In my thoracic oncology tumor board today, we discussed a situation that comes up fairly often: a patient has a collapsed lung lobe from a tumor near the middle of the chest, with some regional lymph nodes involved, and the surgeon thinks he’s likely to need the whole lung removed because the location of the tumor is nestled in just the wrong place.  The patient has enough lung function to undergo surgery, but losing an entire lung (pneumonectomy) is a big loss, and he’s already only a debatable candidate to be able to undergo surgery safely.  So the question emerges, “Can we give pre-operative chemotherapy specifically with the intent of shrinking a cancer enough to enable a less extensive surgery than would be needed if no pre-operative therapy is done?”

It’s a question that doesn’t have a clear answer.  The concept of “downstaging” a cancer with neoadjuvant (pre-operative) chemotherapy or chemo/radiation is an appealing potential appeal of the strategy, but there isn’t clear evidence that it really works.  In the ChEST trial that has been recently published that compared pre-operative cisplatin/gemcitabine chemotherapy followed by surgery to surgery alone, the recipients of neoadjuvant therapy were less likely to have undergone a pneumonectomy (17% vs. 25%) and more likely to have received a lobectomy (70% vs. 60%) .  On the other hand, the SouthWest Oncology Group (SWOG) ran a similar neoadjuvant chemotherapy trial and found that there were no differences in the pneumonectomy rates with or without pre-op chemo — 17% in both arms.  What gives?

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This is the first part of a case presentation I did with two great colleagues: Dr. Anne Tsao, who is a medical oncologist and lung cancer expert at MD Anderson Cancer Center in Houston, and Dr. Alex Farivar, who is a terrific thoracic surgeon at my own institution, Swedish Cancer Institute in Seattle.

This case is an elderly gentleman who has a very indolent but growing lung lesion.  His story brings up questions of how concerned to be in following a nodule in a patient of advanced age and with competing medical issues, whether surgery that is less than a lobectomy might be considered, as well as the systemic therapy options for bronchioloalveolar carcinoma.

Here are the audio and video versions of the podcast, along with the transcript and figures.

expert-round-table-tsao-and-farivar-pt-1-bac-audio-podcast

expert-round-table-tsao-and-farivar-pt-1-bac-figures

expert-round-table-tsao-and-farivar-pt-1-bac-transcript

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   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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   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.

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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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   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.

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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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  I had described earlier this week (prior post here) how the long-term follow up of one of the more important adjuvant chemotherapy trials for early stage resected NSCLC patients showed that there may be long-term adverse effects of chemotherapy.  My last post also suggested that the benefit of pre-operative chemotherapy in another trial appeared to be limited to the patients with stage IIB and IIIA disease and wasn’t present for stage IB and IIA patients.  It would really be ideal if we could predict which patients should receive adjuvant chemo, so we can spare the people who don’t need it or won’t benefit from it the negative effects.

   One of the emerging approaches that is still investigational but is promising is the concept of molecular signatures, or gene signatures.  A technology called microarray gene analysis now exists to take a tissue sample (which must be snap frozen at the time of surgery, a significant limitation for broadening the availability of this test) and then check for levels of dozens of genes all at once.  The concept of the “gene signature” has emerged, which is a collection of a few to a dozen or more genes that have patterns of being expressed at higher or lower levels that are consistent with overall more aggressive or less threatening behavior.  I’ve described some of this work in a prior post here. 

   We can add another provocative study to the mix, based on the adjuvant chemotherapy trial designated as BR.10 and led by NCI-Canada (abstract here).  This trial, which included participation throughout North America by the other cancer cooperative groups, randomized stage IB and II patients to observation or chemo with cisplatin/navelbine for four cycles after surgery:

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   In my last post I described the results of the ChEST trial that showed a borderline statistically significant improvement in survival of patients who received cisplatin/gemcitabine chemotherapy for stage IB to IIIA NSCLC prior to surgery.  This study was very similar to another neoadjuvant chemotherapy trial, known as SWOG 9900, which also randomized patients to upfront surgery or 3 cycles of pre-operative chemotherapy followed by surgery.  In the SWOG trial, run at a few hundred sites throughout the US, the chemotherapy used was the commonly used carboplatin/taxol combination, for three cycles prior to surgery, compared to surgery alone:

Also just as with the ChEST trial, SWOG 9900 was closed to accrual quite early (2004), with only 354 of 600 planned patients enrolled, because it was felt to be unethical to continue enrolling patients onto a trial on which half of the patients would not receive chemo, in the wake of multiple positive trials that had recently been presented and showed a significant benefit from the addition of chemo.

