This issue of Patterns of Care continues our efforts to quantitatively assess clinical practice patterns in a number of different areas of oncology. For this unique foray — our first ever into supportive care — we commissioned a web-based survey of 100 US-based medical oncologists with the goal of better understanding how these individuals manage the side effects and complication risks associated with many common systemic agents used to treat solid tumors, particularly and specifically, “targeted biologic agents.” The snapshot that emerges suggests that the recent introduction of a litany of new therapies and regimens has forced oncologists to suddenly wear a number of new primary care hats in order to manage a spectrum of novel toxicities. Below find a few thoughts on the challenges associated with administering a number of these agents and combinations that were not widely used prior to the year 2000, along with some related “stat bites” from the survey. — Neil Love, MD DrNeilLove@ResearchToPractice.com

1. The many and sometimes not so purely targeted TKIs

The good news is that many of these oral agents are associated with impressive efficacy, and the associated risks are rarely life threatening. The less-than-good news is that it takes meticulous attention and constant vigilance to keep patients on these therapies because of a number of side effects, including fatigue, hand-foot syndrome and diarrhea. It will be fascinating to see how these challenging toxicities impact the current adjuvant renal cell cancer trial comparing one year of sunitinib to sorafenib to placebo in a double-blind design. Investigators tell us that it’s pretty clear who is receiving an active drug, and many patients have difficulties reaching the one-year point.

Despite these challenges, the TKIs are having a significant impact in a number of interesting tumor types. In hepatocellular cancer, after more than 100 Phase III randomized trials of systemic therapy failed to change the outcome of these patients, for the first time sorafenib has been demonstrated to improve survival, and this agent is now the standard first-line systemic therapy. It is now being investigated in combination with local treatments such as RFA (radiofrequency ablation) or TACE (transarterial chemoembolization).

Similarly, clinical investigators specializing in renal cell cancer tell me their waiting rooms are now much more crowded, in part because patients are living longer as a result of the impact of sunitinib as the standard first-line therapy for metastatic disease. Waterfall plots are equally impressive, demonstrating benefits for most patients.

In breast cancer, lapatinib is a welcome new alternative for patients with HER2-positive disease, although recent reports of significant diarrhea and skin rash when combined with paclitaxel have led to modifications of the designs of a number of new adjuvant and neoadjuvant trials.

Perhaps the most exciting TKI story (in solid tumors anyhow) is in non-small cell lung cancer, in which approximately 10 percent of patients — mostly nonsmokers — have EGFR tumor mutations that predict exquisite sensitivity to erlotinib or gefitinib. While these agents also often bring with them a troublesome rash and even a strange abnormal eyelash growth, the response in these patients is about as close as we’ve come in solid tumors to the magic that is imatinib in CML.

2. Bevacizumab

Bevacizumab — a highly interesting anti-VEGF antibody — has been a major topic of discussion since Herb Hurwitz’s stunning ASCO 2003 presentation demonstrating a progression-free and overall survival advantage to adding this agent to chemotherapy (IFL) in metastatic colon cancer.

Bev is now out there in breast, lung and colon cancer and a bunch of other less common tumors, but I still don’t hear anyone — not even Lee Ellis or Rakesh Jain — explaining for sure how this agent works. We also have yet to find an effective predictor of response or toxicity, although emerging evidence about hypertension and SNPs — as discussed in a fascinating paper by Schneider et al in the October 1^st issue of JCO — are at least providing some hints.

One of the most important qualities of bev is that it doesn’t seem to make many patients feel more ill, and while hypertension and proteinuria are not infrequent, these problems are reported to be relatively easy to control for most patients. Serious complications with bev are uncommon, and the modest increase in arteriovenous events associated with the agent needs a lot more definition.

The scariest acute bev toxicity is the pulmonary hemorrhage seen in lung cancer. This event — which may be part of a brisk tumor response — is, thankfully, quite infrequent (one to four percent) and may be less of a concern in a clinical scenario (metastatic non-small cell) in which more than 80 percent of patients will die within two years despite “standard treatment.” It’s interesting that a quarter of docs believe that central tumor location is the most important predictor of this potentially catastrophic event, although Alan Sandler, the principal investigator of ECOG trial E4599, the seminal bev study in metastatic lung cancer, repeatedly has rejected this association.

The toxicities of this agent will be totally reexamined if it works in the adjuvant setting, a question being addressed in breast and lung cancer, but most critically, in the colossally important NSABP-C-08 trial and the AVANT study, arguably the most important current oncology trials currently complete and waiting for results.

3. Cetuximab/panitumumab

As of ASCO 2008, this class of agents is now a consideration for the most common solid tumor, as discussed on the Lung Cancer Update audio series by the principal investigator of the FLEX trial, Dr Robert Pirker, and the ASCO discussant of this historic study, Dr Tom Lynch. As noted in the above stat bite, oncologists in community practice know a lot about cetuximab and its cousin, panitumumab, from treating colorectal cancer, and a major quality of life concern is dermatologic toxicity.

