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An Effective Treatment for (some patients with) Leptomeningeal Carcinomatosis in Lung Cancer?
Leptomeningeal carcinomatosis, also referred to as carcinomatous meningitis, is an uncommon but certainly not rare complication in lung cancer that I consider to be among the most dreaded. This occurs when cancer cells are in the cerebrospinal fluid (CSF) that bathe and cushion the brain and spinal cord, and cancer cells deposit on the meninges, the lining around the brain and spinal cord.
(click on image to enlarge)
Meningeal carcinomatosis is a diagnosis that I need to consciously remind myself to think about when I see a patient with lung cancer experience a rapid clinical decline that isn’t associated with radiographic evidence of significant progression in the extracranial cancer we’ve been following, or when I see a patient with a constellation of neurologic signs and symptoms that just don’t fit together for an anatomically-based lesion like a brain metastasis, stroke, or peripheral neuropathy.
One central reason that leptomeningeal carcinomatosis is also especially dreaded because we really tend to do so poorly in treating it. Craniospinal radiation therapy (RT) has been tried, and there is the option of giving chemotherapy directly into the CSF through a series of lumbar puncture (spinal tap) procedures or through an Ommaya reservoir that is implanted into the skull to deliver chemo right into the fluid collections inside the center of the brain. Unfortunately, none of these options has been effective (particularly in lung cancer, though results in breast cancer treatment have been more favorable), and most thoracic oncology experts and general oncologists have favored a focus on comfort care as the primary intervention.
ZEPHYR Trial of Zactima (Vandetanib) vs. Placebo Negative
It’s been a while since there was anything to discuss about Zactima (vandetanib), an oral targeted therapy being investigated by AstraZeneca that has the potential to inhibit both the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF), key targets of two important pathways in cancer treatment. They launched a total of four large trials looking at the activity of Zactima added to second line chemo, or compared head to head with the FDA-approved EGFR inhibitor Tarceva (erlotinib) in one trial or placebo in another trial. We learned some preliminary results of first three trials more than a year ago, and more complete information was presented at the American Society for Clinical Oncology (ASCO) meeting in early June of 2009. Those results overall indicated that Zactima could provide a modest but real improvement in progression-free survival (PFS) but no real improvement in overall survival (OS) when added to standard second line chemotherapy (statistically significant difference in PFS in a larger trial with Taxotere (docetaxel), and a similar magnitude of improvement in PFS but not reaching statistical significance in a smaller, less “well-powered” (to show a statistically significant difference) trial adding Zactima to Alimta (pemetrexed). The head to head comparison of Zactima to Tarceva showed equivalent activity.
Interview with Dr. Matthew Horton, Pathologist, Part 2: Neuroendocrine Lung Tumors & Bronchioloalveolar Carcinoma
This is a continuation of my discussion with Dr. Matthew Horton, a pathologist with a special training and a great expertise in lung pathology who works here in Seattle at a company called CellNetix.
This portion of our discussion covers the spectrum of neuroendocrine lung tumors, ranging from carcinoids to small cell lung cancer and large cell neuroendocrine carcinomas; we then turn to a discussion of bronchioloalveolar carcinoma (BAC), including everything from a little history to a look forward at a new interpretation of BAC. Below you’ll find the audio and video versions of our discussion (the video with a few images of what we’re talking about), and the associated transcript and figures.
Dr-horton-pt-2-neuroendo-lung-tumors-and-bac-audio-podcast
Dr-horton-pt-2-neuroendo-lung-tumors-and-bac-transcript
Podcast: Play in new window | Download (40.2MB) | Embed
Stereotactic Lung Radiotherapy (SBRT) vs. Wedge Resection for Stage I NSCLC
The subject of stereotactic lung radiotherapy (SBRT) for cure of stage I disease has been extensively covered on GRACE with good cause: we may be witnessing a major change in how we treat early stage cancer. Multiple strategies for improved surveillance are being developed, and hopefully one or more will be successful, resulting in more frequent detection of early stage disease. If so, we will have what my mentor calls a “delicious dilemma” – what is the best way to cure these early-stage patients? Before turning to an important new article in JCO on the subject, I refer the curious reader to recent coverage on GRACE that leads up to the subject at hand:
Limited Resection vs. Radiation for Marginal Patients with Early Stage NSCLC : 11/15/2007 by Dr. Jack West
o Review of evidence that older patients may do as well with a limited, smaller resection
o Yendamuri / MD Anderson report from 2007 JTO: 160 patients with stage I NSCLC from 1988 to 2005 treated with either 3D-conformal radiation or limitted resection — surgery beat radiation in overall cohort but if you matched for similar characteristics, they were equivalent.
