Small gains in pancreatic and gastric cancers add up


Two small steps forward emanated from the ASCO Gastrointestinal Cancers Symposium going on this week, and they both raise the difficult issue of very small gains and what they mean.

In patients with advanced pancreatic cancer, the addition of the chemotherapy agent Abraxane (albumin-bound paclitaxel) to the standard chemotherapy Gemzar (gemcitabine) improved survival by a median of a little under two months. There are no standard therapies for stomach cancer in the second line, and in another study presented, the use of Taxotere (docetaxel) in this setting improved survival by a median of 1.5 months.

What are we to make of these small gains? Are they worthwhile? The answer depends on who you ask, but from my perspective as a medical oncologist, these are truly welcome advances. First of all, we have to recognize that these are average gains, and for a small number of patients the gains could be much longer--maybe exceeding a year. Second, while we recognize that side effects and financial costs have to be reflective of the overall benefit, we also know that these small steps add up, and more importantly lay the foundation for bigger improvements down the line.

We never would have enjoyed the success of drugs like Herceptin for breast cancer or stem cell transplant for leukemia if it were not for the chemotherapy underpinnings that themselves may not be as glamorous or ground-breaking, but are very important components of treatment. However, as we help our patients and families through difficult treatment decisions, we have to be very frank about the projected risks and benefits and must have realistic expectations to temper the hope we all naturally experience.


Drug approvals: Are we in a new age yet?


With all the news of cancer drug shortages and the FDA's controversial decision to withdraw approval of Avastin (bevacizumab) for breast cancer, we are also getting some positive developments.

Just recently (on Aug. 26), the FDA granted accelerated approval to Xalkori (crizotinib), the newest member of an emerging generation of "niche" drugs. These are drugs that work in very defined subsets of patients, based on certain biological characteristics.

In the case of Xalkori, this is confined to the approximately 3 to 9 percent of patients with non-small cell lung cancer (NSCLC) who carry a chromosomal translocation that results in overexpression of the ALK protein (anaplastic lymphoma kinase). In fact, the approval of this drug is accompanied by the approval of a gene-based test to detect this translocation in tumor tissue. This approval comes on the heels of the approval of Zelboraf (vemurafenib) just eight days earlier for advanced melanoma, and again, only for the subset who harbor a mutation in the BRAF gene, and also approved with a diagnostic kit called the cobas 4800 BRAF V600 Mutation Test. In this case, the mutation is more common, seen in about half of all melanomas.

The big question is whether these two approvals herald the new age of personalized drugs. The now old story of Herceptin that many regard as one of the first targeted therapies, was spread out over 17 years from discovery of the gene to drug approval (or 11 years if you go from the discovery of HER2 amplification in breast cancer).

The new generation of drugs is being developed in a just a few years based on our exponentially growing body of data on mutations carried in cancers and new clinical trial designs that rapidly test drugs and verify biomarkers that predict response. Moreover, they seem to be quite effective with a higher percentage of patients responding, but not to the point that permanent cures are expected.

One can only hope that we are truly in the new era – and there are several indicators that this is the case. The Cancer Genome Atlas (TCGA) program is one of several worldwide that is collaboratively sequencing tumor genomes. Drug companies are investing more effort into biomarker analyses and integrating them earlier in the clinical trial process. Healthcare reform is demanding that drugs have a larger impact and that they not be used indiscriminately. Finally, the public's expectations are rising – they want more information about their cancers and access to clinical trials.

While it is possible that the initial wave of "low-hanging fruit" of "druggable" gene targets will soon be exhausted, it is more likely that we will have more targets and drugs than we can test. The bottleneck will really be in the patient clinical trials and how quickly and widely they can be deployed and fully enrolled. There will still be negative trials and other disappointments, but perhaps we are entering a new era where the bar of success is being raised.


The evolving PARP inhibitor story


The story of PARP inhibitors for breast cancer continues to unfold following Monday's presentation at ASCO. There are a lot of teaching moments in this story regarding the PARP inhibitor iniparib. The initial dramatic results from the randomized phase 2 trial comparing chemo alone or combined with iniparib appropriately led to a more definitive trial. But there is a reason we define phase 2 trials as designed to give preliminary estimates of activity.

