2190 Concomitant Chemoradiotherapy for Patients with Nonmetastatic Breast Carcinoma Side Effects, Quality of Life, and Daily Organization Geneviève Macquart-Moulin, M.D.1 Patrice Viens, M.D.2 Dominique Genre, M.D.2 Marie-Laure Bouscary, M.D.1 Michel Resbeut, M.D.2 Gwenaëlle Gravis, M.D.2 Jacques Camerlo, M.D.2 Dominique Maraninchi, Ph.D.2,3 Jean-Paul Moatti, Ph.D.1,3 1 INSERM Research Unit 379, “Epidemiology and Social Sciences Applied to Medical Innovation,” Marseilles, France. 2 Paoli-Calmettes Institute, Regional Hospital for Cancer Care, Marseilles, France. 3 University of the Mediterranean, Aix-Marseilles II, Marseilles, France. Supported by the Association for Cancer Research. The authors thank all of the members of the medical staff of the outpatient clinic of the PaoliCalmettes Institute for their assistance and their interest in quality of life research. Address for reprints: Geneviève Macquart-Moulin, INSERM U 379, Institut Paoli-Calmettes, 232, Boulevard de Sainte-Marguerite, 13273 Marseilles Cedex 9, France. Received May 26, 1998; revisions received September 21, 1998 and January 6, 1999; accepted January 28, 1999. © 1999 American Cancer Society BACKGROUND. This study was designed to investigate the personal experience of patients with nonmetastatic breast carcinoma who were treated with the concurrent administration of radiotherapy and chemotherapy in terms of side effects and quality of life (QL). METHODS. One hundred nine patients with nonmetastatic breast carcinoma, recruited between May 1995 and February 1997, were included in a protocol combining chemotherapy with mitoxantrone and cyclophosphamide, administered intravenously in 4 cycles of 21 days, and concomitant radiotherapy. Side effects of treatment and its impact on patients’ daily lives were measured using ad hoc questionnaires; QL was measured by the European Organization for Research and Treatment of Cancer QLQ-C30 QL questionnaire, and pain was measured by a visual analogue scale (VAS). RESULTS. All patients agreed to participate. The mean number of chemotherapy and radiotherapy symptoms per cycle were: 7.2 6 2.5 and 2.4 6 1.8, respectively. Chemotherapy symptoms generally were more frequent and distressing than those of radiotherapy. The average pain score reported on the VAS by patients during treatment was 3.0 6 2.0. Multidimensional QL assessment showed that treatment mainly affects physical functioning and global QL. Multivariate analysis showed that the main determinants of QL at the end of treatment were fatigue, pain, and loss of appetite experienced during treatment. Moreover, 62.8% of patients required specific help for transportation to the hospital and/or home upkeep. CONCLUSIONS. The concurrent administration of chemotherapy and radiotherapy deteriorates patients’ QL but in a proportion similar to sequential administration while presenting the advantage of a shorter duration of treatment. However, increased fatigue, pain, and loss of appetite as well as difficulties in patients’ daily lives have to be taken into account in therapeutic decision-making analysis. Cancer 1999;85:2190 –9. © 1999 American Cancer Society. KEYWORDS: nonmetastatic breast carcinoma, chemotherapy, radiotherapy, physical symptoms, quality of life, daily life. I n the current adjuvant treatment of breast carcinoma, chemotherapy frequently is added to radiotherapy. However, the sequencing of radiotherapy and chemotherapy has been a matter of debate.1,2 A recent randomized study compared chemotherapy followed by radiotherapy with radiotherapy followed by chemotherapy.3 Results showed that local relapse was more common when chemotherapy was administered first, but distant relapse was more common when chemotherapy was administered after the completion of radiotherapy. In conclusion, the authors suggested the administration of che- Quality of Life during Concomitant Chemoradiotherapy/Macquart-Moulin et al. 2191 motherapy first for those patients who have a high risk of distant recurrence. To avoid the potential risks of sequencing radiotherapy and chemotherapy, we developed a program of radiotherapy and chemotherapy in which both treatments are administered together. In addition to the potential clinical benefits, this approach could be of value for the patient, because it reduces the overall duration of treatment. However, concurrent administration of radiotherapy and chemotherapy also could be expected to have negative consequences in terms of side effects and quality of life (QL) during treatment. We therefore explored the psychosocial impact of such concomitant treatment to provide additional information about the modalities of administration of chemotherapy and radiotherapy in the adjuvant treatment of nonmetastatic breast carcinoma. This study was designed to investigate the personal experience of patients with breast carcinoma who submitted to an adjuvant concomitant chemoradiotherapy protocol. Data obtained encompassed both chemotherapy and radiotherapy side effects as well as patients’ QL during treatment and the impact of treatment on patients’ daily lives. receptors and was started after the completion of the chemoradiotherapy sequence. All radiotherapy was administered in 2 Gy fractions through a linear accelerator. 