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Tumor Size as a Critical Factor in Weighing Value of Adjuvant Chemo
While there are good reasons to not pursue chemo after surgery for stage I NSCLC, there are several factors that argue at least for strong consideration of adjuvant chemotherapy for higher risk patients. Because stage IB generally has a less favorable prognosis than stage IA, it’s not suprising that the debate about which patients should or should not be receiving post-op chemo has centered more on the stage IB population, which have much more commonly been included in trials testing the value of adjuvant chemotherapy. Now we’ll focus on why tumor size has emerged as probably the most important factor in borderline cases where we might consider adjuvant chemotherapy but aren’t definitely convinced.
In my last post I enumerated reasons to not pursue adjuvant chemo for stage I patients, in whom the separation between T1 cancers and T2 cancers is usually the size, with a cutoff of greater or less than 3 cm (involvement if the pleural lining on the outer edge of the lung can also make a smaller tumor a T2 lesion). In that post, I described several positive adjuvant chemotherapy trials that did include stage IB patients, including the IALT trial (abstract here), Canadian BR.10 trial (abstract here), and the ANITA trial (abstract here), but in all of these cases, the stage I patients showed little or no benefit while the benefits were much greater for stage II and IIIA patients. And then there is the very important CALGB 9633 trial (preliminary 2004 abstract here, revised 2006 abstract here) that randomized over 300 patients, all with resected stage IB NSCLC, to 4 cycles of carbo/taxol or observation alone. As described in detail in my prior post, the preliminary results of the trial were positive overall, with a 12% improvement in overall survival at four years in recipients of carbo/taxol, but the curves came together and were not significantly different for overall survival (but were better for progresison-free survival) for those receiving adjuvant chemotherapy. But at the time that the revised negative results for the overall study were presented, Dr. Strauss presented an analysis of his trial outcomes that showed that the stage IB patients who had cancers of 4 cm or larger had a significant benefit from chemotherapy, while there was no benefit from the patients with tumors that were less than 4 cm:
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The Case Against Post-Operative Chemotherapy for Stage I NSCLC
Over the last several years, chemo for resected early stage NSCLC has become a standard of care, but while it’s pretty widely accepted for stage II and IIIA patients after surgery, the role for chemo is much more debatable for stage I patients. I’ll try to explain why, starting with the downside, and then turn to some of the reasons to consider it.
Several years ago, the first large randomized trial that showed a survival benefit for adjuvant (post-operative) chemo, the International Adjuvant Lung Trial (abstract here) included over 1800 patients ranging from stage I to stage III, and it showed a rather modest, 4% survival benefit at 5 years. The trial looked at different subsets, and there were no significant differences, but the benefits were greater in the patients at higher risk for recurrence, with higher stage and more extensive lymph node involvement:
(Click image to enlarge) Continue reading
How Should We Treat Frail Patients with Locally Advanced NSCLC?
Despite the fact that a very significant proportion of the “real world” patients have considerable medical problems such as markedly decreased lung function (pretty common with many years of smoking), weight loss (5 or 10% of body weight is usually considered a problem), or otherwise are not able to be very active. The vast majority of clinical trials for potentially curative, combined modality (chemo and radiation) approaches of chemotherapy and radiation have often been restricted to patients with a good performance status (PS), which means that patients are either unrestricted in their activities or are symptomatic but able to perform light work activities. Chemoradiation approaches, and especially those that include concurrent chemotherapy and thoracic radiation therapy (RT), are generally accompanied by considerable acute side effects and a treatment related death rate in the 5-6% range even in quite fit patients. With such challenges even for the healthier patients, this precluded those with marginal PS at baseline from participating in more rigorous multimodality strategies. So how should we manage patients with a PS of 2, corresponding to an ability to care for themselves but unable to work? The short answer is, we don’t have enough information to say, but there are a few studies that have addressed this very under-studied population.
