Effect of concurrent chemotherapy and radiotherapy on breast cosmesis: a study of patients' perceptions

The&east (1998) 7, 131436 0 1998 Harcoun Brace &‘I Co. Ltd

ORIGINAL ARTICLE

Effect of concurrent chemotherapy and radiotherapy on breast cosmesis:a study of patients’ perceptions N. J. Warner, A. M. Rangan*, A. 0. Langlands and J. Boyages* Department of Radiation Oncology, Westmead Hospital, *NSW Breast Cancer Institute, Westmead, NSW, Australia S U M M A R Y. The effect of concurrent chemotherapy and radiotherapy on breast cosmesis in the conservative treatment of breast cancer is controversial. The aim of this study was to investigate the effect on cosmesis of adding concurrent chemotherapy to conservative surgery and radiotherapy in the treatment of stage I or II carcinoma of the breast. Eligible patients were invited to complete a questionnaire examining physical changes contributing to cosmesis, patients’ perceptions of these changes and the presence or absence of late side-effects. Responses were received from 145 women who did not receive chemotherapy and 39 who did. The mean overall cosmetic score (treated breast compared to untreated breast, measured on a scale of l-10) was not significantly different between those who received concurrent chemotherapy and those who received radiotherapy alone (6.92 vs 6.95, P = 0.87). Breast appearance, perceptions of physical changes and treatment side-effects were similar in the two groups. We conclude that concurrent administration of chemotherapy (in this instance, intravenous CMF: cyclophosphamide, methotrexate and 5-fluorouracil) and radiotherapy in the treatment of early breast cancer has no detrimental effect on breast cosmesis as judged by patients.

INTRODUCTION

surgery and radiotherapy with or without concurrent chemotherapy. The aim of this study was to determine whether patients treated by concurrent chemotherapy and radiotherapy after surgery had an adverse cosmetic outcome compared to patients treated by surgery and radiotherapy alone. The perceptions of these patients to the physical changes contributing towards cosmesis, and side-effects of treatment were investigated.

Current treatment regimens for early breast cancer using combinations of surgery, chemotherapy and radiotherapy are directed towards maximizing locoregional control and cosmesis whilst minimizing complications; Chemotherapy in selected groups of patients can improve relapse-free survival and may improve local control.‘*2 Both surgery and radiotherapy affect the overall cosmetic outcome of breast-conserving treatment.3-5 The impact of adjuvant chemotherapy on breast cosmesis in patients who also receive surgery and radiotherapy is more controversial. Several studies have addressed this issue: some have reported adverse effects of adjuvant chemotherapy (including oral or intravenous CMF [cyclophosphamide, methotrexate, and 5fluorouracil] and anthracycline-containing regimens) on cosmesis,4@ but others have reported no adverse effects.“” The effect on cosmesis of different sequencing of chemotherapy in relation to radiotherapy is another area of uncertainty. Most studies investigating the effects of concurrent treatments have involved few patients.6’9 This paper reports the cosmetic outcome of a population of patients with early breast cancer treated by conservative Address correspondence PO Box 143, Westmead,

to: J. Boyages, NSW NSW 2145, Australia

Breast

Cancer

PATIENTS

AND METHODS

Patient selection and treatment details Two groups of women were recruited to this study of breast cancer: women treated with conservative surgery, radiotherapy and chemotherapy (CS+RT+CT); and women treated with conservative surgery and radiotherapy alone (CS+RT). The study was approved by the Western Sydney Area Health Service Human Research Ethics Committee. All patients were treated for unilateral stage I or II breast cancer at Westmead Hospital between October 1986 (when concurrent RT and CT was first introduced) and March 1994 (to allow a minimum 2-year follow-up). Patients were eligible if they met the following criteria: aged under 55 years at diagnosis (to achieve similar age distribution between both groups); conservation treatment (conservative