   Dr. Kathy Pisters from MD Anderson Cancer Center in Houston led the trial and presented the data at ASCO 2007 (abstract here).  Importantly, 2/3 of the patients had stage IB/IIA NSCLC.  This was a higher percentage than comprised the European adjuvant trials.  This is because North American trials separate out the patients with N2 nodes involved and treat them separately (the stage IIIA patients on SWOG 9900 had T3N1 NSCLC), while many stage IIIA, N2 European patients receive surgery and approach them the same way as stage II patients. 

   Surprisingly, only 77% of patients received all three cycles of carbo/taxol before surgery: this isn’t much better than the  ~70% rate of successful administration in many platinum-based trials in the adjuvant setting, and it’s notably lower than the 85% rate of delivering 4 cycles of the same carbo/taxol post-operatively in another trial (CALGB 9633, described in a prior post here).  It’s also lower than the 85% rate of delivery of the three cycles of  neoadjuvant cisplatin/gemcitabine given in the ChEST trial.  But for whatever reason, their delivery of pre-op carbo/taxol was less than we might have hoped and expected.

   At the same time, the response rate was 38%, very similar to that seen in the ChEST trial of cis/gem (35%).  And several patients were bothered by problematic muscle and joint aches, as well as neuropathy.  Most concerning, though, were the three deaths during pre-op chemo, which is really higher than you’d expect for treating 169 early stage patients, especially with carbo/taxol.  There was also no decrease in the rate of pneumonectomies on this trial with chemo (a potential benefit of neoadjuvant chemo is that you might shrink cancers that need a pneumonectomy before chemo but only require a lobectomy after chemo); that rate was 17% in both arms of the study.  There were also a few more peri-operative deaths on the chemo arm – specifically, 4 of the 24 patients (17%)  who had a pneumonectomy after chemo died, while none of the 25 patients who had a pneumonectomy without prior chemo died in the weeks after surgery.  There’s still some debate about whether certain types of chemo increase the rate of surgical complications later, but in truth the 0% death rate after pneumonectomy on the surgery alone arm was unusually good.  The mortality rate after pneumonectomy is generally in the 4-10% range.

   Despite these challenges, the progression-free  survival (PFS) and overall survival (OS)  rates were better for recipients of chemo compared to those who received surgery alone.  Neither result was quite statistically significant, but the trends were clear and convincing (to me), and they appear to be of the same magnitude as the benefits seen with adjuvant chemo.  The 5 year PFS benefit was 10%, and OS benefit was 7% with addition of chemo:

   A potential issue that Dr. Pisters raised in her discussion of the SWOG 9900 trial at ASCO last year is that the trial may have been more positive if a cisplatin-based doublet had been used instead of carboplatin, since there is some evidence  that cisplatin is a little more effective than carboplatin for NSCLC, which may be the difference of a few percent more patients being cured, even if it’s a more challenging approach in most settings.

   My overall impression is that the results of both SWOG 9900 and the ChEST trials look very similar to those of recent adjuvant chemo trials, but the numbers here are too small, since these trials both closed early.  At the same time, I expect that the SWOG 9900 trial was very limited in being able to show much of a difference because 2/3 of the patients were stage IB and IIA patients who probably didn’t get much of a benefit from chemo, if this trial is similar to the ChEST trial in that respect (see prior post).  We’ve never seen a breakdown of efficacy outcomes as a function of a patient’s stage, but I’d love to see this analysis done.  We might well find that the chemo has striking benefits in higher risk patients and nonexistent or even harmful effects in lower risk patients.

  In contrast with post-operative chemotherapy, which has become a standard treatment approach to reduce the probability of recurrence of resected stage II and IIIA NSCLC (still pretty controversial for stage IB), pre-operative chemotherapy (also known as neoadjuvant, or induction chemotherapy) is less well studied and isn’t a typical approach.  However, a recent study called ChEST, the Chemotherapy in Early Stages Trial, was presented at ASCO (abstract here) and showed a borderline positive survival benefit with neoadjuvant chemotherapy, despite the fact that the trial was stopped very early.  As a trial of chemo followed by surgery vs. initial chemo followed by surgery, and post-operative chemotherapy had been shown in several trials to improve survival in this population, the Data Safety Monitoring Board felt it was unethical to continue a trial in which half the patients receive no opportunity for chemo either before or after surgery.

   As shown below, the trial enrolled 270 of an initially planned 700 patients before closing early, and these patients were randomized to receive upfront surgery or three cycles of cisplatin/gemcitabine followed by surgery:

Importantly, more than half of the patients enrolled had stage IB or IIA disease.  As you’d expect, this group has a better prognosis than patients who have stage IIB or IIIA resected NSCLC, and therefore potentially less to gain from chemo. 

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