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Prophylactic Cranial Irradiation for Stage III NSCLC: Some Answers, Some Open Questions
In my last few weeks as a GRACE guest faculty, I have been struck by the number of forum discussions that deal with brain metastases. Brain metastases are a growing problem in non-small cell lung cancer (NSCLC), as well as in multiple other cancers. Why is this? Twenty years ago, patients who developed brain metastases were usually at the end-stage of their cancer, with widely metastatic disease and few systemic treatment options. The prognosis for these patients was very poor, but not really because of the brain metastases. Brain metastases were simply a marker that the cancer was taking over and patients often were on hospice care at that point. Some of the fatalism of those days still holds over to today, but the clinical picture of a patient with brain metastases has changed dramatically.
Now, we have many more effective systemic therapies. Unfortunately, most of those therapies do not penetrate the blood-brain barrier (BBB) very well. The brain thus becomes a “sanctuary site” for cancer cells, where they can hide out and start to grow while the cancer cells in the rest of the body are susceptible to chemotherapy or targeted therapies. I am increasingly seeing brain metastases in stage IV patients with good control of cancer in the rest of their body. I am also seeing more patients with earlier stage lung cancer where the brain is the only place that the cancer has relapsed. This is particularly true of patients with locally advanced (stage III) NSCLC. And this was the motivation behind a rather disappointing trial that was presented at ASCO recently.
Patients with stage III lung cancer have very high rates of brain metastases. Published studies show rates of brain metastases of 30-55%. More importantly, up to 30% of patients have brain metastases as the first site of recurrence. Even though many patients do well with treatment for brain metastases, it would certainly be desirable to prevent this from happening. In small cell lung cancer (SCLC), for instance, prophylactic cranial irradiation (PCI) is now standard practice for both limited-stage and extensive stage patients. Not only does PCI decrease the incidence of brain metastases but it improves survival in SCLC, another disease where the brain is a common site of relapse.
The investigators of tthe trial by the Radiation Therapy Oncology Group (RTOG 0214) hoped that similar results would emerge for patients with locally advanced NSCLC. The trial included patients with stage IIIA and IIIB NSCLC who had undergone treatment and had not progressed with their initial treatment (chemoradiation for most, with 1/3 of patients having undergone surgery). The primary endpoint of the trial was overall survival. Secondary endpoints included disease-free survival, incidence of CNS metastases, neurocognitive function, and quality of life. The trial was designed with a target accrual of 1058. This target accrual for a clinical trial is calculated by statisticians as the number needed to accurately access your hypothesis. Unfortunately, accrual of patients was VERY slow, and though the trial was open for six years, only 356 patients were enrolled. For this reason, the trial closed early.
Correlation of Rash with Survival on FLEX Trial: Predictive or Prognostic?
Completing our tour of clinical factors that we might use for predicting benefit with the EGFR monoclonal antibody Erbitux (cetuximab) in the FLEX trial is the development of a rash. We’re actually discussing rash separately from the other clinical factors from the FLEX trial that we discussed in the prior post for a couple of reasons. First, rash on the treatment isn’t something you can know about until you’ve committed yourself to at least starting the treatment (you can’t have an Erbitux-induced rash before giving Erbitux). Second, it’s not really clear whether this rash is predictive of doing particularly well with Erbitux or prognostic of doing well in general (on Erbitux or anything else).
For years, the EGFR inhibitor side effect of rash has been associated with more favorable outcomes, as I’ve described in one of my earliest posts, on the potential significance of a rash on EGFR inhibitors. The investigators who developed the FLEX trial decided prospectively (pre-planned, not a “fishing expedition”) to look at how patients did as a function of whether they developed a rash in the first 21-day cycle of treatment (all patients alive at day 21 were included). They found that 55% developed a rash to some degree, while 33% developed a grade 1 (mild) rash, 18% developed a grade 2 (moderate) rash, and 5% developed a grade 3 (severe) rash.