One early study that demonstrated the feasibility of an attenuated concurrent chemoradiation approach in marginal patients not able to safely receive standard platinum-based chemotherapy and radiation was SWOG 9429 (abstract here). This multicenter, single arm study (everyone received the same treatment) accrued 60 “poor risk” patients, defined as having a PS of 2 with low blood protein levels or >10% weight loss, insufficient lung function reserves for more aggressive combined therapy (measured by the amount of air someone can blow out of their lungs in one second, called the FEV-1, for forced expiratory volume), or medical problems that made it infeasible to give standard cisplatin (including hearing loss, kidney problems, congestive heart failure, or peripheral neuropathy). The treatment approach included a relatively low dose of carboplatin IV on days 1 and 3, along with etoposide the first four days of a 28-day cycle. Chemo was given for a total of two cycles concurrent with daily chest radiation to 61 Gray (Gy) — a full dose. This trial demonstrated feasibility of this approach, with moderate acute toxicity and no treatment-related deaths, as well as encouraging efficacy: the median overall survival of 13 months, and the two-year survival was 21%; these numbers are in the ballpark of results from trials with more vigorous patients. Probably significantly, the majority of enrolled patients had a good PS and compromised pulmonary function, with only 18% of enrolled patients having a PS of 2. Continue reading
Comparison of Iressa to Single Agent Chemo in First Line treatment for Elderly Advanced NSCLC Patients: The INVITE Trial
In addition to a direct comparison of iressa to chemo in the second line setting for advanced NSCLC (see recent post on INTEREST trial), as conducted with the INTEREST trial I described in a recent post, a very similar comparison of Iressa to chemo was also performed in another setting where single-agent chemo is also the treatment of choice. Specifically, the INVITE trial evaluated iressa vs. navelbine as a single agent in previously untreated advanced NSCLC (abstract here).
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As discussed in one of my early posts, there is room to debate whether single agent approaches or older patients should receive single-agent chemo or standard platinum-based doublets (particularly carboplatin-based instead of the more challenging cisplatin doublets). Among the most commonly used single chemo agents in the elderly population is navelbine (also known as vinorelbine), based on it being proven to improve survival compared with supportive care alone in the memorably named ELVIS trial (Elderly Lung Cancer Vinorelbine Italian Study – paper here). We’ve seen the results of a trial in which tarceva was compared to the chemo doublet of carbo/taxol in patients with a marginal performance status (not the same population as elderly), and as I described in a prior post, the recipients of chemo fared better than those who received tarceva. So did the INVITE trial show similar results for gefitinib in the elderly compared to a single chemo agent? Continue reading
The INTEREST Trial of Chemo vs. Iressa as Second Line Treatment for Advanced NSCLC
In a post several months ago, I described the results of a trial from Japan, designated V-15-32, that directly compared Iressa to Taxotere as a second line therapy. Although overall comparable, the study showed that Japanese patients receiving Iressa had a higher response rate, but despite that had a lower median and one year survival. Although Iressa overall has not shown the same degree of clinical benefit as the very similar drug Tarceva, these results were perhaps a bit surprising because EGFR inhibitors have been most effective in Asia, where a higher proportion of lung cancer patients are never-smokers and/or have an EGFR mutation. But the Japanese trial had the problem that more patients randomized to Taxotere received a potentially effective therapy (different agent with potential activity in previously treated patients) after the trial drug than patients on the Iressa arm.
One of the trials presented at the Presidential Symposium at the recent World Conference on Lung Cancer in Seoul, Korea, was called the INTEREST trial (I don’t remember what the acronym stands for, except that it was a major stretch), led in North America by my friend Ed Kim from MD Anderson Cancer Center. This trial (abstract here) had almost the exact same design as the Japanese study, again randomizing previously treated patients to either Iressa 250 mg daily or Taxotere IV every three weeks.
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The INTEREST trial was run around the world, accruing 1466 patients from 149 centers in 24 countries, making it the largest trial in previously treated patients with NSCLC that has ever been conducted. The Taxotere dose was also 75 mg/m2 every 3 weeks, the FDA-approved standard in the US based on a proven survival benefit in North American trials, while the Japanese V-15-32 trial used 60 mg/m2, which is the standard in Japan and appears to be a dose with the same general toxicity and effectiveness as a higher dose in North American/European populations. Otherwise, the INTEREST trial asked the same question as the Japanese trial but in a broader audience. Specifically, one of the reasons it was so big is that it was looking to see whether the two approaches could be proven to have the SAME survival/clinical benefit, which requires more patients than showing that one is better than another. The trial was also designed to look at whether patients with EGFR gene amplification as measured by the FISH test. Continue reading
Making Sense of the “JMDB” Trial
In my recent post on the JMDB trial that randomized patients between cisplatin/alimta and cisplatin gemcitabine in first line treatment of advanced NSCLC, the take home conclusions were that overall efficacy was very similar, with the cis/alimta arm looking a little better in several side effect parameters, most notably a less significant decline in blood counts and lower risk for fevers with a low white blood cell count. Also, the study showed the quite intriguing finding that those with adenocarcinoma and large cell tumors did signficantly better with cisplatin/alimta, while those with squamous cell carcinomas did notably (not quite statistically significantly) better with cisplatin/gemcitabine.