If you flip a coin just 10 times, it will probably not land on "heads" exactly at the known and expected rate of 50%. As you get to 1000 times, you will start to get closer and closer to 50%. The same is true for larger trials – they get you closer to the "real truth." So what is the real truth about PARP inhibitors? We are far from there, but what we now know is that iniparib is actually a very weak PARP inhibitor, but it does damage tumor DNA, and it does have activity when added to chemotherapy.

The larger study was not identical to the first study in that more patients were receiving first-line therapy (57%) and more of the patients who progressed on the chemotherapy-only arm crossed over to have iniparib added as allowed by the protocol (96%). This crossover might have obscured the effect of iniparib on survival, but should not have affected progression-free survival. In the end, the time to progression was longer by conventional statistics, but the statistical design of this trial was ambitious, looking for both progression-free and overall survival as primary endpoints. The necessary adjustments in the formula that defines a "significant" difference resulted in neither endpoint being significantly better with the addition of iniparib. In the subgroup of patients who had one or two prior chemotherapy regimens for advanced breast cancer, there were statistically significant differences in progression-free and overall survival. Even so, one of the audience members asked whether a two to three month difference is worthwhile.

The story is far from over and iniparib might still be a useful drug and have a much greater impact in the right patients in the right situation. More analysis from this trial is needed – for example, tissue biomarkers might shed some light on the biological subtypes more likely to respond. This may also require more homework for scientists to more sharply define how the drug actually works. The next trial will probably focus on patients who have already progressed on one or more chemotherapy regimens for advanced breast cancer. This is representative of the trials and tribulations in the new era of cancer research – we are at that awkward phase where personalized medicine is expected but have not yet refined our tools.


A few more answers (and questions) about the PARP inhibitor trials


The Feb. 28 posting regarding PARP inhibitors drew several comments I thought should be addressed. There has been considerable interest in PARP inhibitors because of the early activity cancers associated with BRCA1 and BRCA2 mutations, as well as triple-negative (estrogen, progesterone and HER2 receptor-negative) breast cancer.

The fact that the follow-up and more definitive phase 3 trial comparing chemotherapy with or without the PARP inhibitor iniparib (also known as BSI-201) did not confirm the dramatic survival benefits seen in the earlier and smaller phase 2 trial raised a lot of questions.

Our readers have responded with queries and some degree of dismay, including those who are currently on the expanded access trial with this drug. The evolution of descriptors from "spectacular" to "exciting" to "not meeting its endpoint" is a repeated theme in science as we go from preliminary data, where conclusions are shakier (but tantalizing because they are new) to more definitive studies, where the results are more reliable, but may not always confirm the earlier findings.

However, there are some details in this particular case that are worth mentioning, some of which were alluded to in comments from our readers. The phase 2 and 3 trials had equivalent treatment arms, but the endpoints were not the same. The phase 2 trial was initially designed to see if cancer could be stabilized in more patients receiving iniparib added to chemotherapy compared with chemo alone. There was an unexpected improvement in survival with the addition of iniparib - greater than has been seen with any other drug. This led to the phase 3 trial being designed with very high expectations – that both survival and disease-free survival would be improved. Therefore, both these endpoints were built into the statistical analysis plan. When the result fell short of the "p-value," or the level of statistical significance, the trial was declared to have not met its endpoint. However, it is important to note that there still could be an important benefit for all patients. Just not by the definition set for this trial, which was expected to win FDA approval.

It is also possible that patients receiving first-line therapy were not the same as those receiving second or third line therapy, since those who have very aggressive cancer initially might not qualify for later lines of therapy. This type of selection bias could result in a different biological profile such that PARP inhibitors might work better in those who are able to make it to second/third line treatment, as was demonstrated in the Phase III trial.

Of course, these are all speculative reasons for these results, and only diligent completion of the planned trials will ultimately answer these questions. In the meantime, we should recognize the elegance of targeting DNA repair, and those who are on clinical trials with PARP inhibitor should certainly continue, with the same hope that this drug can make a difference.

The truth will eventually emerge, and while it is possible that we might be disappointed, the data so far suggests that PARP inhibitors will be effective drugs – it remains to be seen which inhibitor (since they all seem to be different) and which patients will benefit (since we don't know which tumors really rely on this enzyme).

Science is not only about cold facts – it involves drama, emotions and contradictions. But ultimately, truth prevails with well-designed studies and patients – just not as soon as we would like.


