|Year : 2015 | Volume
| Issue : 2 | Page : 35-38
Associations of Age and Chemotherapy with Late Skin and Subcutaneous Tissue Toxicity in a Hypofractionated Adjuvant Radiation Therapy Schedule in Post-mastectomy Breast Cancer Patients
Mohammad Akram1, Ghufran Nahid1, Shahid Ali Siddiqui1, Ruquiya Afrose2
1 Department of Radiotherapy, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
2 Department of Pathology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
|Date of Submission||05-Feb-2015|
|Date of Acceptance||08-Apr-2015|
|Date of Web Publication||28-Apr-2015|
Dr. Mohammad Akram
Department of Radiotherapy, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh 202 002, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Aim: This retrospective study was conducted to evaluate the associations of age and two different types of chemotherapy regimens with late skin and subcutaneous tissue toxicities in an adjuvant hypofractionated radiation therapy (HFRT) schedule.
Methods: We retrospectively reviewed the records of 120 breast cancer patients. Patients underwent modified radical mastectomy (MRM) and received anthracycline- and taxane-based chemotherapy before the application of HFRT. Late skin and subcutaneous toxicity were evaluated in accordance with the Radiation Therapy Oncology Group grading scheme. Univariate logistic regression analysis was used to predict the associations of old age (> 50) and taxane-based chemotherapy with late skin and subcutaneous tissue toxicities.
Results: Grade 2 skin toxicity was found in 44 (42.3%) patients and Grade 2 subcutaneous tissue toxicity was found in 38 (36%) patients. Neither Grade 3 nor Grade 4 toxicity was observed. There was higher but not statistically significant risk of Grade 2 skin and subcutaneous tissue toxicity in patients over 50 years old. Types of chemotherapy were not significantly associated with Grade 2 skin toxicity and subcutaneous tissue toxicity.
Conclusion: Old age (> 50) and taxane-based chemotherapy do not adversely affect late skin and subcutaneous tissue toxicity in adjuvant HFRT schedule in post-MRM breast cancer patients.
Keywords: Age, breast cancer, chemotherapy, hypofractionation, skin and subcutaneous tissue toxicity
|How to cite this article:|
Akram M, Nahid G, Siddiqui SA, Afrose R. Associations of Age and Chemotherapy with Late Skin and Subcutaneous Tissue Toxicity in a Hypofractionated Adjuvant Radiation Therapy Schedule in Post-mastectomy Breast Cancer Patients. Cancer Transl Med 2015;1:35-8
|How to cite this URL:|
Akram M, Nahid G, Siddiqui SA, Afrose R. Associations of Age and Chemotherapy with Late Skin and Subcutaneous Tissue Toxicity in a Hypofractionated Adjuvant Radiation Therapy Schedule in Post-mastectomy Breast Cancer Patients. Cancer Transl Med [serial online] 2015 [cited 2019 Dec 11];1:35-8. Available from: http://www.cancertm.com/text.asp?2015/1/2/35/155918
| Introduction|| |
Breast cancer is the second most common cancer in the world and has the highest incidence among women with nearly 1.7 million new cases diagnosed in 2012. This represents about 12% of all new cancer cases and 25% of all cancers in women.  The incidence of breast cancer is increasing in India. It is the most common cancer in urban women and second common cancer in rural Indian women.  The majority of patients present in advanced stages of the disease. More than 50% of patients have late and locally advanced disease. 
Radiation-induced skin and subcutaneous tissue toxicity are a commonly observed phenomenon affecting the majority of the breast cancer patients treated with radiation.  Although acute toxicity is more frequently observed, late toxicity is particularly concerning due to its persistent effect. The severity of skin and subcutaneous toxicity is influenced by various treatment and patient-related factors. ,, Treatment-related factors include the fraction size (the dose delivered with fraction), the total dose delivered, the volume of tissue irradiated, the type of radiation,  and the addition of chemotherapy.  Patient-related factors include breast size, smoking, age, and infection resulting from surgical wound.  Patient genetic constitution also influences risk of normal tissue toxicity. 
The increase in fraction size (larger daily dose of radiation than the conventional 2 Gy per fraction) with reduced total dose and number of fractions is known as hypofractionated radiation therapy (HFRT). Currently, it offers disease control rates and toxicity profiles equivalent to those of the conventionally fractionated regimen. ,, HFRT is a convenient and attractive alternative to the patients as it is less time-consuming. Skin and subcutaneous tissue toxicity occurring with conventional fractionation have been described in various studies.  However, there are insufficient data on the late skin and subcutaneous tissue toxicity following HFRT, especially in postmastectomy patients. Moreover, the impact of associated factors such as chemotherapy, stage of the disease, age and comorbid conditions including hypertension and diabetes on the late skin and subcutaneous tissue toxicity was not separately analyzed in previous studies. Among these factors, we have analyzed the impact of age and type of chemotherapy on the late skin and subcutaneous tissue toxicities in an adjuvant HFRT schedule.