Dr. Le, Radiation Oncologist from Stanford, on Radiation Options for Early Stage NSCLC: 12/19/09
o PET/CT can improve radiation planning
o We have better control now for respiratory motion
o Review of ongoing studies
Interview with Dr. Vivek Mehta, Radiation Oncologist: Early Stage and Locally Advanced NSCLC: 1/15/2009
o Great review of the biologic difference between small fractions every day for seven weeks (traditional radiation) vs. giving a huge dose in 1-5 fractions (stereotactic radiation)
o Simple-language review of why existing comparisons of surgery and radiation are not fair:
o Surgery can show patients to be of a higher stage so stage I patients in a surgical group truly are stage I while in radiation studies, some patients are really more advanced
o Since there is no randomization, radiation patients are sicker; they are often in this group because they are too sick for surgery and would die earlier no matter what you did
o Postoperative radiation vs. brachytherapy
Interview with Lung Cancer Pathologist Matthew Horton, Pt 1: Intro to NSCLC Subtypes
I had the opportunity to sit down with Dr. Matthew Horton, a pathologist who works with my own group at Swedish Cancer Institute in Seattle, at a pathology company called CellNetix. He did subspecialty training in lung pathology and is a terrific resource for my colleagues and me, and now for a wider audience.
The first part of our discussion focused on the major subtypes (called histologies) of NSCLC, including adenocarcinomas, squamous cell carcinomas, large cell carcinomas, and the related large cell neuroendocrine carcinomas, along with a significant fraction of NSCLC tumors that can’t be classified despite our efforts. So check out the links below for the audio and video versions of our discussion (the video with a few images of what we’re talking about), and the associated transcript and figures.
dr-horton-intro-to-lc-path-nsclc-subtypes-audio-podcast
dr-horton-intro-to-lc-path-nsclc-subtypes-transcript
dr-horton-intro-to-lc-path-nsclc-subtypes-figures
Podcast: Play in new window | Download (26.6MB) | Embed
Circulating Tumor Cells in Lung Cancer
Welcome back. This is the second part of a discussion of the potential value of circulating tumor cells (CTCs) in cancer management. Please see the prior post for a general introduction to the concept of CTCs and how they have been studied in various cancers. We’ll now turn to research on CTCs in the setting of lung cancer.
CTCs in SCLC
Like breast cancer cells (described in the first part of this discussion), SCLC cells are DAPI and cytokeratin positive and CD45 negative (the pattern of particular proteins on the cells), making the cellsearch technology in its current form potentially applicable to them. A British study sought to evaluate potential biomarkers in SCLC, including CTCs. 50 patients were evaluated and CTCs could be detected in all but 7—each of these 7 patients had limited stage disease. Stated another way, 86% of patients overall, and 100% of patients with extensive stage disease, had detectable CTCs. Median CTC number was much higher for patients with extensive-stage disease at 237 (range 1-44,896) compared to limited-stage disease at 2 (range 0-91). CTCs were also assayed at 22 days after therapy; they fell to a median of 1 (range 0-2960). In fact, at day 22, CTCs were detectable in only 60% of patients, compared to 86% at baseline. The median survival for patients with >300 CTCs (highest quartile) was 134 days, compared to 443 days for patients with <2 CTCs (lowest quartile). The number of CTCs at day 22 was also prognostic, with a hazard ratio of 1.43.
There is also an interesting case report about the use of CTCs for diagnosis of SCLC. A 71 year old man presented with a lung nodule, with fine-needle aspiration (FNA) biopsy revealing a low-grade neuroendocrine tumor. Staging was performed which demonstrated widespread metastatic disease, including liver and bone. Noting that this is unusual for low-grade neuroendocrine tumors, his physicians dug deeper. They ran his blood for CTCs with cellsearch and 27 CTCs were detected. Since neuroendocrine tumors (other than a rare type called Merkel carcinoma) don’t express EpCAM, they shouldn’t have CTCs detectable by cellsearch. Liver biopsy was performed demonstrating that his cancer was really SCLC; he subsequently had a partial response to carbo/etoposide.
