© 2001 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 30, 135-142,
2001
© 2001 Oxford University Press
Side Effects of Chemotherapy and Combined Chemohormonal Therapy in Women With Early-Stage Breast Cancer
Affiliations of authors: Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA.
Correspondence to: Eric P. Winer, M.D., Breast Oncology Center, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115 (e-mail: ewiner{at}partners.org).
 |
ABSTRACT |
|---|
 TopNotes Abstract IntroductionShort-Term Side EffectsLong-Term or Sustained Side...Summary and ConclusionsReferences |
|---|
The decision to receive chemotherapy or chemohormonal therapy involves careful consideration of both the potential benefits and possible risks of therapy. There are substantial short- and long-term side effects from chemotherapy. By convention, short-term side effects include those toxic effects encountered during chemotherapy, while long-term side effects include later complications of treatment arising after the conclusion of adjuvant chemotherapy. These side effects vary, depending on the specific agents used in the adjuvant regimen as well as on the dose used and the duration of treatment. There is also considerable variability in side effect profile across individuals. This review will focus on the short- and long-term toxicity seen with the most commonly used adjuvant chemotherapy and chemohormonal therapy regimens.
|
INTRODUCTION |
|---|
|
TopNotesAbstractIntroductionShort-Term Side EffectsLong-Term or Sustained Side...Summary and ConclusionsReferences |
|---|
The role of adjuvant systemic therapy has been studied extensively in women with early-stage breast cancer. Chemotherapy and chemohormonal therapy improve disease-free and overall survival in women with operable breast cancer (1). The absolute benefits of adjuvant chemotherapy vary depending on the treatment regimen, the characteristics of the tumor (e.g., hormone receptor status), the medical and demographic characteristics of the woman (e.g., comorbid conditions and age), and the absolute risk of disease recurrence. In women with a relatively high risk of disease recurrence, the improvement in disease-free and overall survival associated with adjuvant chemotherapy can be quite substantial. In contrast, in women with small tumors and/or negative lymph nodes, the absolute benefits of treatment may be quite small. Decision making about adjuvant therapy—particularly adjuvant chemotherapy—can be complex. Women and their physicians must consider the potential benefits of treatment as well as the possible risks and anticipated side effects.
Side effects from chemotherapy can be divided into short-term effects and long-term effects. Table 1
lists short-term and long-term effects of adjuvant chemotherapy. Short-term effects typically occur during the course of treatment and generally resolve within months of the completion of therapy. In contrast, long-term effects can have a later onset and sustained impact—often lasting for many years. In the case of some of the rare long-term effects, many years may elapse before any symptoms develop.
|
|
SHORT-TERM SIDE EFFECTS |
|---|
|
TopNotesAbstractIntroductionShort-Term Side EffectsLong-Term or Sustained Side...Summary and ConclusionsReferences |
|---|
The most frequently encountered short-term side effects seen with standard adjuvant chemotherapy regimens and their relative frequency and severity are listed in Table 2
. Fatigue, which is listed as a short-term effect, has been recognized in recent years as a common side effect of cancer chemotherapy (2–7). The assessment of fatigue with standard toxicity grading scales has probably underestimated the prevalence of this problem, and there are few studies of women receiving adjuvant chemotherapy that have detailed self-reports of fatigue. For this reason, it is particularly difficult to determine the prevalence, severity, and duration of fatigue in women receiving adjuvant chemotherapy. There is evidence that some patients cite difficulties with fatigue for months and even years after adjuvant chemotherapy (7,8), but it is not known to what extent such findings differ from age-matched control subjects. Because of the presumed underreporting of fatigue in many studies, it is not possible to assess with confidence the prevalence and severity of fatigue associated with different adjuvant regimens.
|
Treatment-related side effects are often gauged by standardized criteria from the National Cancer Institute. In Table 2
, we have characterized the frequency and usual severity of the most common short-term side effects using the reported toxic effects in 12 adjuvant trials conducted in the late 1980s and 1990s (9–21). We have focused on recent trials that have used many of the modern supportive care measures that are currently available; however, some of these trials were conducted before the availability of the serotonin antagonists for the prevention and treatment of emesis. Therefore, reported rates of nausea and vomiting may be somewhat higher than would be seen today. Side effects characterized as mild correspond to reported grade 1 or 2 toxic effects, whereas those characterized as moderate and severe correspond to grade 2 or 3 and grade 3 or 4 toxic effects, respectively. We characterized the frequency of side effects as follows: fewer than 1%, almost never; 1%–5%, rare; 6%–20%, uncommon; 21%–50%, common; 50%–95%, frequent; and greater than 95%, almost always. Similar regimens administered in different trials and by different investigators (9–21) had remarkably similar side effect profiles. It should be noted that, although neuropathy is listed as a short-term side effect, the extent to which this persists over time has not been well characterized. In general, the non-anthracycline-containing regimens are associated with fewer grade 3–4 short-term toxic effects than are anthracycline-based regimens. Neuropathy is rarely seen with either the combination chemotherapy of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or the methotrexate and 5-fluorouracil (MF) regimens. In contrast, emesis (i.e., nausea and/or vomiting), alopecia, and myelosuppression (principally neutropenia) are seen commonly to very commonly with the CMF regimen. Mucositis is seen less frequently with intravenous CMF, compared with oral CMF. Despite the frequency of these side effects, they are often of either mild or moderate severity. Complete alopecia can be seen with these regimens, but when alopecia occurs with CMF, it is frequently partial. Because cyclophosphamide is administered orally for a total of 84 days in the classic oral CMF regimen, nausea with this regimen is sometimes more persistent than with other programs. The MF with leucovorin regimen, used in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocols B-14, B-19, and B-20 (11,13,22), is generally associated with even fewer grade 3–4 short-term toxic effects than classic cyclophosphamide-containing regimens. Because of concern that the MF with leucovorin regimen is inferior to CMF (11), it is not used frequently, although when it is used in combination with tamoxifen, the benefits of CMF and MF appear to be similar (13).