| Methods|| |
We retrospectively reviewed the records of 120 patients with post-modified radical mastectomy (MRM) breast cancer registered in Department of Radiotherapy at Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, India from October 2011 to February 2013. These patients were subjected to our adjuvant HFRT protocol, defined by 4250 cGy/16 fractions/22 days at 265 cGy per fraction, 5 days/week after completion of adjuvant chemotherapy. Eligible patients for this protocol had histologically confirmed breast cancer, were older than 18 years of age and had stage 2 and 3 disease. These patients received 2-3 cycles of neoadjuvant chemotherapy to reduce the tumor size and spread, and then underwent surgery in the form of MRM. Patients with negative histological margins were included. Patients were excluded if they had any skin disease that may have interfered with the accurate representation of radiation toxicity or had any surgery other than MRM.
Of 120 patients, 64 (53.3%) were treated with FEC (5 fluorouracil 600 mg/m2, epirubicin 80 mg/m2, cyclophosphamide 600 mg/m2 on day 1, cycle repeated every 3 weeks × 6 cycles) and 56 patients (46.7%) with TC (docetaxel 100 mg/m2, cyclophosphamide 600 mg/m2 on day 1, cycle repeated every 3 weeks × 6-8 cycles) in the form of neoadjuvant and adjuvant chemotherapy prior to the execution of radiotherapy. Adjuvant HFRT was started 2-3 weeks after completion of chemotherapy.
All patients receiving radiation therapy were treated in the supine position with the ipsilateral arm raised above the shoulder and immobilized. The chest wall was irradiated by two opposing tangential fields, and the axilla and supra- and infraclavicular fossa were treated by single anterior field. The arrangement of the beams was decided upon after evaluating a treatment plan for target volume coverage, dose homogeneity, and volume of the underlying lung and heart. Patients were treated with a cobalt-60 teletherapy unit. All patients were treated 5 days a week from Monday to Friday. The fractionation regime was 42.5 Gy/16 fractions/3.1 weeks at 2.65 Gy/fraction.
Follow-up and toxicity assessment
Patients were evaluated weekly during the treatment course for acute toxicities. The follow-up of these patients was done every 3 months for the 1 st year and then every 6 months for subsequent years. Late skin and subcutaneous toxicity were evaluated in accordance with the Radiation Therapy Oncology Group (RTOG) grading scheme. , This grading is based on a subjective evaluation of the irradiated area for which a Grade 0 (no toxicity), 1 (mild toxicity), 2 (moderate toxicity), 3 (severe toxicity), or 4 (ulceration) was assigned based on the combined toxic effects of atrophy, pigmentation change, and telangiectasia. We performed the physical examinations including inspection and palpation on areas within HFRT fields and compared these areas with surrounding areas.
Univariate logistic regression analysis was used to predict the associations of old age (> 50) and taxane-based chemotherapy with severe skin and subcutaneous tissue toxicity. P < 0.05 was considered significant. We used X (version) statistical package to perform the analysis.
| Results|| |
The final analysis included patients with a minimum regular follow-up of 1-year after completion of treatment. The cut-off date of the study was May 2014.
Eight patients failed to complete the treatment. Seven patients were lost to follow-up after an initial two to three follow-up visits. One patient died before completing the 1-year follow-up. The final analysis for late skin and subcutaneous toxicity included 104 patients. Patient characteristics are listed in [Table 1]. Maximum duration of follow-up in our patients was 30 months and median duration of follow-up was 22 months.
Age ranged from 30 to 69 years with a median of 47 years. Over 80% had locally advanced disease. During the median follow-up period of 22 months, we observed that 2 patients (1.9%) had local recurrence and 5 patients (4.8%) had distant recurrence in the form of liver, lung and bone metastasis [Table 1].
In this study, Grade 2 skin toxicity was found in 44 (42.3%) patients and Grade 2 subcutaneous tissue toxicity was found in 38 (36%) patients. No patient in this study presented with Grade 3 and Grade 4 toxicity.
On a univariate logistic regression analysis with age, there was a higher association of Grade 2 skin and subcutaneous tissue toxicity with patients over 50 years old. However, age was not a statistically significant factor to either toxic effect (skin P = 0.53, odds ratio [OR] 1.29, subcutaneous tissue P = 0.12, OR 1.91) [Table 2] and [Table 3].
Similarly, we did not found any significant association of chemotherapy (taxane- and anthracycline-based) with Grade 2 skin toxicity (P = 0.90, OR 1.05) or subcutaneous tissue toxicity (P = 0.29, OR 0.66) [Table 2] and [Table 3].
| Discussion|| |
The current study, a single-center retrospective analysis, was conducted on patients with locally advanced breast cancer, where all patients received systemic chemotherapy and were then subjected to MRM. In these patients, HFRT was delivered to the chest wall, axilla, and supraclavicular region. However, most of the previous literature about HFRT describes early breast cancer patients to whom breast conservative surgery was more commonly offered. Thus, HFRT was delivered to the whole breast in these studies. In addition, the impact of age and type of chemotherapy on late skin and subcutaneous tissue toxicity was not separately analyzed in previous studies.
