2019|
|Date of Web Publication||24-Nov-2020|
Consultant Oncologist, Dr. Rai - Comprehensive Blood and Cancer Center Oncology Services, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Treatment breaks during radiation for locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the important factors affecting the loco-regional control rate. We prospectively analysed the role lower pre-treatment hemoglobin (pre-T Hb) status and its influence on treatment breaks amongst patients undergoing concurrent chemoradiation (CRT).
Methods: One hundred and twenty HNSCC (T3-T4a, N1-N2c) patients treated by CRT were prospectively analysed for influence of pre-T Hb on treatment breaks. Sub-sites included oral cavity, oropharynx, hypopharynx & larynx. All patients received radiation to a total dose of 66Gy to PTV along with weekly Inj. Cisplatin 40 mg/m2. All patients were evaluated weekly and at the end of 6 weeks by hemogram, physician and radiological examination.
Results: Our study population had a mean age (±standard deviation) of 55 (± 10.7) years (range: 27 - 69 years), 85 men and 35 women with a performance status of the Eastern Cooperative Oncology Group (ECOG) 1-2. The mean pre-T Hb calculated (using receiver operating characteristic curve [ROC]) was 10.3 g/dL. Among 120 patients, in the pre-T Hb of ≤10.3 g/dL group, 44 (75.9%) patients had treatment breaks of ≥5 days and 11 (17.7%) patients had treatment breaks < 5 days; in the pre-T Hb of >10.3 g/dL group, 14 (24.1%) patients had treatment breaks of ≥5 days and 51 (82.3%) patients had treatment breaks < 5 days (P = 0.001).
Conclusion: Lower pre-T Hb level of ≤ 10.3 g/dL is statistically significantly associated with higher treatment breaks of ≥ 5 days.
Keywords: Pretreatment hemoglobin, radiotherapy, treatment breaks
Key Message: Lower pretreatment hemoglobin cohort showed more treatment interruptions, even after correction of anemia in locally advanced head and neck squamous cell carcinoma during concurrent chemoradiation. This could be due to varying tumor biology or host factors rather than anemia itself.
|How to cite this URL:|
Narayanasamy RK, Muthusekar R M, Nagalingam SP, Thyagarajan S, Ramakrishnan B, Perumal K. Lower pretreatment hemoglobin status and treatment breaks in locally advanced head and neck squamous cell carcinoma during concurrent chemoradiation. Indian J Cancer [Epub ahead of print] [cited 2021 Mar 2]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=301406
| » Introduction|| |
Locally advanced head and neck squamous cell carcinoma (HNSCC) is a potentially curable malignancy.
Concurrent chemoradiotherapy (CRT) is the cornerstone of HNSCC treatment and organ preservation, requiring 30 to 35 days of treatment over 6 to 7 weeks while being costly and toxic. It has been shown that gaps in treatment yield poorer outcomes for patients with HNSCC,,,,, with accelerated tumor regrowth occurring during treatment breaks.
As the intensity of treatment regimens have escalated in recent years, clinical outcomes, in general, have improved at the cost of impacting the mucosal lining of the oral cavity, pharynx, and cervical esophagus, resulting in varying degrees of ulcerative mucositis. Ulcerative mucositis is a root cause of unscheduled treatment breaks, which prolongs the total radiation treatment time.
When radiotherapy or CRT is used in HNSCC, unplanned treatment breaks and prolongation of the treatment time are associated with lower survival and locoregional control rates. Diligent patient compliance is crucial, and unplanned treatment interruptions reduce cure rates.
Continued investigation is needed to identify superior radiation treatment regimens, technology, and supportive care that reduce unplanned radiation treatment breaks with the goal of improving clinical outcomes in HNSCC.
Unplanned radiation treatment breaks resulting from ulcerative mucositis and the associated acute side effects negatively impact treatment outcomes for many types of tumors, but the detrimental effect appears greatest in head and neck cancer.,
Lower pretreatment hemoglobin status and cancer
Cancer itself can cause or exacerbate lower pretreatment hemoglobin (pre-T Hb) either by suppressing hematopoiesis through bone marrow infiltration or production of cytokines that lead to iron sequestration or by reduced red blood cell production. In addition, cancer treatment itself may be a major cause of anemia.,
Cancer-induced anemia and anemia of chronic disease result from multiple causes and the fine interplay of pro and antiapoptotic factors inducing a fine-tuned selective differentiation of the trilineage-committed hematopoietic stem cell. A slight disruption of this equilibrium will present as one of the many facets of blood count changes from anemia to thrombocytosis, as commonly seen in cancer patients.