Updates from the Miami Breast Cancer Symposium


The Miami Breast Cancer Conference kicked off last week with the customary pre-symposium that focused on a variety of subject, mostly surgical in nature, but also covered unusual topics that most clinicians only see rarely.

The important aspect about rare cases is that we all have to be prepared to take care of them and know something about how to diagnose and treat them. The topic of male gynecomastia (enlargement of the breast), which can be seen in men with no underlying cause or, in some cases, can be due to genetic or hormonal abnormalities or to certain drugs, can be approached with techniques similar to liposuction. Removal of benign tumors in women, such as the rather common fibroadenoma, can sometimes result in large scars, so the route of approach is important. In many cases, the incision can be hidden in the lower fold of the breast where there is a natural crease that is hidden from view. In fact, even for breast cancer operations, more breast surgeons are using techniques borrowed from plastic surgeons to offer patients the cosmetic benefits that were once not felt to be warranted for such a situation.

Unusual malignancies were also reviewed. Metaplastic breast cancer is a rare form of cancer that looks more like lung cancer under the microscope and appears to not respond to chemotherapy or radiation. Newer biological analyses suggest that these cancers follow a different developmental pathway, but this has not solved the dilemma of how to treat these cancers – so for now, we tend to follow the same treatments used for typical cancers. The same holds for breast cancers that arise due to genetic predisposition in carriers of BRCA 1 or 2 gene mutations. These clearly have a distinct biology and we are starting to learn more about how they behave, but to date we still use drugs like chemotherapeutic, hormonal and biological therapies based their stage and the proteins they make – just like other breast cancers. Newer drugs such as PARP inhibitors may in the future find a role specifically for hereditary cases. For now, the more important consideration is to establish a genetic predisposition in the first place by checking family history and performing genetic counseling and testing when appropriate. If there is a mutation, then the consideration of removal of the ovaries (oophorectomy) and careful surveillance of the breast or preventive mastectomy should be given – with oophorectomy appearing to actually lower the chances of dying from both breast and ovarian cancer.

An update of practice-changing developments over the past year was presented. The major advances were the ability to possibly use less surgery – in particular, when a sentinel node is involved. Whereas this previously meant automatic lymph node dissection and the accompanying risk of permanent arm swelling (lymphedema), there may now be the opportunity to omit a full dissection in selected cases.

Also, the use of intraoperative radiation therapy as opposed to six weeks of standard external beam radiation was found to be equivalent in terms of recurrence risk. However, both these approaches remain controversial because the follow-up time is short – just a few years, so there is still a possibility that patients might be exposed to more risk of recurrence.

In the area of medical oncology, newer therapies for bone metastases (Xgeva or generic name denosumab) and a novel chemotherapy for refractory breast cancer (Halaven or generic name eribulin) were discussed – both recently approved by the FDA. These agents offer benefits over their predecessors, but we still have a long way to go in the area of advanced metastatic breast cancer.

As we concluded the final day of the meeting, I was struck by the lively debate surrounding early data that are potentially practice changing. The most heated arguments involved the interpretation of the American College of Surgeons Z0011 study, where patients with 1 to 3 positive sentinel nodes who were to receive post-operative radiation were randomized to completion axillary dissection compared to no further surgery.

The study authors posited that the likelihood that more recurrences would be seen in the no dissection group over time was very small. However, at this conference, it is clear that many feel that it is premature to abandon dissection in this setting because of the fact that patient accrual and the number of recurrence events were lower than projected as well as the limited follow-up time. Others felt that we were negating data that sufficiently rules out a significant increase in recurrence and therefore denying patients less invasive surgery and less chance of lymphedema.

More debate was held regarding intraoperative radiotherapy, which was shown, again with rather short follow-up, to result in low and similar recurrence rates compared with external beam radiation. Defining factors that identify candidates for accelerated partial breast irradiation and hypofractionation raised some finer points of disagreement.

A rousing and entertaining debate drew out both the powers and limitations of gene profiling in decision-making. As rapidly as these assays have been incorporated into decision-making for adding chemotherapy to hormonal therapy for node-negative, hormone receptor-positive cancer, is it possible that standard pathological indices that can yield the same discrimination? Can gene profiling be extended into node-positive cases?

Controversy can be a good thing – and in fact, tends to accompany most new findings. We should not adopt new data abruptly for all applicable patients because ongoing peer review and longer term follow-up may change the risk/benefit ratio over time.