It was very interesting to see that the patients who developed a rash on Erbitux did far better than those who did not. In fact, it was also interesting to see that the patients who didn’t develop a rash on Erbitux had a worse median survival than the patients who were assigned to chemo alone:
FLEX Trial Survival by Rash
(click on figure to enlarge)
Clinical Factors on the FLEX Trial: Do Certain Patient Groups Benefit More or Less with Erbitux?
In the last post that presented the highlights of the FLEX trial that tested the benefit of adding Ebritux (cetuximab) to standard chemo. The trial was technically positive, statistically significant, but the results in the overall population of the trial were so marginally superior with Erbitux that a very logical follow-up question is whether we might identify certain subgroups of patients who benefit more, enough to definitely add Erbitux, while not pursuing it for other subgroups that appear to benefit much less.
It’s important to add a word of caution about interpreting information gleaned from patient subsets. Clinical trials are generally designed to have enough patients to show differences in the entire trial with everyone. Nevertheless, when you dissect it ten different ways, the smaller subgroups don’t have adequate numbers to show significant differences, even when they may really exist. At the same time, doing multiple different comparisons escalates the chance that you’ll randomly find differences that aren’t real, and that occur just as a product of random chance. In fact, trials are generally powered to consider a difference as significant only if the probability of the difference happening by chance is less than 5%, but if you slice and dice the results to do ten different subgroup tests, the likelihood of at least one coming up positive just by chance is now 22%.
So these comparisons aren’t really conclusive and are better suited for shaping our ideas for future research than for guiding our treatment decisions. In reality, people (present company included) tend to pick and choose which subgroups they focus on to support their inclinations, while discarding other comparisons.
To provide the general picture, there’s a figure called a forest plot that shows the performance of multiple subgroups simutaneously. Here, the size of the different subgroups is represented by the size of the black ovals, and the position of the oval to the relative to the vertical line shows whether the Ebritux group did better (if the oval is to the left of the vertical line, sometimes referred to as “unity”) or the chemo alone arm did better (if the oval falls to the right).
FLEX Trial Forest Plot
(Click on image to enlarge)
FLEX Trial Redux
I covered the highlights of the FLEX trial, reported at the Plenary Session of ASCO 2008, a full year ago, but in that time, we never showed the survival curves or covered all of the details. It’s time to rectify that, now that it’s actually been published, and we’re left to reflect on whether certain subgroups benefit more or less, and how the subject of the FLEX trial, the EGFR monoclonal antibody Erbitux (cetuximab) should be used in treating advanced NSCLC.
The European sudy compared standard chemotherapy alone to the same chemotherapy with weekly Erbitux in previously untreated advanced NSCLC. It included over 1100 patients, who were screened as needing to have the EGFR protein on their tumor by a test called immunohistochemistry (IHC), because this is the target that the EGFR monoclonal antibody is supposed to bind to. The definition of a positive test for EGFR by IHC was extremely liberal, since only a single cell with the protein was required for patients to be enrolled. Even with such liberal criteria, 15% of the screened patients had no EGFR protein on a single cell and were excluded from the trial.
As with most recent trials with targeted agents, it was degined to give up to six cycles of chemo with or without the novel agent,in patients who didn’t show progresison after six cycles, patients assigned to the experimental arm (with the new agent) would continue on weekly Erbitux as a maintenance therapy. The specific chemo used was cisplatin/navelbine (vinorelbine), a combination rarely used for metastatic NSCLC in the US but a common standard in Europe.
Putting this all together, the trial design is shown here.
FLEX Trial Design
(click on figure to enlarge) Continue reading
Get ready to throw out your Premarin (again): Thoughts on hormones and lung cancer
The role of hormones in the development and progression of lung cancer in women has generated much interest. Unfortunately, a lot of the data to date has been observational, which doesn’t establish a “cause and effect” relationship. The Nurses Health Study (more on this below) is a good example: a large cohort of women was observed over time. The women completed questionaires on all sorts of exposures (diet, hormone replacement therapy, tobacco, etc), and they were followed over time. Then, investigators tried to sort out whether there were differences in exposures between women who got a given disease and those who didn’t. These types of studies can be “hypothesis-generating” but rarely yield clear results. It can be very difficult to isolate one exposure amongst many other confounding variables.
