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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)

 

Optimal Duration of Therapy for First-Line Advanced Lung Cancer
Author
Howard (Jack) West, MD

The guidelines from the American Society for Clinical Oncology (ASCO) for NSCLC start the discussion on how long to continue first-line chemo as follows: "The optimal duration of chemotherapy remains a matter of debate." Just in case you thought it was only me saying that we don't know the exact answer for one issue or another, the evidence-based guidelines are filled with hedge comments like this. So I'll cover what we know and what we don't know, and how it leads most oncologists to give between 4 and 6 cycles of platinum-based doublet chemotherapy for either advanced NSCLC ("wet" stage IIIB with a malignant pleural effusion or metastatic/stage IV) or ED-SCLC.

We often treated for 6 cycles of longer in patients who weren't showing evidence of clear progression after 6 cycles, and some people still do. However, prolonged chemotherapy can increase cumulative side effects, and there was no evidence that prolonged treatment improved survival. This became especially important in the last few years, now that we have therapies with a proven survival benefit as second-line therapy or later. Patients are living longer and have an increasing number of options for treatment after first-line, so we want to ensure that patients have the best balance of effective treatment and good quality of life as possible, and that they are candidates for later therapies while still having strength and good organ function (liver, kidney, and also bone marrow function with good blood counts). It is therefore increasingly important to determine when we've reached a point of diminishing returns and should stop a treatment.

We have a small amount of actual evidence to answer the question for NSCLC. Dr. Mark Socinski at Univ. of North Carolina at Chapel Hill ran a randomized trial (abstract here) in which 230 patinets with previously untreated advanced NSCLC to carboplatin and paclitaxel every three weeks for 4 cycles only, or the same treatment on an ongoing basis until they showed evidence of progression. Patients would go on to receive paclitaxel on a weekly basis at the time of progression. The trial design is shown here:

Socinski Duration of therapy trial (click to enlarge)

There was no improvement in overall survival or greater response rate in the group that received ongoing doublet chemotherapy, but they did experience a higher rate of neuropathy serious enough to interfere with activities of daily living or even be disabling (grade 3 or 4, respectively).

Socinski results on duration of therapy

In addition, a very similar trial from the UK (abstract here) supported the exact same results. This trial gave an older chemo regimen that isn't routinely used any in the US anymore (cisplatin, vinblastine, and mitomycin C) to 308 previously untreated patients with advanced NSCLC, comparing the differences between three and six cycles. They found that there were just slight differences favoring longer treatment in terms of response rate (31% vs. 38% for ), and median survival (6 vs. 7 months), but these were not statistically significant.

In fact, these trials and others have shown that it's very unlikely to have ongoing tumor shrinkage beyond four cycles, and beyond the point of 3-4 cycles, tolerability of treatment also becomes an increasingly important factor. Moreover, with additional therapies that are likely to provide some clinical benefit available in the second-line setting and potentially beyond that, I strongly suspect that the benefits for prolonged first-line therapy are even more diluted by the growing number of effective options that will follow.

The existing clinical trials, which are useful as a window of what the field considers to be optimal care, generally include 4-6 cycles of treatment. In the trials of chemo combined with the EGFR inhibitors Iressa and Tarceva, the trials gave doublet chemo for up to six cycles, along with concurrent EGFR inhibitor, followed by ongoing EGFR inhibitor therapy until progression in patients who hadn't shown progression after six cycles. Similarly, the ECOG 4599 trial that led to the approval of Avastin in lung cancer and was just published in the New England Journal of Medicine (abstract here) gave up to six cycles of carbo/paclitaxel along with Avastin every three weeks, and then maintenance Avastin in patients who hadn't shown progression after six cycles of chemo. Meanwhile, in the trials that are focusing on maintenance therapy, adding drugs like Erbitux (cetuximab) or Tarceva immediately after chemo as a sort of planned early second-line treatment, the first line therapy is often just four cycles of a platinum-based doublet, as shown here in an example:

SWOG 0342 schema

Conclusion: it isn't very well studied, but the available evidence suggests 3-4 cycles is as good as more, and most oncologists recommend 4-6 cycles as the point of diminishing returns.

For ED-SCLC, there's no direct comparisons, but the same ideas apply. Most of the older studies gave six cycles of platinum-based chemo. However, newer trials have generally treated with four cycles, including the Japanese trial by Noda and colleagues and the current SWOG trial 0124, as we recognize that SCLC generally responds quickly and cumulative toxicity is a concern. In a trial by Hanna and colleagues (abstract here) that compared cisplatin/irinotecan on a weekly schedule with cisplatin/etoposide and found no significant differences in efficacy outcomes between the two arms, patients could continue treatment beyond four or even six cycles at the discretion of the treating physicians, except that they were required to discontinue treatment for prohibitive severe side effects or progression of cancer. You can see the breakdown of treatment patterns among these research-oriented oncologists:

Hanna SCLC Cycles Administered Breakdown

So 33% of patients on the cisplatin/irinotecan arm continued beyond 4 cycles, and 48% on the cisplatin/etoposide arm did, a difference that is not explained in the paper. Only 3-8% of patients continued treatment beyond six cycles, and a mere 2-4% were receiving 8 cycles or more, for a variety of reasons ranging from side effects to disease progression to patients begging for mercy (or just saying they've had enough) to physicians recommending against more therapy in the setting of having reached a point of diminishing returns.

That's what we know, and we can come back to the starting point and say that there are no standards etched in stone. However, the available evidence and the general consensus of general practice as well as the design of current clinical trials that are set to provide the gold standards of treatment generally pursue 4-6 cycles of first-line chemo for both NSCLC and SCLC.

These conclusions don't necessarily apply to treatment in the second-line setting and beyond, and I'll talk about that next.

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