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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 2  |  Page : 325-332

Safety and feasibility of concurrent capecitabine and hypofractionated postmastectomy radiotherapy


Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission07-Sep-2013
Date of Acceptance17-Nov-2013
Date of Web Publication31-Aug-2015

Correspondence Address:
Alshimaa M Alhanafy
Lecturer of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Menoufia University, Menoufia 32513
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.163880

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  Abstract 

Objective
The aim of the study was to evaluate the toxicity, feasibility, and efficacy of concurrent capecitabine (Xeloda) with adjuvant radiotherapy in the treatment of high-risk breast cancer patients.
Background
Breast cancer ranks as the first malignancy affecting women. Patients with breast cancer have high risk of locoregional and/or distant failure: the locoregional failure rate is variable depending mainly on the disease stage and the adjuvant treatment. Different radiotherapy schedules are used in the adjuvant treatment of breast cancer. Concurrent chemoradiotherapy is the standard for many solid tumors; it is promising to be investigated in breast cancer.
Patients and methods
This study was conducted at the Clinical Oncology Department, Menoufia University Hospital, and included patients with a high risk of breast cancer after mastectomy and adjuvant chemotherapy. They were randomized to receive radiotherapy 40 Gy in 15 fractions through 3 weeks with or without concurrent capecitabine 825 mg/m 2 every 12 h on radiotherapy days. Patients were assessed for treatment regularity, toxicity, and recurrence.
Results
In this study, 100 patients were enrolled from April 2011 to October 2011 and followed up for 2 years; patients were randomized into 50 patients in each treatment group. Generally, the incidence of acute and late toxicities were comparable in both treatment groups with no incidence of grade III/IV early toxicity; only a mild increase in gastrointestinal side effects was noticed with capecitabine; however, 96% of the patients were able to finish their concurrent capecitabine therapy and all patients finished radiotherapy; no radiotherapy interruption occurred due to toxicity. Most of the late radiation adverse effects were grade I/II. Regarding efficacy, the concurrent capecitabine arm had better disease control locally and systemically and better disease-free survival, but the difference was statistically insignificant.
Conclusion
Concurrent capecitabine with postmastectomy hypofractionated radiotherapy is highly feasible, safe, and effective, but a longer follow-up is recommended.

Keywords: breast cancer, concurrent capecitabine, hypofractionation, postmastectomy radiotherapy


How to cite this article:
Alhanafy AM, Hashem TA, El-Fetouh MA, Abd El-Ghany AE, Shaltout EA. Safety and feasibility of concurrent capecitabine and hypofractionated postmastectomy radiotherapy. Menoufia Med J 2015;28:325-32

How to cite this URL:
Alhanafy AM, Hashem TA, El-Fetouh MA, Abd El-Ghany AE, Shaltout EA. Safety and feasibility of concurrent capecitabine and hypofractionated postmastectomy radiotherapy. Menoufia Med J [serial online] 2015 [cited 2020 Feb 16];28:325-32. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/325/163880


  Introduction Top


Breast cancer ranks as the first malignancy affecting women, accounting for 29% of all female cancers. Breast cancer is second only to lung cancer as a cause of cancer death in women [1] . Breast cancer in Egyptian patients is a biologically more aggressive disease and the median age is one decade younger than that encountered in the western countries. Advanced disease remains very common in Egypt: about 63% of breast cancer patients presented with a disease that extended to the locoregional lymph nodes; mastectomy is still performed in more than 80% of women with breast cancer [2] .

Patients with breast cancer have risk for locoregional and/or distant failure; it has been reported that 5-40% of breast cancer patients treated with mastectomy will develop locoregional recurrence (LRR), the percentage depending on the initial stage of the disease and adjuvant treatment. Randomized trials have demonstrated that radiotherapy reduces the LRR rate after mastectomy by approximately two-thirds. Prevention of locoregional failure is an important goal in oncology management as, on average, only ~50% of postmastectomy LRR can be controlled subsequently [3] .

Postmastectomy radiotherapy (PMRT) in high-risk patients resulted in an improvement of survival and reduction in the rate of LRR and systemic recurrence, which indicates that the locoregional microscopic disease that survives both mastectomy and chemotherapy is the origin of subsequent systemic metastases and LRRs; this indicates that radiation therapy can eradicate this source of metastases effectively in more than 30% of patients who would otherwise be at risk of systemic dissemination [4] . The Early Breast Cancer Trialists Collaborative Group overview confirms that the prevention of four local tumor recurrences prevents, on average, one breast cancer death at 10 years [5] .