All docs in practice are eager for effective solutions to this visible and disturbing problem. One strategy that would certainly help alleviate this problem would be to clone Dr Mario Lacouture, a dermatologist at Northwestern University who focuses his entire practice and clinical research on EGFR-related dermatologic side effects. Mario treats this dilemma as both an art and a science, and perhaps as an alternative to genetic engineering, we can help him encourage and train other dermatologists to give up a few cosmetic procedures and develop expertise in this area.

4. mTOR inhibitor (temsirolimus......TEM-sir-OHli-mus)

It took me a while to get the hang of pronouncing the name of this recently introduced agent, but finally, just like bevacizumab and trastuzumab before it, temsirolimus started flowing out naturally. Most docs in practice have only used temsirolimus (got the hang of it yet?) a couple of times, considering that it is both new and so far confined only to advanced renal cell cancer.

However, as time passes and this interesting agent enters into other treatment areas, along with brethren like everolimus (I actually prefer the initial moniker, the super techno-sounding “RAD 001”), the metabolic changes seen with these agents, such as hyperglycemia and hyperlipidemia, may end up challenging even the most seasoned clinicians.

5. Advances in antiemetics

Aprepitant, palonosetron and other 5-HT3 receptor antagonists have made the use of traditional chemotherapies a less toxic experience and this has, for example, greatly facilitated the rapidly emerging use of adjuvant chemotherapy in non-small cell lung cancer — particularly with cis-based regimens. In our survey, the dichotomy of how physicians approach premedication with common regimens such as FOLFOX and GEM/cis suggests that a significant fraction are either overtreating or undertreating this classic, highly disturbing, traditional chemotherapy side effect.

6. New chemo regimens: TC (docetaxel/cyclophosphamide) for breast cancer

We have tracked the TC story since Steve Jones first presented this important data set at San Antonio several years ago. Steve was a central figure in the creation of “AC” but now finds it somewhat amusing and apropos that his new US Oncology study — at least in his mind — has helped send AC out to pasture.

Dr Jones is pleased that in its place is a less cardiotoxic, leukemogenic and emetic regimen that also seems to be associated with fewer cancer relapses and resulting deaths, and TC has been rapidly incorporated into the treatment landscape of breast cancer.

Questions remain about indications for prophylactic myeloid growth factors with this regimen, but my sense is that there are a few too many neutropenic infections out there that might be prevented. With the recent emergence of the “TIC-TAC-TOE” trial, it could be that five years from now, TC/bevacizumab might be the way to go for many patients as adjuvant therapy.

7. New chemo regimens: FOLFOX (oxaliplatin)

I had the good fortune and honor to interview Dr Aimery de Gramont at the 2003 ASCO meeting, right after he presented for the first time the MOSAIC trial results, demonstrating an advantage to FOLFOX compared to 5-FU as adjuvant therapy for colon cancer. I had held my breath in anticipation of Dr de Gramont’s arrival at our temporary recording studio in New Orleans that day, as a fulminant thunderstorm flooded the streets and pounded the area.

After the soggy but smiling Parisian investigator showed up, we chatted not only about the MOSAIC efficacy findings with FOLFOX but also about the reported incidence of neurotoxicity. A few years later, this critical issue has been muddied by the confusing sequence of events related to the potential preventive role of magnesium and calcium. Another issue is the split between clinical investigators and practicing docs on the use of this agent in older patients, and new studies attempting to reduce the number of treatment cycles to six may lead to a considerable reduction in this important treatment risk.

8. New chemo regimens: Nab paclitaxel

I regularly ask investigators and practicing docs for their thoughts on this controversial agent. What I have commonly found is that most physicians — community-based or academic — believe that in breast cancer, nab offers some advantages compared to its Cremophor^®-bound cousin, and if cost and reimbursement were the same, plain old paclitaxel might have a minimal role in community practice. What that means and how this information should be applied to patient care I have no idea, but I am sure that some health economist somewhere has managed to put a price tag on the potential avoidance of infusion reactions, insomnia and agitation. It is also somewhat concerning that a significant fraction of medical oncologists report using steroid premedications with this agent, a practice not done in trials evaluating this taxane and not done by clinical investigators.

9. Targeted adjuvant therapies of breast cancer (trastuzumab, aromatase inhibitors)

The spectacular 2005 ASCO presentations on adjuvant trastuzumab instantly created 10,000 new cardiologists or, more specifically, medical oncologists who now had to ramp up their knowledge base to deal with a serious cardiac threat for curable patients. The rapid acceptance of TCH (docetaxel, carboplatin, trastuzumab), which does not seem to increase the risk of cardiac dysfunction as much as anthracycline regimens, while providing the same antitumor effect, has resulted in a lot less stress for patients and oncologists. However, our survey suggests that docs are being less meticulous about cardiologic monitoring, maybe because they are less concerned about complications with no anthracycline involved.

The poor AIs have been getting roughed up a lot in publications and meetings lately because of their propensity to cause arthralgias. That may now change instantly with a profoundly interesting Lancet paper just published by Jack Cuzick and colleagues demonstrating a fascinating correlation between vasomotor symptoms and/or arthralgias and relapse rate in patients treated in the ATAC trial. One wonders if the perspective on these symptoms might now change in the same manner as rash with EGFR inhibitors, where docs try to ameliorate this side effect but encourage patients that this may be a sign that the agent is working more effectively.