So a central question, first, is does this make sense? Actually, it very well might, because alimta works partly and potentially substantially by blocking a cellular enzyme called thymidylate synthase (or synthetase) (TS). There was a recent publication (abstract here) that demonstrated that levels of both messenger RNA (the code that is between the DNA and the protein it builds) and TS protein are significantly higher in squamous lung cancers than in adenocarcinomas, and also that the levels were higher in high grade cancers than lower grade ones. Higher TS levels would be expected to be associated with more resistance to alimta, while lower levels would be expected to correlate with sensitivity, as has been shown in some preclinical (lab-based) studies. Continue reading
Erbitux in Context: BMS 099 and other Trials Before FLEX
In my last post, I noted that the FLEX trial of cisplatin/navelbine with or without the EGFR monoclonal antibody erbitux was reported to be positive, demonstrating a significant survival benefit. That’s definitely going to have major implications, since our track record for phase III trials of chemo with or without new drug X was very poor for most of the last several years, until the negative streak was broken by the ECOG 4599 trial with Avastin added to carbo/taxol. Here’s the older scorecard we had:
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Not so good. EGFR inhibitors have been pretty well tested, including both Iressa and Tarceva each in two trials of more than 1000 patients randomized to chemo with or without the EGFR inhibitor, and those trials failed to show a survival benefit overall. But those agents are EGFR tyrosine kinase inhibitors, working on the inside of cancer cells, while erbitux is a monoclonal antibody that works on the outside of the cell against the same target of the EGFR molecule:
FLEX Trial of Chemo +/- Erbitux Shows Survival Benefit
Merck KgAA, the company developing cetuximab/Erbitux, the monoclonal antibody against EGFR, reviewed here) outside of the US, has announced that their pivotal FLEX trial (for First-Line Trial for patients with EGFR-Expressing Advanced NSCLC) is positive, demonstrating a signficant improvement in overall survival, as indicated here. I mentioned it as an important study to define any role for Erbitux in NSCLC, especially since a recent randomized trial I described in a prior post was reportedly negative.
The press release includes no details, just a glimpse of the trial, with a progress report last presented at ASCO 2006 (abstract here). This is a European phase III randomized trial with just over 1000 patients with previously untreated advanced NSCLC that had to have EGFR protein expression by immunohistochemistry (IHC), which is present on about 60-80% of NSCLC tumors. So there was a modest degree of selection of these patients, but a majority of patients would likely be eligible. All patients received doublet chemo with an “old school” combination of cisplatin and navelbine. This is a fine regimen but not commonly used in advanced NSCLC in the US (but still favored as a very good choice in the post-operative setting, since the majority of the best data in this setting is with cisplatin/navelbine). At the time this trial was developed, European oncologists were most commonly giving cisplatin, often with navelbine and gradually giving way in recent years to gemcitabine. Continue reading
A Few Highlights of the Updated Lung Cancer Staging System
A substantial revision of the staging system was presented at the World Conference on Lung Cancer in Korea this week. This project involved multiple lung cancer experts from all over the world and from a variety of specialties over the last several years, who reviewed the data on approximately 100,000 lung cancer cases, both NSCLC and SCLC. They looked at various ways to break down this large database of cases in order to provide a more accurate prognosis for patients. In fact, while we use staging systems to guide our treatments, they are developed primarily as a way to predict the survival of patients by key variables. This new version, which will officially come into effect in 2009 but is being introduced now for the world to become familiar with and to have endorsed by other official cancer groups like the American Joint Committee on Cancer and the International Union Against Cancer.
First, just a few words on the concept of staging. The current cancer staging systems are classified by T N M, which stands for Tumor, Nodes, and Metastases. These are numbered from 0 to some other number. For lung cancer, tumor staging is up to 4, N is up to 3, and M is just up to 1 (you have metastatic disease or you don’t). Various combinations lead to a final stage, and some factors trump others. For instance, you can have any T stage, even just a tiny tumor, but if you have N3 nodal stage (lymph nodes on the other side of the mid-chest from the main, or primary, tumor) and no metastases, the overall stage is IIIB. If you have a metastatic spot (M1), you have stage IV disease, no matter what the T stage or N stage. This page has a summary. Continue reading
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