Short-term side effects with the anthracycline-based regimens (15,17,19,20) tend to be more frequent and more severe than those with non-anthracycline-containing treatment. Emesis and myelosuppression are very common with all of these regimens and can be severe in nature. Complete alopecia is seen with almost all anthracycline-based regimens. Mucositis appears to be more common with the 5-fluorouracil-containing regimens, such as combination chemotherapy with cyclophosphamide, doxorubicin (Adriamycin), and 5-fluorouracil (CAF) or 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC), as opposed to doxorubicin and cyclophosphamide (AC). When paclitaxel is used as part of a sequential regimen, neuropathy and myalgias can be seen occasionally, although symptoms are generally mild. Of note, when higher doses of paclitaxel (i.e., 225 mg/m2) were used, as in NSABP B-28, the neuromuscular toxicity was more frequent and may have been more severe (23) than with lower doses (i.e., 175 mg/m2), as those used in Cancer and Leukemia Group B (CALGB) 9344.
An increased risk of thrombosis has been reported in several trials of adjuvant therapy. The risk of thrombosis appears to occur during active treatment and to abate over time. In a trial comparing shorter and longer chemotherapy regimens, Levine et al. (24) reported an increased risk of thrombosis on both arms, but only during the period of active treatment. Women on the shorter-duration chemotherapy arm stopped having thrombotic episodes when chemotherapy was stopped, whereas women in the longer arm continued to have thrombotic events for the full duration of their treatment. There is evidence that the use of concurrent chemohormonal therapy results in a higher rate of thromboembolic complications than does the use of tamoxifen alone (13,25–27). In NSABP B-20 (13), in which women were randomly assigned to receive tamoxifen alone or administered concurrently with either MF or CMF, the incidence of thrombosis was 1.9% in the tamoxifen-treated group, compared with 6.5% and 7.5% in the patients treated with tamoxifen plus MF and tamoxifen plus CMF, respectively. In a Canadian trial comparing tamoxifen alone with chemotherapy plus tamoxifen, the incidence of thrombosis was 2.6% on the tamoxifen-alone arm and 13.6% in the CMF plus tamoxifen arm (P<.0001) (27). The use of concurrent chemohormonal therapy may also be associated with a higher rate of thrombosis than chemotherapy alone (26). Given the greater risk of thrombosis associated with tamoxifen in women over 50 years (28,29), combination therapy may be particularly problematic in older women (27). A U.S. Intergroup Trial (30) compared CAF followed by tamoxifen with CAF and concurrent tamoxifen in postmenopausal women. To date, no results comparing these two arms of the study have been reported concerning either efficacy or thrombosis risk. Because of concern about the increased risk of thrombosis, many physicians choose not to administer chemotherapy and tamoxifen concurrently outside of a clinical trial.
Because short-term side effects typically resolve with therapy, the duration of treatment has a major impact on the total side effect burden that a woman may experience. Most treatment regimens are approximately 4–6 months in duration. The AC regimen, however, is substantially shorter and is completed in 12 weeks. The last dose of AC is actually administered 9 weeks after the first dose (9), and, as a result, the duration of short-term side effects is reduced. In a randomized trial comparing AC with 6 months of CMF, investigators from the NSABP concluded that the shorter regimen was associated with a lower total side effect burden (9). The perception that AC is a relatively well tolerated regimen has led to its widespread use over the past decade.
The impact of adjuvant chemotherapy on quality of life has been evaluated in several studies. The International Breast Cancer Study Group randomly assigned patients to either three or six cycles of chemotherapy and demonstrated a more rapid improvement in quality of life with the shorter treatment regimen compared with the longer treatment regimen (31). Other investigators have demonstrated that quality of life improves rapidly with the completion of therapy. Levine et al. (15) showed that quality of life actually improved throughout the course of adjuvant therapy, suggesting some measure of psychological and physical adaptation to a new diagnosis of breast cancer, surgery, and ongoing chemotherapy. Since no studies have measured quality of life before the diagnosis of breast cancer, it is unknown when or if quality of life following adjuvant therapy returns to the prediagnosis baseline. Research in breast cancer survivors suggests that the majority of women diagnosed with early-stage breast cancer return to fully active lives by 1 year after diagnosis, although women who received adjuvant chemotherapy may be more likely to have some residual symptoms, such as sexual dysfunction (32,33). More research is clearly needed to characterize the recovery trajectory, in terms of both physical and psychological health, following a course of adjuvant chemotherapy.