Round Table Case-Based Discussion — Drs. Laskin and Sandler on First Line and Maintenance Chemo
This is a continuation of the round table format, discussing real life case management with my colleagues who are lung cancer experts at other institutions, This case is the second half of discussion centered around a never-smoking Asian woman who doesn’t have an EGFR mutation, and specifically the decision-making process of what first line chemotherapy-based treatment to recommend and whether to continue with maintenance therapy. My guests for the discussion are Drs. Janessa Laskin, medical oncologist from British Columbia Cancer Agency in Vancouver, BC, and Alan Sandler, medical oncologist and Director of Hematology/Oncology at Oregon Health & Science University in Portland.
Here is the video version, audio, transcript, and associated figures.
rt-laskin-sandler-never-smoker-egfr-wt-1st-line-chemo-and-maint-rx-audio-podcast
rt-laskin-sandler-never-smoker-egfr-wt-1st-line-chemo-and-maint-rx-transcript
rt-laskin-sandler-never-smoker-egfr-wt-1st-line-chemo-and-maint-rx-figures
Podcast: Play in new window | Download (27.7MB) | Embed
New Year, New Stats
Happy new year, GRACErs! The change in the calendar brings out contemplation. Most of the year, the gym in my building is quiet and hardly used so I can calmly read my journals on the exercise bike. The exercise hopefully compensates for my otherwise sedentary, nerdy lifestyle and I find that I do good thinking there. Now, after the new year, as in every year, the gym has been briefly very busy. During an otherwise not so impressive workout, I read an article that I think may be of interest to some in this community.
The Journal of Clinical Oncology rang in the new year with a review of our advances and failures entitled: “Clinical Cancer Advances 2009: Major Research Advances in Cancer Treatment, Prevention, And Screening—A Report From the American Society of Clinical Oncology”. The statistics are a bit depressing so for those who prefer to avoid these numbers, please stop reading. I promise not to be offended and will write more stuff without stats for you. For those who find these statistics interesting and useful for advocacy, feel free to read on.
Round Table Case-Based Discussion — Drs. Laskin and Sandler on Molecular Testing in a Never-Smoker
Here is the first podcast of what we plan will be an ongoing series of round table discussions with cancer experts about real case scenarios and how we make decisions in practice. My guests for the discussion are Drs. Janessa Laskin, medical oncologist from British Columbia Cancer Agency in Vancouver, BC, and Alan Sandler, medical oncologist and Director of Hematology/Oncology at Oregon Health & Science University in Portland.
The first case we discussed is a relatively young Asian never-smoking woman with an advanced lung adenocarcinoma, focusing first on the changing standards for sending tissue for molecular testing, as well as the limitations of that. Here is the video version, audio, transcript, and associated figures.
round-table-laskin-sandler-never-smoker-mutn-testing-audio-podcast
round-table-laskin-sandler-never-smoker-mutn-testing-transcript
round-table-laskin-sandler-never-smoker-mutn-testing-figures
Podcast: Play in new window | Download (0.3KB) | Embed
A new tyrosine kinase inhibitor to overcome resistance to T790M?
LM is a 73 year old patient of mine. She typifies the idea of functional age over chronologic age —physiologically, she’s more like a 50 year-old and remains extremely active despite having had lung cancer since the spring of 2006. The targeted therapy Tarceva (erlotinib) was her first treatment, which worked for over two years. She was then treated with three different cytotoxic chemotherapy regimens, with a theme of response followed by progression. Each time, the progression was caught on imaging before she suffered any bad cancer symptoms, and treatment with each of these three regimens went well, with fairly minimal side effects.
This strategy worked for a year until this summer, when she progressed again. We switched her therapy to taxol (paclitaxel), with the thought that she might again respond with minimal side effects. Unfortunately, she suffered from a low white blood cell count (neutropenia) and severe fatigue. We then tried navelbine (vinorelbine), but she progressed. She is very motivated for additional therapy but wishes to avoid cytotoxic agents. Because she is an Asian never-smoker with an adenocarcinoma and a history of two-year response to Tarceva, I assume that she had a mutation in the epidermal growth factor receptor (EGFR) and then developed resistance. Are additional agents available to her?
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