Institute,

131

132

The Breast

breast surgery, axillary dissection and radiotherapy to the breast only); and no evidence of locoregional recurrence or distant relapse at the time of follow-up. Patients who had not attended clinical follow-up for at least 2 years prior to the study commencement date were excluded. The surgical treatment of both groups included wide local excision of the primary breast tumour plus re-excision if indicated, and axillary clearance of lymph nodes in all cases. The volume of excised tissue (length x breadth x width, cm3) was recorded for primary lumpectomy and re-excision. Radiotherapy to the breast was given to all patients, using tangential fields without bolus. Both fields were treated daily using 6 MV photons over a period of 5-7 weeks. The usual dose to the breast was 4650 Gy (1X-2.0 Gy per fraction). The primary tumour bed was either boosted with electrons (86%), or with an iridium implant (14%). The mean boost dose was 13.6 Gy. The tumour bed received a mean total dose of 60.2 Gy in all patients studied. No patients underwent radiotherapy to the axilla, internal mammary chain or supraclavicular fossa. Chemotherapy patients (CS+RT+CT) were eligible if they had received concurrent chemotherapy and radiotherapy. The chemotherapy regimen used was CMF (cyclophosphamide 600 mg/m’, methotrexate 40 mg/m’ and 5-fluorouracil600 mg/m*), given intravenously on day 1 of a 21-day cycle. All patients in this group completed 6 cycles of chemotherapy with no drugs omitted during radiotherapy. This regimen has been shown to produce results equivalent to those of conventional oral CMF in our department.” It was selected for its lower toxicity and its requirement for only 6 visits to complete the schedule in 15 weeks without delay in radiotherapy or chemotherapy.

Cosmetic assessment All eligible patients were invited to complete a questionnaire, previously pilot-tested in a clinic environment. The questions examined the present appearance of the treated breast, the patient’s views on any differences between the breasts, pre- and post-treatment bra cup sizes, functional effects on the shoulder and arm, and potential treatmentinduced late effects. Each question had a choice of predetermined semiquantitative responses. Patients were also asked to give a global assessment of cosmetic appearance of their treated breast compared to the non-treated breast. This was scored using two different scales. The first was a continuous scale of l-10 (overall cosmetic score), where a score of 1 indicated no resemblance between breasts and a score of 10 indicated identical appearance of the breasts. The second scale used four categories: excellent, good, fair and poor (cosmetic rating), to describe the appearance of the treated breast in relation to the non-treated breast.‘* The

questionnaire was sent to each patient a maximum of 3 times, if no reply had been received within 2 weeks of the previous mailing. The questionnaire is available on request. It is the policy of our department to record both a doctor and a patient assessment score of cosmetic appearance at clinical follow-up on each anniversary of first treatment. This score compares the cosmetic appearance of the treated breast to that of the other breast, on a scale of l-10. These data were available and analysed for a subset of patients. The most recently recorded scores were used to enable the best comparison with the current questionnaire scores.

Statistical analyses Differences between groups were assessed using Student’s t-tests (continuous data) or x2 tests (categorical data). A level of 0.05 was taken as being statistically significant. The significance of correlations between patient, tumour and treatment characteristics and overall cosmetic score were assessed by x2 tests or Pearson correlation coefficients. Responses to the questionnaire items about physical appearance were combined into three categories to enable statistical analysis: no difference; small difference; or large difference. Multiple linear regression analysis was undertaken to identify factors that could be associated with overall cosmetic score. The factors entered into the model were age at diagnosis, clinical tumour size, presurgery bra cup size, volume of tissue resected, re-excision performed, total radiotherapy dose and the use of chemotherapy. All data were analysed using SPSS for Windows.13

RESULTS Two hundred and forty-seven eligible patients were invited to take part in the study. Of these, 188 were treated by surgery and radiotherapy alone and 59 received additional chemotherapy. Completed questionnaires were returned by 145 patients (77.1%) who did not receive chemotherapy and 39 (66%) who did receive chemotherapy, giving an overall response of 184 patients (74.5%). Among the 63 nonresponders were 12 untraced women, 5 who failed to return the questionnaire by the due date, 2 who had undergone subsequent mastectomy and 1 who had developed local recurrence since last review. Patient, tumour and treatment characteristics were similar between responders and non-responders, indicating no selection bias. There were no statistical differences between the two treatment groups (CS+RT and CS+RT+CT) with respect to demographic variables (age, menopausal status), clinical tumour size, number of nodes resected, mean volume of tissue resected at surgery and radiotherapy technique and dose (Table 1). The primary tumour position

Chemotherapy, radiotherapy and cosmesis Table

1

Patient,

tumour

and treatment

Characteristic

Patient data Mean age at diagnosis Premenopausal (%)

(years)

Tumour data Mean clinical tumour size (cm) Positive lymph nodes (%) Treatment

characteristics

Table

Treatment CS+RT n= 145

groups* CS+RT+CT n = 39

P value

45.1 60.8

43.8 76.9

0.20 0.17

2.2 12.5

2.3 74.4

0.41
(cm3)