46 Gy (4 to 6 mv photons) were delivered to the mammary gland with a boost of 14 Gy (electrons) on tumoral bed in the case of free margins and a boost of 14 Gy or 19 Gy (electrons) in the case of involved margins. After mastectomy, when indicated, 46 Gy were delivered on chest wall with a boost of 10 Gy (electrons) in the case of tumor size of more than 5 cm or of more than 4 involved axillary nodes. The axillary lymph node area was never irradiated. The supraclavicular area and internal mammary area received a total dose of 50 Gy (mixed photons and electrons for internal mammary gland) in case of internal tumors or in case of histologically involved axillary lymph nodes. The supraclavicular fossa and the internal mammary lymph nodes were irradiated effectively in, 89.9% and 94.9% of patients, respectively. Radiotherapy started 1 week after the beginning of chemotherapy and lasted 5 weeks. PATIENTS AND METHODS Chemotherapy side-effect questionnaire Study Patients The questionnaire, which was tested in a previous study,4 was comprised of 19 items corresponding to symptoms commonly associated with chemotherapy of breast carcinoma: nausea, vomiting, loss of appetite, change in taste, diarrhea, weight loss and gain, mouth sore, stomach pain, headache, hair loss, skin rash, articular and muscular pain, cystitis, hot flush, fever, conjunctivitis, and fatigue. For each symptom, patients were asked three questions: 1) whether they had experienced this symptom, at least once, during the previous 3 weeks (yes or no); 2) what was the duration of such a symptom (using a four-point scale: ,2 days, 3– 6 days, 1–2 weeks, all the time); 3) to what extent the symptom had been distressing for the patient (using a four-point Likert scale: not at all, a little bit, quite a bit, very much). Because duration was not relevant for three symptoms (hair, weight loss/gain), severity was evaluated instead. Patients who were suffering from breast carcinoma with no metastases and less than nine involved axillary lymph nodes received an adjuvant treatment associating polychemotherapy and concomitant radiotherapy. They were recruited at the Paoli-Calmettes Institute (Regional Hospital for Cancer Care) in Marseilles between May 1995 and February 1997. Chemotherapy doses were based on ideal body weight. The protocol was comprised of mitoxantrone (12 mg/m2) and cyclophosphamide (600 mg/m2) administered in four cycles of 21 days in outpatient clinic. Mitoxantrone was administered as a 15-minute intravenous (I.V.) infusion, and cyclophosphamide was administered as a 30-minute I.V. infusion. Antiemetic prophylaxis consisted of granisetron (Kytril®) administered in 1-mg tablet form 1 hour before the start of each cycle of chemotherapy and within 12 hours after the first administration. Complete blood count was performed on Day 1 of each cycle, and chemotherapy was administered if the neutrophil count was .1.5 3 109/L and the platelet count was .100 3 109/liter. If a patient did not meet these criteria, then chemotherapy was delayed until hematological recovery. No dose reduction was planned. Tamoxifen (20 mg once a day for 3 years) was given to menopausal patients with positive estrogen Instruments for Measurement of Side Effects and QL The instruments described below were used in the QL form presented to patients. Radiotherapy side-effect questionnaire This questionnaire was developed on the model of the chemotherapy questionnaire. It included eight items: breast pain, loss of nipple sensitivity, altered skin pigmentation, breast redness, breast lesion(s), problems with arm (edema, difficulty in elevation), difficulty swallowing, and cough. Breast pain, problems with arm, difficulty swallowing, and cough were measured 2192 CANCER May 15, 1999 / Volume 85 / Number 10 in terms of duration and distress, and other radiotherapy symptoms were measured in terms of severity and distress. Duration, severity, and distress levels were evaluated on a four-point-scale, as in the chemotherapy questionnaire. Visual Analogic Scale Patients were asked to evaluate pain by using a Visual Analogic Scale (VAS).5 For the pretreatment period, patients had to report present pain, whereas, for the other measures that were evaluated prior the start of each cycle of chemotherapy, they were asked to evaluate maximal pain experienced during the previous cycle. European Organization for Research and Treatment of Cancer QLQ-C30 (version 1) This 30-item questionnaire is a cancer specific, patient-based measure designed for self administration. It is comprised of five functioning scales (physical, role, emotional, cognitive functioning, and social functioning). There are three symptoms scales (fatigue, nausea and vomiting, and pain) and six single items (dyspnoea, insomnia, loss of appetite, constipation, diarrhea, and financial difficulties). The questionnaire also includes two global questions about the patient’s health status and overall QL, allowing a global QL scale to be obtained. All scores obtained from scales and