Download Postchemotherapy arthralgia

Original research
Canadian clinical investigations
Postchemotherapy arthralgia
A single-institution chart review of breast cancer patients
treated with adjuvant chemotherapy
Alison Haynes, BKin; Joy McCarthy, MD, FRCPC; Kara Laing, MD, FRCPC; Stewart Rorke, MD, FRCPC;
Muhammad Zulfiqar, MD, FRCPC; Adnan Zaidi, MD, FRCPC; Michael LeBlanc, BSc Pharm
abstract
Rationale: Many of the immediate effects of chemotherapy are widely known, but the late effects postchemotherapy
have not been extensively described. The purpose of this study was to determine the statistical occurrence of
postchemotherapy arthralgia (PCA) in breast cancer patients in a single institution. The study further attempted to
determine if certain chemotherapy regimes, comorbidities or menopausal status correlate with PCA symptoms.
Methods: This retrospective chart review included all patients from the Dr. H. Bliss Murphy Cancer Centre with
Stage I, II or III breast cancer who received adjuvant chemotherapy during the 2005 calendar year. Information
collected included the incidence of reported PCA and correlating factors.
Results: A total of 56 charts were eligible for the study, with 51 satisfying the inclusion criteria. Of the eligible charts,
18 (35.3%) reported PCA and 33 (64.7%) did not report PCA. Of the charts reporting PCA, 5 cases (27.8%)
were recorded at ≤ 8 weeks postchemotherapy, and 10 (55.5%) between 8 weeks and 16 weeks, inclusive.
The remaining 3 charts (16.7%) reported PCA at ≥ 16 weeks. Within the PCA group, 5 patients (27.8%) were treated
with fluorouracil + epirubicin + cyclophosphamide (FEC100) for a total of 6 cycles. Five patients (27.8%) were
treated with 3 cycles of FEC100 plus 3 cycles of docetaxel. Four cases (22.2%) received 6 cycles of docetaxel
+ doxorubicin + cyclophosphamide (TAC) and 3 (16.7%) were given 4 cycles of doxorubicin + cyclophosphamide
(AC). The remaining patient (5.5%) was treated with dose-dense epirubicin + cyclophosphamide (EC) for 6 cycles
plus 4 cycles of paclitaxel. Of the 18 patients in the PCA group, 10 (55.5%) were premenopausal and 8 (44.5%)
were postmenopausal prior to chemotherapy. Of the 10 premenopausal PCA patients, 6 (60%) were reported as
having become postmenopausal following chemotherapy. Eleven patients (61.1%) in the PCA group were estrogen
and/or progesterone receptor (ER/PR)-positive. Of these positive patients, 7 (63.6%) were treated with tamoxifen
and 4 (36.4%) received an aromatase inhibitor (AI). Seven (38.9%) patients in the PCA group were ER/PR-negative.
Conclusions: Our findings have highlighted that PCA is a common, unpleasant postchemotherapy event for a large
proportion of breast cancer patients. It would be beneficial for physicians to inquire about symptoms of PCA and
document the details in the patient chart. Furthermore, prospective studies should include specific questions such
as character, onset, severity and treatment to help define the typical pattern of PCA. Such information could be
used to diagnose this side effect and potentially help differentiate between PCA and onset of metastatic disease.
Rationale
An estimated 22,300 new cases of breast cancer were diagnosed in Canada in 2007.1 Approximately 5300 women
died of this malignancy, making it the second leading cause
of cancer deaths.1 Current guidelines for the treatment in
Stages I–III breast cancer include adjuvant chemotherapy
for selected patients. These patients often have no diseaserelated signs or symptoms, allowing evaluation and quantification of acute and chronic chemotherapy-induced toxicities
Alison Haynes, BKin is a Doctor of Medicine Candidate at the Faculty of Medicine, Memorial University of Newfoundland; Joy McCarthy,
MD, FRCPC is a medical oncologist at Eastern Health, Director of Clinical Trials at the Dr. H. Bliss Murphy Cancer Centre and Clinical Assistant
Professor at the Faculty of Medicine, Memorial University of Newfoundland; Kara Laing, MD, FRCPC is a medical oncologist and Clinical
Chief of the Cancer Care Program at Eastern Health and Associate Professor at the Faculty of Medicine, Memorial University of Newfoundland;
Michael LeBlanc, MSc Pharm is a Clinical Oncology Pharmacist at Eastern Health; Stewart Rorke, MD, FRCPC, Adnan Zaidi, MD,
FRCPC and Muhammed Zulfiqar, MD, FRCPC are medical oncologists at Eastern Health and Clinical Assistant Professors at the Faculty of
Medicine, Memorial University of Newfoundland.