Radiotherapy Dose to whole breast (Gy) Total dose to tumour bed (Gy) Boost dose (Gy) Boost technique: electron (%) iridium implant (%) Area of boost (cm*) *CS: conservation

surgery,

RT:

Responses

Attribute

details

Surgery Re-excision (%) Mean nodes resected (n) Mean nodes positive (n) Mean volume excised tissue

2

about physical

Response

Change in breast Much smaller Somewhat smaller No difference Somewhat larger Much larger

appearance

Treatment CS+RT (%I

CS+RT+CT (%) n = 39 15.4 48.7 12.8 23.1 0

Appearance of scar Not noticeable at all Somewhat noticeable Very noticeable

n = 145 36.6 52.4 11.0

n = 39 23.1 64.1 12.8

n= 137 35.0 42.3 9.5 9.5 3.6

n = 37 13.5 51.4 16.2 16.2 2.7

10.3 19.4 2.0 354

0.02 0.12
46.4 59.8 13.3

46.3 60.7 14.5

0.93 0.25 0.24

Nipple position to other side No difference Slightly higher Much higher Slightly lower Much lower

85.7 14.3 55.9

85.7 14.3 54.7

1 .oo

*CS: conservation

size

groups*

n= 145 13.8 57.2 17.9 11.0 0

28.5 17.2 0.2 382

radiotherapy,

to questions

133

compared

surgery,

RT: radiotherapy,

CT: chemotherapy.

0.81

CT: chemotherapy. Table

within the breast (by quadrants) was also similar for the two groups. As expected, the group treated with chemotherapy had significantly more positive lymph nodes (mean 2.0) than the group that did not receive chemotherapy (mean 0.2). The re-excision rate in the CS+RT group was significantly higher at 28.5% compared to 10.3% for those patients who received chemotherapy, but the overall volume of excised tissue was similar between the two groups. Patient-reported physical changes to the breast as a result of treatment, and the attitudes towards these changes are shown in Tables 2 and 3. More than 80% of women recorded a change in breast size, although 75% of these women were not concerned by this change. Only 66.3% reported a noticeable scar and 62.5% a change in nipple position, but only 15.8% and 17.9%, respectively, were concerned by these changes. None of these physical changes or attitudes were statistically different between treatment groups. Using multiple linear regression, factors identified as being predictive of overall cosmetic score included change in breast size, nipple level and appearance of scar. Although these factors were interdependent, change in breast size and nipple level contributed most of the variability of overall cosmetic score. A positive association was found between the physical changes recorded in the breast and the women’s concern about these changes (P < 0.001). Seventy-four per cent of patients rated their breast appearance as good or excellent; only 5% reported a poor result, with no difference between the two treatment groups

3

Responses

Attitude

to questions

about attitude

Response

Concerned Not at all Somewhat Very

about

size difference

Concerned Not at all Somewhat Very

about

appearance

Concerned Not at all Somewhat Very

about

nipple

*CS: conservation

surgery,

of scar

position

RT: radiotherapy,

to physical

changes

Treatment CS+RT (%I

groups* CS+RT+CT (%I

n= 126 73.8 23.8 2.4

n = 35 77.1 20.0 2.9

n = 140 82.9 13.6 3.6

n = 39 87.2 12.8 0

n= 105 74.3 23.8 1.9

n = 34 82.4 17.6 0

CT: chemotherapy.

(P = 0.87; Fig.). The mean overall cosmetic scores (measured on a scale of l-10) for each group also were not significantly different (6.95 in the CS+RT group vs 6.92 in the CS+RT+CT group, P = 0.95). There was a highly significant positive association between breast appearance, rated as poor, fair, good or excellent, and overall cosmetic score (P < 0.001). Relatively few women felt embarrassed by the appearance of their treated breast (15.8%); however, one-third (32.8%) felt that their choice of clothes had been affected. Women who felt embarrassed were more likely to have changed their choice of clothes after treatment (P = 0.003). Women who reported mat their treatment had no effect on

134

The Breast Table

80% 70% -E g 60%-5 B 0 50% -2 s 40%--k a 30%

4

Treatment

side-effects

Side-effect/Response

Treatment CS+RT (%)

Arm swelling None Mild or moderate Severe

II= 143 58.0 37.8 4.2

n = 39 48.7 51.3 0

Telangiectasia None Present but not prominent Prominent appearance

II= 143 72.7 20.3 7.0

n = 39 76.9 20.5 2.6

Breast discomfort None Some Significant

n = 144 25.0 65.3 9.7

n = 39 17.9 76.9 5.1

n= 145 62.5 34.8 3.5

It = 39 59.0 38.5 2.6

n=

n = 39

Shoulder None Some Significant

movement

restriction

Numbness or paraesthesia on medial upper arm None Some Considerable

20% 10% 0% :

t CS+RT

Fig. Patients’ ratings of their own breast cosmesis surgery (CS) and radiotherapy (RT) with or without chemotherapy (CT).