Conventionally, fractionated breast radiotherapy delivers 25 daily fractions of 2 Gy to a total dose of 50 Gy over 5 weeks; several alternative schedules of hypofractionated radiotherapy using a lower total dose delivered in fewer larger fractions are used in the UK and Canada, with the advantages of decreasing the machine work load and better patient appropriateness. Several consensus recommended hypofractionated radiotherapy schedules as the treatment option for whole breast irradiation and PMRT such as NCCN, NICE, and SIGN clinical guidelines [6],[7],[8] .

A commonly used regimen is 40 Gy in 15 fractions over 3 weeks; the START B trial compared this schedule with conventional fractionation in patients after breast conservative surgery and after mastectomy; the 10-year results were published recently; the rate of LRR was lower in 40 Gy compared with 50 Gy; the rates of late normal tissue effects are at least as good as the accepted conventional radiotherapy schedule [9] .

Theoretically, the use of a larger fraction size, a shorter overall radiotherapy time and the use of radiosensitizing agents could be translated to clinical benefit in patients at a high risk of recurrence. The use of concurrent chemoradiotherapy is considered as the standard treatment for head and neck sqamous cell carcinoma, cervical cancer, esophageal cancer, rectal cancer, and anal cancer and is an area of investigation in other cancers including breast cancer [10] .

Adjuvant chemotherapy, with several agents including anthracyclines and taxanes, used synchronously with radiotherapy, aimed to improve the outcome, was associated with increased toxicity, which led to treatment interruption and the use of suboptimal doses of chemotherapy or the use of nonstandard agents and suboptimal doses of radiotherapy [11] .

Concurrent chemoradiotherapy has attracted renewed interest after publication of the results of the SECRAB trial; this study included 2296 patients who had undergone surgery (mastectomy or breast conservative surgery) and received chemoradiation: they could be treated only with cyclophosphamide, methotrexate and fluorouracil (CMF) with or without anthracycline chemotherapy. A variety of different radiotherapy schedules were permitted: 40 Gy in 15 fractions over a 3-week schedule was used in more than 60% of patients. Synchronous treatment was significantly more beneficial than sequential therapy, with a 35% reduction in the risk of local recurrence, with only a modest increase in acute skin toxicity and telangiectasia in patients treated with synchronous treatment, mainly in schedules that fractionated over more than 3 weeks [12] .

Capecitabine (Xeolda®) is an oral prodrug of 5-fluorouracil, a very active agent in the treatment of many solid tumors as a single agent or in combination with chemotherapy or radiotherapy. The addition of capecitabine to standard adjuvant chemotherapy seems to improve breast cancer-specific survival and benefits patients with a rapid cell proliferation rate and those patients with positive lymph node [13] .

Capecitabine is converted to 5-fluorouracil through thymidine phosphorylase enzyme. Radiation has been shown to increase the tumor enzyme levels preferentially, improving the likelihood of capecitabine-mediated radiosensitizing and therefore increasing the therapeutic benefit; this combination is commonly used to treat rectal cancer [14] .

Gaui et al. [15] examined the concomitant use of breast irradiation and capecitabine as a second-line neoadjuvant treatment, and they concluded that it is feasible, well-tolerated, and effective.


  Patients and methods Top


This prospective randomized study was conducted at the Clinical Oncology Department. After approval of the Local Institutional Ethical Committee of Menoufia University Hospital, patients were recruited in the period from April 2011 to October 2011, and written informed consent was obtained from 100 patients who participated in this study with the following criteria.

Inclusion criteria

Patients with high-risk breast cancer (T3 or T4 primary tumor and/or four or more positive axillary lymph nodes) after mastectomy and axillary lymph node dissection, age 18-69 years and with WHO performance status 0-1 were included.

Exclusion criteria

Patients with stage IV disease, contraindication to radiotherapy and uncontrolled systemic disease were excluded.

Pretreatment assessment

History and physical examination and baseline investigations were performed; chest radiograph, and pelviabdomenal ultrasound, the left ventricular ejection fraction (LVEF should be ≥ 55%), bilateral arm circumference measurement, liver and kidney function, and complete blood count were performed.

Study design

Patients were randomized into two groups. Group A: radiotherapy only, 40 Gy in 15 fractions over 3 weeks, at 2.67 Gy per fraction; group B: the same radiotherapy schedule with concurrent capecitabine (Xeolda®) 825 mg/m 2 every 12 h on radiotherapy days.

