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:

 (Click to enlarge)

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.

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   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.

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   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.

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   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.

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   I’ve covered stage IIIA NSCLC in several prior posts, mentioning that it’s a clinical setting that is among the most controversial, but I don’t think I’ve really described my real world approach.  To review, the controversy is that for stage IIIA NSCLC with mediastinal lymph node involvement on the same side as the tumor (N2 nodes), some people would recommend surgery as a main treatment strategy, and others would recommend chemo and radiation without surgery.  The trials that have directly compared a surgical to a non-surgical approach have shown no significant survival benefit for either approach.   However, one key study demonstrated that patients who underwent surgery had a lower risk of a recurrence of lung cancer, but this was largely offset by a higher risk of treatment complications and even death related to the more aggressive treatment of chemo and radiation followed by surgery (see prior post).

    There is also the question for people who are planned to undergo surgery of whether they should start with surgery or receive “induction”/neo-adjuvant therapy beforehand.  And if they receive induction therapy, should it be with chemo alone or chemo and radiation together?   The typical standard is that for patients who have mediastinal node involvement identified before planned surgery, we usually give chemo with or without radiation as well before surgery.  You could make the argument that it’s just as good to give it afterward, but stage III NSCLC is a setting in which the risk of recurrence with surgery alone is very high, and I’d feel far more optimistic about getting in chemo +/- radiation as well as surgery by starting with induction therapy and following with surgery, rather than starting with surgery and hoping to get additional therapy post-operatively.   Too many patients can’t or won’t take more treatment after a big lung surgery to really expect that you can deliver it in the adjuvant (post-operative) setting.

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    To begin with, my overall impression is that the preponderance of evidence on adjuvant (post-operative) chemotherapy supports that it can reduce the recurrence risk and improve the survival at five years, which I’d presume to be pretty close to the “cure rate”.   The benefit isn’t uniformly distributed for all patients: higher risk patients, as defined by stage and other additional factors like number of lymph nodes involved and the grade of the cancer, also matter.  Our current standards converge on recommendations favoring post-operative chemo for stage II patients and the minority of patients who have “surprise” N2 nodal disease not detected before surgery and are therefore stage IIIA and without evidence of residual disease.  These patients derive a clinically significant benefit from chemo that more than offsets the small but real risk of serious side effects.

   I consider it important to remember that 0.5 - 1% of patients on most of the clinical trials of adjuvant chemotherapy died from the treatment, and the trial population is non-representative of the broader “real world” population that is sicker and older than the patients who went on these trials, on average.  And the most recent updates of one large adjuvant trial (prior post here) raises the specter that the risk from chemo may be not be captured completely in the first five years and that the outcomes may be more disappointing with follow-up beyond five years.  Overall, I consider this to be far more of a concern for the patients I would already consider to be marginal for adjuvant chemo — stage IB, or those who are already pretty frail and may be more harmed than helped by chemo.  The emerging story is telling me that it’s not just that adjuvant chemo either helps or it doesn’t help.  While it may help some, there could be detrimental effects, so it’s worth being judicious in deciding whether to pursue it: more is not necessarily better. 

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