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Angiogenesis in First Line Advanced NSCLC: Focus on Avastin (Bevacizumab)
Video presentation describing the concept behind angiogenesis and the evidence on the anti-angiogenic agent avastin (bevacizumab) in NSCLC.
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Or access via web link here.
Slide/figure images from the video presentation are available as a pdf here: Angiogenesis FL Adv NSCLC Vodcast images
Transcript is here: Angiogenesis FL Adv NSCLC Vodcast Transcript
Podcast: Play in new window | Download (33.0MB) | Embed
Clinical Factors of Prognosis in Surgical Series: A Focus on Smoking Status
In my last post I wrote about the prognostic value of molecular markers like EGFR and K-Ras that have generally been studied in patients with advanced NSCLC and treated with EGFR inhibitors, but these studies looked at prognosis in patients with early stage NSCLC who underwent surgery. These studies also provided some interesting results on the prognostic value of some clinical variables as well.
The Japanese surgical series of 397 patients with resected adenocarcinomas (abstract here) reported several associations of survival with clinical variables, as shown in the figures below:
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Some of these findings are very intuitive. In the top right, we see that patients with stage I adenocarcinomas have a far superior survival to patients with higher stage cancers. Since staging is designed as a method to predict prognosis, these results corroborate what we’d expect. I’ve also written a prior post about more poorly differentiated cancers being associated with a worse prognosis than better differentiated cancers, as is shown in the bottom right panel. And there has been a growing collection of evidence that, as a population, women with lung cancer have a more favorable prognosis, stage for stage, than men (see prior post), as shown in the panel on the lower left.
EGFR and K-Ras Mutations in Patients with Early Stage NSCLC
We’ve seen clear evidence that patients who have tumors with certain mutations in the EGFR gene are highly likely to respond to oral EGFR inhibitors like tarceva (erlotinib) or iressa (gefitinib) — with response rates that are in the 70% range and often last for many months or even a few years (see prior post). On the other hand, K-Ras mutations are associated with a very low probability of responding to EGFR mutations (see prior post).
But the overall favorable or unfavorable results of these mutations may not be limited to their associations with how patients respond to EGFR inhibitors and/or other systemic therapies. I’ve noted how patients with advanced NSCLC and EGFR mutations have a superior survival even if they don’t receive an EGFR inhibitor. Another approach to assessing the prognostic value of mutations is to look at survival of patients with resected earlier stage NSCLC tumors.
The Amazing Case of Rob F: Oligo-Metastatic NSCLC as a Truly Chronic Disease
One of the issues that we’ve commonly discussed and debated here is the question of when a local approach like surgery and/or radaition may be appropriate for I recently saw a patient of mine who I first met more than four years ago. At that time, he was only 37 years old and had just been diagnosed with stage IIIA NSCLC with several N2 nodes involved, after having quit smoking a couple of years earlier. He had actually initiated treatment with another local oncologist, a plan of chest radiation along with concurrent weekly carbo and taxol. He had also met with one of the expert thoracic surgeons I work very closely with, Dr. Eric Vallieres, who felt that he would be a good candidate for surgery after chemo and radiation. In truth, the extent of his disease in his mediastinum (midchest) was enough that I felt that an alternative approach of aggressive chemotherapy and radiation without surgery was a reasonable alternative. But Rob was one of the most informed and proactive patients I’ve encounted in my own practice and came to learn as much about the controversy around how to manage stage IIIA NSCLC as his physicians. Not only did he shape the plan that led him to surgery after “induction” chemo and radiation, he pushed for post-operative prophylactic cranial irradiation (PCI), though that isn’t a standard approach at this time (and I had expressed some misgivings despite the compelling rationale). He had also received a few doses of post-operative chemo with gemcitabine and navelbine, which was as much as even an aggressive-minded man in his late 30s could take after chemo, radiation, and surgery.