CS+RT+CT after conservative concurrent

choice of clothes were significantly older than those who reported either some or considerable impact on their choice of clothes (45.7 years vs 42.7 years, P = 0.009). Those women whose choice of clothes was affected by the treatment reported a lower cosmetic score (P c 0.001). Treatment-induced side-effects (Table 4) were similar in the two groups. The presence of persistent breast discomfort (75.0% for CS+RT and 82% for CSRT+CT) and ipsilateral upper inner arm numbness or paraesthesia (83.4% CS+RT and 87.2% CS+RT+CT) were common. Some degree of arm swelling was reported after CS+RT (42.0%) and CS+RT+CT (51.3%), (P = 0.17). Likewise, restriction of shoulder movement was reported by 37.5% CS+RT and 4 1.1% CS+RT+CT, even though no patient received radiotherapy to the axilla. There was no significant association between the number of resected axillary nodes and arm swelling or restriction of shoulder movement (P = 0.70 and 0.59, respectively). The frequency of telangiectasia was similar in both groups, (27.3% CS+RT and 23.1% CS+RT+CT, P = 0.60). Telangiectasia was also adversely associated with the overall cosmetic score (P = 0.03). Mild or moderate breathlessness or chest infection within 6 months of treatment was reported by 16.8% of all women, although they often commented on the difficulty of recalling this information. Severe breathlessness, consistent with pneumonitis, was

16.6 64.1 19.3

Breathlessness or chest infection symptoms within 6 months of treatment No Mild or moderate Severe *CS: conservation

surgery,

145

RT: radiotherapy,

n=

78.6 17.9 3.6

groups* CS+RT+CT VJ)

12.8 79.5 7.7 140

n = 38

78.9 13.2 7.9

CT: chemotherapy.

recorded by 5/140 (3.6%) in the CS+RT group and 3138 (7.9%) in the CS+RT+CT group (P = 0.44). There were no differences in bra cup sizes prior to treatment between those who received chemotherapy and those who did not (P = 0.19). There was a significant association between bra cup size (as a measure of breast size) and total volume of tissue resected at surgery, even after controlling for tumour size (P = 0.007). Bra cup size prior to treatment did not affect the overall cosmetic score (P = 0.33). Using a multiple linear regression model with the outcome variable being overall cosmetic score and independent variables being age at diagnosis, clinical tumour size, presurgery bra cup size, volume of tissue resected, re-excision performed, total radiotherapy dose and the use of chemotherapy, the only factor found to be predictive of overall cosmetic score was volume of tissue resected (1.= -0.36, P c 0.001). The median duration of follow-up for all patients was 52 months (range 20-109 months) with no significant difference between the two groups. The mean cosmetic scores did not change with duration of follow-up, with scores of 7.2, 7.1, and 6.8 for women followed up for less than 3 years,

Chemotherapy, radiotherapy and cosmesis 3-5 years and more than 5 years, respectively (P = 0.67). The development of telangiectasia was no more frequent in those women who were treated over 5 years ago than in those treated more recently (P = 0.21). Doctors’ and patients’ cosmetic scores from the radiation oncology records were available for 100 women who completed questionnaires. The most recently recorded score was used. Mean cosmetic scores for doctor (clinic), patient (clinic) and patient (questionnaire) were 7.9, 8.5 and 7.2, respectively. The patient scores recorded in the clinic setting were significantly higher than the doctor scores and those recorded in the questionnaire (P < 0.001).

