Rapid pain relief treatment options in patients with NSCLC: results of a phase II study on loading dose ibandronate and a systematic review
Oncology, infection and vascular disease (English)Up to 80% of the non-small cell lung cancer (NSCLC) patients experience cancer induced bone pain (CIBP). Scarce data is available about the severity of CIBP in lung cancer patients. In 20% of these patients Quality of Life (QoL) worsens after a diagnosis of bone metastases, and bone metastases are associated with lower overall survival (OS). Due to the high incidence, chronic character and negative impact on QoL and OS, CIBP is an important issue that needs to be addressed in metastatic NSCLC.
We performed an open-label, multi-center single arm phase II study, including NSCLC patients with uncontrolled CIBP (brief pain inventory (BPI) ≥ five over last seven days). Patients were only eligible if they did not start any anticancer therapy (either systemic therapy and/or bone radiotherapy) within the four weeks before study entry. Six milligram ibandronate was given intravenously on day 1-3. The primary endpoint was bone pain response. Pain response was defined as a 25% decrease in worst pain score over day five-seven compared to pain score at baseline as determined by the “worst pain scale” of the BPI, with no more than a 25% increase in mean analgesic consumption over the same three-day period compared to baseline analgesic consumption.A Simon’s Optimal 2-stage design was used. Nineteen patients were enrolled in the first phase of the study, 18 were evaluable for response. Eighteen patients completed ibandronate treatment according protocol. Two patients experienced ≥grade 2 hypophosphatemia, which was possibly treatment related. In four patients (22.2%), a pain response was observed. According to the stopping rule, further enrollment was discontinued. The patient demographics and response evaluation are shown in Table 1. In conclusion, loading doses of ibandronate lead to insufficient rapid pain relief in NSCLC patients with CIBP.
Additionally, we performed a systematic review on treatment options for rapid pain relief in bone metastasized NSCLC patients. We excluded radio-isotopes and radiotherapy as rapid pain relief treatment option. Radio-isotopes were excluded because of limited data in NSCLC, relatively short duration of action and the chance of bone marrow suppression when radio-isotopes are used in combination with chemotherapy. Radiotherapy was excluded as it cannot be administered to patients with multiple painful bone metastases, furthermore it takes up to six weeks for the onset of an analgesic effect. A systematic search of the literature published between 1994 and September 2018 was performed using PubMed, the Cochrane Library and the ClinicalTrials.gov database. Published studies were identified using a search strategy based on the PICO method. To include single arm trials, the control intervention was not included in the search strategy. We included five studies (one phase II trial, four other prospective trials in which the phase was not mentioned) in this systematic review. In total 301 NSCLC patients were included. Only in the trial van Gangi et al. patients received pain modifying therapy alone, in all other trials other anticancer treatment (mainly chemotherapy) was given. The study of Gangi et al. had pain score as primary objective, three other studies assessed bone pain or change in BPI as secondary objectives (Francini et al., Yoh et al.,and Zarogoulidis et al.). The main characteristics of the included studies are shown in Table 2. The method of pain score differed between the studies. Pain was measured directly by means of the BPI in Yoh et al. and Zarogoulidis et al., whereas in two other studies (Gangi et al. and Davidov et al.) the pain was measured indirectly with the use of analgesics. The single-arm study of Yoh et al. was the only study which found a significant effect of treatment on pain score. They showed that treatment of both chemotherapy and zoledronic acid reduced pain score at six weeks compared to baseline. Francini et al. assessed the effect on pain of zoledronic acid versus ibandronate acid (both in combination with systemic therapy). They showed a rapid pain reduction at one month of zoledronic acid in favor of alendronic acid, but this pain reduction disappeared at three months despite continuous bone targeted agent use.
Regardless of the frequent occurrence of CIBP combined with the negative effects on QoL and OS, studies evaluating treatment modalities to rapidly reduce CIBP are lacking. Our systematic review shows that there is no high-level evidence to recommend a specific treatment for rapid pain relief. We found that recommendations to use most of the treatment options for rapid bone pain relief in NSCLC are based on low-level evidence, or are validated in other patient populations. Therefore, randomized trials evaluating treatment options with rapid pain relief for CIBP are necessary in lung cancer patients.
Patient demographics and response evaluation.
Main characteristics of included studies.