single items range from 0 to 100. A high score for a functional scale and for the global QL scale represents a high level of functioning or global QL, whereas, inversely, a high score for a symptom scale/single item corresponds to a high level of symptoms or problems. The reliability of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, as measured by Cronbach’s alpha coefficient,7 ranged from 0.61 for nausea/vomiting to 0.90 for fatigue at the first evaluation (pretreatment) and from 0.46 for physical functioning to 0.91 for fatigue at the last evaluation (21 days after the last cycle of chemotherapy). Questionnaire about organization of daily life This detailed questionnaire was study specific and contained 16 self-report questions that were related principally to the pursuit or not by the patient of her occupational activity and the assistance needed during treatment: by whom (family, friend[s], partner, employee), how (looking after by a parent or a friend at his/her home, staying in a convalescent home or therapeutic apartment), and/or for what motive (daily care, transportation to hospital, children’ care, shopping, walks), and use of ambulatory care services. Sociodemographic questionnaire This questionnaire contained ten items related to sociodemographic data: date of birth, place of residence, distance from residence to hospital, marital status, life style (alone or with spouse/partner), education, occupation, employment status before disease, number of children, and number of children living at home. Administration of the QL Form All patients who met eligibility criteria were asked to participate in the survey. Oral information was provided for patients on the objectives and the constraints of the study. From the first cycle of chemotherapy (pretreatment), each patient was asked by a nurse or a physician to complete the QL form prior to the start of each session of chemotherapy. The last form, which assessed the impact of the last cycle of chemotherapy, was filled out by the patient at home and returned to the medical team during a follow-up consultation or was sent by mail with a prestamped return envelope. The content of the five QL forms presented to patients varied according to the moment of the evaluation, and special attention was given to minimize patients’ stress (Table 1). The chemotherapy side-effect questionnaire was presented at each cycle beginning at cycle 2, and the radiotherapy side-effects questionnaire was presented at cycles 2 and 3 only (because radiotherapy started about 1 week after the beginning of chemotherapy and lasted 5 weeks). Both questionnaires at each evaluation measured the treatment side effects experienced by patients during the previous cycle of chemotherapy. The EORTC QLQ-C30 was proposed prior the start of chemotherapy (pretreatment) and 21 days after the start of the fourth cycle of chemotherapy. Pain was assessed on VAS in the pretreatment period and at each cycle. Sociodemographic data were included in the first QL form (pretreatment), and the questionnaire that evaluated the organization of daily life during treatment was included the last QL form. According to its length, each QL form could be filled out by patients in an average of 10 –20 minutes. Statistical Analysis The statistical software program, SPSS PC for Windows (version 6.0; SPSS, Inc., Cary, NC) was used for statistical analyses.8 We used nonparametric tests to analyze QL data. The use of nonparametric tests was based on the ordinal measures (answers to items of the ad hoc chemotherapy questionnaire and of the EORTC QLQ-C30 were obtained by using Likert scales), and the nonnormality of distributions was Quality of Life during Concomitant Chemoradiotherapy/Macquart-Moulin et al. 2193 TABLE 1 Content of the Quality of Life Form QL form Questionnaires/scales Sociodemographic questionnaire Chemotherapy side effect questionnaire Radiotherapy side effect questionnaire Visual analogic scale EORTC QLQ-C30 Questionnaire of daily organization No. 1, pretreatment No. 2, cycle 1 No. 3, cycle 2 No. 4, cycle 3 No. 5,* cycle 4a X X X X X X X X X X X X X X X QL: quality of life; EORTC: European Organization for Research and Treatment of Cancer. a Completed by the patient at home 21 days after the start of the fourth cycle of chemotherapy. used to limit assumptions and maintain consistency. Spearman’s rank-correlation coefficients and the Kruskall–Wallis test were used to investigate correlations between QL data as well as between QL data and sociodemographic or clinical data. McNemar, Cochran, and Friedman nonparametric tests were used to test for significant changes over time. For the multivariate analysis, a linear regression model (using ordinary least-squares regression) was performed to determine explanatory variables of patient’s QL at the end of treatment, measured by the EORTC global QL score (depending on variables). A “stepwise regression” approach was chosen. The linear regression model included the International Union Against Cancer (UICC) stage of disease, the level of occupational activity of women before disease, the EORTC global quality of life score reported