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Emerging Results with Avastin: AVAIL Trial Press Release
Last week, Genentech had a press release in which they disclosed some potentially important information about a large randomized trial being done in Europe with Avastin. This study, known as the AVAIL trial, enrolled just over a thousand first-line patients with advanced NSCLC to receive their most common standard chemotherapy, cisplatin and gemcitabine, alone or in combination with Avastin at either of two dose levels, 7.5 mg/m2 and 15 mg/m2. The basic design is as shown in this figure:
(click to enlarge)
Just as in the ECOG 4599 trial (NEJM abstract here), the patients who go through 6 cycles of chemo wihout progression continue to maintenance avastin, until the time of progression, if they received it with chemo. As in the ECOG trial, the patients on the trial was not the entire NSCLC population, but the subset who don’t have squamous cancer, brain mets, problematic high blood pressure, or a need to be on blood thinners. Unlike the ECOG trial, the AVAIL trial also excluded patients who had “central” tumors, out of concern that the location of the tumor was important for bleeding risk. Thus far, we have concentrated on the histology (microscopic appearance) of the NSCLC tumor as more important than the location. In fact, most squamous tumors are also central. Continue reading
Individualizing Treatment Recommendations in Lung Cancer: Who to Treat?
I’m just coming from a meeting on Targeted Therapies in the Treatment of Lung Cancer, which had the interesting format of dozens of 5-minute presentations just introducing or giving a very brief update of many new therapies. Some of these, such as the EGFR monoclonal antibody Erbitux (cetixumab), which I spoke on, have been approved by the US FDA for several years in other cancer settings and are well tested in humans. Others are so new that all that could be said about them is their chemical structure, presumed mechanism of action, description of how they killed some cancer cells in test tube models, and plans for moving ahead in very early trials in humans. I’ll describe some of the agents and classes in the next several weeks, with the caveat that some and perhaps many of these won’t be available for broad trials in lung cancer if they don’t get through several more hurdles.
But today I’m going to talk about the very interesting Keynote Lecture by Dr. Joseph Nevins of Duke Univeristy’s Institute for Genome Sciences and Policy, on the topic of “Predictive Markers for Early Stage NSCLC”. As some of you may be aware from my prior post, other online information, or the general news, Duke has been a leading cancer center in studying genetic differences in lung cancer tumors, and it was investigators from there who recently published an important article in the New England Journal of Medicine on their ability to use genetic profiles to help predict outcomes for early, resected lung cancers. Dr. Nevins has been at the center of the efforts to individualize lung cancer care, and his lecture gave a broad overview of that work, essentially boiling down the questions he and his group are trying to answer as the following:
1) “who to treat”: which patients after surgery can be identified as having higher risk and requiring post-operative chemotherapy? which early stage patients can be identified as having a good enough prognosis to forego chemo?
2) “how to treat”: can gene arrays, the molecular signatures of a tumor, be employed to predict which particular chemotherapy drugs and/or targeted therapies would be most and least helpful for a particular lung cancer? Continue reading
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
Secondhand/Environmental Tobacco Smoke (ETS) and Risk of Lung Cancer
In light of a growing focus on the issue of lung cancer in never-smokers, it makes sense to try to identify potential causes in this population. Among the leading candidates as a cause of lung cancer in never-smokers is secondhand, or environmental tobacco smoke (ETS) exposure. This potential cause was identified more than 25 years ago in the never-smoking wives of heavily smoking Japanese men (Hirayama Br Med J 1981 abstract) Since then several other studies evaluating the association of ETS with lung cancer have been reported. The Environmental Protection Agency noted in its report from 1992 that there was an increased risk for lung cancer from ETS and estimated that it accounts for approximately 3000 lung cancer deaths in the US. It is fair to say, though, that the methods by which these conclusions were reached were imperfect and have been seriously questioned, particularly by smoking advocates (counter-arguments provided by a strong non-believer here), but also by others who just noted that the science behind the calculations was pretty weak.
