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Incidental N2 Nodal Disease and the Heterogeneity of Stage IIIA N2 NSCLC
Probably the most contentious areas of lung cancer management is stage IIIA NSCLC, with N2 nodal involvement, the nodes outside of the lungs, toward the middle of the chest but on the same side as the main tumor. One of the key issues is that the staging is the same whether there’s a single microscopically involved lymph node or multiple enlarged lymph nodes in a few areas of the mediastinum (mid-chest, between the lungs). But the outcomes of these groups of patients is very different, so it may be worth thinking about them a little differently. As shown here, from a retrospective review of just over 700 patients in France who had N2 mediastinal nodes involved (abstract here), outcomes were much better for the subset who had a single lymph node area involved (called a nodal station), and no clinically enlarged nodes (meaning that on a CT scan they didn’t appear abnormally big, defined as more than a centimeter):
(Click to enlarge)
The curves show that the patients with a single (L1 for one level instead of L2 for more than one, in the legend above) non-enlarged (m for microscopic instead of c for clinically involved) nodal area involved have a long-term survival in the range of 35%, while the outcome for patients with visibly enlarged mediastinal nodes and/or more than one level/station involved isn’t as favorable, although there are still long-term survivors. But this retrospective series is limited because it pools together people who had differing rigors of staging, some receiving chemo after and some not, and otherwise just a very heterogeneous population. That’s somewhat helpful for teasing apart signals within that broad range, but it helps to look at patients treated somewhat uniformly.
Management Options for SVC Syndrome
As I introduced in my last post, the superior vena cava SVC syndrome occurs in about 2-4% of lung cancer cases, and lung cancer is the leading reason for it. One of the most important factors in managing it is to determine, usually with CT imaging, the cause of the SVC syndrome — generally whether it’s caused from tumor or a blood clot, such as around a catheter.
To recap, the appearance of a CT scan may look like this, with the large vein known as the SVC compressed between the tumor (in the lung, which is black) and the mass of lymph nodes toward the middle of the chest:
(Click to enlarge)
If this is an initial presentation and there is no diagnosis yet, it’s important to get tissue as one of the first steps. The symptoms usually develop over weeks, and studies have actually shown that it’s rare for there to be significant consequences in taking the time to complete the workup and figure out the cause, rather than just frantically start treating without knowing what you’re treating. The treatment of choice depends in part on whether this is SCLC, NSCLC, lymphoma, or something else. And just jumping in with something like radiation can make it hard to determine the actual diagnosis later.
Introduction to Superior Vena Cava (SVC) Syndrome
Superior vena cava (SVC) syndrome is an infrequent but not rare complication of lung cancer, occurring in 2-4% of cases, most typically an early symptom that leads to the diagnosis. The SVC is the main vein that drains blood back into the heart from the upper body, and it runs in the middle of the chest on the right side, where it is vulnerable to being compressed by a nearby lung cancer or enlarged lymph nodes, such as from lung cancer or lymphoma. Less commonly, SVC syndrome can be caused by a clot within the blood vessel, and it’s also possible to have a combination of external compression and blood clot (clots are more likely to develop where blood flow is compromised). This leads to blockage of the blood flow from the upper body and engorged blood vessels and often swelling of the face, neck, and sometimes upper extremities, as shown in this figure (from this summary article):
The leading symptoms of SVC syndrome are facial edema, distended veins in the neck and sometimes chest, arm edema, shortness of breath, cough, facial plethora/fullness, and less commonly wheezing, lightheadedness, headaches, and even confusion.