in the pretreatment period, the mean number of physical symptoms, the average maximal pain experienced by patients during the entire course of treatment, and the most significant physical symptoms experienced by patients during the last cycle of chemotherapy (symptoms expressed in terms of duration/severity and/or distress by the chemotherapy questionnaire). All P values quoted are two-sided. RESULTS Patients’ Sociodemographic and Clinical Characteristics From May 1995 to February 1997, 109 patients were included in the chemoradiotherapy protocol. Patients’ sociodemographic characteristics are listed in Table 2. The mean age of patients was 50.8 years (range, 23–73 years). Table 2 shows that nearly half of the patients lived in an area no farther than 20 kms from the outpatient clinic. A high proportion of women (73.3%) lived with a partner, and 50% had children living at home. Because some women were older than 60 years TABLE 2 Patients’ Sociodemographic Characteristics (n 5 109) Characteristic Valuea Age (yrs) Distance from residence place to hospital ,20 kms 20 to 100 kms .100 kms Marital status Married Not married Living as a couple Yes No Children at charge None One Two or more Level of education Lower level of education Secondary school/university graduat Occupational activity before disease Yes No Occupation of active women Executive/middle management Professional/teacher Employee/worker 50.8 6 11.8 53 31 19 51.5 30.1 18.4 67 42 61.5 38.5 77 28 73.3 26.7 49 22 27 50.0 22.4 27.6 68 40 63.0 37.0 58 48 54.7 45.3 6 17 32 10.9 30.9 58.2 Number and percentage excepted for age (mean 6 standard deviation). Incomplete numbers correspond to missing data. a of age (29 patients), only 54.7% of patients had an occupational activity before their disease. Forty-four percent of women were menopausal. Thirty-nine patients (35.8%) had no axillary lymph node involved, and only 13 patients (11.9%) had more than three axillary lymph nodes involved. The majority of women (78.9%) had undergone a tumorectomy. Seventy-eight percent of patients had a ductal carci- 2194 CANCER May 15, 1999 / Volume 85 / Number 10 noma, and American Joint Committee on Cancer stage of disease was 0 for 14 patients (12.8%), Stage I for 34 patients (31.2%), Stage II for 51 patients (46.8%), Stage III for 5 patients (4.6%), and not applicable or not done for 5 patients (4.6%). Patients’ Participation and Compliance All patients included in the clinical protocol were asked to participate in the QL study. All of the patients agreed to participate (participation rate, 100%). A total of 524 QL forms were available for statistical analysis, respectively, 109, 107, 106, 105, and 97, from the pretreatment period to the fourth cycle of chemotherapy. The average rate of missing values was 2.1% for the chemotherapy questionnaire (1.5% for the items of the duration/severity dimension and 2.8% for that of the distress dimension), 2.6% for the EORTC QLQ-C30 questionnaire, 4.5% for sociodemographic data, 5.5% for the radiotherapy questionnaire (5% for the items of the duration/severity dimension and 6% for that of the distress dimension), 10.9 % for the pain VAS, and 11% for the patient daily life organization questionnaire. Frequency and Characteristics of Symptoms The mean number of symptoms associated with the chemotherapy treatment was 7.2 6 2.5 (range, 0 –17). Table 3 summarizes the patients’ declared frequency of chemotherapy symptoms, their duration/severity, and the degree of distress that patients associated with them during 415 cycles of chemotherapy. In 50% of cycles or more, patients experienced nausea, hair loss, change in taste, headaches, and hot flushes. Furthermore, long term hot flushes, change in taste, conjunctivitis, articular pain, skin rash, and stomach pain were present in more than 45% of cycles. The four most distressing symptoms were vomiting, cystitis, stomach pain, and hot flushes. Surprisingly, the least distressing symptom was weight loss. The frequency trend of chemotherapy symptoms, measured by the self-report questionnaire, was tested in a subgroup of 91 patients who completed this questionnaire at each cycle of chemotherapy. A significant increase (P , 0.05) in the frequency of some symptoms was observed across cycles. It was the case for vomiting, change in taste, hair loss, and hot flushes. The results also show a statistically significant increase in duration/severity of nausea, loss of appetite, change in taste, headache, and hair loss. However, distress associated with each symptom remained constant across cycles, with the exception of muscular pain, which tended to be associated with a higher distress in the latter cycles. The mean number of specific radiotherapy symptoms experienced within 213 cycles in which radio- therapy was concomitant to chemotherapy was low: 2.4 6 1.8 (range, 0 –7). Thirty-four percent of patients did not report any symptoms. Table 3 shows the relatively low frequency of most radiotherapy symptoms (l,40% of cycles, except for breast redness), with a weak percentage of long term and distressing symptoms (,20% of cycles) except for arm problems. Fatigue, which