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Global differences: Shouldn’t every curable patient have the right to the best treatment?
One of the things we learn when studying the clinical research in lung cancer is that “global studies” often include patients with locally advanced (stage III) NSCLC along with those who have advanced (stage IV) NSCLC. Part of the confusion has been the ungainly status of stage IIIB NSCLC with a malignant pleural effusion — historically termed “wet IIIB disease” — in the IIIB camp but not having the curability of patients with “dry IIIB disease” –unresectable locally advanced NSCLC without a malignant pleural effusion. But while North American (at least US) trials over the past 10-15 years that are meant for patients with incurable advanced NSCLC have nearly always included only patients with wet stage IIIB disease (now moved to stage IV in the newest and most accurate lung cancer staging system) and stage IV NSCLC, trials done in other parts of the world, and especially in Europe, have often allowed patients with unresectable dry stage III NSCLC to be included as well. In their trials, patients with stage III NSCLC typically comprise only about 10-15% of the overall trial population, but I must confess that I’ve gone from just shrugging my shoulders and saying to myself, “I guess that’s how they do it”, to a perspective where I’m more inclined to articulate that this is inappropriate and objectionable, for two reasons.
Introduction to Locally Advanced, Unresectable Stage III NSCLC
When I was a medical student, the question about lung cancer that was always asked on “the Boards” had to do with the difference between stage IIIA and stage IIIB non-small cell lung cancer (NSCLC). The reason this question was always asked is because patients with stage IIIA NSCLC might be considered for surgery, whereas patients with stage IIIB NSCLC would not be considered for surgery and instead would be treated with chemotherapy and radiation. The idea is that young doctors should be able to make that distinction and to direct patients to the appropriate specialist/treatment. While I guess it makes a good test question, this distinction is too simplistic and doesn’t really give anyone a good understanding of the complexities of managing stage III lung cancer. And, in reality, all patients with suspected stage III lung cancer should be evaluated by a multidisciplinary team that includes thoracic surgeons, radiation oncologists, pulmonologists and medical oncologists. If the Medical Board would write a test question aimed at getting across this important principle, I’d breathe a big sigh of relief for lung cancer patients.
Locally Advanced NSCLC in the Frail/Elderly: Podcast of Case Discussion with Drs. Hesketh and Kelly
Here is the second of three cases covering issues in managing elderly and frail patients with lung cancer that I discussed with experts Paul J. Hesketh from Lahey Clinic and Karen Kelly from Kansas University Medical Center. Both major experts in lung cancer, they have a lot of experience and have been leaders in publishing on the understudied population of elderly and poor performance status patients with lung cancer. This particular case covers treatment options for a patient with unresectable stage III non-small cell lung cancer (NSCLC).
Here is the audio and video versions of the podcast, along with the figures and transcript.
loc-adv-nsclc-in-frail-and-elderly-patients-hesketh-and-kelly-audio-podcast
loc-adv-nsclc-in-frail-and-elderly-patients-hesketh-and-kelly-transcript
loc-adv-nsclc-in-frail-and-elderly-patients-hesketh-and-kelly-figures
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Dr. Shirish Gadgeel on Managing Locally Advanced NSCLC
Our next podcast slide presentation comes from Dr. Shirish Gadgeel, medical oncologist at Wayne State University in Detroit. He came out to Seattle for a physician education program I run and was kind enough to stay for our NSCLC Patient Education Forum, where he spoke on our Current Standards of Care for Locally Advanced (Stage III) NSCLC.
Here’s his presentation in audio and video formats, along with the transcript and copies of the slides.
gadgeel-management-of-locally-advanced-nsclc-transcript
gadgeel-management-of-locally-advanced-nsclc-figures
gadgeel-management-of-locally-advanced-nsclc-audio-podcast
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Consolidation Tarceva after Chemo/Radiation for Locally Advanced NSCLC: At Least It Isn’t Significantly Harmful
Perhaps the most unexpected clinical trial result in lung cancer over the past 5 years was the finding in the large Southwest Oncology Group (SWOG) 0023 trial that randomized several hundred patients to maintenance therapy with either the oral EGFR inhibitor Iressa (gefitinib) or a placebo after chemo/radiation concurrently and then consolidation taxotere (docetaxel). While just about everyone in the lung cancer community expected to see either a significant benefit or, at worst, no real effect from maintenance Iressa, the actual trial was stopped early and demonstrated a statistically and I would say clinically significant decrease in overall survival with maintenance Iressa. The median overall survival (OS) in the final publication was a full 12 months lower in patients who received Iressa compared with those who received the placebo .
