Inaugural bone metastases in non-small cell lung cancer: a specific prognostic entity?

Metastatic lung cancer accounts for approximately 58% of newly diagnosed lung cancer as described by a large french prospective epidemiological study conducted in 2010 [1].

It has been estimated that 30% to 65% of patients with metastatic lung cancer will develop bone metastases [2] and median survival from the time patients develop bone metastasis is classically considered as less than 6 months [3].

However, with the introduction of new therapeutic agents such as antiangiogenic therapies or EGFR inhibitors, especially in adenocarcinoma, median survival for patients with advanced stages has increased from approximately 6 months to 12 months [4] thereby extending their disease course and potentially increasing the risk of subsequent skeletal-related-events (SREs). SREs are defined as pathologic fractures, spinal cord compression, a requirement for radiation or surgery to the bone, and malignant hypercalcemia, leading to significant morbidities or are associated with shortened survival.

Few data are available regarding the prognosis of patients having an inaugural SRE in non small cell lung cancer (NSCLC). Sugiura et al. reported a median survival of 7.2 months from the time patients develop bone metastasis in the disease course [5] and a recent study by Bae et al., assessing pronostic factors for 196 non-small cell lung cancer with bone metastasis at the time of diagnosis, showed that ECOG performans status 0–1 and single metastasis were associated with prolonged survival for these patients with synchronous bone metastasis [6].

Lung cancer patients presenting a SRE at diagnosis are challenging, and require a multidisciplinary therapeutic approach, both systemic and local, on the bone disease. Accurately estimating the survival of these population is also helpful for surgical decision-making [7, 8].

In this study, we retrospectively analysed 55 NSCLC patients revealed by an inaugural SRE. Our first objective was to investigate the influence of bone metastatic involvement on overall survival. Secondary aims were to report epidemiologic characteristics of this population and to assess clinical and biological prognosis factors of survival and progression-free-survival. We also performed an analysis of patients with single bone metastasis.

Inaugural SRE in NSCLC patients remains of pejorative prognosis, with a median survival of 8.5 months and mean survival of 13.4 months. Our study indicate that locally advanced thoracic T-stage, weight loss > 10%, elevated C-reactive protein at diagnosis, and TTF-1 status are independent prognosis factors for survival.

If absence of visceral spreading, and/or solitary bone metastasis appear to be variables associated with longer survival respectively of 12.6 and 14.2 months in univariate analysis, these trend is not meaningful in multivariate analysis.

To our knowledge, one study have focused on skeletal metastases as the primary symptom revealing lung cancer [9], reporting an incidence of bone metastases revealing lung cancer of 2.4% on a population of 1062 patients treated between 1976 and 2001, while we report an incidence of 4.5%. Adenocarcinoma is the first histologic subtype represented in our serie, accounting for 78% of our patients. Kagohashi in 2003 reported an adenocarcinoma rate of 67% on 24 patients with revealing bone metastasis [9].

Incidence of adenocarcinoma is rising on the lasts epidemiologic reports -accounting for more than 45% of the newly diagnosed cases - and has become the first histology in women, independently of the smoking status [10, 11]. It has a tropism for bone dissemination: metastatic spreading in lung cancer differs according to histologic subtype and 45% of patients having adenocarcinoma are metastatic to bone [12]. Interestingly, most of our patients present small primary tumor (Tx-T1-T2 accounts for 71% of patients), with node involvement cN0-N1 showing that bone metastases are more related to early spreading in the bone than to primary tumour volume.

Revealing bone site is mainly located on axial skeleton (70%). Our findings are comparable to previous observations, where 70% of symptomatic lesions are located in thoracic vertebra, 20% in lumbar vertebra and only 10% in the cervical spine [13, 14].

Our reported cumulative survival rates at 6 months, 1 and 2 years are very closed to those reported by Sugiura [5] assessing prognostic factors in a serie of 118 patients with bone metastases from lung cancer (59.9% at 6 months, 31.6% at 1 year, and 11.3% at 2 years) and a median survival of 7.2 months.

It has been described how the incidence of SRE in the disease course of NSCLC patients strongly affects survival. In a study of Tsuya et al. [14] on 135 patients with stage IV NSCLC, median survival for the patients experimenting a SRE was 6 months versus 1 year, although not significant, and median survival after SRE was 4.5 months. In the medico-economic study by Delea [15] conducted on 534 patients of whom 55% had experienced a SRE, median survival after the first SRE was 4.1 months.

In surgical series focusing on skeletal metastases in lung cancer, Weiss et al. report a median survival time after surgery of 3 months, and a cumulative 12-months survival after surgery of 13% [7]. Nathan et al. found that in patients with various histologic types of bone metastases, lung cancer patients had the shortest median survival time of 4 months [8]. These surgical series illustrate the major difficulty in selecting NSCLC patients who are likely to benefit from heavy surgical procedures. In attempting to accurately assess the survival expectancy of bone metastatatic patients, orthopaedic surgeons have established a scoring system for the preoperative evaluation of skeletal metastasis [16, 17]. Katagiri et al. reported five prognostic factors discriminant for survival, namely, site of primary lesion, performans status, presence of visceral or cerebral metastasis and multiple skeletal metastases [16]. Forsberg has recently developed and validated BETS models (Bayesan Estimated Tools for Survival at 3 months and 12-months) including data such as hemoglobin concentration, preoperative absolute lymphocyte count, ECOG performans status, presence of a complete pathologic fracture, number of bone metastases and primary oncologic diagnosis [17].