Address for correspondence: Dr. Joy McCarthy, MD; Dr. H. Bliss Murphy Cancer Centre, 300 Prince Philip Drive, St. John’s NF, A1B 3V6.
Tel: (709) 777-7802; Fax: (709) 709-8756; Email: [email protected]
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ΠVOL. 7, N0. 2, may 2008
©2008 Parkhurst, publisher of Oncology Exchange. All rights reserved.
Original research
— information that is used when considering treatment options
and informing patients of potential risks and side effects.
To date, minimal research has been done to explore the rates
of postchemotherapy arthralgia (PCA) as a chemotherapyinduced toxicity in breast cancer patients. Loprinzi et al2 first
described chemotherapy-induced arthralgia in breast cancer
patients with an examination of 8 case reports describing
what was termed “postchemotherapy rheumatism” in women
who had completed chemotherapy with cyclophosphamide
+ methotrexate + 5-fluorouracil (CMF). Smith3 and Warner
et al4 have documented similar findings in breast cancer
patients, and PCA has also been described in the setting of
other cancer treatments.5-7 Thus, although PCA has been
mentioned in the literature, reports have been limited to a
few cases and have not quantified the occurrence rates.
We conducted a retrospective study to determine the
prevalence of PCA by reviewing the charts of Stage I–III
breast cancer patients who had received adjuvant chemotherapy. We also identified potentially confounding factors
such as menopausal status, estrogen and progesterone
receptor (ER, PR) status and chemotherapy regimen.
Methods
The study was conducted in accordance with the Memorial
University of Newfoundland Human Investigation Committee
for ethical research guidelines. The Newfoundland and
Labrador Cancer Registry at the Dr. H. Bliss Murphy Cancer
Centre (HBMCC) in St. John’s, Newfoundland, was used
to identify all patients with Stage I, II or III breast cancer
who received adjuvant chemotherapy at the HBMCC during
the 2005 calendar year. Inclusion criteria included:
• breast cancer patients with pathologic diagnosis of Stage
I–III disease,
• prescription for adjuvant chemotherapy in 2005 at the
HBMCC, and
• completion of the planned course of chemotherapy.
Exclusion criteria were Stage IV disease or ductal carcinoma
in situ (DCIS), patients not receiving adjuvant chemotherapy,
patients not treated at the HBMCC and patients not completing chemotherapy treatment. All staging was based on
the American Joint Committee on Cancer Staging Manual,
Sixth Edition. Local medical oncologists decided on each
patient’s chemotherapy regimen based on staging, pathologic features, medical comorbidities, and, where appropriate, patient preference (e.g. regarding expected toxicities).
A total of 56 charts were screened for the study, and 51
were eligible under the inclusion criteria.
A retrospective chart review was conducted and reviewed
for relevant clinical data. The following information was
extracted from each chart using a standard recording sheet:
chart number, date of birth, pathologic diagnosis, comorbidities, chemotherapy regimen (type, number of cycles,
start and end dates), ER and PR status, type of hormonal
therapy if ER- and/or PR-positive (ER/PR-positive), prechemotherapy menopausal status, postchemotherapy menopausal status, presence of documented arthralgia (joints
involved, severity and treatment), the timing between completion of chemotherapy and reported arthralgias and prechemotherapy arthritis status (if applicable). Arthralgia was
©2008 Parkhurst, publisher of Oncology Exchange. All rights reserved.
defined as any new or exacerbated joint symptoms such as
pain and stiffness occurring following adjuvant chemotherapy.
Prechemotherapy arthritis was defined as pre-existing diagnosed arthritis and/or arthritic symptoms reported by the
patient to the oncologist and documented in the chart.