To me, not only did this study demonstrate that giving consolidation EGFR inhibitor therapy was probably a bad idea, at least outside of a clinical trial, it also suggested that we don’t necessarily know as much as we presume we do about how trials will turn out, so it makes sense to do the studies rather than just start a new strategy without the evidence to back it up.
Managing Locally Advanced NSCLC: Summary from a Talk to Patients & Caregivers
Here is the third portion of a talk I did at the Seattle-based non-profit Cancer Lifeline in May, and this section focuses on our current standards for managing unresectable locally advanced (stage III NSCLC). This covers theissues of sequential vs. concurrent chemo with radiation and the important issue of whether additional consolidation chemo after the radiation is feasible and advisable. It also covers the emerging key trials being done in this treatment setting.
Here is the presentation in video format, the audio version, transcript, and a pdf file of the figures.
Cancer Lifeline Part 3 Locally Advanced NSCLC Audio Podcast
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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.
Interview with Dr. Suresh Ramalingam: Current Standards and Controversies in Locally Advanced NSCLC
Dr. Suresh Ramalingam is a longtime friend of mine and a national leader in the field of lung cancer. He is the Director of the Lung Cancer Program at the Winship Cancer Institute at Emory University in Atlanta, and he was kind enough to sit down with me to talk about his perspective on the current optimal treatment for patients with stage III, or locally advanced, NSCLC. We also spoke about managing metastatic disease, which will be covered in a separate podcast. It’s an audio interview, but if people watch the video version, there are some figures synchronized with the discussion.
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What I Really Do: Locally Advanced, Unresectable NSCLC
The setting of unresectable, stage IIIA or IIIB NSCLC (without a malignant pleural effusion) is currently one for which what we feel is best for the patient isn’t necessarily something for which we have good evidence. For fit patients, there is a strong consensus that giving concurrent chemo with radiation provides a modestly but consistently higher cure rate than giving chemo and radiation sequentially. But that concurrent chemoradiation plan lasts for only 6-8 weeks, but whether there’s more we should be doing, or what we should do, is entirely unclear.
As described in a prior post, several studies in the last decade have shown that about two cycles or 6-8 weeks of weekly chemotherapy along with about 60-66 Gray of radiation over 6-8 weeks is associated with the best survival results we’ve seen in unresectable, locally advanced NSCLC (somewhere in the 20% range long-term, and a median of about 16-18 months). There are two main approaches in North America for the chemotherapy. Some use the SWOG approach that showed very promising early results (prior post here), giving cisplatin and etoposide. The other very common alternative that is widely used in a community setting is weekly carboplatin/taxol. Until very recently had relatively little published experience to support it, but in the last few years now has been included in a few trials that demonstrate survival in the same ballpark as what we routinely see with cisplatin-based chemo: examples include RTOG trials such as described in a prior post and another abstract.
Erbitux with Radiation in More Marginal Patients with Locally Advanced NSCLC
One of the core ideas in the management of stage III, or locally advanced, NSCLC is that unresectable disease that is being treated with curative intent is most effectively treated with a combination of concurrent systemic (“whole body”) therapy and chest radiation to all of the visible cancer. The systemic therapy, which has been conventional chemotherapy, is given to both make the radiation work better and to treat potential micrometastatic disease, cancer cells in the bloodstream that can’t be reached by radiation but could potentially be killed off by a treatment that goes throughout the bloodstream.
The challenge, though, is that concurrent chemo and radiation is hard on people, with a rate of treatment-related deaths of about 5-7% of people even on clinical trials (which often select for a fitter population than are seen in the “real world” of many ineligible patients). So we reach a point where the aggressiveness of the treatment can be associated with problems that are as threatening or worse than the underlying disease. And this is a particular problem for older and/or frailer patients, which happens to cover a significant proportion of people with lung cancer.
Part of the promise of targeted therapies all along has been that they could potentially substitute for standard chemotherapy as a systemic therapy that is perhaps as effective as chemo but with fewer side effects. Most of our work with these agents has been to just add them to our current standards, but it still makes sense to consider using them as a substitute in patients for whom conventional chemo is really at the upper limits of what is tolerable. And it’s clear that doing chemo concurrent with radiation is overall more effective than doing them sequentially, but perhaps we could get the tolerability of a sequential approach with the efficacy of concurrent therapy by doing a program of targeted therapy (and no chemo) concurrent with chest radiation.
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