Radiotherapy technique

All patients were planned through simulator-based conventional two-dimensional planning. In both groups, two tangential chest wall fields and a supraclavicular field was added according to the indicated treatment targets, as shown in [Figure 1]. All patients were treated with a 6-MV photon linear accelerator.
Figure 1: Radiotherapy treatment targets in both groups

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Toxicities and were assessed according to Common Terminology Criteria for Adverse Event v4.03 (CTCAE) [16] , and the Late Effects Normal Tissue task force Subjective, Objective, Management, and Analytic (LENT-SOMA) breast scoring system [17] . After patients finished radiation therapy, at every visit, patients were assessed for treatment-related toxicity and tumor recurrence.

Statistical analysis

Data were analyzed using the statistical package for social science (SPSS, version 16; SPSS Inc., Chicago, Illinois, USA) program for Windows. Two types of statistics were performed; descriptive and analytic statistics. Results were considered significant at the 5% critical level (P ≤ 0.05).


  Results Top


This study included 100 women with breast cancer; each treatment group included 50 patients. The mean age was 52 and 49 years in groups A and B, respectively. Twenty percent of the studied patients were stage II and 80% were stage III. In both groups, patients' characteristics and other treatment parameters were comparable and the difference was not statistically significant.

In this study, all patients finished their entire course of radiotherapy (100%). Patients were regular on radiotherapy without interruption in (89%). Radiotherapy parameters in both arms were comparable as shown in [Table 1].
Table 1 Radiotherapy details in both treatment groups

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In group B, concurrent capecitabine was feasible with a high percent of patients (96%) as shown in [Figure 2]; only two out of 50 (4%) patients had capecitabine dose modification: the first patient experienced grade (G) I infield dermatitis and did not complete her capecitabine course and completed her course of radiotherapy. The second patient needed holding of capecitabine till recovery as she suffered from GII diarrhea.
Figure 2: Feasibility of radiotherapy and capecitabine in group B

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Early treatment-related toxicities included radiation dermatitis, acute radiation pneumonitis, treatment-related fatigue, hematological toxicities (only anemia was detected) and gastrointestinal tract (GIT) toxicities, as shown in [Table 2]. All early toxicities were GI/GII. Radiation dermatitis had a peak incidence in the last few fractions of the radiation therapy and the week after radiotherapy; no treatment interruption was needed and the incidence was close in both groups. Also, acute radiation pneumonitis was observed equally in both groups: in one patient in each treatment arm (2%), both with GI.
Table 2 Early treatment-related toxicity in both treatment groups

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Most of the capecitabine side effects were GIT adverse events; most of them were GI, so no treatment modification was needed, and one patient with GII diarrhea. Other adverse effects such as cardiac ischemic attacks, hand and foot syndrome (HFS), and hepatic and renal toxicities were absent.

Late skin and subcutaneous tissue toxicities, chest wall pain and/or tenderness, skin dyspigmentation, subcutaneous tissues fibrosis/fat necrosis and lymphedema were comparable in both treatment groups, and most of them were GI and GII, except one patient with GIII lymphedema in group A, and three patients with GIII fibrosis with fat necrosis (one in group A and two in group B), as shown in [Table 3].
Table 3 Late treatment-related toxicity in both treatment groups

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No decrease in LVEF was observed with treatment and during the follow-up duration, and no other cardiac toxicity was detected. Also, symptomatic rib fracture, telangiectasia, radiation-induced brachial plexopathy, symptomatic lung fibrosis, and other late toxicities were absent in both groups during this phase of follow-up.

Regarding the efficacy, the concurrent capecitabine-treated group had less disease recurrence locoregionally as well as systemically at 2 years; one patient in group A had isolated chest wall recurrence compared with none in group B. One patient in each group had both LRR and distant metastases (DM). DM occurred in seven patients in group A compared with five patients in group B, as shown in [Figure 3]; disease-free survival showed a trend toward improvement with the addition of capecitabine to radiotherapy; however, the difference was statistically insignificant, as shown in [Figure 4].
Figure 3: The type of recurrence in both groups

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Figure 4: Kaplan– Meier disease free survival curve for both groups

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  Discussion Top


The current standard treatment sequence of adjuvant treatment in breast cancer is chemotherapy followed by radiotherapy; delaying radiotherapy until after chemotherapy may lead to a higher rate of local recurrence: 14 versus 5% if radiotherapy is given first. This is especially important with the use of longer chemotherapy regimens for 6-8 cycles; concurrent chemoradiotherapy will continue to gain importance in the treatment of a variety of malignancies because of the biological synergy effect that can increase the efficacy of the treatment and improve the therapeutic index [18] .

This study included 100 patients with breast cancer: 50 patients in each treatment group; both groups were comparable regarding patients' characteristics and other treatment parameters with no statistically significant difference between them.

In this study, all patients finished their entire course of radiotherapy (100%), and 96% finished concurrent capecitabine with radiotherapy without interruption or modification; only two (4%) patients had capecitabine dose modification.