The objective of this article is to review data on the association between lower pre-T Hb and treatment breaks and possible strategies to prevent radiation treatment breaks in the management of HNSCC.
We studied interruption rates in consecutive patients attending our outpatient department (OPD) who met the study criteria.
| » Materials and Methods|| |
We did a nonrandomized single-institutional observational study on patients meeting our study criteria. Consecutive HNSCC patients attending our oncology OPD were evaluated by complete history, physical examination, clinical evaluation, endoscopic evaluation, blood and radiological investigations along with oncological staging workup as per American Joint Committee on Cancer (AJCC) Staging Criteria 7th Edition published in 2010. Patients with pre-T Hb status <11 g/dL were given hematinic support and/or blood transfusion.
(i) Head and neck sites including oral cavity (OC), oropharynx (OP), hypopharynx (HP), and larynx (LX) (ii) Patient age ≥18 years and ≤70 years (iii) the Eastern Cooperative Oncology Group (ECOG) performance status 1/2 (iv) HNSCC of stage III / IV A.(v) Patients who are able to undergo concurrent chemoradiation (vi) Patients who come for follow-up of at least 6 weeks after completion of treatment.
(i) Past history of malignancy. (ii) Past history of radiation in head and neck region. (iii) Past history of uncontrolled comorbidities like diabetes, hypertension, (iv) and other fatal and nonfatal comorbid conditions that can affect the outcome of the treatment or the overall survival (OS) in general.
Our study enrolled 120 consecutive patients of HNSCC stage III / IV A only. Patients were divided into lower and regular hemoglobin groups based on the pre-T Hb status of ≤10.3 g/dL. Only during the analysis of data, patient groups were categorized into two.
HNSCC from various sites—OC, OP, HP, and LX—with 6 weeks of follow-up alone were enrolled, precluding any attrition post-enrollment. The study criteria involved only accounting for Hb level prior to radiation therapy. In addition to pre-T Hb levels, patient variables such as age, gender, tumor site, tumor (T) stage, nodal (N) stage, ECOG performance status, the grade of mucositis, and treatment breaks of more than 5 days were analyzed.
All eligible patients got treated by CRT with radiation dose consisting of conventionally fractionated 66 Gy, 2 Gy per fraction, five fractions per week over 6.5 weeks. Radiation technique was individualized. However, in general, the technique involved immobilization with Aquaplast mask in a supine position with shoulder retraction; treatment volume, consisting the primary tumor site, involved lymph nodes and all draining lymph nodes at risk.
All patients received concurrent weekly cisplatin 40 mg/m2 during radiation.
Patient review / follow-up / analyses
All patients were reviewed weekly by clinical examination and blood investigations (hemogram, blood urea, and serum creatinine) during the treatment.
Response assessment was done 6 weeks after treatment clinically and radiologically similar to pretreatment workup and using response evaluation (RECIST) criteria.
Microsoft Excel sheet was used for data entry; data analyses were done using Statistical Package for the Social Sciences (SPSS) Version 25.0. All P values <0.05 were considered statistically significant.
Continuous variables were assessed for normality using Shapiro–Wilk's test. Normally distributed variables were expressed as mean ± standard deviation (SD), otherwise as median (interquartile range). Categorical variables were expressed in percentage. Non-normally distributed continuous variables were analyzed by Mann–Whitney U test. Receiver operating characteristic curve (ROC) was drawn to determine the cut-off value of pre-T Hb (in g/dL) distinguishing partial response and complete response. Comparison of categorical variables was done by Chi-square test or Fisher's exact test based on the number of observations.