may be associated with chemotherapy as well as radiotherapy, was present globally in 89.4% of cycles (Table 3). This symptom lasted more than 1 week in 61.8% of cycles and was distressing for patients in more than two-thirds of cycles. Furthermore, the duration and the distress associated with this symptom increased significantly across cycles (P , 0.001 for both statistics). The percentage of cycles with persistent and distressing fatigue was significantly higher in the last two cycles (cycles 3 and 4), although chemotherapy was administered alone, than in the first two cycles, in which radiotherapy and chemotherapy were concomitant: 71.7% versus 51.9%, respectively (P , 0.0001) and 74.7% versus 62.4%, respectively (P 5 0.01). The average maximal pain reported on VAS by patients during their treatment was 3.0 6 2.0 (range, 0 – 8.7) and was constant across cycles. Impact of the Treatment on Patients’ QL Results from the EORTC QLQ-C30 core questionnaire completed by patients are listed in Table 4. This questionnaire reports patients’ experience during the week before interview, except for physical functioning and global QL, which refer to patient status at the time of interview. The analysis was performed on patients who had completed both the pretreatment questionnaire and the final questionnaire (n 5 97). Of six functional scales, two were found to be significantly lower after the completion of treatment. They related to physical functioning and global quality of life (P 5 0.001 for both statistics). For other functional scales, no statistically significant differences were observed. However, compared with the pretreatment period, mean scores of these scales were lower. Of nine symptom scales/items, five were found to be significantly higher 21 days after treatment completion. They related to fatigue, nausea/vomiting, and dyspnoea (P , 0.001 for all statistics) as well as appetite loss and sleep disturbance (P 5 0.02 for both statistics). Because patients were asked to describe their symptoms the week prior to the completion of the questionnaire, these results demonstrate that some symptoms last 15 days or more after the last cycle of chemotherapy. Furthermore, we must note that global QL in the pretreatment period did not depend significantly on sociodemographic or clinical Quality of Life during Concomitant Chemoradiotherapy/Macquart-Moulin et al. 2195 TABLE 3 Frequency and Characteristics of Symptoms Cycles with symptoms Symptom Chemotherapy symptom (415 cycles) Nausea Hair loss Change in taste Headache Hot flush Lack of appetite Stomach pain Muscular pain Articular pain Vomiting Sore mouth Weight gain Weight loss Skin rash Conjunctivitis Diarrhoea Cystitis Fever Radiotherapy symptom (213 cycles) Breast pain Loss of nipple sensitivityc Breast pigmentationc Breast rednessc Breast lesionsc Problems with arm Difficulty for swallowing Cough Chemotherapy/radiotherapy symptom Fatigue Entire treatment (415 cycles) Chemo 1 radiotherapy (213 cycles)d Chemotherapy alone (202 cycles)e No. % Percent of cycles with long term/ severe symptomsa 348 307 223 214 207 205 165 158 130 118 102 95 89 84 53 44 40 37 83.9 73.9 53.7 51.6 49.9 49.4 39.8 38.1 31.3 28.4 24.6 22.9 21.4 20.2 12.8 10.6 9.6 8.9 28.9 25.1 64.3 25.9 71.4 36.8 49.0 39.8 54.0 8.6 41.6 14.7 16.8 53.1 64.1 15.9 23.7 20.0 57.4 54.1 56.6 55.4 61.3 36.2 63.2 52.0 50.8 71.3 49.5 35.3 13.5 51.3 58.0 48.8 71.1 25.8 69 63 63 82 14 72 72 66 32.4 37.7 37.7 49.1 8.4 33.8 33.8 31.0 19.0 8.9 14.6 15.6 3.7 23.1 18.6 18.6 15.2 8.9 6.5 11.5 6.1 21.0 19.1 14.5 371 187 184 89.4 87.8 91.1 61.8 51.9 71.7 68.5 62.4 74.7 Percent of cycles with distressing symptomsb a Symptoms that persisted more than 1 week. Symptoms that were declared to be quite a bit or a lot distressing by patients. c Only for women who did not undergo mastectomy. d Cycle 1 1 cycle 2, because radiotherapy covered only the two first cycles of chemotherapy. e Cycle 3 1 cycle 4, in which chemotherapy was administered alone. b variables. However, it appears that women with an occupational activity before disease had higher global quality of life scores than women without an occupational activity. Similarly, women with UICC Stage I or Stage II disease exhibited higher global QL scores than others. Results of the multivariate analysis are displayed in Table 5. They show that QL life at the end of treatment is associated with the average maximal pain reported by patients during the entire treatment and with the duration of articular pain, loss of appetite, and fatigue experienced during the last cycle of chemotherapy. Patients’ Daily Lives Analysis of data about organization of daily life was performed on the subgroup of patients who completed both the pretreatment and the last QL form (n 5 97). Among patients who had an occupational activity before their disease (n 5 54), 85.7% had to stop this activity during the treatment. Most patients (83.1%) remained living in their home, whereas 16.9% had to move to a convalescent home or a therapeutic apartment. A total of 62.8% patients required specific assistance for daily life during treatment. The majority of people who provided