Regarding surgical outcomes, we showed that inaugural spinal epidural metastasis (SEM) strongly impact outcome, with a median survival of 3 months for the nine patients who suffered from SEM, as Schiff et al. who reported a median survival of 2.75 months after laminectomy for inaugural SEM [18].

We also confirmed some biological parameters already known to be predictive of pejorative survival, such as hemoglobin rate, neutrophil and white blood cell count [19, 20], whereas lymphocytopenia was not statistically significant. Moreover, we found that pretherapeutic C-reactive protein level below 7 mg/L was strongly correlated with survival in multivariate analysis. In a study conducted by Wilop on 210 patients with NSCLC stage IV, evolution of CRP allowed to identify two subgroups of patients with significant differences in survival (18,8 vs 7,5 months) [21].

Another relevant histological marker is the thyroid transcription factor-1 (TTF-1). The meta-analysis by Berghmans et al. showed that TTF-1 positivity was associated with a statistically significant longer survival in NSCLC: combined HR of eight studies was 0,64 and 0.53 in the adenocarcinoma subgroup [22]. We also found this impact of TTF-1 positivity both in univariate and multivariate analysis, with a MS of 15.4 months versus 6.45 months for negative TTF-1 patients (HR = 0.54), and believe that TTF-1 status is a reliable marker for survival.

Hypercalcemia is also a well-known adverse pronostic factor confirmed by our univariate analysis: median survival is 11.2 months vs 5 months for hypercalcemic patients (HR = 2.38; CI95% 0.96-5.88, p ≤ 0.008). In advanced stage, reported rates of hypercalcemia are of 12,5-35% [23], and 22% in the present study.

Indeed, if none of our patients experimented inaugural malignant hypercalcemia, preventing hypercalcemia during the disease course and incidence of second SRE is a major concern in this population.

Despite their inaugural revealing SRE, only 60% of our patients received biphosphonates. In previous phase III study, Rosen et al. demonstrated the long-term efficacy of zoledronic acid in preventing SRE in patients bearing skeletal metastasis [24]. Moreover, Hirsh et al. suggested that patients who had already experienced a SRE were at higher risk for subsequent SREs than patients with skeletal involvement without SRE. This over-risk was based on the SRE history of patients from Rosen’s phase III study evaluating zoledronic acid where this biphosphonate reduced the risk of SREs by 31%, prolonging the median time to first SRE by nearly 4 months [25]. In our study, 37% of the patients experienced a second SRE. Bae et al. reported a very closed rate of 33% second SRE in the population of 86 patients with first inaugural SRE [6] and a prescription rate of biphosphonates of 4.5%.

Administration of biphosphonates is here associated with an increased survival in univariate analysis- but not in multivariate analysis- with a median survival of 15.4 versus 5.2 months (HR = 0.4, CI95% 0.2-0.79; p = 0.001). Previous studies already showed a survival advantage of nearly 6 months for patients who had been treated with biphosphonates [26, 27].

More recently, Denosumab, a human monoclonal antibody against RANKL, confirmed its superiority over zoledronid acid giving an overall survival improvement in a population of 811 NSCLC patients with bone metastases [28, 29]. In conclusion, biphosphonates or denosumab should be early administrated in the course of the disease for these patients who were shown to be at higher risk of developing subsequent skeletal-related-event.

Finally, although the prognosis in NSCLC patients with inaugural SRE remains poor, respectively seven and two of the 55 patients ( 12,7% and 3.6%) are alive at 2 and 5 years. Case reports of long NSCLC survivors at 5 years with sole bone metastasis were reported with bone locations on distal extremities [30]. Bae et al. reported that patients with single bone metastasis had a survival 2.4 times longer than others [6].

A study by Okamoto [31] analysing predictive factor of long survival in stage IV non small cell lung cancer, found that multimodal treatment including a locoregional treatment like surgery, and early nodal status were significantly associated with longer survival. A long term improvement survival at 5 years can be achieved for patients after surgical resection of solitary metastases in brain or adrenal gland of non-small cell lung cancer [32]. We believe that an accurate early staging by PET-TDM and full body RMN may allow to better select oligometastatic patients in order to shift them to more aggressive therapy. Selected patients with single bone metastasis could benefit from a combination of surgical lung resection on the primitive tumor and intensified treatment on the skeletal metastasis, such as surgery and/or hypofractionated stereotactic body radiation therapy with dose escalation in a curative intent [33, 34].

Despite its shortscomings, this retrospective study represents one of the largest follow-up of patients with an inaugural SRE revealing non-small lung cancer. Few patients with single bone metastasis and no visceral dissemination were able to achieve survival up to 5 years. In multivariate analysis, variables significantly associated with shorter overall survival are locally advanced T stage, weight loss ≥ 10%, inaugural spinal epidural metastasis, elevated C-reactive protein and negative TTF-1 status. Thus, a better selection of oligometastatic NSCLC patients likely to require or benefit from surgical procedure on inaugural skeletal metastasis can be made.