At ASCO this year, the Women’s Health Initiative (WHI) Study investigators presented important new findings from this landmark study of hormone replacement therapy (HRT). Most women are familiar with the earlier reported findings of this study because those findings led physicians to STOP recommending HRT for post-menopausal women (previously considered beneficial). Most may not be familiar with the details of the study design so here is a refresher. This study enrolled healthy post-menopausal women with no history of breast cancer. Over 16,000 women were enrolled: half were randomized to HRT with estrogen plus progesterone, the other half received placebo. The investigators were primarily interested in the risk of breast cancer and cardiovascular disease. Other cancers specifically studied included endometrial cancer and colorectal cancer. The study was stopped early, because the investigators found significantly more risks than benefits associated with HRT compared to placebo. Specifically, women who received HRT were 30% more likely to develop cardiovascular disease, 26% more likely to be diagnosed with breast cancer, and had a 40% increased risk of stroke.
Though the study stopped early, the women continued to be followed. In a recent update, the investigators noted an increase risk of malignancy (other than the three previously studied cancers) in women who took HRT. They decided to analyze the risk of lung cancer in the two cohorts of women.
MSH2 and Platinum Resistance in Early Stage NSCLC: It’s Not All ERCC1
In 2007 there was much excitement about the publication of a study by the researchers behind the landmark IALT adjuvant chemotherapy trial, which suggested that patients with early stage NSCLC could be divided into those who benefited greatly from cisplatin-based adjuvant chemotherapy and those who did not. The marker that defined these patients was called excision repair cross-complementation group 1 (ERCC1), a critical protein in the repair of DNA damage from platinum, and patients with low levels who did not receive chemotherapy after surgery had a much worse prognosis than those with high levels.
More importantly, the patients with high levels of ERCC1 did not seem to get any benefit from chemotherapy, with a survival numerically (but not significantly) worse than patients who did not receive chemotherapy. Patients with low ERCC1 levels, whose tumors presumably could not repair DNA damage as well, had a markedly better survival after platinum-based adjuvant chemotherapy compared to the group who didn’t get chemo. Dr. West covered this in a post in 2007, and I think accurately captured the state of excitement at the time on this potentially very useful test.
IALT ERCC1 Survival Curves
(Click on image to enlarge)
Of course, 2 years later we still do not routinely test for ERCC1, and presumably many patients get adjuvant chemotherapy that will be unlikely to benefit from it (or do not get it when they probably should). I’m not sure why this hasn’t been tested more aggressively, but it may be because of the underwhelming results to date from ERCC1-guided treatment of patients with metastatic NSCLC. In these patients, low ERCC1 levels seem to predict for increased response rate and time to progression, but don’t seem to have much impact on survival. This may be because of the heterogeneity of metastatic cancer, such that a biopsy to test ERCC1 in one lesion does not accurately reflect ERCC1 levels everywhere. Alternatively, ERCC1 may not be the whole answer…
Pre-Op vs. Post-Op Chemo Showdown: The NATCH Trial
Post-operative, or adjuvant, chemotherapy is a standard approach for higher risk patients with resected early stage NSCLC, based on several randomized trials that have been presented and published in the last few years that show a survival benefit from chemotherapy. All of the trials that have shown a statistically significant survival benefit have given chemotherapy after surgery, but it’s hard to envision why the same chemotherapy given before surgery wouldn’t be just as good or better. Pre-operative, or neoadjuvant, chemo allows treatment of potential micrometastases at the earliest possible opportunity. Probably more importantly, if it’s helpful to give chemotherapy to reduce the risk of recurrence with early stage NSCLC, we’d suspect that more patients can actually get their intended chemo if it’s given before surgery vs. after.
