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Who Benefits from Third-line Treatment for Advanced NSCLC?

Please Note: New Treatments Have Emerged Since this Original Post
Dr Pennell

This week I read a fascinating paper in the Journal of Thoracic Oncology by Dr. Nicolas Girard and colleagues at the Centre Hospitalier Universitaire de Besançon in France. I thought this would make a timely post as this seems to be one of the common questions that comes up again and again on the discussion boards. Namely, once the initial treatment or treatments for advanced NSCLC have stopped working, is it worthwhile proceeding to third or even later-line treatment? This is not a trivial question. We have very good data now that first-line platinum-based chemotherapy prolongs survival in advanced NSCLC without compromising quality of life (QOL), and this is not controversial. We also have data for three different second-line agents, namely Taxotere (docetaxel), Tarceva (erlotinib), and Alimta (pemetrexed) that show that these agents can modestly prolong life after failure of first-line chemotherapy. However, we only have one proven third-line agent (Tarceva), based on the same trial that led to the drug’s approval in second-line, and there are no drugs that have a proven benefit either for survival or for improved QOL after that. Nonetheless, many patients progress after second line treatment (or more) and are still relatively fit enough to receive more chemotherapy if there is good reason to give it. So is there? A wise oncologist once told me there are only 2 reasons to give chemotherapy when the goal is not to cure. To paraphrase, those reasons are to help a patient live longer (improve survival) or to feel better (improve symptoms). Without any data to guide us that chemotherapy does one or the other of these things, there is no good reason to continue to give patients chemotherapy that can cause significant side effects and even potentially shorten their lives.

Which brings us back to third-line chemotherapy: Does it prolong survival or relieve symptoms? Well, we do have data supporting Tarceva in this setting and it is approved for this purpose. But what about traditional chemotherapy, or what if Tarceva was already given in second-line treatment? Who benefits from this treatment, and can we identify those patients that have the best chance of benefit ahead of time so that high risk patients might be spared the side-effects? In the study above, Dr. Girard looked at all of the NSCLC patients at his hospital between 2000 and 2006 and identified those who had received third-line chemotherapy. There were only 173 patients (28%) out of the 613 who received first-line chemotherapy who went on to receive second and then third-line treatment. 75% of those patients had significant symptoms from their cancer, and half of them had a performance status of 2, which indicates that they were relatively debilitated and spent up to half of their days in bed. My first observation from these numbers is that a minority of patients ever gets third-line chemo, and thus probably represents a relatively specialized group to begin with. About 72% of patients received single agent chemotherapy, predominantly Gemzar (gemcitabine) but also Taxotere, Alimta, and a few others, while most of the rest (24%) received EGFR TKIs (Tarceva or Iressa). The response rate to third-line therapy, or those who got significant shrinkage of their cancer, was only 6%. Although this looks small it is actually pretty much what I would expect, since the second-line agents all have response rates under 10% but still prolong survival. However, an additional 30% of patients achieved some disease stabilization, while the remaining 64% had rapid disease progression. So does this seem like a worthwhile treatment to you? Two thirds of patients had rapid disease progression and only 6% had a response, so why even bother? Good question! Remember reason number 2 earlier in the post: Does the chemo make the patient feel better? Despite meager radiographic improvements, it turns out that 92% of patients treated with third line therapy had improvement of their cancer-related symptoms or improvement of the performance status. That seems like a potentially worthwhile reason to me. The authors also looked at patient characteristics to see what might indicate who would survive longer with 3rd line chemotherapy. Age less than 70 years, lack of smoking history (likely a marker for EGFR mutations that would benefit from EGFR TKIs), performance status of 0 or 1, minimal weight loss, and no disease outside the lungs were all good prognostic signs. The best indicator of who would benefit, though, was disease control (response or stable disease) with first or second-line chemotherapy.

(click to enlarge)

(click to enlarge)

In other words, if the cancer grew through the best and second-best choices of therapy, trying even more was unlikely to help. Patients who progressed in this way had a median survival of only 4 months with 3rd line therapy, compared to 10 months for those who had disease control with 1st and 2nd line chemo. This is the type of useful information that can really help us in decision making with out patients. I think that doctors should have a tough discussion about potential benefits to more therapy in those patients with very resistant tumors, because the potential for harm may really outweigh the small potential benefit. Does this mean that no one who progresses through 1st and 2nd line chemo should get more treatment? No, every case needs to be considered individually. For example, I would never hesitate to offer Tarceva to a never smoking woman with adenocarcinoma in the third or even later lines, since the odds of success would be relatively high if she happened to have an EGFR mutation. Alternatively, a relatively healthy patient who has significant shortness of breath and pain from her cancer, and who had at least stable disease for some time with prior therapy, would be a good choice for considering more treatment to help relieve her symptoms. Even for those patients who have really resistant disease, I wouldn’t refuse treatment if they recognized the risks and still wanted to try. My job is not to talk people out of treatment, only to let them know what I think about risk versus benefit. Some patients really define themselves as fighters and are willing to try something even if the chance of benefit is tiny, and that’s OK. But at least they should go into it with their eyes open, and recognize that it is OK to stop treatment too when the odds favor making them worse rather than better.

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