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Where do we go from here with Avastin?
Although Avastin has been approved for first-line treatment of advanced NSCLC, at this point it cannot be universally employed. Patients with squamous cancers account for something in the range of 30% of patients, while patients with brain metastases amount to about 10-15% of patients. Another 5-10% may have hemoptysis, or the symptom of coughing up blood, and many others are on therapeutic blood thinners for a history of blood clots or atrial fibrillation. The trial of Avastin in lung cancer (called ECOG 4599) also did not include patients who had a marginal performance status, defined as being able to care for oneself but not able to work, and patients moderately limited in how active they can be, whether due to fatigue or shortness of breath or other issues, account for a lot of patients in the real world. We also still have trouble predicting which patients will have bleeding complications that can be serious or even fatal, even if only patients who meet the eligibility criteria are given Avastin. We are somewhat concerned about the risk of bleeding in patients with cavitary lesions (with an empty space in the middle, shown below)
and those with central cancers near major blood vessels, but those patients would be eligible for Avastin according to the trial and the approval guidelines. Finally, while most oncologists expect that Avastin would give similar benefits if added to different chemo regimens, we don’t have proof of that yet, nor do we know with certainty that it is safe when combined with other chemo agents.
So trials are now being done to clarify whether Avastin can be given safely to patients with hemoptysis who have received radiation to treat that issue, and to patients who have squamous cancers who may have received prior treatment with radiation to minimize bleeding risk. Other trials are evaluating Avastin in patients with treated brain metastases. Multiple trials are carefully assessing whether the patients with central cancers or cavitating tumors are at significantly greater risk for bleeding, and also will clarify whether women show a benefit with Avastin outside of the ECOG trial. Multiple ongoing trials are combining Avastin with other chemo drugs to ensure that it is safe in other regimens.
Avastin with Chemo: Standard of Care for a Subset with Advanced NSCLC
Avastin (bevacizumab), an antiangiogenic agent that works by blocking the blood vessel stimulating factor vascular endothelial growth factor (VEGF), has already been FDA approved and commercially available for colon cancer, but it has now been approved by the FDA for first-line treatment of non-squamous NSCLC in combination with standard chemo of carboplatin and paclitaxel (taxol). This is because the combination of chemo and Avastin was found in a large randomized trial publsihed in the New England Journal of Medicine (abstract here) that the combination improved survival when combined with chemo alone for patients with advanced/metastatic NSCLC who hadn’t received chemo before. This trial, with nearly 900 patients, compared carboplatin and paclitaxel (Carbo/Taxol) alone to the same two-drug chemo with Avastin every three weeks, and people who went through six cycles of chemo and Avastin without having progression of disease went on to receive Avastin alone as maintenance therapy until their cancer showed progression:
(Click to enlarge)
Staging BAC: Not the Ideal System Yet
Right now we use the same conventional staging system for BAC as with other lung cancers. I don’t have a great alternative just yet. I can tell you that as the lead investigator on several BAC trials, there are huge differences in the natural history of their cancer, regardless of what our treatment does. For instance, the trials for BAC are generally for metastatic/recurrent disease, which can mean anything from a single 1 cm spot coming up 4 years after a lobectomy for lung cancer (expect years and years of doing well, whether on treatment or not), to both lungs filled with BAC lesions (still can be variable, but often a lot less favorable). That’s all still in the same patient group, making it pretty hard to figure out what the treatment is really doing. A trial will look great even if you give sugar cubes if it’s filled with people who have a small amount of
slow-moving BAC.
Using “response rates”, or the frequency of the measured tumors shrinking by 50% or more is a challenge because BAC can appear more like wispy clouds that don’t have clear edges than discrete masses you can draw circles around. So the wisps or cloudy infiltrates in the lungs can become less dense from a useful treatment, and you might breathe easier, but it may not be a response because the edges don’t change.
Moving Toward Individualized Treatment Recommendations for Chemotherapy after Lung Cancer Surgery
A recent trial by Olaussen and colleagues was just published in the New England Journal of Medicine that suggested that in the future oncologists may become better at identifying the patients who are more or less likely to benefit from chemotherapy after surgery for early stage non-small cell lung cancer. At this point, the marker that was being evaluated is not readily available and hasn’t been validated, but it’s a very promising lead. In this trial, the group with tumors that have low expression of this protein, called ERCC-1 (which repairs DNA damage induced from cisplatin-based chemo), did better with chemo than if they didn’t get it. The other group, who had high expression of ERCC-1 on their tumors, did better if they didn’t get chemo than if they did. Because chemo can have some unpleasant and sometimes dangerous side effects, clarifying who is more likely to benefit and who will get just side effects and no benefits would be a great help.
This adds to the conclusions from work of others, such as Dr. Rafael Rosell in Barcelona, Spain and by Dr. Gerold Bepler at Moffett Cancer Center in Tampa, FL, who have both done studies suggesting that tumor markers can soon help us predict who will benefit from certain types of chemotherapy and who will be less likely to benefit.
The limits of this study are that it was retrospective, or reviewing what was available after the fact, and that it included only tissue from a subgroup, about 40% of tumors from patients on the study. This work needs to be corroborated by further trials, especially ones that look at these questions prospectively (planned going into the study, so everyone’s tissue is included). These marker studies are not routinely performed or widely available. Before using such markers for clinical decision-making, we need to standardize how the marker studies are done and interpreted. However, this work is an early indication of how we hope to further treatment recommendations for patients with cancer in the near future.
Defining Bronchioloalveolar Carcinoma (BAC): One End of a Spectrum
The clinical syndrome of BAC is characterized by spread primarily through the lungs, a higher proportion of never-smokers or light former smokers, a greater proportion of women, and often progresses more slowly than most other lung cancers. This clinical and radiographic (scans) scenario isn’t necessarily seen only with “pure BAC” under the microscrope from a biopsy, but rather can be a spectrum from pure BAC to part non-invasive BAC pattern and part invasive adenocarcinoma, and on the other end of the continuum is invasive adenocarcinoma, as shown in the illustration of how these appear under a microscope.
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| Pure BAC | Adeno w/BAC Features | Invasive Adeno |
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