Incremental adoption, starting with those most likely to benefit and least likely to harm, is a much more tenable pattern that can be adapted over time as the data matures. The feedback I received from attendees suggests that this type of discourse, even though not conclusive, provides the clinician with the tools to formulate their own adoption patterns and arms them to better discuss these nuances with their patients and colleagues.

No consensus could be found for the size threshold below which adjuvant trastuzumab (Herceptin) would not be considered in HER2-positive, node-negative breast cancer. Also, the definition of HER2 positivity itself might need to be adjusted in early-stage breast cancer with the finding that NSABP trial cases that were centrally reviewed as being HER2-negative seemingly benefitted from trastuzumab – this has led to a randomized trial testing this agent in HER2-negative cases (expression values of 1+ and 2+, but negative by FISH analysis).

Other "what will I do on Monday" moments arose over the use of adjuvant bisphosphonates. All the momentum from early positive trials dissipated when the large, well-powered AZURE trial reported negative results in San Antonio. Here, we don't appear to have any real positive data unless one invokes the unplanned subset analysis of this trial showing a benefit in the 5 years postmenopausal subset. This is consistent with the smaller ABCSG-12 randomized trial in patients who had medical ovarian ablation with hormonal therapy – this study did yield fewer recurrences with zoledronate. Still, most presenters felt that bisphosphonates should only be used in the setting of osteopenia/osteoporosis.

Similarly, the use of bevacizumab (Avastin) in the first line for advanced breast cancer was questioned with the now solid finding that survival is not improved with this agent despite a clear advantage conferred in progression-free survival. But most feel that this agent should still be an available option even though there are no predictive factors to identify those who might derive a more substantial benefit.

Less debate was held over the use of eribulin (Halaven), a new anti-microtubule-directed chemotherapy for very refractory advanced breast cancer after 2 to 5 prior chemotherapy regimens, which yielded a survival advantage over single agent therapy chosen by the treating investigator.

Conversely, therapies for triple-negative as well as BRCA-associated remain undefined – defaulting to standard recommendations that are used for all subtypes. Whether or not PARP inhibitors will ultimately emerge as effective therapies in this area will have to await further study and longer follow-up from the recent phase 3 trial of carboplatin plus gemcitabine with or without iniparib. This trial recently reported that the primary endpoint was not met, dashing hopes of replicating the earlier and strongly positive Phase II trial of the same design. However, there is still a clear benefit apparent in the second- and third-line setting from the recent trial – whether or not the results will be enough for approval in this setting remains to be seen. Moreover, iniparib may not even exert its effects through PARP inhibition, since it is a weaker inhibitor and has a different toxicity profile compared to other such agents in clinical development.

One of the hallmarks of this conference has been the emphasis on basic science developments that are on a trajectory impact on practice. The latest frontier of whole genome sequencing is demonstrating intratumoral heterogeneity and evolutionary patterns that belie metastases (even to specific sites) and drug resistance. These could hold the key to better classifications and therapies aimed at residual tumor cells. Cancer stem cell biology may also reveal avenues to address recalcitrant cancer cells, with the beginning of testing of inhibitors of stem cell maintenance pathways known as Notch, Hedgehog and Wnt.

There was also discussion of down-to-earth established aspects of breast cancer that are now in need of re-evaluation. One of the more notable trends has been the idea that we might be overclassifying and subsequently overtreating very well-behaved cases of low grade ductal and lobular carcinoma in situ. These entities may represent a biological spectrum, with atypical hyperplasia on the lower risk end, and therefore several speakers issued a call to use the term ductal intra-epithelial neoplasia (DIN) of several grades along this continuum as a more appropriate classification system.

This longwinded memo is just a cross section of the 2011 Miami Breast Cancer Conference. For those who have never attended, the 2012 conference next March promises to deliver more thoughtful and invigorating discussions of how breast cancer clinicians should take evolving scientific and clinical progress and apply these in their practices.


A disquieting moment: Two steps backwards?


Just about all of us attending the San Antonio Breast Cancer Symposium were disappointed and puzzled by two negative studies that went counter to all the early clinical data and biological theories in two important areas. While we recognize that this can sometimes be the normal course of science, it is never what we expect when we attend a meeting amid all the buzz about the latest news.