Despite the high prevalence of breast cancer among older women, researchers have only recently focused on treatment questions in this patient group. Few randomized trials have included many women over 65 years of age (34–36). It is widely assumed that older patients are less tolerant of chemotherapy than younger patients. Although a few small studies have reported significantly increased toxicity in the elderly, recent larger studies provide evidence to the contrary. Crivellari et al. (37) studied the use of adjuvant CMF and tamoxifen in elderly women. Although women aged 65 years or older had greater hematologic and mucosal toxicity than younger women, quality-of-life measures suggested that the subjective burden of treatment was similar for older and younger patients. Begg and Carbone (38) examined 19 Eastern Cooperative Oncology Group studies that included a total of 780 patients aged 70 years or older. In comparison with younger individuals in the trials, older patients had increased hematologic toxicity; otherwise, the incidence of severe toxic effects was similar between groups. In a more recent prospective study, Dees et al. (39) treated 44 women aged 35–79 years with early-stage breast cancer with four cycles of adjuvant AC chemotherapy. In this cohort, although myelosuppression was increased in older women, neutropenic complications, alteration in cardiac function, and change in quality-of-life scores were not significantly related to age. Pharmacokinetic analyses did not demonstrate age-related differences in the clearance of doxorubicin or cyclophosphamide. Although patients in these studies may represent a highly selected group, it is reassuring that the older patients appear to tolerate chemotherapy nearly as well as the younger patients. Additional research in this area is clearly warranted.
|
LONG-TERM OR SUSTAINED SIDE EFFECTS |
|---|
|
TopNotesAbstractIntroductionShort-Term Side EffectsLong-Term or Sustained Side...Summary and ConclusionsReferences |
|---|
In addition to the short-term side effects from chemotherapy, there are a number of sustained or long-term consequences of treatment. Some of these long-term effects, such as premature ovarian failure, are commonly seen in certain subgroups of patients. Others, such as secondary leukemia, are extremely rare consequences of treatment. Nevertheless, these rare effects must be considered in decision making about adjuvant therapy, particularly when the absolute benefits associated with treatment are of small magnitude.
Premature Ovarian Failure
Premature ovarian failure or premature menopause is a common consequence of adjuvant chemotherapy in premenopausal women. The risk of premature menopause appears to be related to patient age, the specific chemotherapeutic agents used, and the total dose administered. The effect of treatment duration and dose intensity, independent of total dose, is uncertain. While premature ovarian failure may have a beneficial effect on breast cancer prognosis (40), particularly in women with hormone receptor-positive tumors, early menopause may have important physiologic and psychosocial consequences. For women who wish to consider becoming pregnant after breast cancer, risk of infertility following chemotherapy is a major concern. Other problems related to premature ovarian failure include menopausal symptoms, such as hot flashes, genitourinary problems, and both psychological and psychosexual difficulties (33,41,42). Women who experience premature menopause have accelerated bone mineral density loss (43–46). Premature menopause may also contribute to increased cardiovascular morbidity, although data to support this concern in women with breast cancer are lacking. For many of these symptoms or complications, there are nonhormonal interventions available (47). However, patients commonly express concerns over menopausal symptoms and their bone and heart disease risk during longer follow-up.
Table 3 shows the proportion of women who experience premature menopause with adjuvant chemotherapy (48). The table is broken down by treatment regimen and age. The vast majority of women over the age of 40 years experience menopause after treatment with CMF or cyclophosphamide, epirubicin, and 5-fluorouracil (CEF). In women under the age of 40 years, the risk of ovarian failure from these regimens is lower but is by no means uncommon. MF has been reported to be associated with an approximately 10% incidence of premature menopause, but this has not been analyzed as a function of patient age. AC is associated with a lower incidence of premature menopause in both younger and older women, probably because of the lower cumulative dose of cyclophosphamide with this regimen. The effect of adjuvant taxane therapy on premature ovarian failure is not well characterized. In one small retrospective study (49), the addition of paclitaxel to AC did not appear to substantially increase the overall risk of chemotherapy-related amenorrhea; however, larger studies are needed to make any definitive conclusions. In women under the age of 30 years, premature ovarian failure with any of the available regimens is distinctly uncommon. Three separate reports (50–52) have provided estimates for the incidence of premature ovarian failure in 20% or fewer women. In two of these studies (50,52), there were no patients under the age of 30 years who experienced premature menopause. In another report, Goodwin et al. (53) evaluated the incidence of ovarian failure in women who received no systemic therapy compared with those who received either chemotherapy or chemotherapy followed by tamoxifen. Young women (under the age of 30 years) had a very low incidence of menopause regardless of the therapy received. As expected, the incidence of chemotherapy-related amenorrhea increased with age.
|
Chemotherapy-related amenorrhea may be reversible in that some women will resume menstrual function months or years after treatment. However, the vast majority of women who remain amenorrheic 1 year after treatment will not regain ovarian function. The possibility of delayed (i.e., occurring even years after treatment) premature menopause has not been explored thoroughly. In the pediatric oncology population, there is evidence that adolescent girls who receive chemotherapy experience an earlier than expected menopause as they age (54). It is certainly plausible that a young woman who receives chemotherapy and does not experience chemotherapy-related amenorrhea will nevertheless go through menopause earlier than she would have in the absence of chemotherapy.
Weight Gain
Weight gain has been reported in 50% or more of women receiving adjuvant chemotherapy, with mean gains of 2.5–5.0 kg (55–58). More significant weight gain, as much as 10–20 kg, has been reported by some investigators in as many as 20% of patients. Weight gain appears to be more common in premenopausal women than postmenopausal women, and women who experience menopause with chemotherapy also seem to be at greater risk of weight gain (55–57). Regimens that are longer in duration may increase the risk of weight gain, and weight gain may be less common with the shorter AC regimen (59). Weight gain, particularly when substantial, can have a profound influence on a woman's physical health and psychological adaptation. In addition, retrospective studies (60–63) have suggested that weight gain may increase a woman's risk of disease recurrence.