What I Really Do: EGFR Inhibitor Rashes
Though EGFR inhibitors like tarceva can produce some terrific and long-lasting results in many patients, they aren’t toxicity-free. The “targeted therapies” we use just have a very different side effect profile from standard chemo, and the EGFR inhibitors are well known to have skin-related side effects as the leading problem, with loose stools/diarrhea as a less nearly ubiquitous second place issue. In fact, it’s become increasingly well accepted that it’s desirable for patients receiving drugs like tarceva (erlotinib), iressa (gefitinib), or erbitux (cetuximab) to have some degree of a rash: in the studies that have looked at this issue, patients who have no rash don’t have as good a survival and almost never show a significant response, with a frequently seen association of a “severity of rash-dependent” association in which patients with more problematic rashes tending to do the best (see prior post).
This might lead some people to presume that it’s helpful to increase the dose beyond the standard amount, but there’s no evidence that this is the case. A previous trial that escalated dose beyond the standard for patients who didn’t have a rash actually showed disappointing results (see prior post), and my interpretation is that someone’s ability to benefit from EGFR inhibitors is “more nature than nurture”. By this I mean that the people who are going to get a major rash are just very sensitive to the effects, good and bad, of these agents, and the people who don’t generate a skin response can’t be forced into a rash any more than you could transform that male ex-smoker with squamous cancer into a female never-smoking Asian patient with an adenocarcinoma. It’s just not going to happen.
The other implication of this work is that you don’t need to suffer from a terrible rash to be the beneficiary of an EGFR inhibitor: you just need to be a person who could have a terrible rash. Since many of the patients who are most sensitive to rash and other side effects of these drugs could be so bothered by these problems that they stop them and are disinclined to ever try them again, but may be the biggest beneficiaries, I think it’s far more important to get people on a dose that they can tolerate long term. The biggest breakthrough with this class of drugs is that there are some people who can take them and show no progression for a year or even many years, but you can’t do that if every day is endless misery because of the side effects.
Trial of Ongoing Chemo vs. Switch to Iressa for Japanese Patients with Advanced NSCLC
An interesting trial presented at ASCO 2008 came out of Japan, asking the question of whether there is an advantage to continuing first line platinum-based doublet chemo for up to six cycles or whether it might be better to give just three cycles and then switch from chemo right to the EGFR inhibitor iressa in Japanese patients with advanced NSCLC (abstract here). I haven’t mentioned it before because the trial, although interesting and with some provocative findings, didn’t clearly provide conclusions that would lead to obvious management changes.
For trial 0203, the West Japan Thoracic Oncology Group (WJTOG) enrolled 600 patients with previously untreated advanced NSCLC, with asymptomatic brain metastases permitted. Unlike North American NSCLC patients, among whom 10-15% are never-smokers, 31% of the patients in this Japanese trial were never-smokers; about 78% had adenocarcinomas (a higher proportion than in North America or Europe). They were randomized to receive chemo for six cycles vs. three followed by Iressa. The chemo could be carbo/taxol or cisplatin with gemcitabine, taxotere, navelbine, or irinotecan, all comparable in activity.
What I Really Do: Transition from First to Second Line NSCLC
The general approach to NSCLC is in transition right now, as the line between first and second line therapy are becoming increasingly blurred. A few years ago, the clear standard was that we usually stop first line chemo after four to six cycles, then follow a patient clinically and radiographically until they show evidence of progression, at which time we’d start second line treatment. But now, a growing proportion of our standard treatment protocols include a maintenance phase of ongoing treatment with a targeted therapy after 4-6 cycles, usually of platinum-based chemo with that same targeted therapy. So while we don’t have established proof of the value of maintenance therapy, it’s most common to continue avastin (bevacizumab) as a single agent after 4-6 cycles with platinum-based doublet chemo. While erbitux (cetuximab) is less clearly established and less commonly used, the trial that demonstrated a survival benefit also included a maintenance phase. Erbitux, however, is a more practically challenging situation than with avastin because erbitux is a weekly treatment, not especially convenient for ongoing maintenance therapy.