DISCUSSION We investigated the effect of adding concurrent chemotherapy using intravenous CMF to conservation treatment for stage I or II carcinoma of the breast and documented the results on the cosmetic outcome of the breast, women’s attitudes and late side-effects. No difference existed in cosmetic outcome of the breast between women who received chemotherapy and those who did not, when measured with scales of similar design used in other studies.3s’2 This suggests that the use of this chemotherapy regimen in conservation treatment with surgery and radiotherapy has no detrimental effect on breast cosmesis. It therefore allows completion of all post-surgical treatments in 15 weeks, whereas sequential chemotherapy-radiotherapy may take from 20 to more than 30 weeks. The present study is based largely on patients’ subjective assessments of their breast cosmesis. Of particular interest is that physical changes relating to a difference in breast size, nipple level and prominence of scar were reported by SO%, 65% and 66%, respectively, but concern about these changes was expressed by only 35%, 18% and 16%, respectively. The importance of the patients’ perspectives on cosmetic outcome must be included in discussing treatment options with patients. Many authors have reported factors influencing cosmetic results after conservative surgery and radiotherapy. Surgical factors are important and include the site, orientation and length of surgical scar, separate incisions for breast and axillary surgery and the volume of tissue resected.14 In this study we found that volume of tissue resected was inversely associated with cosmetic outcome. This is similar to our previous study in which women who had surgery considered to be less than optimal were less likely to rate their cosmetic outcome as good or excellent.’ The impact of radiotherapy on breast cosmesis was reviewed by K~rtz’~ who found that high radiation doses to the whole breast (70-80 Gy), without boost, resulted in significant breast retraction. Hence, lower dose regimens

135

(45-50 Gy) plus a boost to the tumour bed, have become increasingly common with correspondingly improved cosmetic scores and no adverse effect on local control. The main radiotherapeutic parameters adversely influencing cosmesis were the use of a three-field versus a two-field technique and a large volume implant to boost the tumour bed.3s4All patients in this study had their axilla treated surgically. Most boosts (86%) were administered using electrons. The issue of the impact of adjuvant chemotherapy on cosmesis remains controversial. Our results show no detrimental effect from the addition of concurrent intravenous CMF to radiotherapy, and are similar to those of Danoff et a1.9 Markiewicz et al* reported that the use of concurrent intravenous CF chemotherapy and radiotherapy followed by CMF or anthracycline-containing chemotherapy adversely affected cosmetic outcome at 3 years, although this was no longer apparent at 5 years. However, Gore et al,6 Olivotto et al4 and Abner et al7 found that concurrent chemotherapy (oral or intravenous, CAF or CMF) and radiotherapy resulted in significantly impaired cosmesis compared to radiotherapy alone. Most other reports on the cosmetic implications of concurrent chemotherapy in the treatment of early breast cancer have involved some modification of the chemotherapeutic regimen during the radiotherapy, usually the omission of one or more agents for the duration of the radiotherapy. The omission of methotrexate or doxorubicin had been cited as a possible reason for the favourable cosmetic results with concurrent therapy by Markiewicz et al8 The regimens in our study were not adjusted: all three CMF drugs were given as scheduled, both during and after radiotherapy, and most patients received two cycles of chemotherapy during radiotherapy. Side-effects are reported more frequently in patients who receive concurrent chemotherapy and radiotherapy than in those who receive radiotherapy alone.16 Similarly, an increase in arm oedema (greater than 2 cm) has been reported in patients who received concurrent chemotherapy and radiotherapy to the axilla.” However, these investigators found no difference in incidence of clinical pneumonitis and the use of chemotherapy. In our study, the incidence of arm oedema and symptoms suggestive of pneumonitis did not differ in the two groups. The large number of women reporting continuing breast discomfort (76.5%), numbness or paraesthesia on the inner aspect of the upper arm (84.2%) and, to a lesser extent, restriction of shoulder movement (38.3%), is important information when discussing treatment options with patients. Of note, patients gave themselves lower cosmetic scores when they responded to the questionnaire (mean, 7.2) than they gave verbally in the clinic (mean, 8.5). The scores reported from the questionnaire are more valid responses because they were reported away from the clinic without

136 The Breast pressures to please the doctor. We conclude that concurrent administration of an effective adjuvant regimen - intravenous CMF with radiotherapy - in the treatment of early breast cancer has no detrimental effect in terms of breast cosmesis and late side-effects. The advantage of concurrent treatment is that neither modality is arbitrarily delayed. Concurrent therapy using intravenous CMF does allow a considerable shortening of overall treatment time, perhaps by as much as 15 weeks, when compared to sequential oral CMF and RT, and reduces the number of hospital visits and the cost significantly. These issues of patient utility must be considered and included in discussions of treatment.

10.

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11.

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