this assistance were recruited among close relatives (for 92.5% of patients who re- 2196 CANCER May 15, 1999 / Volume 85 / Number 10 TABLE 4 Patients’ Quality of Life in Pretreatment and 21 Days After the Last Cycle of Chemotherapy (n 5 97) TABLE 5 Linear Regression Model: Explanatory Variables of Patients’ European Organization for Research and Treatment of Cancer Global Quality of Life Score at the End of Treatment Mean 6 SD score Variable Functional scalesa Physical functioning Role functioning Emotional functioning Cognitive functioning Social functioning Global quality of life Symptom scales/itemsb Fatigue Nausea and vomiting Pain Dyspnea Sleep disturbance Appetite loss Constipation Diarrhea Financial difficulties Pretreatment 21 days after the last cycle of chemotherapy Variable EORTC global quality of life score at the end of treatment (unstandardized regression parameter estimate [B parameter]a P value Pain during entire treatment (0–10)b Muscular pain duration (1–4)c Fatigue duration (1–4)c Loss of appetite duration (1–4)c Multiple R2 20.18 (0.08) 22.31 (0.99) 26.80 (1.24) 22.07 (1.00) 0.50 0.02 0.02 , 0.001 0.04 — P value 77.8 6 23.7 54.7 6 43.6 63.5 6 25.8 74.4 6 27.2 67.4 6 31.7 62.2 6 19.0 69.2 6 22.9 51.6 6 35.7 59.7 6 29.1 68.2 6 32.8 63.6 6 31.5 52.8 6 19.5 0.001 NS NS NS NS 0.001 39.3 6 26.9 9.7 6 17.6 28.6 6 28.9 14.5 6 22.2 35.1 6 34.2 17.0 6 25.1 23.5 6 32.9 5.0 6 16.2 13.6 6 24.2 56.5 6 30.9 25 6 26.7 28.5 6 28.7 30.5 6 28.8 45.9 6 38.3 26.2 6 33.5 29.8 6 36.1 7.8 6 21.5 18.8 6 28.7 ,0.001 ,0.001 NS ,0.001 0.02 0.02 NS NS NS SD: standard deviation; NS: not significant. a Higher scores represent a high level of functioning. b Higher scores represent a high level of symptom/problem. quired help). The need for assistance was due mainly to transportation to hospital (57.7%) or/and home upkeep (52.4%). Surprisingly, assistance did not depend significantly on patient age, education level, activity before disease, or number of children at home. Finally, 29.4% of patients used ambulatory care services, such as nursing help, during treatment. DISCUSSION The purpose of this study was to evaluate side effects and QL experienced by breast carcinoma patients during an adjuvant, concomitant chemoradiotherapy protocol with the objective of exploring the potential cumulative effects of the two treatments. Of course, a limitation of this study is the lack of a comparative group. However, comparisons with data from the literature about QL during breast carcinoma treatment in which chemotherapy and radiotherapy are administered alone or in sequence can be of interest. Some difficulties arise for these comparisons, because investigators usually evaluated toxicity of chemotherapy at base of mitoxantrone using the World Health Organization (WHO) criteria9 or self-administered instruments that are not as detailed as our chemotherapy EORTC: European Organization for Research and Treatment of Cancer. a A negative B indicates a negative, inverse correlation. The standard error of coefficient is noted in parentheses. b Average maximal pain experienced by patients during entire treatment. c Symptom experienced by patients during the last cycle of chemotherapy. side-effect questionnaire.10,11 Except for the study by Sprangers et al.,12 similar problems exist with the assessment of radiotherapy side effects.13–15 Contrary to The Breast Cancer Chemotherapy Questionnaire (BCQ)16 and the Functional Assessment of Cancer Therapy-Breast (FACT-B),17 also devised specifically for breast carcinoma patients, the EORTC QLQ-BR,23 tested in the study by Sprangers et al.12 includes side effects related to both chemotherapy and radiotherapy. Unfortunately, this module, which was developed by the Study Group on Quality of Life of the EORTC to be administered in conjunction with the EORTC QLQC30, was not available in French at the time of study. This led us to adopt the EORTC core questionnaire to measure multidimensional QL of patients and to develop specific instruments to measure treatment side effects. The addition to the EORTC QLQ-C30 of the two specific side-effect questionnaires (chemotherapy and radiotherapy) permitted us to cover a broad range of side effects addressed, by example, by the QLQBR23 module, notably in questions 32–35, 37, and 38 as well as in questions 47–50 and 53. Nausea frequency in our study (84%) was similar with that reported in Bennett’s study10 (80% of cycles for nausea/vomiting) in which cyclophosphamide, mitoxantrone, and fluorouracil (CNF) versus cyclophosphamide, doxorubicin, and fluorouracil (CAF) chemotherapy was administered after radiotherapy (Table 6). Conversely, it was higher than in the study carried out by Greene (25–55% of patients according to the moment of the measure),11 in which breast carcinoma patients received CNF chemotherapy alone. Hair loss was severe for 25% of cycles in our Quality of Life during Concomitant Chemoradiotherapy/Macquart-Moulin et al. TABLE 6 Literature Data: Comparison of Symptom Frequency Experienced by Patients with Nonmetastatic Breast Carcinoma during Concomitant Chemoradiotherapy with that Reported by Patients Receiving