One meta-analysis (a collection of data from multiple smaller trials to try to determine a conclusion based on the pooled data asking the same question) reviewed 19 different studies that focused on never-smoking women and estimated an approximately 20% increased risk of developing lung cancer from exposure to ETS. Another report by the International Agency for Research on cancer estimates a 25% increased risk of developing lung cancer from ETS in women, and a 35% increase in men (full review article from J Natl Cancer Inst here). A large European trial (Vineis British Medical Journal full article here) comparing patients who developed cancer with an otherwise similar matched control population included over 123,0000 never or former smokers (3/4 were women) and found a 34% increased risk of lung cancer from ETS in the overall population, but only a 5% increased risk in never-smokers. Overall, there was not a statistically significant difference in risk for developing lung cancer from ETS. Continue reading
Lung Cancer Among Never-Smokers: New Data on Frequency and Characteristics
My good friend Heather Wakelee, along with her colleagues at Stanford, just published an important study in the Journal of Clinical Oncology on the incidence of lung cancer among never-smokers, essentially the first and most comprehensive work defining the magnitude of the problem. I’ve mentioned that never-smokers with lung cancer are a particular interest of mine, and that this population is emerging as a distinct subpopulation with different characteristics and response to therapies, especially EGFR-based therapies. Dr. Wakelee’s paper describes several issues about never-smokers with lung cancer on a much larger scale. Continue reading
Limited Resections for Very Small NSCLC Tumors and BAC
While lobectomy or pneumonectomy may be the surgical treatment of choice for most NSCLC tumors in younger, fit patients, a limited resection may be an ideal choice in certain settings. In my previous post I discussed the data supporting a limited resection in older patients, who are likely to have competing health risks that may make it less critical to pursue the most aggressive surgical strategy. Another situation in which a sub-lobar resection may be particularly appealing is when the tumor is quite small and/or has characteristics suggestive of an indolent natural history. In such cases, a lobectomy may be more surgery than is required. There are trials now asking the question of whether patients with the most favorable features based on size or histology (microscopic characteristics) may do as well or better with limited resections than the standard lobectomy or pneumonectomy. Continue reading
Lobectomy vs. Limited Resection: Different Approach Based on Age?
While the prevailing standard of care for resectable lung cancer is a lobectomy or pneumonectomy, we want the surgery to be as appropriate as possible for patients. That means not short-changing patients by doing a lesser surgery than they need to do as well as possible with the cancer, but also not overtreating patients with a more aggressive surgery than they need. There are two main variables that potentially alter the equation and may make a sublobar resection a more appropriate consideration. The first is in cases in which the patient has competing risks of survival and/or medical problems that make a more aggressive surgery less necessary or more morbid (side effect-ridden, longer time for recovery, etc.) than average, or both. The second situation is when the cancer has more favorable features than most, so even in healthier patients it may not be necessary to do a more extensive surgery. I’ll explore the first scenario now.
As I mentioned in a previous post introducing the different types of lung surgery, an influential trial by the now defunct Lung Cancer Study Group indicated that survival is superior in patients who receive a pneumonectomy or lobectomy compared to those who receive a segmentectomy or wedge resection (abstract here). However, there was actually no difference in survival in the first three years, wit
h improvement only emerging with longer follow-up. This suggests that patients with competing health risks may not be as well served by a more aggressive surgery. Thoracic surgeons have therefore asked whether elderly patients may do as well or better with a sub-lobar resection that involves less blood loss and recovery time without a significant compromise of cancer-related survival. One important study suggest that’s the case. Continue reading
Types of Lung Cancer Resection: From Pneumonectomy to Wedge Resection
Surgery is the standard treatment for early stage lung cancer, sometimes also including other types of threrapy in addition. There are many types of lung cancer surgery, and there is still active debate about whether a pneumonectomy or lobectomy should be the preferred surgery for lung cancer, or whether a sub-lobar resection, either a segmentectomy or a wedge resection, is appropriate for certain patients. We need to start with some definitions. There are two lungs (OK, everyone knew that…), and the right lung is bigger than the left one, because the heart sits predominantly on the left side of the chest. The lungs are divided into lobes, which in turn are divided into smaller segments. There are three lobes in the right lung (the right upper, middle, and lower lobes), and two in the smaller left lung. The left side has a projection called the lingula, which is a projection of the left upper lobe, and is a smaller but analogous structure to the middle lobe on the right side. The lobes are in turn divided into smaller anatomic segments.
A pneumonectomy is an easy concept: it’s the removal of a whole lung. This is commonly done, and may be required for a cancer that is central in the chest or large enough that it involves pretty much the entire lung. While no type of lung cancer is trivial, a pneumonectomy can be particularly challenging for patients, in light of all of the lung tissue that is removed (especially a right pneumonectomy, since it is the bigger lung). The majority of lung surgeries, however, are lobectomies, in which 1/3 of the right lung, or 1/2 of the left lung is removed, as illustrated here (this and other figures here are courtesy of my good friend and great thoracic surgeon Eric Vallieres, also at my institution).
(click to enlarge) Continue reading
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