Management of Bone Metastases
General approaches and treatment considerations for patients with bone metastases from lung cancer
|
|
|
XGEVA (Denosumab) for Lung Cancer: Survival Benefit Suggested by Retrospective Subset Analysis of Key Trial
Late last year, I reviewed the approval of the agent XGEVA (denosumab) for patients with skeletal metastases from solid tumors after a randomized phase III trial demonstrated a significant reduction in the rate of development of skeletal-related events compared with the pre-existing standard of Zometa (zoledronic acid) for bone metastases. Importantly, there was no difference in overall survival in the trial as a whole, which included patients with multiple myeloma or solid tumors other than breast cancer and prostate cancer (which were each studied in separate trials). A few months later, the publication of the phase III trial came out, and I actually wrote the accompanying editorial, in which I argued that while the results showing improvement in the endpoint of skeletal-related events, no improvement in survival, marginally better side effect profile, but considerably higher cost made XGEVA a very compelling option but not necessarily an iron-clad unchallanged standard of care when the cost vs. benefit of the agent over Zometa is taken into consideration.
Though I suggested that the results were provocative but not overwhelming from the bird’s eye view, I raised the point that if overall survival (OS) were to be improved in a subset of patients, the argument favoring XGEVA would be more compelling, as was noted in a very limited way for patients with NSCLC in the randomized trial:
It is therefore notable that, in a post hoc analysis of OS in the Henry et al11 trial, the HR for NSCLC was statistically superior with denosumab for patients with advanced NSCLC.
Among the many interesting presentations from the World Conference on Lung Cancer in Amsterdam was one by Dr. Giorgio Scagliotti that provides far more detail on the post hoc (retrospective) analysis of patients with lung cancer from this trial. Dr. Weiss provided a summary of the presentation in his great review of that day, but here I’ll provide a little more information (primarily just the “picture’s worth a thousand words” synopsis).
The overall trial enrolled 1776 patients with a range of cancer types, of which 40% had NSCLC and 9% had SCLC: this large subset of 811 patients with lung cancer served as the basis for this presentation. Looking at the entire group with lung cancer, there was a statistically significant 20% improvement in OS that translated to a 1.2 month prolongation in median OS, as illustrated in the figure below:
(click on image to enlarge)
Surgery for Bone Metastases? When, Why, and How?
When is surgery necessary or just particularly helpful for bone metastases? There are situations in which invasive approaches may be appropriate for the long bones (of the arms and legs). First, surgery can be helpful for persistent or increasing pain despite completing palliative radiation therapy. It is also an attractive option for a single well-defined lytic cancer lesion (a tumor that destroys bone, in contrast to a blastic bone lesion that creates extra bone but chaotically, so it is still structurally unstable) that is involving more than 50% of the strong outer cortex of a bone. Surgery is also indicated for involvement of the upper (or proximal) femur, the thigh bone, that involves a fracture of the part of the femur that is part of the hip joint, or if there is diffuse involvement of metastatic disease in a long bone. Surgery can provide structural stability to avoid a serious fracture and extended disability, and also provide pain relief at the same time. The stabilizing surgery involves a lot of hardware, and the surgery is similar to a sterile version of working in a machinist’s shop (at least that was my impression when I had my limited role in med school surgical rotation).
However, surgery would not be recommended for patients who are so debilitated that the time for recovery would be expected to include most of their expected survival (weeks), or for patients who are so debilitated that a rigorous surgery would be more dangerous than their body can handle and would likely cause more harm than good.
For compression fractures of a spinal verterbra, which can be weakened by cancer as well as garden variety osteoporosis, there are also minimally invasive procedures known as vertebroplasty or kyphoplasty that can be performed by specialist orthopedic surgeons or interventional radiologists. Both of these procedures entail inserting a needle under anesthesia and imaging guidance into a vertebra that has collapsed and is causing pain. At that point, cement can be directly injected into the vertebra to prop and keep it decompressed (normal size/height), which is the procedure called vertebroplasty. The very related procedure of kyphoplasty first inflates a balloon through the end of the needle in the middle of the collapsed verterbal body in order to prop it open, and then fills the balloon with cement.