The first was in the area of personalized medicine--more specifically, the field called pharmacogenomics, which refers to the analysis of gene variants in drug metabolism enzymes to customize recommendations for specific drugs and doses. We all inherit different versions of the gene that encodes an enzyme called CYP2D6, which metabolizes the hormonal therapy tamoxifen into a more active form called endoxifen.

While preliminary studies showed that those who inherit a low activity version of this gene might have a higher risk of recurrence or progression on tamoxifen, it appeared that a new method to steer patients to the right therapy might be emerging. However, these early results were on smaller groups of patients.

More recent and much larger updates presented on Thursday showed no difference at all based on CYP2D6 genotype, even though tests are already commercially available and used by some oncologists. The consensus from the presenters, including the commentator, Dr. Matthew Goetz from Mayo Clinic, (one of the original investigators to observe differences in clinical outcomes), is that for now, doctors should discuss the controversy with patients, but not use CYP2D6 testing routinely to make decisions about tamoxifen. However, it is still recommended that drugs that inhibit CYP2D6, notably certain anti-depressants, should be avoided in patients taking tamoxifen. This is not really a big step backwards for patients because it doesn't necessarily take any benefits or options away. But it is an unexpected turn in the road where all the pieces of the puzzle were starting to fall together, only to be contradicted for the moment.

Another negative confirmation, however, was really a setback. Every indication was that bisphosphonates (a class of drugs used to protect the bone from both osteoporosis and bone metastases) might also prevent metastases. Several studies had suggested this earlier. In a smaller study of premenopausal patients receiving hormonal therapy, the drug Zometa had already been shown to lower the risk of recurrence. The supposition was that it made the bone a less fertile ground for breast cancer cells to colonize and use it as a springboard to metastasize elsewhere. But after a long anticipated wait, a much larger study yielded absolutely no difference in patients who received Zometa compared with those who did not. A secondary analysis hinted that in postmenopausal patients, there might be a benefit, but this was not statistically significant and no recommendations can be made at this time to use Zometa as a way to further reduce recurrence risk above what chemotherapy and hormonal therapy can achieve.

A large North American study was recently completed, but the results of this one are not expected for several years. The good news is that these studies took longer to analyze because fewer women are recurring after early-stage breast cancer than ever before. Still, we would like to get this down to zero and still have a ways to go. Progress is just never linear, but even negative data helps us create better experiments and trials for the future.


Combining HER2 drugs: Does it work?


The HER2 protein is made in high levels in about one-fifth of all cancers, and while this used to be a dangerous sign, it is now an important target, and the antibody drug Herceptin has significantly improved the outlook for these tumors. It improves the cure rate after surgery and even after cancer has spread; it can extend life but is not curative.

At the San Antonio Breast Cancer Symposium, three key trials were presented that attempted to improve how well Herceptin works by combining it with other drugs. All studies were done in patients receiving preoperative (also called neoadjuvant) therapy because that is a quick way to estimate if a particular treatment will be effective in the long-term, by looking at how many patients have what is called a complete pathological response--or complete disappearance of tumor cells at the time of surgery.

Chemotherapy was given in all studies. One study found a higher response rate when pertuzumab was added to Herceptin and chemotherapy. The combination of the two antibodies was also better than pertuzumab and chemotherapy. Another study looked at the addition of the oral kinase inhibitor against HER2, Tykerb (also known as lapatinib), which is also approved--but only in patients who have already gotten Herceptin. The combination of Herceptin and Tykerb was clearly better, but there were more side effects, particularly diarrhea, with Tykerb. The third study, called Neo-ALLTO had three arms, all with the chemotherapy Taxol--one with Herceptin, the other with Tykerb and the third arm with both. Again, the response rate was best with the combination.

This was a very exciting validation of the fact that blocking the HER2 pathway more completely with two drugs is a more effective strategy. However, all the presenters stressed that the neoadjuvant model is only an estimate of a potential benefit, and this has to be confirmed in clinical trials that are ongoing in patients with early-stage breast cancer that are enrolling enough patients to actually compare the number of recurrences--this is the gold standard that would be required before these combinations can be approved. One of these trials is nearing completion, but will probably take two years or so to yield definitive results. But the bigger issue here is that of the many biological pathways that are being addressed in cancer are still not fully effective because tumor cells become resistant by bypassing the point at which the targeted drug works. We need to further explore how that same pathway can be blocked at different levels if this theory proves to be true.