Sequential Chemoradiotherapy Study Instrument for measuring toxicity Bennett et al., 198810 LASA Alonso et al., 19959 Greene et al., 199411 WHO criteria Self-care diary Symptom(s) Present study vs. literature data Nausea Mouth sore Alopecia Alopecia Nausea Vomiting Mouth sore Change in taste Loss of appetite Fatigue Alopecia 5 m m n m 5 5 5 5 5 m LASA: Linear analogue self-assessment; WHO: World Health Organization. study, for 4% in the study by Bennett, and for 36% (WHO Grade 3) in that of Alonso et al. (CNF vs. CAF chemotherapy alone).9 Other symptoms, such as mouth sore, change in taste, loss of appetite, and fatigue, produced reports similar to that assessed in Greene’s study, in which symptoms were measured by using a self-care diary (Table 6). However, some long term and/or distressing symptoms, such as hot flush, stomach pain, and articular pain, were not assessed in the studies discussed above. Our results from the radiotherapy side-effects questionnaire confirm a fact already known by clinicians, i.e., radiotherapy side effects are largely less frequent, severe, and distressing than chemotherapy side effects. It must be recognized that, among the side effects assessed in our study, arm edema is due more to surgery than to radiotherapy. Furthermore, cough has to be more related to events such as mucitis rather than to pneumonitis, which is unlikely to occur acutely during radiation. Few studies to our knowledge have attempted to measure adverse effects and, particularly, cosmetic effects of radiotherapy in breast carcinoma patients as well as the associated distress. One study15 has focused more on psychological symptoms than physical symptoms, except for fatigue, which otherwise appeared as the most frequent side effect of radiotherapy. However, Greenberg et al.14 found that, contrary to their hypothesis, fatigue, which was evaluated during radiation treatment for breast carcinoma, did not increase linearly with cumulative radiation dose over time. In addition, compared with other patients who received treatment, the fatigue scores found in their study were lower. An interesting 2197 finding of our study is that patients experienced fatigue less often when they received chemotherapy and radiotherapy simultaneously than when they received chemotherapy alone. Because radiotherapy was concomitant with the two first cycles of chemotherapy, this finding suggests, as in the other studies, that fatigue is due more to the duration of treatment than to the effects of the current administration of chemotherapy and radiotherapy, per se. Regarding the cosmetic problems induced by radiotherapy, it is difficult to compare our results with those of previous studies. Indeed, Read et al.13 investigated morbidity and cosmesis after lumpectomy and radiotherapy in 184 patients with breast carcinoma, but the assessments were performed only at 5–7 months after surgery. The study by Sprangers et al.12 approached these effects by means of the QLQ-BR23, but their results were not analyzed and presented in the manner used in the current report; therefore, comparison between the two studies is not feasible. Another study published in 199618 evaluated the interaction of sequence and type of chemotherapy and hormonal therapy given with radiation therapy on the cosmetic outcome and the incidence of complications of patients with Stage I and II breast carcinoma who were treated with breastconserving therapy (79% of patients in our study). That study demonstrated that cosmesis was not influenced detrimentally by the addition of chemotherapy to radiation therapy in breast-conservation treatment. Our results, which show few cosmetic problems in study patients, and those of Markiewicz et al.18 are in favor of the absence of deleterious effect on cosmesis of the concurrent administration of chemotherapy and radiotherapy. The relatively high and constant pain intensity reported by patients during treatment may be considered as the consequence of cumulative effects of disease, surgery, chemotherapy, and radiotherapy. For example, one study that was performed in 1995 among 569 patients with breast carcinoma demonstrated that pain was more common after breast-conserving surgery than after radical surgery.19 Surgical complications and postoperative radiotherapy and chemotherapy increased the risk of chronic pain and other symptoms. Another paper by the same authors, which was published the next year,20 investigated in more depth the problem of pain in 93 patients with breast carcinoma who submitted to different treatment modalities during the first year after radical and conservative surgery. The incidence of 1-month and 6-month posttreatment chronic pain in the breast area and in the ipsilateral arm was significantly higher after conservative surgery than after radical surgery. In the posttreatment period, pain intensity in the ipsilat- 2198 CANCER May 15, 1999 / Volume 85 / Number 10 eral arm was significantly higher than the intensity of pain before surgery. Pain-intensity scores in that study were similar to ours both before treatment and 1 month after treatment. Multidimensional QL assessment in