At the same time that we have first line treatment extending out beyond 4-6 treatments until progression, there are studies moving second line treatment earlier, so that there is a seamless transition to starting right after first line treatment ends, usually after 4 cycles. An initial study with taxotere (docetaxel) IV every three weeks after 4 cycles of carboplatin/gemcitabine that tested immediate vs. delayed second line therapy (starting at the time of progression) showed a highly positive difference in progression-free survival favoring immediate second line taxotere, and a strong trend toward superior overall survival (see prior post for details). While that trial raised the attention of many oncologists to this question, it didn’t lead to a sea change in how we manage patients. Most of the other experts I spoke with agreed that we’d like to see another trial show a similar result, which is what we got this year with a trial of alimta (pemetrexed) vs. placebo IV every three weeks after four cycles of any of several platinum-based doublets. As highlighted in a prior post, this study showed results that I would consider remarkably similar to the taxotere trial, again with a highly significant improvement in progression-free survival and a nearly statistically significant improvement in overall survival (p = 0.06) that was nearly three months in absolute terms. The key shortcoming of the trial was that only half of the patients randomized to placebo went on to receive any second line therapy, since there are many parts of Europe that don’t consider it a clear standard of care, and that’s where the study was primarily completed. Even with that important caveat, I would consider the results to be so compelling that it merits a change in my practice. What’s more, the results with alimta were limited to the patients with non-squamous NSCLC, who actually had a 5 (!) month improvement in overall survival, while the squamous patients actually had a detriment in their survival on the alimta arm (hence the change in the FDA label that removes the approval of alimta for patients with squamous NSCLC).
The Troubling Symptom of Bronchorrhea in BAC
Warning: this symptom can be a little gross, so the delicate flowers out there should skip this post.
One of the more unusual but quite vexxing symptoms we sometimes see in lung cancer is called bronchorrhea, which is the copious production of watery sputum, specifically at least 100 ml per day. The setting in which it’s most frequently seen is in bronchioloalveolar carcinoma (BAC), and we typically think of it as being a manifestation of the mucinous subtype. In its worst form, patients can drain vast amounts of phegm each day, typically worst in the morning. Patients have told me that they lean their head down off the bed to drain a half a liter or more at a time before starting their day. Though rare, there have been frequently cited cases that have been life-threatening because of severe electrolyte imbalances that develop from losing so much fluid and salt (case report here). Interestingly, there’s a sheep virus that appears clinically remarkably similar to BAC (though there hasn’t been a human form of the virus ever isolated, despite searching), and I’ve seen video footage of researchers demonstrating bronchorrhea by lifting the hind legs of the sheep into the air, putting a beaker under its nose, and letting the watery mucus drain out for several minutes. Sorry, I told you this post has some indelicate moments. I don’t think that video’s on YouTube yet.
Unfortunately, bronchorrhea is a very difficult symptom to treat effectively. Among the things that have been tried and were written up as possibly successful in individual cases have been steroids (abstract here), inhaled indomethicin (a non-steroidal anti-inflammatory drug)(abstract here and here), a drug called octreotide (reference here), radiation therapy to the most “consolidated” area of lung (reference here), and most recently EGFR tyrosine kinase inhibitors like iressa (full text here, another abstract here, and there are several other reports out there).
The ideal situation is to treat the underlying cancer effectively, rather than just the symptom. In that sense, the EGFR inhibitors are pretty unique in being the best treatment if a particular person’s BAC happens to respond. Based on the fairly large phase II studies that have been done with iressa and tarceva in BAC, the response rate with this class of drugs is in the 15-25% range (see prior post for review). So for the patients who respond to an EGFR agent, it’s a potentially dramatically helpful treatment for a long time. For the majority of patients who don’t respond to one of these agents, the others are things that can be tried, but most of what’s been reported is a single case of a treatment that worked, not a trend of multiple cases. In truth, it’s probably never going to possible to run a study and enroll 20 patients to get a particular treatment, because bronchorrhea is an uncommon symptom of an uncommon disease. But these are a few things that people may try, and I’d be very interested if there are people out there who have had success with any of these approaches. Another one I’d be inclined to try, although I’ve never seen mention of it being done before, is inhaled lasix, the effective diuretic, which is an approach I’ve heard of hospice folks using to treat secretions.