Balancing the benefits and risks of hormonal therapy for early-stage breast cancer


About two-thirds of women with breast cancer have hormone receptor-positive breast cancer, and hormonal therapy is recommended following surgery. For post-menopausal women, aromatase inhibitors (AIs) are now the preferred class of therapy, as they outperform tamoxifen with 3%-5% fewer recurrences seen, even though a difference in the death rate has not been observed.

A series of studies was presented at the San Antonio Breast Cancer Symposium on Thursday that attempted to discern if there are any factors that might allow us to better individualize treatment recommendations in this situation.

One of larger studies, called the TEAM trial, compared the sequence of tamoxifen followed by the AI Aromasin (exemestane) to Aromasin for five years. This trial had already shown that these regimens are equivalent in terms of recurrence risk, but in this analysis, the presence of the family of growth factor receptors known as HER1, HER2 and HER3 was associated with a higher risk of recurrence regardless of the regimen used, so it did not help doctors and patients decide which regimen would be best.

Another sophisticated trial looking at multiple genes expressed over time in the tumors of patients receiving the AI Arimidex (anastrozole) suggested that inflammation and immune reactions might predict a lower chance of response to therapy. Dr. Dunbier from the Royal Marsden Hospital in London speculated that such an immune reaction in the breast, sometimes seen by the pathologist as white cells "infiltrating" the tumor, might activate growth signals. While this finding is too early to apply in the clinic, it might shed some light on the biology of why some tumors are more aggressive and might require other therapies, even immune therapies; this may lead to focused trials in this area.

Another series of trials attempted to look at rare side effects of AIs. We have witnessed situations in medicine where rare side effects, such as heart attacks associated with the nonsteroidal pain drug Celebrex (celecoxib), were not picked up until years after the drug was approved. So it is important to continually examine these side effects over time. With AIs, there was a suggestion that the risk of heart attack might be slightly elevated.

One study attempted to look at "real life" use of hormonal therapy by examining insurance claims and pharmacy data on 44,000 women with breast cancer and 44,000 women without breast cancer who were matched for age and other characteristics. There did not appear to be a difference in heart attacks with either tamoxifen or AIs, and there was a decreased stroke rate with either hormonal therapy in all breast cancer patients, a finding that has been observed before.

Bone fractures were more common with AIs--again, something that was already known. Another analysis looked at pooled data from several trials comparing tamoxifen to AIs and was able to detect very small increases in certain risks; for example, cardiac side effects were seen in 4.2% of patients on AIs and 3.4% of patients on tamoxifen, a difference of 0.8%. These small differences could not be picked up in individual trials. These risks can also be expressed as the number of patients you would need to treat to see one additional harmful event of an AI compared with tamoxifen--in the case of a cardiac event (like heart attacks), that would be 132 patients. This analysis also showed more bone fractures with AIs (7.5%) compared to tamoxifen (5.2%), or one extra fracture for every 46 patients treated. More uterine cancers were seen with tamoxifen, but very low rates overall--0.5% with tamoxifen and 0.1% with AIs, or one additional case for every 250 patients treated. These types of numbers are useful for making any medical decision and weighing the benefits (less recurrence risk) versus the risks in a numerical way. When we think of personalized medicine, it is also about making tailored benefit/risk analyses; that's why these "meta-analyses" are important.


ODAC's decision on Avastin in breast cancer raises many questions


The story surrounding the FDA's process for the final approval of Avastin (bevacizumab) for advanced breast cancer raises many questions about the standards on drug approval in this changing era of targeted therapy and personalized medicine.

In early 2008, the FDA granted an "accelerated" approval on the basis of a trial that showed a significant delay in the time to progression, but no difference in survival time, when added to Taxol (paclitaxel) as first-line treatment. This meant that final approval would be dependent on subsequent trials showing similar degrees of benefit. When two additional trials were submitted for review, both showed significant improvements in time to progression, but again with no difference in survival. The advisory panel to the FDA voted on July 20 this year to NOT recommend full permanent approval.

Did the FDA and the advisory panel change the ground rules, now asking for a survival benefit when none of the trials were designed to enroll enough patients to do this? Or was it that the difference in progression time was not as large in the subsequent trials, even though statistically, one cannot compare these values across trials.