patients with nonmetastatic breast carcinoma using the EORTC QLQ-C30 shows that the impact of treatment is obvious; however, it affects mainly patients’ physical functioning and global QL, whereas, compared with the pretreatment period, emotional, cognitive, role, and cognitive functions remain unchanged. Several studies have attempted to evaluate the impact of adjuvant treatment on QL before, during, and after treatment.21–27 Among the most recent, the study by Hürny et al.27 investigated QL during therapy and after disease recurrence in patients with lymph node positive, operable breast carcinoma who were included in two trials of the International Breast Cancer Study Group. Those authors concluded that, although adjuvant chemotherapy had a measurable impact on patients’ QL, this impact was transient and minor compared with patients’ adaptation/coping after diagnosis and surgery. The conclusions of this study are similar to those of Campora et al.,24 indicating that the majority of patients with breast carcinoma respond normally to adjuvant chemotherapy. QL assessments at the end of the treatment period, in our study, suggest that the disappearance of a certain number of physical symptoms due to treatment (and particularly to chemotherapy) will have as a consequence further improvement of patients’ QL. However, pain experienced by patients during treatment, duration of articular pain, fatigue, and loss of appetite at the last cycle of chemotherapy compromise global QL at the end of treatment. Except when it is related to chronic anemia, for which transfusions or erytropoietin (for treatment as well as for prevention)28 –30 can be offered, clinicians are not able to treat fatigue. Psychological support alone may represent a possibility. Pain, which often is present already before surgery in the breast area and in the ipsilateral arm, may be intensified by radiotherapy and also by chemotherapy, which induces many other painful symptoms. This should incite clinicians to relieve pain before as well as during and after treatment. Generally, physicians should attempt to detect symptoms that persist and about which patients do not necessarily complain. We have not found references in the literature concerning the organization of daily lives for patients who underwent chemotherapy alone or chemotherapy plus radiotherapy. However, the study by Campora et al.24 indicated that, in 83–90% of cases, pa- tients who received chemotherapy alone took care of themselves. Our results are slightly less optimistic: Although 83.1% of patients lived at home during treatment, about 63% have needed help (principally by close relatives) for transportation to the hospital and/or home upkeep. It is obvious that the addition of chemotherapy and radiotherapy may complicate daily life for patients who have to come to the hospital for radiotherapy every day (weekends excepted) for 5 weeks. However, fatigue itself may complicate daily life and incite women to seek help. An interesting finding from a social point of view is that a high proportion of active women (85.7%) had to stop their occupation during treatment. This may have been due to difficulties that were related directly to the disease and its treatment. However, considering the minimum symptoms identified, it is likely than other problems exist. These problems may be difficulties for patients to conciliate their work, their family lives, and the constraints due to treatment and to obtain flexible time management with employers. Another possibility is the reluctance of patients to talk about their disease and/or to reveal its effects as well as those of the treatment to their colleagues. In conclusion, this work shows that concomitant administration of chemotherapy and radiotherapy induces certain side effects that deteriorate patients’ QL but in a proportion similar to that observed with sequential protocols. Although some of these effects, such as fatigue, pain, and loss of appetite, detract from QL at the end of treatment, the results suggest that the advantage of shortening the duration of treatment compared with sequential protocols does not seem to be offset by an increase in distress associated with side effects. Moreover, concomitant chemoradiotherapy may require that women have an adequate organization of their daily lives during treatment and will need more assistance during this period. These results can provide clinicians with adequate data to give to patients for obtaining their informed consent to undergo such treatment. Moreover, this work demonstrates that the psychosocial effects of treatments are measurable, and their recognition may be helpful to clinicians in routine care and even in the therapeutic decision-making process. However, the results of our study probably are not directly generalizable. Indeed, mitoxantrone is reputed to be less toxic, particularly in terms of alopecia, than the most commonly used anthracyclin (adriamycin) and the equivalence of its efficacy is discussed. So, additional studies on concomitant radio-chemotherapy using adriamycin are mandatory. 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