The underlying cause of weight gain with chemotherapy is uncertain. For years it was assumed that weight gain occurred because women receiving chemotherapy simply ate too much. Studies that have monitored dietary intake have failed to support this view (57,64,65). Preliminary evidence suggests that weight gain may be caused by decreased physical activity during therapy (59,64,65). Studies (58,59,64–66) have also suggested that there may be changes in resting metabolic rate and that lean body mass can decline following a course of chemotherapy. Interventions focusing on exercise and on increasing lean body mass may help to ameliorate weight gain among women receiving adjuvant breast cancer chemotherapy (65).
Long-Term Cardiac Effects
Cardiotoxicity has been a major concern, since anthracycline-based regimens have been used more commonly in the adjuvant setting. The incidence of anthracycline-induced cardiac dysfunction increases with the increasing cumulative amount of anthracycline (either doxorubicin or epirubicin) administered. Other risk factors may include advancing age and a history of cardiac disease (67,68). In general, most adjuvant chemotherapy regimens restrict cumulative doses of doxorubicin to less than 360 mg/m2 and of epirubicin to less than 720 mg/m2—doses thought to fall within a relatively safe range with clinically acceptable rates of cardiac complication. Valagussa et al. (69) reported a 0.8% incidence of congestive heart failure in a group of more than 500 women who received approximately 250 mg/m2 of doxorubicin, with a median follow-up of 80 months. Zambetti et al. (70) performed a more detailed assessment of cardiac function in a group of 355 women who were disease free at a median follow-up of 11.5 years. Forty-four percent of the women received CMF only, and the remainder received CMF followed by doxorubicin, with a median cumulative doxorubicin dose of approximately 300 mg/m2. Women were assessed by physical examination, history, electrocardiogram, and echocardiogram. Although clinical congestive heart failure was very rare in both groups, 8% of the patients receiving doxorubicin were characterized as having systolic dysfunction, defined as an ejection fraction of less than 55%. In contrast, fewer than 2% of the CMF group had evidence of systolic dysfunction. In a recent U.S. Intergroup trial using CAF in postmenopausal women, the reported incidence of congestive heart failure was approximately 2% (30). Of note, the patient population was somewhat older than in many adjuvant trials, and the total planned dose of doxorubicin was 360 mg/m2.
The existing data concerning long-term cardiotoxicity are relatively reassuring, and the absence of clinical symptoms in the vast majority of patients is encouraging. However, the possibility of long-term subclinical systolic dysfunction, as seen in the Zambretti study, merits further investigation. Physicians can counsel women without pre-existing cardiac disease that the incidence of symptomatic cardiac problems with anthracycline-based regimens is extremely rare. There is reason to have some limited concern about the potential for very long term toxicity; it is not presently known whether anthracycline exposure increases the risk of cardiac compromise with subsequent cardiac stressors (e.g., hypertension) or a subsequent cardiac event (e.g., a myocardial infarction). In women with baseline cardiac dysfunction or in those who are at risk for compromise based on their medical history, it may be prudent to evaluate cardiac function before and after anthracycline-based adjuvant therapy, although data in support of this are limited.
Concern has been raised that breast/chest irradiation would increase the risk of cardiac toxicity. In a randomized trial of 5 versus 10 cycles of AC, there was an increased risk of cardiac events in the group of women who received 10 courses of treatment (median cumulative dose of doxorubicin, 442 mg/m2) (71). This effect seemed to be more pronounced in women who received high dose volume of cardiac irradiation. There appeared to be no excess cardiac risk in women who received five cycles of AC (median cumulative dose of doxorubicin, 225 mg/m2) with radiation therapy. In a retrospective analysis from Valagussa et al. (69), a total of four (0.8%) of 501 women treated with doxorubicin developed congestive heart failure, with a median follow-up in excess of 6 years; of the 114 women who received doxorubicin and left-sided breast irradiation, three (2.6%) developed congestive heart failure. Any increased concern with left-sided irradiation and the use of doxorubicin is probably less worrisome with the availability of modern radiation planning.
Chemotherapy-Associated Leukemia
Leukemia or myelodyspastic syndromes (MDSs) associated with adjuvant therapy are very rare, but devastating, complications of treatment. Curtis et al. (72) conducted a case–control study in almost 82 700 women who were treated for breast cancer during the 1970s and 1980s. On the basis of their work, the total dose of cyclophosphamide appears to be an important risk factor, with a substantially higher risk in women who receive more than 20 000 mg of the drug. With typical CMF regimens, which use significantly lower cumulative doses of cyclophosphamide, Curtis et al. (72) estimated that an additional five cases of leukemia would be seen in 10 000 women over the course of 10 years. Other investigators have used very different methodologies, making it difficult to compare across studies and with different regimens. There is some suggestion that the risk with anthracycline-based regimens may be greater than with classic CMF type regimens (12,15,73–78). With anthracycline-based regimens, the overall incidence of leukemia in women with breast cancer after standard-dose adjuvant therapy is approximately 0.1%–1.5% at 5–10 years' follow-up (12,15,30,77,79). In studies with 6 months of adjuvant anthracycline and cyclophosphamide therapy (e.g., CAF), the incidence of leukemia or MDS has been found to be as high as 1.5% (15,77), with an even greater risk associated with the addition of adjuvant radiation therapy (77). After four cycles of standard AC chemotherapy (cyclophosphamide at 600 mg/m2 and doxorubicin at 60 mg/m2 per cycle), the risk is probably quite low. This regimen was used as the standard arm of NSABP protocol B-22 (12), and the incidence of leukemia or MDS in this group was 0.1%, with a median follow-up of 5 years. Among women who received an increased dose or dose-intensive regimens of cyclophosphamide and doxorubicin on NSABP protocols B-22 and B-25 (12,77), the incidence of leukemia and MDS was higher. In both studies, there was no benefit in disease-free or overall survival observed among women who received the higher dose or dose-intensive regimens, and rates of leukemia and MDS ranged from 0.1% to 1.2%. It is reasonable to speculate that the higher doses of cyclophosphamide, up to 2400 mg/m2 per cycle, may have contributed to the higher frequency of leukemia and MDS in these studies. In the preliminary report of the NSABP B-28 trial (23), five (approximately 0.3%) cases of leukemia developed in the approximately 1500 patients who received standard-dose AC followed by paclitaxel. Whether there is any additional increase in risk with the addition of the taxanes is unknown.
