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TOP - February 2016, Vol 9, No 1 - Conference Correspondent

Pain Syndrome After Stopping Treatment with Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), and dramatically improved survival for these patients. Many patients with CML treated with a TKI have deep, sustained remissions. Clinical trials have shown that some good responders can safely stop TKI treatment without remission. It has, however, become evident that about 1 in 4 patients who stop treatment with a TKI experience musculoskeletal pain (ie, TKI withdrawal syndrome [WS]).

A study reported at the recent American Society of Hematology (ASH) annual meeting found that patients were more likely to develop TKI WS if they had a medical history of arthritis or joint pain, as well as longer duration of TKI treatment.

"These results suggest that patients and physicians should be aware of the potential for TKI WS and risk factors, and recommendations should be proposed for patients who require long-term treatment who have a history of arthritis," said lead author Marc G. Berger, MD, Centre Hospitalier Universitaire de Clermont-Ferrand, France.

Dr Berger and colleagues analyzed the TKI WS in a cohort of 428 patients drawn from 2 clinical trials: STIM2 (n = 204) and EURO-SKI (n = 224). Almost half were men, and median age was 77.5 years. Of these patients, 41.6% were low risk, 41.9% intermediate risk, and 16.5% high risk. TKI WS was reported in 102 (23.8%; 100 after imatinib and 2 after nilotinib) patients.

TKI WS was characterized by bone and joint pain affecting the upper limbs, shoulders, and cervical area. Although most symptoms were grade 1 or 2, 22% of these patients had grade 3 symptom severity.

Nonsteroidal anti-inflammatories, corticosteroids, or local infiltration treatments were prescribed. Median duration of TKI WS was 7 months (range, 3-30 months).

The researchers sought to identify characteristics that could predict the occurrence of TKI WS. No differences in age, sex, risk score, breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog transcript, or duration of CML were observed between patients who developed the syndrome and those who did not.

Duration of TKI therapy appeared to be a median of 8 months longer in patients who developed TKI WS. No biologic inflammatory syndrome was present, and imaging results did not discriminate between the 2 groups. However, it appeared that a medical history of joint pain or arthritis put patients at risk for TKI WS (22.9% in the WS group vs 9.8% in controls; P = .002).

A multivariate analysis confirmed the significance of a medical history of joint pain and duration of TKI treatment as risk factors for the syndrome.

Among 19 patients who had developed TKI WS and experienced a CML relapse requiring further TKI treatment, 7 (36.8%) patients had pain disappearance within a median of 3.5 weeks.


Berger MG, Pereira B, Oris C, et al. Osteoarticular pain after discontinuation of tyrosine kinase inhibitors (TKI): a French cohort. Presented at: American Society of Hematology 2015 Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL. Abstract 137.

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DCIS: Anastrozole or Tamoxifen?

The use of hormonal therapy to prevent breast cancer recurrence has been well-studied in women diagnosed with invasive breast cancer, but the most benign form of breast cancer–ductal carcinoma in situ (DCIS)–has been less well-studied in this regard. Two large studies reported at the 2015 San Antonio Breast Cancer Symposium (SABCS) add to our knowledge base about the use of the aromatase inhibitor anastrozole versus tamoxifen in postmenopausal women with DCIS.

The large, randomized, double-blind, placebo-controlled IBIS-II trial compared tamoxifen versus anastrozole in 2980 postmenopausal women with DCIS. The key finding was that there was no significant difference between these 2 hormonal therapies in preventing breast cancer recurrence at a median follow-up of 7.2 years. The study did show expected adverse effect profile differences between these 2 agents.

Anastrozole and tamoxifen had a similar effect on preventing recurrence in postmenopausal women with DCIS. The rate of recurrence for all breast cancers (including invasive and DCIS) was 7.4% for tamoxifen versus 6.6% for anastrozole at a median follow-up of 7.2 years, representing 11% fewer recurrences with anastrozole. There were 67 cancers reported in the anastrozole group versus 77 in the tamoxifen group; the difference was not statistically significant. In an exploratory, post hoc subgroup analysis of the rate of invasive breast cancers only, it appeared that tamoxifen was superior for estrogen-receptor–positive/human epidermal growth factor 2–positive (ER+/HER2+) DCIS, whereas anastrozole seemed to have a better effect on HER2-negative (HER2–) and ER+/HER2– cancers. However, these findings are suggestive only and do not carry much weight.

"The differences in efficacy were small. There is no clear difference between these agents in efficacy, but there were significant differences in toxicity profiles," said lead author Jack Cuzick, MD, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, United Kingdom.

The rates of fracture and joint-related symptoms were higher with anastrozole, and more vasomotor and more gynecologic symptoms (except vaginal dryness) were observed with tamoxifen.