Of note, he had received this care through another oncologist, but he transferred his care to me about a year after he had completed these treatment. However, before he came to me, he had undergone a repeat PET/CT that showed an upper abdominal lymph node that lit up on PET, with no other abnormalities. In fact, he had just undergone an exploratory where they found and removed that node, which was recurrent cancer. He came to me for consideration of post-operative therapy, and the entire team had an extensive discussion of the possibilities (this team definitely including the patient, along with surgeon, radiation oncologist, and myself). Though we were without any real precedent and a potential of making him feel worse for no clear benefit, he was young, aggressive, knowledgeable of the balance of potential risks and benefits, and we thought it might still be possible to cure him. He had gone a year and had a single lymph node recurrence, with no evidence of any disease elsewhere. In fact, due to some manipulations that the surgeons had done at the time of his surgery, that lymph node was felt to potentially have drained directly from the surgical bed, so there was a chance that this area of disease hadn’t spread through the bloodstream.
GRACEcast Audio Interview: Dr. Janessa Laskin on Adjuvant Chemotherapy
Interview by medical oncologist Dr. Howard (Jack) West with fellow medical oncologist and lung cancer expert Dr. Janessa Laskin from the British Columbia Cancer Agency in Vancouver, BC, Canada on current standards and controversial topics in post-operative (adjuvant) chemotherapy for early stage, resected NSCLC.
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Incorporating Tumor Cavitation into Response Assessment
As I described in a post last year, one of the common features of angiogensis inhibitors is that lesion often cavitate, shrinking not only from the outside in, but hollowing out and dying from the inside out. One of the concerns has been that cavitating lesions may be at higher risk for bleeding, but the work I described in the prior post suggested no clearly increased risk of severe bleeding complications among patients who develop tumor cavitation on anti-angiogenic agents. But another issue is that tumor cavitation may be a relevant measure of response that is being missed by out current systems of measuring response by only assessing the outer dimensions of a tumor.
Investigators in Ontario, Canada looked at this issue by assessing the frequency of this cavitary response in a couple of recent trials they ran through the National Cancer Institute of Canada (abstract here). This report looked retrospectively at 33 patients who received doublet chemo with an antiangiogenic agent (in this case, the oral VEGF inhibitor cedirinib, also known as AZD-2171) and found that 8 (24%) experienced tumor cavitation during treatment. This wasn’t seen in any of the 18 patients treated with chemo alone on another trial of chemo alone that ran over a similar time line in Canada (and it’s rarely seen with chemo alone in general).
A typical situation is shown in the figure below, in which a mass doesn’t change outer dimensions, but it hollows out early in treatment, then progresses by the filling in of the center of the tumor.
It’s probably very relevant that the overall volume of viable cancer has decreased substantially early in treatment, but that response isn’t captured by our current system. Nor is the clear increase in tumor bulk as the cancer grows internally, since outer dimensions again don’t change.
The investigators tested how many patients would have experienced a change in their official response if an alternative definition of response was used in which tumor measurements included not just outer dimensions but subtracted the hollowed out portion of any cavitating lesion. And progression would be defined not only by outer dimensions but by the filling in of cavitation:
When they did tumor measurements by both the current standard (outer dimensions only) and the new alternative that incorporates measurement of the tumor cavity, a few of the patients had differences in their response assessments, going from stable disease to a partial response, or from stable disease to progression. They started with small numbers of patients and just assessed these issues retrospectively, so you really couldn’t say anything definitive. But it was interesting to see that the current system probably misses some meaningful anti-angiogenesis-induced responses and can keep people on an ineffective therapy for too long while they progress within the stable shell of a tumor.
The invstigators suggested that this new technique needs to be tested in trials moving forward, and I agree. But even this early work could be useful
Screening Trial for Never-Smokers
One of the principles of screening is that the likelihood of detecting a cancer depends greatly on the risk that a person being screen has for developing that cancer. Low risk means that it is very likely that any abnormality that is detected is more likely to be unrelated to cancer. And because of that, nearly all of the screening efforts thus far have focused on patients with a significant smoking history.
But there are some patients who have a higher risk, even despite an absence of a smoking history. Among those would be considered at higher risk without a smoking history would be people with a significant family history of lung cancer (particularly an increased risk among people with a family history of lung cnacer in never-smokers, though the risk is still quite low), and people with a significant history of exposure to secondhand smoke. And now there’s a study being done by a group that has a particular interest in the risk of lung cancer from secondhand smoke: flight attendants.