The latency period and cytogenetic abnormalities appear to be different with doxorubicin-induced leukemia than those that arise after exposure to cyclophosphamide alone (75). Leukemias that are associated with exposure to alkylating agents typically present 5–7 years after treatment and are frequently preceded by an MDS. Topoisomerase inhibitors, such as anthracyclines, can give rise to secondary leukemias 6 months to 5 years after therapy. There are no methods of screening for these disorders in survivors of breast cancer, although they should be considered in the evaluation of patients in whom cytopenia develops after the treatment of breast cancer. Because of the rarity of leukemia after adjuvant therapy, concern about this complication seems most reasonable in women who are at low risk of breast cancer recurrence and who are likely to derive a very small benefit from adjuvant chemotherapy.
Cognitive Dysfunction
Cognitive dysfunction after adjuvant therapy has received increasing attention in both the medical and lay literature in recent years. Three studies have been published (80–82) in which women who had received or were receiving chemotherapy underwent neuropsychiatric testing and were compared with a control group. Schagen et al. (81) evaluated 39 women who were approximately 2 years out from six cycles of CMF (with or without subsequent tamoxifen) and compared them with 34 women who had received local therapy only. Twenty-eight percent of the CMF group, compared with 12% of the control subjects, had evidence of cognitive dysfunction, predominantly characterized by difficulties with concentration, memory, word-finding, and motor-testing. Furthermore, hormonal therapy did not appear to influence patients' self-reports of symptoms or cognitive function. In a study by van Dam et al. (80,83), a dose–effect relationship was seen between chemotherapy and cognitive dysfunction. At a mean of 2 years since the completion of last nonhormonal therapy, impaired cognitive dysfunction was seen in 32% of the patients treated with high-dose chemotherapy, in 17% of the patients treated with standard-dose chemotherapy, and in 9% of the women with stage I breast cancer who did not receive chemotherapy. Brezden et al. (82) surveyed a group of 31 women receiving chemotherapy, another group of 40 women who had received chemotherapy in the past, and a group of healthy control subjects. Impaired cognition was seen more frequently in women on active treatment compared with control subjects, and cognitive difficulties did not appear to be related to anxiety or depression. While these results are provocative, it is important to note that, in two of the studies (80,81), there was no association between self-reports of cognitive dysfunction and scores on the formal testing; the women who complained of cognitive difficulties were not the same women who performed poorly on the testing. Furthermore, in none of these studies were patients assessed longitudinally to assess for change in functioning with therapy. Anecdotally, many patients complain of what has commonly been termed "chemo brain," with complaints of forgetfulness and difficulty concentrating. The possibility of persistent impaired cognition is of great concern to patients as they make decisions about adjuvant treatment, but neither the anecdotes nor the research studies conducted to date permit any firm conclusions. Prospective longitudinal studies are warranted to pursue the hypothesis that cognition may be impaired in women following adjuvant chemotherapy.
|
SUMMARY AND CONCLUSIONS |
|---|
|
TopNotesAbstractIntroductionShort-Term Side EffectsLong-Term or Sustained Side...Summary and ConclusionsReferences |
|---|
How should women and their physicians use information about side effects to make decisions about adjuvant therapy? A woman with a new diagnosis of breast cancer needs to consider her risk of disease recurrence and death in the absence of therapy, the potential benefit of chemotherapy, and her post-treatment risk of recurrence and death. For an individual woman, it is the absolute, not the relative benefit, of therapy that is important. This benefit needs to be considered in the context of the short-term and long-term side effects from treatment.
In making these decisions, women and their physicians need to know the frequency, duration, and severity of side effects. This information, at least for broad groups of women, is available. Unfortunately, for many of the side effects, clinicians have relatively little ability to predict who is at greater or lesser risk of experiencing a given adverse effect. Improving the ability to predict an individual woman's risk of both long- and short-term side effects with various treatments will allow her to make an even more informed decision regarding therapy. Perhaps even more importantly, the impact of side effects on a woman's ability to carry on her daily activities has not been well evaluated. Many women want to know whether they will be able to continue to care for their families, work, and pursue the activities they enjoy—that is, continue with their lives, despite treatment. Future research focusing on this aspect of patient care is needed.