Results
During the 2005 calendar year, 56 Stage I, II and III
breast cancer patients received adjuvant chemotherapy at
TABLE 1. Characteristics of patients with and
without postchemotherapy arthralgia (PCA)
Characteristics
PCA
No PCA
number of
number of
patients (%) patients (%)
total
18 (35.3%)
33 (64.7%)
Stage I
1 (5.6%)
9 (27.3%)
Stage IIA
10 (55.5%) 15 (45.5%)
disease stage
Stage IIB
6 (33.3%)
4 (12.1%)
Stage IIIA
0
4 (12.1%)
Stage IIIB
1 (5.6%)
1 (3.0%)
Stage IIIC
0
0
tumour grade
Grade I
0
9 (27.3%)
Grade II
7 (38.9%)
7 (21.2%)
Grade III
11 (61.1%)
17 (51.5%)
prechemotherapy arthritis reported
yes
3 (16.7%)
8 (24.2%)
no 15 (83.3%)
25 (75.8%)
PCA onset
≤ 8 weeks
5 (27.8%)
> 8 weeks, ≤ 16 weeks
10 (55.5%)
≥ 16 weeks
3 (16.7%)
chemotherapy
FEC 100 5 (27.8%)
10 (30.3%)
FEC100–docetaxel 5 (27.8%)
6 (18.2%)
TAC 4 (22.2%)
4 (12.1%)
AC 3 (16.7%)
12 (36.4%)
other
1 (5.5%)
1 (3.0%)
prechemotherapy menopausal status
premenopausal 10 (55.5%)
10 (33.3%)
postmenopausal 8 (44.4%)
22 (66.7%)
males
0
1 (3%)
postchemotherapy menopausal status*
premenopausal 0
3 (30.0%)
postmenopausal 6 (60%)
1 (10%)
not reported
4 (40%)
6 (60%)
hormonal status & treatment
ER/PR-positive
11 (61.1%)
23 (69.7%)
- receiving tamoxifen
7 (63.6)
19 (82.6%)
- receiving an aromatase inhibitor
4 (36.4%)
4 (17.4%)
ER- and PR-negative
7 (38.9%)
10 (30.3%)
* of the patients premenopausal prior to chemotherapy
ΠVOL. 7, N0. 2, may 2008
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Original research
the HBMCC. Five charts were excluded due to failure to
complete chemotherapy in 4 patients and progression to
metastasis in 1. Of the 51 charts that met the inclusion criteria and were eligible for the study, 18 (35.3%) contained
reports of PCA and 33 (64.7%) had no documented reports
of PCA (NPCA). Mean age was 49.4 years in the PCA group
(range 38–62 years) and 52.4 years in the NPCA group
(range 33–70 years). Table 1 (page 25) other lists patient
characteristics. Prechemotherapy arthritis was documented
in 3 of the 18 PCA patients (16.7%), and 15 (83.3%) did
not report arthritis prior to chemotherapy. In the NPCA
group, 8 of the 33 patients (24.2%) had documented arthritis,
while the other 25 (75.8%) did not report arthritic symptoms
as a comorbidity. Of the patients reporting PCA, 5 cases
(27.8%) were reported at ≤ 8 weeks postchemotherapy, and 10
(55.5%) between 8 weeks and 16 weeks, inclusive. The
remaining 3 patients (16.7%) reported PCA at ≥ 16 weeks.
Within the PCA group, 5 patients (27.8%) were treated
with fluorouracil + epirubicin + cyclophosphamide (FEC100)
for a total of 6 cycles; 5 (27.8%) were treated with 3 cycles
of FEC100 plus 3 cycles of docetaxel; 4 (22.2%) received
6 cycles of docetaxel + doxorubicin + cyclophosphamide
(TAC); 3 (16.7%) were given 4 cycles of doxorubicin +
cyclophosphamide (AC) and the remaining patient (5.5%)
was treated with dose-dense epirubicin + cyclophosphamide
(EC) for 6 cycles plus 4 cycles of paclitaxel. Of the patients
in the NPCA group, 10 (30.3%) were treated with 6 cycles
of FEC100; 6 (18.2 %) received 3 cycles of FEC100 plus
3 cycles of docetaxel; 4 (12.1%) in the NPCA group received
TAC; 12 (36.4%) had AC chemotherapy and the remaining
patient (3.0%) was treated with CEF.