Still, we don’t have the trials to support the idea that neoadjuvant chemotherapy is as good or better than adjuvant chemotherapy. Some trials of pre-operative chemo have suggested a similar magnitude of benefit as post-operative chemo, but haven’t been large enough to have the improved survival be significant. Overall, we might suspect that neoadjuvant chemotherapy is a strong alternative, and a “meta-analysis” of multiple studies showed that three was no significant difference in outcomes between these strategies, but neoadjuvant chemotherapy hasn’t been studied well enough to be readily adopted as a standard of care.
Talk with Patients: Relapsed SCLC and Amrubicin
A few weeks ago, I gave a talk at a Seattle non-profit called Cancer Lifeline, at which I described some of the highlights of current lung cancer treatment and the direction of ongoing research. I recorded that lecture (which does include some stray sounds in the background), and I thought it would be helpful to make it available to people online.
The talk lasted over an hour, so we’re breaking it up into pieces on a discrete topic. The first one is on SCLC and specifically relapsed disease, where I focused primarily on work with amrubicin.
Here is the slide set, the transcript, a link to the audio (mp3) version, and then the video podcast presentation. More topics to come.
cancer-lifeline-talk-part-1-sclc-figures
cancer-lifeline-talk-part-1-sclc-transcript
Audio version Cancer Lifeline Talk Part 1 SCLC
Podcast: Play in new window | Download (26.5MB) | Embed
Maintenance Tarceva: Ready for Prime Time? Part 2: The ATLAS Trial
Last week we discussed SATURN, the first of 2 recently presented trials testing the role of maintenance Tarceva (erlotinib) in advanced NSCLC patients. Today I will discuss the ATLAS trial, the last of the 4 major maintenance therapy trials (along with immediate versus delayed Taxotere (docetaxel) and maintenance Alimta (pemetrexed)). In the SATURN trial of maintenance Tarceva or placebo after 4 cycles of first-line chemotherapy, Tarceva prolonged progression-free survival (PFS) by about 1 week although the true benefit may have been more robust than that number indicates.
The ATLAS trial was of nearly identical design to the SATURN trial. Patients with advanced NSCLC were randomized after completing 4 cycles of platinum doublet chemotherapy with Avastin (bevacizumab) to either maintenance Avastin plus Tarceva or Avastin plus placebo. The goal, or primary endpoint, was to show improved PFS with the combination of Avastin and Tarceva.
ATLAS and SATURN Trial Designs
(click on image to enlarge)
Risk/Benefit from Adjuvant Chemo for Early Stage NSCLC: Maturing Data Help Us Discriminate Likely Beneficiaries
Over the last 5 years, it’s become standard to consider and often recommend post-operative chemotherapy to patients with higher risk, early stage lung cancer in order to reduce the risk of it recurring and increase the cure rate. In that time, we’ve also seen that there are subgroups of patients who may be harmed by chemo. This may be because their risk of recurrence is not high enough to justify the potentially detrimental effects of adjuvant chemotherapy, or because they are relatively resistant to chemo, or a combination of these issues.
One of the most influential messages from a trial in which carbo/taxol was given to patients with resected stage IB lung cancer is that the patients with tumors 4 cm and larger seemed to benefit from chemo, while those with tumors smaller than 4 cm did not. This is still a controversial point: another important trial, known as BR.10, was led by NCI-Canada gave cisplatin/navelbine to patients with stage IB and II resected NSCLC and showed a 15% improvement in 5-year survival, but the publication showed that the benefit was only in the patients in the stage II category. Stage IB patients didn’t get the benefit with post-operative chemotherapy.
This past ASCO included a presentation of the longer-term, updated results for that BR.10 trial of adjuvant chemo vs. observation alone. These updated reports are really relevant, because we need to care about long-term survival, and more mature follow up of the IALT trial and some other work has shown that some of the early survival benefits may weaken with longer-term follow-up. In contrast, the more mature analysis from BR.10, with a median follow-up of 9 years, shows that the advantage with chemotherapy is still significant over time, with 5-year survival at 67% vs. 56%.
BR.10 Trial Mature OS Results
(Click on figure to enlarge)
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