Decisions about adjuvant chemotherapy are complex. No woman with localized breast cancer can know that she definitely will experience a recurrence in the absence of therapy, and even if she did, there is no guarantee that treatment will prevent such a recurrence. For that matter, even women with very early stage disease are at some risk of a systemic recurrence after local therapy alone. The potential benefits of adjuvant treatment need to be considered in conjunction with the risk of short-term and long-term side effects. Not only should the patient and physician consider the frequency and intensity of the side effects, but they must also consider how any particular side effect may impact an individual woman's life. Decisions about adjuvant treatment are often not clear-cut, but by weighing the advantages and disadvantages of a course of treatment, patients and their physicians can hope to make informed and thoughtful choices.
|
NOTES |
|---|
E. P. Winer and H. J. Burstein have received a research grant-in-aid from Bristol-Myers Squibb (New York, NY).
|
REFERENCES |
|---|
|
TopNotesAbstractIntroductionShort-Term Side EffectsLong-Term or Sustained Side...Summary and ConclusionsReferences |
|---|
1 Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1998;352:930–42.[CrossRef][ISI][Medline]
2 Broeckel JA, Jacobsen PB, Horton J, Balducci L, Lyman GH. Characteristics and correlates of fatigue after adjuvant chemotherapy for breast cancer. J Clin Oncol 1998;16:1689–96.[Abstract]
3 Berger AM. Patterns of fatigue and activity and rest during adjuvant breast cancer chemotherapy. Oncol Nurs Forum 1998;25:51–62.[Medline]
4 Sitzia J, Huggins L. Side effects of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy for breast cancer. Cancer Pract 1998;6:13–21.[CrossRef][ISI][Medline]
5 Jacobsen PB, Hann DM, Azzarello LM, Horton J, Balducci L, Lyman GH. Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates. J Pain Symptom Manage 1999;18:233–42.[CrossRef][ISI][Medline]
6
Bower JE, Ganz PA, Desmond KA, Rowland JH, Meyerowitz BE, Belin TR. Fatigue in breast cancer survivors: occurrence, correlates, and impact on quality of life. J Clin Oncol 2000;18:743–53.
7 Jacobsen PB, Stein K. Is fatigue a long-term side effect of breast cancer treatment? Cancer Control 1999;6:256–63.[Medline]
8
Lindley C, Vasa S, Sawyer WT, Winer EP. Quality of life and preferences for treatment following systemic adjuvant therapy for early-stage breast cancer. J Clin Oncol 1998;16:1380–7.
9 Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, et al. Two months of doxorubicin–cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990;8:1483–96.[Abstract]
10
Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma [published erratum appears in N Engl J Med 1994;331:139]. N Engl J Med 1994;330:1253–9.
11
Fisher B, Dignam J, Mamounas EP, Costantino JP, Wickerham DL, Redmond C, et al. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996;14:1982–92.
12
Fisher B, Anderson S, Wickerham DL, DeCillis A, Dimitrov N, Mamounas E, et al. Increased intensification and total dose of cyclophosphamide in a doxorubicin–cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 1997;15:1858–69.
13
Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 1997;89:1673–82.
14
Pritchard KI, Paterson AH, Fine S, Paul NA, Zee B, Shepherd LE, et al. Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group. J Clin Oncol 1997;15:2302–11.
15 Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1998;16:2651–8.[Abstract]
16 Henderson IC, Berry D, Demetri G, Cirrincione C, Goldstein L, Martino S, et al. Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (pts) with node-positive primary breast cancer (BC) [abstract]. Proc ASCO 1998;17:101a.
17 Bonneterre J, Roche H, Bremond A, Kerbrat P, Namer M, Fumoleau P, et al. Results of a randomized trial of adjuvant chemotherapy with FEC 50 vs. FEC 100 in high risk node-positive breast cancer patients [abstract 473]. Proc ASCO 1998;17:124a.
18 Fetting JH, Gray R, Fairclough DL, Smith TJ, Margolin KA, Citron ML, et al. Sixteen-week multidrug regimen versus cyclophosphamide, doxorubicin, and fluorouracil as adjuvant therapy for node-positive, receptor-negative breast cancer: an Intergroup study. J Clin Oncol 1998;16:2382–91.[Abstract]
19 Hutchins L, Green S, Ravdin P, Lew D, Martino S, Abeloff M, et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of Intergroup trial INT 0102 [abstract]. Proc ASCO 1998;17:1a.
20
Buzdar AU, Singletary SE, Theriault RL, Booser DJ, Valero V, Ibrahim N, et al. Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 1999;17:3412–7.
21 Jonat W. Zoladex versus CMF adjuvant therapy in pre/peri-menopausal breast cancer: tolerability and amenorrhea comparisons [abstract 333]. Proc ASCO 2000;19:87a.
22
Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996;88:1529–42.
23 Mamounas EP. Evaluating the use of paclitaxel following doxorubicin/cyclophosphamide in patients with breast cancer and postive axillary nodes. Adjuvant Therapy for Breast Cancer–NIH Consensus Development Conference. Bethesda (MD): NIH, November 1–3, 2000.
24 Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MD, Hryniuk W, et al. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 1988;318:404–7.[Abstract]
25 Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV, Brown AM, Wickerham DL, et al. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 1990;8:1005–18.[Abstract]
26
Rivkin SE, Green S, Metch B, Cruz AB, Abeloff MD, Jewell WR, et al. Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol 1994;12:2078–85.
27
Pritchard KI, Paterson AH, Paul NA, Zee B, Fine S, Pater J. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 1996;14:2731–7.
28
Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999;91:1829–46.
29
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–88.
30 Albain K, Green S, Ravdin P, Cobau E, Levine J, Ingle K, et al. Overall survival after cyclophosphamide, adriamycin, 5-FU, and tamoxifen (CAFT) is superior to T alone in postmenopausal, receptor (+), node (+) breast cancer: new findings from phase III Southwest Oncology Group Intergroup Trial S8814 (INT-0100) [abstract 94]. Proc ASCO 2001;20:24a.
