An Exploratory Study Of Second-line Treatment For Bone Metastatic In Breast Cancer With A Loading Dose Of Ibandronate

PurposeIn the first partwe evaluate the efficacy, life quality benefits, safety in patients after second-line treatment for refractory breast cancer metastatic bone pain with a loading dose of ibandronate. In the second part,we evaluate the changes in bone metabolism markers(serum bone alkaline phosphatase, tartrate-resistant acid phosphatase and cross-linked carboxy-terminal telopeptide of type I collagen)of breast cancer patients with bone metastases after treatment with a loading dose of ibandronate, so as to understand their relevance and efficacy in the appraisal of bone metabolism markers in clinical evaluation. MethodsIn the first part, a prospective,non-randomized observational study was conducted from January 2010 to April 2014 among 130 cases of breast cancer patients with bone metastases were admitted to our department whose primary foci and metastasis were stable after first-line treatment with pamidronate or zoledronic acid but did not achieve satisfactory pain relief or had increased pain. They were treated with second-line treatment at the first dose loading-dose of ibandronate(injection administration of 6 mg per injection, for 3 consecutive days, followed by repeated administration every 3-4 weeks) meanwhile currently available treatments remained unchanged. A series of entities were observed for these patients before and after treatment such as, pain score, analgesic consumption, Karnofsky performance status(KPS) score, effective analgesic time, holding time. Meanwhile, their blood biochemical indices and safety were documented.In the second part, a prospective, non-randomized observational study was conducted 80 cases who were admitted to our department according to the criteria of the first part. A a series of factors were observed in 80 patients before and after treatment, such as pain score, analgesic consumption, Karnofsky performance status(KPS) score, and changes in bone metabolism markers(serum bone alkaline phosphatase, tartrate-resistant acid phosphatase and cross-linked carboxy-terminal telopeptide of type I collagen). Data on blood biochemical indices and safety related information including renal and liver function were documented. Result1、A total of 126 patients were included. The pain score was 6.05±1.44 points before ibandronate treatment; while this reduced to 3.78±1.55, 2.89±1.67 and 2.61±1.66 in the 7th, 14 th and 21 th days after treatment, respectively. These patients showed a significantly reduced pain scores(P < 0.001). Before treatment, mean daily oxycodone dosage was 60.48±19.67 mg, which decreased to 36.11±20.28 mg, 25.65±19.56 mg and 22.46±18.71 mg in the 7th, 14 th and 21 th days, respectively. These patients showed a significantly reduced daily oxycodone dosage(P < 0.001). Prior to treatment, the mean patient’s KPS score was 81.59±8.14, while after treatment scores were 87.78±7.79, 91.51±6.94 and 92.54±7.04 in the 7th, 14 th and 21 th days, respectively, with post-treatment scores being significantly increased compared to pre-treatment(P < 0.001). Among them, 89 cases had effectively alleviated bone pain and the remission rate was 70.6%. The effective analgesic time of patients with middle pain was significantly shorter than patients with severe pain(P< 0.05). The effective rate of pain relief for middle bone pain and severe bone pain was 73.2% and 67.3% respectively which difference was not significant(P=0.09). In subgroup analysis, the efficacy of loading-dose was not related to menstruation condition and the metastasis sites however the efficacy was higher for younger patients, hormone receptor negative and patients with combined treatment however the difference was not significant. Besides, few adverse drug reactions including asymptomatic decrease of serum calcium, muscle soreness and fever, no obvious renal or liver toxicity were observed among the 126 patients.2、A total of 62 patients were included in the final analysis. One week before treatment the mean BAP level was 35.27±29.27 μg/L, and were 29.27±24.01 μg/L, 24.12±17.63 μg/L in the 3rd and 6th weeks after treatment, respectively. The mean TRACP-5b level measured 10.23±6.90 U/L, followed by 6.57±4.32 U/L and 5.98±4.67 U/L in the 3rd and 6th weeks, respectively. The pre-treatment mean ICTP level in patients was 13.04±7.79 μg/L, and in the 3rd and 6th weeks was 9.61±6.30 μg/L and 7.95±5.16 μg/L respectively. Compared to the level before treatment, the mean level of BAP, TRACP-5b and ICTP levels in the subsequent 3rd and 6th weeks all decreased significantly(P <0.001). The pain score was 5.82±1.47 points before ibandronate treatment; while this reduced to 2.58±1.54 and 2.60±1.75 in the 3rd and 6th weeks after treatment, respectively. Before treatment, mean daily oxycodone dosage was 57.10±19.45 mg, which decreased to 10.16±16.55 mg and 19.68 in the 3rd and 6th weeks after treatment, respectively. Prior to treatment, the mean patient’s KPS score was 81.13±9.25, while after treatment scores were 92.26±6.88 and 93.06±7.15 in the 3rd and 6th weeks, respectively. Compared with scores pre-treatment, patients showed significantly increased KPS scores(P < 0.001), and reduced pain scores and administration dose of analgesic drug(oxycodone)(P < 0.001) in the 3rd and 6th weeks. Other than a few adverse reactions including asymptomatic decrease of serum calcium, muscle soreness and fever, no obvious renal or liver toxicity was observed among the 62 patients. Conclusion1. The second-line treatment for breast cancer metastatic bone pain with a loading dose of ibandronate can improve the life quality and reduce the amount of analgesic drugs which was effective and well tolerated. For patients who had first-line treatment with bisphosphonates, e.g. pamidronate, zoledronic acid and so on, but still suffer less-relieved pain, increased pain or aggravating bone destruction, loading dose of ibandronate is a good choice for second-line treatment.2. The serum level of bone metabolism markers(BAP, TRACP-5b and ICTP) decreased by varying degrees after treatment with a loading dose of ibandronate. Compared to the value before treatment, the differences were statistically significant indicating relevance with the clinical effect of medical treatment for bone metastasis. As a result, they can be used as reference index for curative effect evaluation of bisphosphonates.