Tales from the Clinic: Surgery after Chemo/Radiation
In prior posts I’ve described the special circumstance of a Pancoast tumor, which is a tumor at the top of the lung that tends to grow into the spine, ribs, and sometimes the nerves going to the arm. These cases are a major challenge because surgery is often something to consider, because they often grow locally more than speading to the rest of the body, but surgery can be a special challenge because the vertebrae are generally not considered to be resectable. But some of our cases test the limits of what might be resectable, especially since our center has an orthopedic surgeon who has done special training at a surgical center in Paris that does surgeries on the spine that are not supposed to be surgically manageable. This has led our surgeons to to try some amazing and ambitious combined lung and spine operations on a few patients with lung cancer who would not have undergone surgery almost anyplace else. Is that a good thing? The patients who have done well think so, but this work has raised some tough questions, as illustrated by the case of Julia K.
Julia was a 56 year-old server in a restaurant in Maui with a history of smoking for about 30 years but having quit about a decade before having increasing left shoulder and back pain. As is typical for a waitress with presumed musculoskeletal back and shoulder pain, this didn’t send off any alarm bells, and her pain continued and worsened for about 4 months before her doctor ordered a chest x-ray, which was very abnormal and led to a CT, which revealed an approximately 6 cm tumor invading her second and 3rd ribs on her left toward the back, with what appeared to potentially be invasion or at least encroachment on the vertebrae:
On learning this, she left Maui and returned to her childhood home of Rochester, Minnesota (big change from Maui, I imagine), where she had an extensive workup at the Mayo Clinic. Her biopsy showed a poorly differentiated NSCLC (no histology reported), and she was subsequently decided to move to Seattle to be with and receive support from her best friend, who lived here. She was referred to me and the rest of our team for management.
Interview with Dr. Vivek Mehta, Radiation Oncologist: Early Stage and Locally Advanced NSCLC
As we move forward in our audio/visual odyssey, we’re going to add audio interviews with experts in various aspects of cancer care. The first of these is from our own Vivek Mehta, who sat down with me to go over current radiation approaches for patients with early stage NSCLC, as well as management locally advanced NSCLC.
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And along with that is the transcript for this interview, here. Dr. Vivek Mehta Interview I Transcript
We’re still trying to get the optimal setup, which this isn’t. There’s some background noise, but it’s all audible. And things will only get better. There are a few more in the works.
Differences in Never-Smoker vs. Current/Ex-Smokers Receiving Chemo
A quick point on the importance of biology over treatment. Years ago, I highlighted the results in the TRIBUTE trial of chemo with placebo or combined with erlotinib (tarceva) at the same time (biomarker study abstract here), which showed that patients with EGFR mutations had a much better survival whether they received an EGFR inhibitor or not:
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Here, biology was the prevailing factor. We’ve also recently seen that the patients on the IPASS trial of Asian never-smokers or light former smokers who were then randomized to first line chemo or an EGFR inhibitor had a far better survival if their tumor had an EGFR mutation compared to those who did not (see prior post). Similarly, the IPASS trial also showed that patients with EGFR mutations had nearly double the response rate to chemotherapy that patients without EGFR mutations demonstrated. So maybe the benefit of unique biological factors applies to standard chemotherapy as well as “targeted therapies”. Chemotherapy is also targeted and only benefits a subset of patients: we’re just further behind at understanding the relevant targets and discriminating the beneficiaries from others with standard chemo than with agents like EGFR inhibitors.
The recently published trial of cisplatin/alimta (pemetrexed) vs. cisplatin/gemzar (gemcitabine) (abstract here) showed an interesting result among enrolled never-smokers, who comprised 14-15% of the patients on the 1725 patient trial overall. Although we think of never-smokers as doing especially well with EGFR inhibitors, this trial also showed that never-smokers had a markedly longer median overall survival in both chemotherapy arms compared to current or former smokers (15.9 vs. 10.0 months in the cis/alimta arm; 15.3 vs. 10.3 months for the cis/gem arm).
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