Of the 18 patients in the PCA group, 10 (55.5%) were
premenopausal and 8 (44.5%) were postmenopausal prior
to chemotherapy. Of the 10 premenopausal PCA patients,
6 (60%) were reported as having become postmenopausal
following chemotherapy. Four charts (40%) did not document
postchemotherapy menopausal status. Of the 33 patients in
the NPCA group, 10 (30.3%) were premenopausal, 22 (66.7%)
were postmenopausal prior to chemotherapy and 1 was a male
(3%). Of the 10 premenopausal NPCA patients, 3 (30%)
remained premenopausal and 1 (10%) became postmenopausal following chemotherapy. Six charts (60%) did not
document postchemotherapy menopausal status. No formal
definition of menopausal status was used: chart reports
were based on the individual oncologist’s determination of
menopausal status.
Eleven patients (61.1%) in the PCA group were ER/PRpositive. Of these positive patients, 7 (63.6%) were treated
with tamoxifen and 4 (36.4%) received an aromatase inhibitor (AI). Seven (38.9%) patients in the PCA group were
ER- and PR-negative. This compares with 23 (69.7%) ER/
PR-positive and 10 (30.3%) ER/PR-negative NPCA
patients. Among ER/PR-positive NPCA patients, 19
(82.6%) received tamoxifen and the remaining 4 (17.4%)
were treated with an AI.
Discussion
The objective of this investigation was to attempt to quantify the incidence of PCA, and 18 (35.3%) of the 51 charts
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ΠVOL. 7, N0. 2, may 2008
reviewed reported this symptom. Afflicted patients reported
joint stiffness, pain and aches, most commonly occurring
intermittently, and predominantly after inactivity. Often
multiple large and small joints were affected. Furthermore,
symptoms of PCA were reported at various postchemotherapy time intervals. The majority of documented PCA
occurred between 8 and 16 weeks postchemotherapy,
inclusive. Only 3 patients in the PCA group had documented arthritis prior to chemotherapy. As this was a retrospective chart review it was difficult to evaluate how long
patients had experienced PCA. In comparison to the 5%
PCA rate post-CMF reported by Loprinzi et al,2 our results
documented a much higher PCA rate of 35.3%.
The literature describing the rates and characteristics of
PCA is scant. Loprinzi et al’s report2 described 8 patients
who had “postchemotherapy rheumatism” occurring 1–3
months after CMF chemotherapy. The typical pattern of
arthralgia was portrayed as self-limited, migratory arthralgia
with mild periarticular swelling, and characterized by pain
and stiffness exacerbated by inactivity. Smith3 reported a
similar pattern in 8 breast cancer patients. Warner et al4
looked at rheumatic symptoms following adjuvant therapy
in breast cancer patients, through a retrospective review
and telephone interviews, finding that 8 women diagnosed
with breast cancer and no previous rheumatic history developed symptoms of polyarthritis and fibromyalgia following
chemotherapy. Another 15 patients with prior reports of
rheumatic symptoms developed new or exacerbated symptoms
postchemotherapy. Overall, Warner et al concluded that the
patients at highest risk for PCA are those with existing
rheumatic disease and perimenopausal women. Consistently,
findings in the literature (including the current study) show
that the pattern of PCA tends to be arthralgia characterized
by pain and stiffness, exacerbated by lack of activity.
Need for better documentation of PCA
The literature has shown a discrepancy regarding the inflammatory nature of PCA. The majority of previous research has
suggested that PCA-type symptoms are non-inflammatory,2-4
as the physical exam revealed minimal joint inflammation
and patients did not report any relief after nonsteroidal antiinflammatory agents (NSAIDs) and corticosteroid therapy.
However, Kim et al5 chose to classify such symptoms as
chemotherapy-related arthropathy because of findings of
joint inflammation. They also found that their patients had
a good response to NSAIDs — unlike other reports.2-4
Since our study was retrospective, consistent documentation
of treatment was often lacking. Importantly, however, the
charts including this information also mentioned that
NSAIDs provided minimal relief of PCA.
PCA has also been described in the setting of other cancer
treatments.5-7 Kim et al5 described PCA-type symptoms in a
cohort of breast, gastric, lung, colon, cervical, lymphoma,
glioblastoma and bladder cancer patients, suggesting that
PCA could be a postchemotherapy side effect for a variety
of malignancies.
It would be beneficial for physicians to inquire about symptoms of PCA and document the details in the patient chart.
Furthermore, prospective studies should include specific
©2008 Parkhurst, publisher of Oncology Exchange. All rights reserved.