In the meantime, bronchorrhea is often unpleasant, sometimes scary, and potentially life-threatening complication that nobody sees enough to become an expert at managing.
Second Line NSCLC: Avastin/Tarceva Improves Progression-Free but Not Overall Survival vs. Tarceva
One of the central ideas in medical oncology is that if you have two or more anticancer treatments that are active, you test them together to determine whether it’s safe and whether the combination works better than each individually. We’ve been doing this with chemotherapy combinations for decades, but it’s only been in the last few years that we have had more than one targeted therapy in lung cancer with enough activity to move ahead with combination work. Moreover, combinations with new agents is often limited by practical issues like companies needing to cooperative to provide their novel agents to each other if they aren’t commercially available.
The combination of avastin (bevacizumab), an anti-angiogenic drug, with tarceva (erlotinib), an oral epidermal growth factor receptor (EGFR) inhibitor, has been among the best studied targeted therapy combinations. Both agents have been commercially available for several years in oncology, reducing one practical barrier. Secondly, it makes good sense to try to combat the cancer by treating both the cancer cell’s growth and division signaling pathways (with tarceva) and the supporting microenvironment (reducing the tumor blood supply with avastin):
(Click to enlarge)
Carbo/Alimta: Poised to Become a Popular First Line Doublet in NSCLC
With last week’s FDA approval of alimta in the first line setting for NSCLC, we’re likely to see a lot of alimta (pemetrexed) use shift from the second and third line setting to first line. Alimta’s been a very popular choice for previously treated patients, based on issues like the relatively convenient schedule of a ten minute infusion one day every three weeks, no hair loss, and typically less of a drop in blood counts than seen with some other regimens. In the last year, we’ve seen a growing amount of data using it in combination with either cisplatin or carboplatin in the first line setting. While the official approval of alimta was with cisplatin and only in patients with non-squamous cancers (see prior post), I suspect that it’ll be the carbo/alimta combination that really makes an impact. Historically, US-based oncologists and their patients have preferred carboplatin for it’s easier side effect profile and greater convenience (cisplatin is usually given with loads of fluids to protect the kidneys, leading to long days in the outpatient infusion center or an overnight hospitalization stay). And based on the responses I saw on a recent audience response system for a case-based lung cancer meeting this weekend, the greater interest will again be with carboplatin instead of cisplatin.
So what data do we have to support this combination in lung cancer? Early safety and efficacy studies were done in Italy (article here) and at MD Anderson Cancer Center in Houston (article here) and were certainly encouraging. A friend of mine at MD Anderson, Dr. Ralph Zinner, led their trial and raved about how well tolerated the regimen was, with some patients continuing without progression for 8 or 10 or even more cycles. With a median overall survival of over 13 months, these results were favorable (we expect most trials from MD Anderson to exceed the numbers seen for trials around the country, due to selection bias in the population who come there), but a special appeal was the tolerability of the regimen.
Paul Newman’s Death from “Cancer” (Not Lung Cancer, mind you…)
Paul Newman died last week at the age of 83. A beloved actor and philanthropist, he was debonair, charming, dedicated to his family, thoughtful, and generous, with his “Newman’s Own” brand raising millions for disadvantaged children. What’s not to love?
I was certainly saddened to hear of his death, but what disappointed me was that the true cause of his death was almost conspicuously absent. The official releases in the major news outlets (example here, but many others are exactly the same), which was a spoon-fed piece from his publicist, was that he had died from cancer, but that was about all that was said. If you go to great lengths, you could find a story that scratched the surface enough to reveal that he had died of lung cancer (example here, and this even includes a much appreciated spotlight on the disease). Why make it a state secret? Continue reading
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