Either way, researchers and advocacy groups are both split on whether the FDA advisory panel made the right call and what the final FDA ruling should be, which is due by September 17. For other indications in advanced lung, colon, and refractory brain cancer, Avastin produces a survival advantage. However, does delay in progression in its own right represent a real benefit? The FDA has the charge of ensuring that new drugs have a favorable benefit/risk profile, but it does not specifically define what the rules are for measuring each of these. In some cancers, prolongation of progression is tightly linked to an improvement in survival, but this is not solidly the case in breast cancer. Also, progression delay might improve quality of life, but such evidence is hard to generate, and was not clearly shown in the two Avastin trials. The issue of the economic cost of small incremental benefits is also being raised, but the FDA is not supposed to take that into account--still, some wonder whether this factor somehow crept into the advisory board's decision.

The way the FDA thinks and decides on these issues still remains somewhat veiled. While FDA officials are very open about discussing their thoughts and regularly meet with companies ahead of time to review trial designs and strategies for approval, none of these discussions bind them to their ultimate decision. This leaves companies trying to figure out the quickest and surest path to approval, not necessarily representing the best scientific or societal plan, or even for that matter, the best thing for the company itself.

This sage may tell us that NOW is an opportune time for governmental agencies (both regulatory and Medicare/Medicaid), patient advocates, the pharmaceutical industry, and clinical researchers to all come to the table to discuss a framework, or "rules of the game," for moving forward in light of both health care reform and new discoveries in cancer biology personalized medicine.


Sentinel nodes: A convergence of knowledge from different trials


One of the most important incremental steps in breast cancer has been to lessen the amount of axillary surgery that is needed to stage breast cancer. Sentinel node biopsy appears to lead a much lower risk of lymphedema compared to a standard axillary node dissection. (Axillary node dissection is the removal of some of the lymph nodes in the underarm area to determine the extent to which the cancer has moved outside the breast. This information helps determine staging of the cancer and could impact treatment choices. A sentinel lymph node biopsy only removes the closest one or few nodes to which cancer are likely to spread from the primary tumor.)

However, sentinel node biopsy was a genie that got out of the bottle too early and was widely adopted before it was formally proven to be as effective and accurate as axillary dissection.

Nevertheless, credit is due to several cooperative trial groups that conducted important randomized studies informing us of several points. Those findings were announced at this year's annual meeting of the American Society of Clinical Oncology.

First of all, there was a general confirmation that not only was a negative sentinel node status indicative of no further positive nodes remaining, but that omitting a dissection does not lead to higher recurrence rates.

A second finding was not only reassuring but possibly "practice changing"--that is, even if the sentinel node is positive, omitting dissection still leads to an equivalent and low recurrence risk. This will change practice patterns over time; although for now, it can only be considered to apply to patients who were eligible for this study--namely, patients with two or fewer positive sentinel nodes, breast tumors under 5 cm, and who had lumpectomy and radiation (which covers most of the area of a dissection). However, the trial only accrued a third of its expected enrollment and this weakens the conclusions. On the other hand, the trend was actually better on the sentinel node-only arm, making it very improbable that there would be significantly more recurrences in that arm if the trial had fully enrolled.

A third finding was that the detection of microscopic deposits of tumor cells that measure less than 0.2 mm does not seem to indicate a higher risk of recurrence. This contradicts other studies, but is very compelling coming from a large trial that did enroll its target number of 4,000 patients. The commentator for this presentation at ASCO affirmed that this trial puts an end to the need to test for these deposits that require antibody staining and analysis.

A fourth finding addressed the very old controversial question as to whether nodal dissection actually carries a therapeutic value in addition to providing valuable prognostic information that affects medical and radiation therapy decisions. At least in patients who have a sentinel node dissection, the answer appears to be "no"--there is no added benefit of a node dissection in terms of disease-free or overall survival. In addition, there are less social and work restrictions, arm swelling, numbness, and tingling, as well as better mobility with sentinel node biopsy compared to axillary dissection.

So, this very notable milestone in treatment advance--in this case, primarily to improve quality of life and functionality--is now quite solidified and even raises the number of eligible patients for sentinel node-only surgery. These trials will certainly generate more important clinical and scientific information as their data and tissue banks continue to be analyzed and explored.

You can read more about these two studies presented at ASCO in "Sentinel Lymph Node Studies Considered Practice-Changing."


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