Chemotherapy after surgery has become increasingly well established as beneficial for many patients who have undergone surgery for early stage NSCLC, at least for stage II and IIIA resected disease (stage IB has had more mixed results and remains quite debatable).  The chemo regimens that have been most clearly shown to confer improved survival are cisplatin-based and can have very challenging toxicity in anybody, especially after a major lung surgery.  In fact, the rates of administering chemo as planned after surgery are generally about 65-75%, and this is in clinically trials that tend to enroll disproportionately younger, fitter, and more aggressively-minded patients than are seen in a broader “real world” experience.  So the question of how feasible it is to administer post-operative chemo in older and potentially less robust patients is an important issue.  Do such patients receive a benefit similar to that seen in younger patients, or does adjuvant chemo potentially represent treatment beyond the point of benefit that may do more harm than good?  We don’t have much information, but one study presented last year provides some useful information that indicates that adjuvant chemotherapy appears to be at least of equal benefit in older compared to younger patients.

   One of the most important trials that demonstrated a survival benefit in patients with stage IB and stage II NSCLC is known as BR.10 (”BR” for bronchus/lung) and was conducted by the National Cancer Institute of Canada along with participation from several other cancer cooperative groups based in the US.  The positive results for this trial were first presented at our international ASCO conference in the spring of 2004, land the updated results were subsequently published in the New England Journal of Medicine (abstract here).  This trial included 482 patients with a median age of 61 to either observation or four cycles of cisplatin with navelbine (also known as vinorelbine) several weeks after surgery.  As I described in an earlier post on the value of adjuvant chemotherapy, this trial demonstrated a 15% improvement in 5-year survival (from 54% to 69%) in the recipients of chemotherapy (essentially confined to the stage II patients, the final publication demonstrated).  These results were a very significant reason why post-operative chemo for appropriate patients became the standard of care over the past few years.  The ASCO presentation from last year on this trial (abstract here) focused on the outcomes of the patients over 65 (Canadian researchers rather uncharitably define “elderly” as over 65, whereas a growing consensus elsewhere in the world considers elderly to be 70 or older).  The outline of the trial is as shown:

 (click to enlarge)

Using the cut-off of age 65, about a third of the patients on each arm were considered elderly.  The analysis did not include any of the only 18 patients who received chemo treatment on a dose level that was quickly found to be too high, so it ended up comparing 67 older patients who received post-op chemo with 78 who did not.

    Not surprisingly, the older patients tended to have a worse performance status, and specifically, fewer were without symptoms (53% vs. 41%, p = 0.01 (below 0.05 means the result is statistically significant, or quite unlikely due to chance alone)).  There were different tumor types in older vs. younger patinets, with the older patients more likely to have squamous cell cancers, and younger patients more likely to have an adenocarcinoma NSCLC.  The older patients also received significantly less chemotherapy than younger ones, with only 40% completing treatment as planned, compared with 56% for younger patients.  This was not because they had significantly higher toxicity rates, rates of hospitalization, or differences in growth factor support (injections to boost blood counts during treatment).  Instead, older patients were more likely to refuse further treatment (40% vs. 23% of younger patients).  Despite the lower rates of actual chemo delivery, patients over 65 who received chemotherapy after surgery had a markedly better survival than the older patients who received post-operative observation alone.  The overall survival at 5 years out was 66% for chemo recipients over 65, compared with 46% survival at 5 years out for the elderly patients on observation.  While the younger patients had a modestly higher survival in either case (5-year survival 64% vs. 56% for patients over 65, but no difference in survival related to lung cancer specifically), the difference between observation and chemo actually wasn’t as striking in patients 65 and younger as it was in older patients (70% vs. 58% favoring chemo, still convincingly beneficial). 

   There were only 23 patients enrolled over 75, and in those patients the survival was clearly worse than in other patients, although not different when looking just at disease-specific survival (so patients over 75 were more likely to succumb to other medical problems).  In this group, the benefit of chemo was not really seen, and it may have potentially been harmful, but so few patients included in the analysis, it seems most appropriate to say that we just don’t have information to address the value of post-operative chemo in patients over 75.

  You may also recall that there is plenty of debate about whether carboplatin subtituted for cisplatin in the post-operative setting provides similar benefit or possibly less.  The CALGB 9633 trial (abstract here) that randomized stage IB patients to carboplatin/paclitaxel vs. observation had preliminary positive results that became less impressive with longer follow-up, leaving us with no hard proof of a survival benefit for post-operative carboplatin-based chemo.  But carboplatin is generally far, far easier to tolerate, and it remains an open question whether older patients, particularly above 70 or 75, may be better served by receiving a cisplatin- or carboplatin-based doublet.  In the absence of more studies with more patients who represent a real world experience with older patients, most of us feel it is best to have a careful discussion of the risks and benefits of these approaches with a patient and their family and individualize the recommendation from there.  In the meantime, the available evidence certainly suggests that older patients (at least up to about 75) can improve their survival with adjuvant chemo at least as much as younger ones.