31 Hurny C, Bernhard J, Coates AS, Castiglione-Gertsch M, Peterson HF, Gelber RD, et al. Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. International Breast Cancer Study Group. Lancet 1996;347:1279–84.[CrossRef][ISI][Medline]
32 Ganz PA, Rowland JH, Meyerowitz BE, Desmond KA. Impact of different adjuvant therapy strategies on quality of life in breast cancer survivors. Recent Results Cancer Res 1998;152:396–411.[Medline]
33 Ganz PA, Rowland JH, Desmond K, Meyerowitz BE, Wyatt GE. Life after breast cancer: understanding women's health-related quality of life and sexual functioning. J Clin Oncol 1998;16:501–14.[Abstract]
34 Goodwin JS, Hunt WC, Humble CG, Key CR, Samet JM. Cancer treatment protocols. Who gets chosen? Arch Intern Med 1988;148:2258–60.[Abstract]
35 Kennedy BJ. Age-related clinical trials of CALGB. Cancer Control 1995;2:14–16.[Medline]
36
Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341:2061–7.
37
Crivellari D, Bonetti M, Castiglione-Gertsch M, Gelber RD, Rudenstam CM, Thurlimann B, et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII. J Clin Oncol 2000;18:1412–22.
38 Begg CB, Carbone PP. Clinical trials and drug toxicity in the elderly: the experience of the Eastern Cooperative Oncology Group. Cancer 1983;52:1986–92.[CrossRef][ISI][Medline]
39 Dees EC, O'Reilly S, Goodman SN, Sartorius S, Levine MA, Jones RJ, et al. A prospective pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer. Cancer Invest 2000;18:521–9.[ISI][Medline]
40 Pagani O, O'Neill A, Castiglione M, Gelber RD, Goldhirsch A, Rudenstam CM, et al. Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) Trial VI. Eur J Cancer 1998;34:632–40.
41 Ganz PA, Coscarelli A, Fred C, Kahn B, Polinsky ML, Petersen L. Breast cancer survivors: psychosocial concerns and quality of life. Breast Cancer Res Treat 1996;38:183–99.[CrossRef][ISI][Medline]
42 Meyerowitz BE, Desmond KA, Rowland JH, Wyatt GE, Ganz PA. Sexuality following breast cancer. J Sex Marital Ther 1999;25:237–50.[CrossRef][ISI][Medline]
43 Kreuser ED, Felsenberg D, Behles C, Seibt-Jung H, Mielcarek M, Diehl V, et al. Long-term gonadal dysfunction and its impact on bone mineralization in patients following COPP/ABVD chemotherapy for Hodgkin's disease. Ann Oncol 1992;3 Suppl 4:105–10.
44 Bruning PF, Pit MJ, de Jong-Bakker M, van den Ende A, Hart A, van Enk A. Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer 1990;61:308–10.[ISI][Medline]
45 Park KH, Song CH. Bone mineral density in premenopausal anovulatory women. J Obstet Gynaecol 1995;21:89–97.
46 Howell SJ, Berger G, Adams JE, Shalet SM. Bone mineral density in women with cytotoxic-induced ovarian failure. Clin Endocrinol (Oxf) 1998;49:397–402.[CrossRef][Medline]
47
Burstein HJ, Winer EP. Primary care for survivors of breast cancer. N Engl J Med 2000;343:1086–94.
48 Burstein HJ, Winer EP. Reproductive issues. In: Harris JR, editor. Diseases of the breast. Philadelphia (PA): Lippincott; 2000. p. 1051–9.
49 Stone ER, Slack RS, Novielli A, Ellis M, Baidas S, Gelmann E, et al. Rate of chemotherapy related amenorrhea (CRA) associated with adjuvant adriamycin and cytoxan (AC) and adriamycin and cytoxan followed by taxol (AC+T) in early stage breast cancer [abstract 224]. Breast Cancer Res Treat 2000;64:61.
50 Hortobagyi GN, Buzdar AU, Marcus CE, Smith TL. Immediate and long-term toxicity of adjuvant chemotherapy regimens containing doxorubicin in trials at M. D. Anderson Hospital and Tumor Institute. NCI Monogr 1986;1:105–9.
51 Valagussa P, De Candis D, Antonelli G, Bonadonna G. VIII. Women's health perception and breast cancer: issues of fertility, hormone substitution, and cancer prevention. Recent Results Cancer Res 1996;140:277–83.[Medline]
52 Weber B, Luporsi E. Ovarian toxicity of breast cancer chemotherapy. Eur J Cancer 1998;34 Suppl 5:S42.
53
Goodwin PJ, Ennis M, Pritchard KI, Trudeau M, Hood N. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 1999;17:2365–70.
54 Byrne J, Fears TR, Gail MH, Pee D, Connelly RR, Austin DF, et al. Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 1992;166:788–93.[ISI][Medline]
55
Demark-Wahnefried W, Winer EP, Rimer BK. Why women gain weight with adjuvant chemotherapy for breast cancer. J Clin Oncol 1993;11:1418–29.
56 Demark-Wahnefried W, Rimer BK, Winer EP. Weight gain in women diagnosed with breast cancer. J Am Diet Assoc 1997;97:519–26, 529; quiz 527–8.[CrossRef][ISI][Medline]
57
Goodwin PJ, Ennis M, Pritchard KI, McCready D, Koo J, Sidlofsky S, et al. Adjuvant treatment and onset of menopause predict weight gain after breast cancer diagnosis. J Clin Oncol 1999;17:120–9.