More gynecologic cancers were found in the tamoxifen group (17; 11 endometrial, 5 ovarian) compared with 1 gynecologic cancer (endometrial) in the anastrozole group. Also, there were 23 skin cancers in the tamoxifen group compared with 12 in the anastrozole group. The difference in skin cancer was driven by nonmelanoma cancers (19 with tamoxifen vs 8 with anastrozole). Other cancers reported at slightly higher rates in the anastrozole group included gastrointestinal, lung, lymphoma/leukemia, and "other," but these differences were not significant.

The fracture rate was higher in the anastrozole group, with 129 fractures compared with 100 in the tamoxifen group. Major thromboembolic events were reported more frequently with tamoxifen: 24 versus 7 with anastrozole. These included pulmonary embolism, 8 with tamoxifen and 5 with anastrozole, and deep vein thrombosis (without pulmonary embolism) in 16 and 2 patients, respectively.

A new finding that has not been reported elsewhere was an increase in stroke and transient ischemic attack in the anastrozole-treated group: 13 strokes compared with 4 in the tamoxifen group, and 13 transient ischemic attacks compared with 5 in the tamoxifen group. Dr Cuzick believes this is an anomaly that deserves further study.


Cuzick J, Forbes JF, Sestak I, et al. Anastrozole versus tamoxifen for the prevention of loco-regional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in-situ (IBIS-II DCIS). Presented at: 2015 San Antonio Breast Cancer Symposium; December 5-8, 2015; San Antonio, TX. Abstract S6-03.

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Dexamethasone Prevents Radiation Pain

Palliative radiotherapy is often used to treat bone metastases, which commonly occur in progressing prostate, breast, and lung cancers. About one-third of patients with bone metastasis treated with radiotherapy experience severe, debilitating pain flare, which typically resolves within 10 days.

Dexamethasone, given preemptively 1 hour before radiation and every day for 4 days afterward (5 doses total), reduces the incidence and severity of pain flare, according to a study presented at the 2015 annual American Society of Radiation Oncology (ASTRO) meeting.

"Pain flare should no longer be considered a barrier to radiation of bone metastasis. Dexamethasone, an inexpensive treatment, can help avoid debilitating pain due to radiation therapy and should now be recommended as standard of care for all patients receiving radiotherapy for bone metastases," stated study coauthor Alysa Fairchild, MD, of the Cross Cancer Institute, University of Alberta, Edmonton, Canada.

The study included 298 patients with 1 or 2 bone metastases. On day 1 of radiotherapy, participants were randomized to receive oral dexamethasone 8 mg or placebo for 5 days. Radiotherapy was given at 8 Gy in 1 fraction directed at the bone metastasis. Patients completed a pain diary from days 1 to 10, and were followed up on day 42.

Pain flare (defined as a 2-point increase in patient-rated worst pain with no decrease in analgesic use or a ≥25% increase in analgesic intake and no decrease in worst pain days 1-10) was reported in 17.6% of patients in the dexamethasone arm versus 29.3% in the placebo arm. Pain flare that did occur was less severe in the patients treated with dexamethasone.

During days 6 to 10 of pain flare, median increase in pain score was 2.5/10 for the dexamethasone arm versus 4/10 for the placebo arm. At the end of the study (day 10), patients who received dexamethasone had significantly less nausea, vomiting, and functional interference compared with placebo.

Commenting on this study, radiologist Brian D. Kavanagh, MD, of the University of Colorado Anschutz Medical Campus, Denver, said, "It is better to prevent the problem of pain flare than to play catch up with pain medications down the road. This study showed that a few doses of an inexpensive, oral, well-tolerated medication can reduce the incidence of pain flare as well as severity, and should change the standard of care."


Chow E, Meyer R, Ding K, et al. Dexamethasone vs placebo in the prophylaxis of radiation-induced pain flare following palliative radiation therapy for bone metastases: a double-blind randomized, controlled, superiority trial. Presented at: 2015 Annual Meeting of the American Society for Radiation Oncology; October 18-21, 2015; San Antonio, TX. Abstract LBA1.

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Counseling Reduces Anxiety Related to Genetic Screening

Now that comprehensive genetic screening for a variety of breast cancer–related genes (multiplex screening) is available, many patients with breast cancer who are BRCA-negative but have a family history of breast or ovarian cancer choose to have multiplex testing to determine their level of increased cancer risk. Counseling with a certified genetic counselor before and after multiplex testing is helpful in improving patients' knowledge and decreasing their anxiety, a study presented at the 2015 SABCS finds.