Garwood et al. [19] reported a lower capecitabine (76%) and radiotherapy (97%) feasibility in a single-arm USA trial with similar high-risk patient criteria and capecitabine daily dose, but with 50 Gy in 25 fractions with or without boost (breast-conserved patients were also included), capecitabine dose modification and/or a modified schedule in 12 (24%) patients due to a clinically significant toxicity; of them, 8% required early discontinuation of treatment; this difference compared with our study may be caused by the difference in the radiotherapy schedule, as they used a conventionally fractionated radiotherapy, and so a longer use of capecitabine for 5-7 weeks instead of only 3 weeks in our study.

Regarding treatment-related acute toxicities, GIT side effects were observed more often in group B, but all were GI/II; the incidence of nausea and vomiting occurred in 4% versus 12% and dysphagia and mucositis occurred in 2 versus 4% in groups A and B, respectively. In group B, GI diarrhea occurred in 4% and GII in 2% of the patients.

These toxicities were milder and less frequent than that reported by Garwood et al. [19] as the reported incidence of nausea and vomiting GI was 44% and GII was 4%, diarrhea GI was 14%, GII was 2%, and GIV was 2%; this variation in the incidence of toxicity may also be due to the difference in the radiotherapy schedule [19] .

Similar to our study, no GIII or IV adverse events were reported in an Egyptian study by Hussen et al. [20] , which included patients with locally advanced breast cancer; the capecitabine dose was similar, but with conventional radiotherapy; the incidence of GI nausea was only 14%, nausea and vomiting was 7%, GII nausea was only 3%, nausea and vomiting was 7% and mucositis GI was 7%, and GII was 3%; this may also be explained by the use of capecitabine for a longer time due to the difference in the radiotherapy schedule.

In our study, the incidence of hematologic toxicities was mild: only two patients with GI anemia in group B (4%), which is in accordance with another Egyptian study by Hussen et al. [20] , who reported only one (3.7%) patient with GI anemia.

In contrast, Garwood et al. [19] reported a higher incidence of hematological toxicity, but they included GI and GII only, with 8% GI and 8% GII; this difference in toxicity might be explained by the ethnic differences, which may result in a difference in the pharmacokinetics and the toxicity of capecitabine between the patients in the Egyptian and the USA populations; this could be further investigated, as a population-based pharmacokinetic analysis of capecitabine showed that the increased toxicity in some patient populations compared with others such as in the elderly is likely due to a change in the renal function. The study of ethnicity as a factor affecting the toxicity profile showed that the pharmacokinetics of black patients were not largely different compared with that of white patients, but in other minority groups, the numbers were too small to draw a conclusion [14] .

Similarly, we did not report any cases of HFS in our study in accordance with the study by Hussen et al. [20] , whereas Garwood et al. [19] reported total 44% incidence of HFS; the mean age of the three studies were comparable:49 years in group B of our study, 45 years in study by Hussen et al. [20] and 52 years in the study by Garwood et al. [19] ; this difference cannot be explained, although the difference in ethnicity might play a role. Also, the short duration of treatment in our study may have a lower probability of occurrence of HFS during treatment, as the onset of incidence of capecitabine HFS was from 11 to 360 days; hence, the longer the duration, the higher the possibility of incidence [14] .

In our study, there was no GIII/IV radiation dermatitis; both arms were comparable in the incidence of GI/II. In group A, GI skin reaction was observed in seven (14%) patients and GII in two (4%) patients, whereas in group B, GI was observed in nine (18%) patients and GII in two (4%) patients. A higher incidence of radiation dermatitis was reported by Garwood et al. [19] with GI 32%, GII 10%, and GIII 14%; this difference could be attributed to the inclusion of breast-conserved patients, with whole breast irradiation, which increases the risk of radiodermatitis and also mandates a higher total dose (boost) with a median radiation dose of 6040 cGy compared with 4000 cGy in our study.

In contrast to our results, Shahid et al. [21] reported in their hypofractionated PMRT study a high incidence of chest wall radiation skin reaction with 40 Gy in the 15-fraction radiotherapy arm; radiation dermatitis was as follows: GI 62%, GII 24%, GIII 11%, and GIV 3%; this high incidence of radiodermatitis could be explained by the use of a 60 CO radiotherapy treatment machine and the addition of posterior axillary boost in some patients.

Bahadur et al. [22] reported a total incidence of radiodermatitis of 21.4% in only hypofractionated radiotherapy 40 Gy in 15 fractions compared with 52.8% in conventionally fractionated radiotherapy. Also, the START B trial [9] acute radiation reaction during radiotherapy was very low, and was recorded in only 16 (0.7%) patients [13 after 50 Gy/25 fractions (1.2%), and three after 40 Gy/15 fractions (0.3%)].