Pre-T Hb status with the cut-off value of 10.3 g/dL was drawn with ROC and, with this value, two groups were formed: Lower hemoglobin group with ≤10.3 g/dL and regular hemoglobin group with >10.3 g/dL. These two groups were analyzed with treatment breaks of 5 or more days.
| » Results|| |
One hundred and twenty HNSCC patients with a median age of 55 years (range: 27-69 years), of which 85 were men (70.83%) and 35 were women (29.17%), were analyzed [Table 1].
Anemia was assessed pretreatment, and the correction was done. ROC was plotted with Hb levels of our study subject, and the value of 10.3 g/dL was obtained based on ROC. Based on this value, our study population was stratified into lower and regular hemoglobin groups: 65 patients (54.17%) having Hb >10.3 g/dL and 55 patients (45.83%) with Hb ≤10.3 g/dL. This pre-T Hb level in the two groups was compared with other variables and assessed for treatment breaks.
HNSCC of different head and neck sites like OC, OP, HP, and LX were taken of which 70 patients (58.33%) were OC, 29 (24.17%) OP, 8 (6.67%) HP, and 13 (10.83%) LX. Among 120 patients, 49 patients (40.83%) were at T3 stage and 71 (59.17%) were at T4a; 60 patients (50%) being N1 and 60 patients (50%) being N2.
Treatment side effects
Mucositis was experienced by all patients undergoing chemoradiation. Patients who suffered from mucositis were given adequate supportive care.
Among 120 patients, 56 (46.67%) had grade 2 mucositis - 48 (85.7%) were >10.3 g/dL and only 8 (14.3%) were ≤10.3 g/dL; whereas, among 120 patients, 64 (53.33%) had grade 3 mucositis - 17 (26.6%) were >10.3 g/dL and 47 (73.4%) were ≤10.3 g/dL (P value <0.005).
To find out an impact of pre-T Hb on treatment interruptions, the study population with treatment breaks of ≥ 5 days was considered as one group and treatment breaks <5 days as another. Among 120 patients, 58 (48.33%) had treatment breaks ≥5 days and 62 (51.67%) had treatment breaks <5 days.
In this study, our aim was to find out the impact of pre-T Hb status with treatment breaks of ≥5 days.
Our results showed that lower pre-T Hb had more treatment breaks ≥ 5 days [Table 2]. More specifically, in pre-T Hb ≤10.3 g/dL group, 44 (75.9%) patients had treatment breaks of ≥ 5 days and 11 (17.7%) had treatment breaks <5 days; in pre-T Hb >10.3 g/dL group, 14 (24.1%) patients had treatment breaks ≥ 5 days and 51 (82.3 %) had treatment breaks < 5 days (P = 0.001).
| » Discussion|| |
Relevance of radiation treatment breaks with tumor cell repopulation
The biological basis for the negative effects of unplanned radiation treatment breaks on clinical outcomes has been attributed to tumor stem cells, leading to recurrence. Approximately 2–4 weeks after the start of radiotherapy, accelerated tumor stem cell repopulation in HNSCC occurs continually during radiation.,
The estimated tumor stem-cell doubling time during accelerated repopulation may shorten from approximately 60 days to 4 days. Tarnawski et al., in a retrospective study, estimated repopulation rates for 1,502 patients with carcinoma of the larynx or pharynx (treated with external beam radiation alone). The probability of tumor control significantly correlated with radiation dose, tumor–node–metastasis stage, overall radiation treatment time, and gap duration.
It was also observed that tumor cell repopulation accelerated more rapidly during a break than during normal days of radiotherapy: 0.75 versus 0.2 cell doubling per day during days with irradiation. This demonstrated the cellular basis for the impact of planned and unplanned radiation breaks on locoregional control, as confirmed in clinical studies.
Relevance of radiation treatment breaks with treatment outcome
Unplanned breaks in radiotherapy for head and neck cancer are associated with significantly worse locoregional control.,,
A retrospective analysis of 2,225 patients from four centers revealed evidence that even a short break may have negative consequences; an unplanned break of only 1 day resulted in a 0.68% lower 2-year local control rate. Other authors have estimated that the tumor control rate is at least 1% lower for every day that radiation treatment is interrupted., Unplanned breaks, especially those of several days or more, also have been reported to result in significantly shorter overall survival and relapse-free survival times. After radiotherapy is held for 6 days, every additional day is associated with a 1–2% lower 5-year relapse-free survival rate.