"Although comprehensive genetic testing is becoming more widely available, the potential for benefits and risks for patients is unknown. This new study shows that when providing patients with counseling before and after testing, most report an increase in knowledge as well as decreased anxiety and uncertainty after learning their test results," said lead author Angela R. Bradbury, MD, of the University of Pennsylvania, Abramson Cancer Center, Philadelphia.

Of 166 women with a personal or family history of breast or ovarian cancer who tested negative for the BRCA1 and BRCA2 genes and completed pretest counseling, 155 decided to undergo comprehensive genetic testing. Data are available on 137 women who received their test results. For 78 (57%) patients, there were no positive findings (no cancer-related genetic mutations were found). Fifteen (11%) patients were positive for known cancer-causing genes, and 44 (32%) had variants of uncertain significance (VUS).

Patients were tested for knowledge and anxiety levels before and after the genetic test, and, in general, they experienced improvements in knowledge and decreases in anxiety as a result of genetic counseling. For example, after pre- and posttest counseling, general anxiety dropped 5%, general knowledge increased by 67.1%, and knowledge of benefits and limitations of testing also increased. Although the perceived utility of test results declined by 17.8%, there was much less of a decline among carriers of cancer-causing genes. No increase in uncertainty of knowledge was reported among women whose test results were VUS.

Medical management changed for only 5 (34%) carriers as a result of multiplex findings, and remained unchanged in 10 (66%). Medical management was changed in only 4% of all 137 women who received test results. The authors of the study note that the patient's experience may vary according to the results they receive. If they test positive for any cancer-causing genes, they may have more short-term anxiety. The authors suggest that this may be a result of the limited amount of information available on some of the genetic mutations that the multiplex test identifies.

The study also suggested that women were more likely to want in-person counseling than telephone consultations.


Bradbury AR, Patrick-Miller L, Egleston BE, et al. Patient reported outcomes of multiplex breast cancer susceptibility testing utilizing a tiered-binned counseling and informed consent model in BRCA1/2 negative patients. Presented at: 2015 San Antonio Breast Cancer Symposium; December 5-8, 2015; San Antonio, TX. Abstract P2-09-01.

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Patient-Reported Outcomes for Anastrozole and Tamoxifen in DCIS

A secondary analysis of quality of life (QOL) in the NSABP B-35 trial focused on patient-reported outcomes in a subgroup of 1193 postmenopausal women with ductal carcinoma in situ treated with tamoxifen versus anastrozole. Evidence from this analysis suggests that either hormonal agent is a good treatment option for preventing breast cancer recurrence, although anastrozole appeared to be slightly better for younger women (ie, aged <60 years).

Lead author Patricia Ganz, MD, Distinguished Professor at the University of California, Los Angeles Jonsson Comprehensive Cancer Center, said that in the entire study population, there was no overall survival difference between the 2 treatments, and both drugs were equally well-tolerated, with no significant differences in physical or mental health-related QOL.

There were, as expected, differences in adverse effect profiles. Tamoxifen significantly increased the severity of vasomotor, bladder control, and gynecologic symptoms compared with anastrozole. Patients treated with anastrozole had significantly increased severity of musculoskeletal and vaginal symptoms compared with those receiving tamoxifen.

The investigators found age-related differences with regard to adverse effects. In general, younger women had more frequent and severe vasomotor and sexual symptoms compared with those aged ≥60 years.

Dr Ganz said that these differences in QOL can inform treatment selection. Specifically, younger women (younger than age 60 years) seem to have fewer disturbing adverse effects if they start treatment with anastrozole, and tamoxifen seems to be a better choice for women aged >60 years.

She gave 2 examples of how to choose between the 2 drugs: "In a lean, 65-year-old woman with osteoporosis and a hysterectomy, I would be concerned about osteoporosis progression on an aromatase inhibitor, so since this woman is at low risk for cardiovascular events and not at risk for uterine cancer, tamoxifen would be a better choice."

"By contrast, for a younger woman with frequent hot flashes, I would stay away from tamoxifen, and, if her bones are healthy, I wouldn't worry about her taking an aromatase inhibitor. On the other hand, if she developed severe joint aches and pains and pain with sexual intercourse, then going on tamoxifen is a good choice, and we can use topical estrogen to help vaginal dryness if she is on tamoxifen, but not if she is taking an aromatase inhibitor," Dr Ganz said.


Ganz PA, Cecchini RS, Julian TB, et al. Patient-reported outcome (PRO) results, NRG Oncology/NSABP B-35: a clinical trial of anastrozole (A) vs tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. Presented at: 2015 San Antonio Breast Cancer Symposium; December 5-8, 2015; San Antonio, TX. Abstract S6-04

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Last modified: July 11, 2023