In this study, there were no cases of radiation-induced symptomatic pneumonitis or lung fibrosis: only two (2%) cases showed GI (asymptomatic) radiation pneumonitis; one patient in each group; both patients had received a supraclavicular field irradiation. We conclude that the addition of capecitabine to radiotherapy is not associated with an increased incidence of lung toxicity.

However, in a retrospective trial from Egypt, El-Sayed and Abdel-Wanis [23] reported a higher incidence of radiation pneumonitis with 9.4% incidence of GI and 2.8% of GII. This high incidence might be explained by the heterogeneity of hypofractionated schedules and techniques used in that retrospective study.

Both treatment groups were comparable in the incidence and the grading of different late radiation effects. The most common type of late toxicity was hyperpigmentation: all were GI and GII total (27%). Also, chest wall pain and or tenderness were observed total GI/II (11%). Chest wall fibrosis was observed in total 11%, and it was comparable in both groups.

Eldeeb et al. [24] published 11-year follow-up results of a PMRT hypofractionated trial, with the 40 Gy in 15 fractions over three weeks. Pigmentation was seen in 20%, fibrosis GII/III was noticed in 37%, pain GII/III was reported in 30%, and telangiectasia GII/III was seen in only 7% of the cases; these higher rates compared with ours may be due to the longer follow-up.

In our study, lymphedema was detected in total 10% of the studied patients; most of the cases were graded as GI/II and were comparable between both groups. Eldeeb et al. [24] reported GII/III arm edema in 17% of the cases at the 6-year follow-up.

Also, Shahid et al. [21] reported a higher incidence of lymphedema GI (14%), GII (13%), and GIII (14%) at 5 years; this difference can be explained by the use of posterior axillary boost in patients without axillary dissection and also the longer follow-up duration.

There was no decrease in LVEF with treatment; also, ischemic heart manifestation, symptomatic rib fracture, telangiectasia, and radiation-induced brachial plexopathy were absent in both groups at this stage during follow-up.

Also, the START B trial [9] demonstrated a low incidence of ischemic heart disease (0.9%), symptomatic rib fracture (0.2%), and symptomatic lung fibrosis (0.2%) at 5 years; these reported cases could be attributed to the larger number of patients and the longer follow-up in these trials, which allowed the detection of these adverse effects with such low incidence.

Our results partially agree with the results reported by Shahid et al. [21] , which showed that there were no cases of rib fractures or severe subcutaneous fibrosis, whereas in contrast to our study, Shahid and colleagues showed a more than 10% decrease in LVEF in 5% of the patients at 5 years.

Regarding the efficacy, at 2 years, isolated LRR occurred in one patient in group A compared with zero incidence in group B: one patient in each group had both locoregional and systemic spread. DM occurred in 16% of the patients in group A compared with 12% in group B.

No previous phase III study directly compared radiotherapy alone with radiotherapy with capecitabine, but in a phase II study, Garwood et al. [19] reported a 1-year infield LRR of 4%, with total 22% recurrence rate in a similar high-risk group of patients compared with 2 and 14% in group B only in our study. Also, Shahid et al. [21] included patients with stage T2-T4 and any N and reported LRR in 10% of the patients and DM in 28% of the patients at 5 years.

In our study, disease-free survival estimates using the Kaplan-Meier curve shows early separation between both arms with more frequent and earlier events in group A; it showed a trend for improvement in the concurrent capecitabine group B, but the difference was statistically insignificant. Similarly, in a study by Shahid et al. [21] , there was no statistically significant difference regarding the 5-year disease-free survival among study groups of different locoregional radiotherapy schedules.

In the START B trial [9] , the Kaplan-Meier and the cumulative hazard rate plots for LRR according to the fractionation schedule illustrate the low event rate in both the conventional and the hypofractionated groups.

The impact of adjuvant radiotherapy on the overall survival is seen only on data with a long (15 years) follow-up duration [5] , and given our short follow-up duration, we recommend longer follow-up to observe any survival advantage.


  Conclusion Top


The use of concurrent capecitabine with postmastectomy hypofractionated radiotherapy is highly feasible, well-tolerated and safe, with most of the toxicities being GI and GII without attenuation of the radiation dose or causing radiotherapy interruption; it is also effective in reduction of disease recurrence, with a trend to improvement of disease-free survival compared with radiotherapy only, but the difference was statistically insignificant, and a longer follow-up is recommended.


  Acknowledgements Top


Conflicts of interest

None declared.

 
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