Just as unplanned radiation treatment breaks are known to have clinical consequences, planned radiation treatment breaks may explain some of the observed results in controlled clinical trials of altered fractionation schedules.
A large randomized phase III study in 1,073 patients with HNSCC compared the following: standard once-a-day radiotherapy (2.0 Gy once daily, 5 days/week for 7 weeks), hyperfractionation (1.2 Gy twice daily, 5 days/week for 7 weeks), accelerated hyperfractionation with a break (1.6 Gy twice daily, 5 days/week for 6 weeks including a 2-week rest after 38.4 Gy), and accelerated fractionation with a concomitant boost (1.8 Gy once daily, 5 days/week for 6 weeks, plus an additional 1.5 Gy once daily to a boost field during the last 12 radiation treatment days).
The combination of accelerated hyperfractionation with a break did not affect locoregional tumor control or survival outcomes when compared with conventional fractionation arm. This finding may have been a result of the inclusion of the planned 2-week break, which appears to negate the benefits of hyperfractionation and acceleration.
Conversely, reducing or eliminating planned radiation treatment breaks and reducing the overall treatment time has shown better tumor control.
Relevance of radiation treatment breaks and concurrent CRT
In contrast to the body of data delineating the negative consequences of radiation treatment breaks and longer total radiation treatment times in radiotherapy alone for HNSCC, there is a paucity of data regarding the influence of the radiation treatment time on outcomes when CRT is used.
Studies provide indirect evidence that prolonged radiation treatment breaks in CRT regimens, whether planned or unplanned, may decrease the beneficial effect of the addition of chemotherapy to radiotherapy., The intensive chemotherapy, despite the planned breaks, seemed to exert continued negative growth pressure on tumor stem cells and maintain the benefit of chemotherapy to radiotherapy by allowing for “recovery” of acutely responding tissues during the 1-week interruptions.
Ulcerative mucositis and radiation treatment breaks
A chart review of 450 patients confirmed the greater risk for ulcerative mucositis associated with intensified therapy—either CRT or higher cumulative radiotherapy doses. Unplanned radiotherapy interruptions were 3.8-fold more common and unplanned chemotherapy breaks were 3.4-fold more common among patients with ulcerative mucositis. In addition, the frequency of radiation treatment breaks was higher with higher grades of ulcerative mucositis.
Strategies to reduce ulcerative mucositis and radiation treatment breaks
Various strategies are possible to reduce associated radiation treatment breaks: compensatory doses of radiotherapy for radiation treatment breaks using a linear-quadratic model, molecularly targeted therapy, cetuximab concurrent with radiation, prophylactic use of feeding tubes, local treatment with oral rinses such as 0.15% benzydamine, or vitamin E hydrolytic enzymes, ice chips, Chinese (herbal) medicine, amifostine, and recombinant human keratinocyte growth factor palifermin.
The clinical significance of the relationship between anemia and poor outcome following radiotherapy is obvious. However, few trials have addressed any possible impact of anemia on normal tissue radiosensitivity and toxicity.,,
Henke et al., in his randomized double-blinded prospective study with 60 patients, found that a decrease in mean hemoglobin of 1 g/dL predicted a reduced risk of developing grade 2 and 3 skin reactions (relative risk [rr] = 0.9 and 0.8, respectively), and grade 3 mucosal reactions (rr = 0.8). It was also found that severely anemic patients developed skin reactions later, at higher doses.
Lee et al. conducted a large prospective study on the effect of anemia in stage 3 or 4 HNSCC treated with conventional radiotherapy with or without the hypoxic cell sensitizer etanidazole. They estimated that grade 3 or greater toxicity at 5 years was 19.8% in patients with normal hemoglobin versus 12.7% in anemic patients (P = 0.063).
Analysis of 238 out of 350 recruited patients in a trial found that there were significant differences between the groups in locoregional control, relapse-free survival, cause-specific survival, and overall survival. The hazard ratios in favor of the normal hemoglobin group were 0.56 (95% confidence interval [CI] 0.34–0.94), 0.57 (95% CI 0.35–0.92), 0.49 (95% CI 0.29–0.85), and 0.43 (95% CI 0.26–0.70). Cox proportional hazards modeling showed that hemoglobin level was a significant predictor of cause-specific survival in addition to disease site, stage, and ECOG status. Nonetheless, there were no statistically significant differences between the groups in the development of acute or late reactions.