Radiation-induced skin toxicity is primarily evaluated by visual inspection which is based on changes in skin color while subcutaneous tissue toxicity is primarily evaluated by palpation. Late skin and subcutaneous tissue toxicity emerge after more than 90 days postradiotherapy. These late effects may present in the form of atrophy and fibrosis, pigmentation changes, telangiectasias, dermal necrosis, and ulceration. Atrophy and fibrosis are directly related to dermal fibroblast response to radiotherapy. Radiation-induced fibrosis is characterized by progressive induration, edema formation, and thickening of the dermis.  Pigmentation changes are quite variable. Some patients experience gradual hyperpigmentation, while others with more darkly pigmented skin may develop depigmentation due to complete eradication of all melanocytes.  Telangiectasias are areas in which multiple, prominent, dilated, and thin-walled vessels are visible in the skin. In these areas, microvessels have lost endothelial cells, are shortened, and become visible through an atrophied dermal layer.  Dermal necrosis is related to microvascular changes that result in dermal ischemia. 
In general, external beam radiotherapy is a well-tolerated treatment. Fisher et al. prospectively assessed skin toxicity over the course of breast irradiation using RTOG toxicity criteria and found < 3% Grade 3 toxicity.
As far as HFRT is concerned, results of three landmark trials (Canadian, Start A and Start B) showed no difference in adverse events and toxicity between conventionally treated and hypofractionated arms. ,, Whelan et al. reported 2.6% Grade 2 skin complication in their HFRT schedule. However, various factors affecting the skin and subcutaneous tissue toxicity in an HFRT schedule have not been separately analyzed in these studies. Examples of these factors which might affect the toxicity outcome are age, chemotherapy regimen, use of boost dose, breast volume and presence of comorbid conditions such as hypertension and diabetes.  Decreasing the volume using conformal RT, use of appropriate fraction size, reducing the dose heterogeneity across the tumor volume are the radiation-related factors which may reduce the skin toxicity in HFRT schedule in post-MRM breast cancer patients. Improved radiation techniques, such as intensity-modulated radiotherapy have been shown to be superior over conventional wedge-based irradiation by delivering a more homogenous dose through the treatment volume and removing the radiation hot spots; it results in an approximately 20% reduction of the frequency of moist desquamation.  An additive response between combined chemotherapy and radiation therapy is expected, but not well-documented in the literature. Anthracycline-based and taxane-based regimens might especially be responsible for enhanced skin and subcutaneous tissue toxicity. However, Hijal et al. observed no adverse effects of chemotherapy in combination with hypofractionated whole-breast irradiation. Regarding the impact of the type of chemotherapy on radiation-induced toxicity, Taghian et al. found that the rate of radiation pneumonitis in the paclitaxel-treated group was 15.4% compared with 0.9% among breast cancer patients treated with RT and nonpaclitaxel-containing chemotherapy.
Ahmad et al. compared two accelerated hypofractionated protocols and reported 6% chronic radiation dermatitis with only 2% Grade 2 toxicity. The effects of two different hypofractionation schedules on chronic radiation dermatitis were not significant. Regarding chronic subcutaneous fibrosis, he found a statistically significant increase in subcutaneous fibrosis among patients receiving 39 Gy (28%) in comparison to 42.4 Gy group (18%). He concluded that subcutaneous fibrosis is more sensitive than acute reactions to altered fraction size. 
We noticed that the grade of late toxicity of skin and subcutaneous tissue in most patients was low, which was consistent with other studies results. ,,,,, Regarding the associations of age and type of chemotherapy with the occurrence of skin and subcutaneous tissue toxicity, the ORs were found to be insignificant in our study. However, old age and TC regimen have been found to be associated with toxicities. Ciammella et al.  reported 18% Grade 1, 1% Grade 2 and no worse late skin toxicity. Regarding late subcutaneous tissue toxicity, Grade 0-1 toxicity was recorded in 98% patients and Grade 2 toxicity in 2% patients while Grade 3 was observed in 1 patient only. The authors reported additional boost dose delivery of radiation as a significant factor for the occurrence of late skin toxicity and diabetes mellitus as a significant factor for the occurrence of late subcutaneous tissue toxicity.
One of the limitations of our study is the subjective assessment of skin and subcutaneous tissue toxicity by means of clinical examination. Landoni et al. reported that late cutaneous reactions can be reliably assessed by ultrasonographic examination, and the results are in agreement with clinically assessed toxicity. Similarly, Yoshida et al. investigated the use of spectrophotometry and ultrasound to quantitatively measure radiation-induced skin discoloration and subcutaneous tissue fibrosis.
Our study concluded that old age and taxane-based chemotherapy do not adversely affect late skin and subcutaneous tissue toxicity of adjuvant HFRT schedule in post-MRM breast cancer patients.
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[Table 1], [Table 2], [Table 3]