58 Aslani A, Smith RC, Allen BJ, Pavlakis N, Levi JA. Changes in body composition during breast cancer chemotherapy with the CMF-regimen. Breast Cancer Res Treat 1999;57:285–90.[CrossRef][ISI][Medline]
59 Kutynec CL, McCargar L, Barr SI, Hislop TG. Energy balance in women with breast cancer during adjuvant treatment. J Am Diet Assoc 1999;99:1222–7.[CrossRef][ISI][Medline]
60 Donegan WL, Hartz AJ, Rimm AA. The association of body weight with recurrent cancer of the breast. Cancer 1978;41:1590–4.[CrossRef][ISI][Medline]
61 Chlebowski RT, Weiner JM, Reynolds R, Luce J, Bulcavage L, Bateman JR. Long-term survival following relapse after 5-FU but not CMF adjuvant breast cancer therapy. Breast Cancer Res Treat 1986;7:23–30.[CrossRef][ISI][Medline]
62 Camoriano JK, Loprinzi CL, Ingle JN, Therneau TM, Krook JE, Veeder MH. Weight change in women treated with adjuvant therapy or observed following mastectomy for node-positive breast cancer. J Clin Oncol 1990;8:1327–34.[Abstract]
63 Faber-Langendoen K. Weight gain in women receiving adjuvant chemotherapy for breast cancer. JAMA 1996;276:855–6.
64
Demark-Wahnefried W, Hars V, Conaway MR, Havlin K, Rimer BK, McElveen G, et al. Reduced rates of metabolism and decreased physical activity in breast cancer patients receiving adjuvant chemotherapy. Am J Clin Nutr 1997;65:1495–501.
65
Demark-Wahnefried W, Peterson BL, Winer EP, Marks L, Aziz N, Marcom PK, et al. Changes in weight, body composition, and factors influencing energy balance among premenopausal breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2001;19:2381–9.
66
Cheney CL, Mahloch J, Freeny P. Computerized tomography assessment of women with weight changes associated with adjuvant treatment for breast cancer. Am J Clin Nutr 1997;66:141–6.
67 Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710–7.
68
Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998;339:900–5.
69
Valagussa P, Zambetti M, Biasi S, Moliterni A, Zucali R, Bonadonna G. Cardiac effects following adjuvant chemotherapy and breast irradiation in operable breast cancer. Ann Oncol 1994;5:209–16.
70
Zambetti M, Moliterni A, Materazzo C, Stefanelli M, Cipriani S, Valagussa P, et al. Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. J Clin Oncol 2001;19:37–43.
71 Shapiro CL, Hardenbergh PH, Gelman R, Blanks D, Hauptman P, Recht A, et al. Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients. J Clin Oncol 1998;16:3493–501.[Abstract]
72 Curtis RE, Boice JD Jr, Stovall M, Bernstein L, Greenberg RS, Flannery JT, et al. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med 1992;326:1745–51.[Abstract]
73
Pedersen-Bjergaard J. Acute promyelocytic leukemia with t(15;17) following inhibition of DNA topoisomerase II. Ann Oncol 1995;6:751–3.
74
Tallman MS, Gray R, Bennett JM, Variakojis D, Robert N, Wood WC, et al. Leukemogenic potential of adjuvant chemotherapy for early-stage breast cancer: the Eastern Cooperative Oncology Group experience. J Clin Oncol 1995;13:1557–63.
75 Thirman MJ, Larson RA. Therapy-related myeloid leukemia. Hematol Oncol Clin North Am 1996;10:293–320.[CrossRef][ISI][Medline]
76
Fisher B, Anderson S, DeCillis A, Dimitrov N, Atkins JN, Fehrenbacher L, et al. Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 1999;17:3374–88.
77
Diamandidou E, Buzdar AU, Smith TL, Frye D, Witjaksono M, Hortobagyi GN. Treatment-related leukemia in breast cancer patients treated with fluorouracil–doxorubicin–cyclophosphamide combination adjuvant chemotherapy: the University of Texas M. D. Anderson Cancer Center experience. J Clin Oncol 1996;14:2722–30.
78
Valagussa P, Moliterni A, Terenziani M, Zambetti M, Bonadonna G. Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer. Ann Oncol 1994;5:803–8.
79
Chaplain G, Milan C, Sgro C, Carli PM, Bonithon-Kopp C. Increased risk of acute leukemia after adjuvant chemotherapy for breast cancer: a population-based study. J Clin Oncol 2000;18:2836–42.
80
van Dam FS, Schagen SB, Muller MJ, Boogerd W, vd Wall E, Droogleever Fortuyn ME, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 1998;90:210–8.
81 Schagen SB, van Dam FS, Muller MJ, Boogerd W, Lindeboom J, Bruning PF. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999;85:640–50.[CrossRef][ISI][Medline]
82
Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2000;18:2695–701.
83
Ganz PA. Cognitive dysfunction following adjuvant treatment of breast cancer: a new dose-limiting toxic effect? J Natl Cancer Inst 1998;90:182–3.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. P. Winer, J. R. Harris, B. L. Smith, H. A. D'Alessandro, and E. F. Brachtel Case 32-2007 -- A 62-Year-Old Woman with a Second Breast Cancer N. Engl. J. Med., October 18, 2007; 357(16): 1640 - 1648. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||