The generally accepted hypothesis is that in the same way that anemia appears to reduce the radiosensitivity of tumor cells because of its impact on hypoxic fraction within tumors, anemia may reduce the radiosensitivity of normal cells, and thus reduce normal tissue toxicity. It is also possible that anemia has no significant impact on normal tissue toxicity. The partial pressure of oxygen (pO2) of normal tissues varies between 20 and 40 mmHg. Even in the presence of anemia, compensatory mechanisms such as increased cardiac output and vasodilatation would result in small changes in the pO2 within this range. These changes are associated with only small changes in the relative radiosensitivity. Hence, it is likely that the variation in radiosensitivity within normal tissues is minimal. This is consistent with the results of the study by Becker et al. While severely anemic patients had significantly lower tumor oxygenation, there was no correlation between anemia and oxygen tension in normal sternocleidomastoid muscles.
The effect of anemia on normal tissue toxicity (and hence, treatment breaks) following radiotherapy for HNSCC is not just restricted to mucositis but several other factors like fatigue.
Cancer-related fatigue (CRF)
Patient reports suggest that cancer-related fatigue is more severe, more persistent, and more debilitating than “normal” fatigue caused by lack of sleep or overexertion and is not relieved by adequate sleep or rest.
A variety of biological mechanisms of CRF have been proposed and investigated over the past 2 decades., These include anemia, cytokine dysregulation, hypothalamic–pituitary–adrenal (HPA) axis dysregulation, five hydroxytryptophan (5-HT) neurotransmitter dysregulation, and alterations in adenosine triphosphate and muscle metabolism, among others.
According to a survey of 1,569 cancer patients, fatigue is experienced by 80% of individuals who receive chemotherapy and/or radiotherapy. The National Comprehensive Cancer Network (NCCN) panel identified anemia as one of the common causative factors in the fatigue experience and, therefore, should be specifically assessed.
Decreased hemoglobin is an important factor for delayed healing of normal tissues, severe mucositis, and fatigue. Lower pre-T Hb could be caused by poor nutritional status, the interaction of pro- and antiapoptotic factors, or disparate tumor biology itself. This requires further evaluation in existing or newer larger studies on lower pre-T Hb and treatment breaks; most importantly, elucidation needs to be done if the tumor biology itself is different in patients with lower pre-T Hb.
The most important finding in our study was that even after correcting the anemia, lower pre-T Hb cohort showed poorer treatment outcome. This could be due to several reasons such as central tumor hypoxia not getting corrected adequately, varying tumor biology in lower pre-T Hb cohort, and differing host factors in lower pre-T Hb cohort. More research is needed to elucidate the cause.
| » Limitations of Our Study|| |
All of our study patients undergo institutional treatment. Post study enrolment, all patients were ensured of a semi-solid or liquid diet with a calorie intake of 2000–2400 calories per day. Furthermore, only patients who discontinue tobacco and alcohol habits are treated in our institution.
Nutrition plays an important role in the development and healing of mucositis. Our study includes only good performance-status patients. Hence, we did not find many variations in nutritional status among both cohorts warranting diversification and analysis. We were unable to estimate the impact of nutrition or continuing tobacco habits in our study.
Our study's cohort classification is not based on the national or international definition of anemia. We obtained ROC with a total number of 120 patients included in the study and the mean value was taken as the cut-off with 90% CI which has sufficient sample size for a statistical significance. A different study cohort may have a different cut-off level based on ROC. Moreover, the term normal or desirable is highly variable in different geographies and populations within the same geography. In this research manuscript, we would like to keep the Hb level open and not suggest any particular value.
| » Conclusion|| |
Our study finds a direct relation to increased treatment breaks with reduced pre-T Hb, causing prolonged treatment, and hence, impairing tumor control probability. Larger existing studies in HNSCC should evaluate the effect of lower pre-T Hb on treatment breaks, normal tissue toxicity, and tumor control probability.
The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Declaration of Helsinki 1975 that was revised in 2000.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]