Original research
questions such as character, onset, severity and treatment to
help define the typical pattern of PCA. Such information
could be used to diagnose this side effect, potentially help
differentiate between PCA and onset of metastatic disease,
and optimize strategies for managing symptoms.
Study limitations
The occurrence rate of PCA in this study may be inaccurate
for a number of reasons. Since this was a retrospective chart
review it is possible that not all cases of PCA were documented, thus underestimating the number of patients experiencing PCA. Further, progress notes in the charts varied
depending on when the patient was diagnosed: some charts
included progress notes up to several months postchemotherapy while others included only several weeks. It was difficult to determine whether PCA was transitory or chronic
in nature. Not all variables were consistently recorded in
the medical records. Although this study attempted to
account for major confounding variables, other factors not
considered, including knowledge of concurrently used
medications, could influence the results. Patients may have
self-medicated with over-the-counter medications and
herbal remedies in an attempt to relieve symptoms of PCA,
masking the true number experiencing PCA: subsequent
reviews could document all medications taken by patients.
Another limitation was that this study involved a single
centre during a 1-year time period.
Suggestions for further research
Despite these limitations, however, our data suggest that
PCA is much more common than recognized in previous
studies. More patients with PCA were premenopausal prior
to chemotherapy than in the NPCA group. Similar to other
reports,4,8 within the 10 premenopausal PCA patients, 6
were postmenopausal after completion of chemotherapy
and 4 charts lacked documentation on menopausal status.
Even with this lack of documentation, it can still be concluded that at least 50% of the PCA patients transitioned
into menopause during or after chemotherapy. Studies have
shown that perimenopausal and postmenopausal women
report increased musculoskeletal pain compared to premenopausal women,9,10 which has been attributed to estrogen deprivation during the perimenopause and postmenopause. A review article by Josse11 suggests that estrogen
deprivation impairs pain suppression by the central nervous
system and predisposes patients to microfractures from
bone loss. Previous literature has questioned whether PCA
was in fact a symptom of menopause.8 Future studies could
explore the possibility of chemotherapy-induced menopause as a possible etiology of PCA.
The incidences of arthralgia and musculoskeletal complications induced by AIs and tamoxifen have been well documented in a review by Mackey and Gelmon.12 The review
postulates that the anti-estrogen effect of AIs is likely the
etiology of the arthralgia, which is reported more commonly with AIs11 than with tamoxifen.13 In our study, 4
PCA patients were treated with an AI and 7 with tamoxifen, and in the NPCA group, 4 with an AI and the remaining 19 with tamoxifen. Compliance of patients in taking
©2008 Parkhurst, publisher of Oncology Exchange. All rights reserved.
oral medications was not examined. Reporting of PCA may
have occurred during AI treatment, making it difficult to
determine whether PCA symptoms were related to chemotherapy or the use of an AI. Overall, the extent of the
impact these medications have on PCA is difficult to determine, and further research is required in this area.
The pathology behind PCA is still unknown, which
makes recommendations for effective management and
treatment of symptoms difficult. Mackey and Gelmon12
outline suggestions for clinical management of arthralgia in
women undergoing adjuvant AI therapy. Nonpharmacologic approaches include application of heat, transcutaneous
electrical stimulation, regular exercise, physiotherapy, massage therapy and acupuncture. Relaxation training, biofeedback methods and individual therapy have been proposed
to target the psychologic aspects of pain. Pharmacologic
approaches include oral NSAIDs, topical anti-inflammatory
creams and antidepressants. If these interventions are not
successful, referral to a rheumatologist for further evaluation may be necessary.
conclusion
Consideration of short- and long-term chemotherapy toxicities must be taken into account when treating cancer
patients. Although not life-threatening, PCA can adversely
affect quality of life. Our findings highlight PCA as a common, unpleasant postchemotherapy event for breast cancer
patients. While the pathogenesis remains uncertain, awareness of PCA is important. It would be beneficial if future
adjuvant chemotherapy trials included PCA as part of the
analysis. Characterization of features such as pattern, severity and treatment is required for PCA to become a recognizable entity, and may enable differentiation of PCA from
metastatic disease — subsequently decreasing the number
of unnecessary investigations. Knowledge of PCA as a recognized side effect can prepare patients for its possible
occurrence, ultimately decreasing patient anxiety. n
Œ
Disclosure
The authors report no potential conflicts of interest pertaining to this article.
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