(Click any of the above images to enlarge)
Both of these procedures can and generally do lead to immediate and very significant pain relief. The majority of patients who have one of these procedures don’t have cancer, just vertebral compression fractures from osteoporosis. My patients who have had this have often had significant pain relief or complete resolution immediately after the procedure and have no recovery time involved.
So while invasive interventions are not often required for management of bone metastases, in certain situations they can be very helpful. I’ll finish up my discussion of managing bone metastases with a post on the potential value of systemic, or “whole body” therapy for bone metastases with bisphosphonates like Zometa/zoledronate and other related drugs.
Pain from Bone Metastases: Treatment Approaches, Focusing on Radiation
We’ve established that bone metastases are common, and now we’ll talk about approaches to manage pain that often accompanies them. As I mentioned previously, sometimes a metastases occurs in a weight-bearing bone, in which case we often recommend a prophylactic surgical procedure to stabilize the bone at risk for fracture. Radiation can also reduce the risk for fracture and improve pain.
Aside from the risk of fracture, reducing pain is an appropriate goal by itself. There are no randomized trials that compare medication to radiation therapy, and either or both can be used. Pain with bony metastases can be caused by many things, but most typically it’s inflammation and swelling of tissues on the outer surface of the bone, which can lead the nerves in the periosteum (the membrane on the outside of the bone) to transmit pain. External beam radiation (also known as radiation therapy, RT, or XRT) is often very effective in reducing inflammation and killing living tumor cells in that area. Up to 90% of patients have complete or partial improvement in their pain with XRT, and about half of the responding patients have complete relief of their pain (Hoegler summary abstract here). While radiation to a painful metastasis has often been given historically as daily fractions Monday-Friday for 2-3 weeks, recent studies have demonstrated that even a single-day radiation treatment can provide the same degree of pain relief 3 months later, although the single-day treatment had a higher likelihood of needing to re-treat the area, and no differences in survival or likeliood of a later pathologic fracture (Hartsell randomized comparison study, abstract here; summary “meta-analysis” abstract here). The more recent trial, with the abstract above, focused on patients with breast or prostate cancer but would presumably be equally applicable to metastases from other cancers. Overall, multiple trials have shown that a short course of 1-5 “fractions” of radiation can achieve comparable pain control and overall results as longer courses of radiaion. There can sometimes be more side effects to surrounding tissues if a single treatment or just a few are done, so this is a particularly appealing for metastases to extremities, where internal organs are not included in the radiation field.
Although it’s rarely done, there was actually a study that demonstrated that patients who received steroids in combination with XRT had more rapid and prolonged pain relief than the patients who received XRT alone (Teshima abstract here). Steroids do have acute and chronic side effects, including overall bone loss. Overall, this isn’t commonly practiced, but it’s a reasonable option.
There are several additional approaches for the common problem of bone metastases, so I’ll continue on this topic next time.
Bone Metastases in Lung Cancer: An Introduction
I’ve discussed the general management of metastatic lung cancer, both SCLC and NSCLC, but there are also several common complications that sometimes require particular management. Bone metastases, for instance, may be treated by the same “whole body” approach with chemotherapy that treats other areas of tumor involvement, but may also benefit from additional approaches. Bone metastases are common in oncology, and approximately 30-40% of lung cancer patients develop bone metastases at some point, about half presenting with evidence of bone involvement at the time of diagnosis (bone metastases general review abstract here). These metastases often have a significant impact on a patient’s quality of life, leading not only to pain but also a risk for pathologic fractures (bone breaks because the bone is weakened by cancer involvement leading to reduced structural integrity), potential compression of the spinal cord and other nerves, and high blood calcium levels as bone is broken down (which can lead to confusion, constipation, numbness/tingling, and other problems). With bone metastases comes a risk of impaired mobility, problems with sleeping and eating normally, and a somewhat worse prognosis overall, although there’s a lot of variability in the population. Continue reading
| Follow us on... |    |
||
Copyright ©2012 GRACE |
|||