Editor’s Note: Cool numbers

Below find some of the more interesting data points that came from this most recent Patterns of Care survey, completed in August and September 2005 by 45 breast cancer clinical investigators and 100 randomly selected US-based medical oncologists.

1.  80%

Fraction of breast cancer specialists who have ordered the Oncotype DX™ assay (Figure 6, page 10).

This percentage contrasts markedly with the fraction of community-based oncologists who have ordered this innovative assay (34%). The clinical scenario targeted in related research reported by the NSABP and Genomic Health is one of the most common in early breast cancer — a patient with an ER-positive, node-negative tumor and, more specifically, a situation in which both the patient and physician are unsure about the value of adding chemotherapy to endocrine treatment.

Our prior Patterns of Care studies have documented that this is perhaps the most common situation in which clinicians utilize online models, such as Peter Ravdin’s Adjuvant!. The Oncotype DX assay appears to provide synergistic information that can be very helpful in assisting in one of the most vexing decisions in current medical oncology.

While one might speculate that the discrepancy in the use of this assay is based on reimbursement concerns (Figure 3, page 7), which perhaps are greater in a community practice setting, it is also quite possible that researchers are more familiar with and confident in the supporting research.

It is particularly plausible that community- based clinicians may not have been exposed to the unpublished NSABP data set reported at the December 2004 San Antonio Breast Cancer Symposium (SABCS) demonstrating a very dramatic benefit from adjuvant chemotherapy in the 25% of patients with high recurrence scores and no benefit in the remaining 75% of patients with low and intermediate recurrence scores.

2.  82%

Fraction of breast cancer clinical investigators who would start a 55-year-old postmenopausal woman with an ER/ PR-positive, HER2-negative, node-positive tumor on an aromatase inhibitor (AI) (Figure 7, page 11).

The optimal long-term adjuvant endocrine treatment strategy for postmenopausal women is a topic guaranteed to generate debate, and at one of our group’s recent CME meetings, several nationally recognized investigators revealed that they start some women with ER/PRpositive tumors on tamoxifen.

Their rationale is that the ATAC study showed minimal difference in relapse rate between anastrozole and tamoxifen in the unplanned analysis of this ER/PR-positive subset.

Other AI trials have not reported a difference based on PR, but a very common counterargument that invariably comes up is that even if the antitumor benefits of these two therapies are equivalent, AIs show a significant toxicity advantage over tamoxifen in terms of thrombotic events and endometrial cancer.

A number of the “tamoxifen first” renegade contingency believe that many breast cancer specialists buy into their theoretical argument that even though there are more recurrences during an initial course of tamoxifen, there might be fewer recurrences in the long run.

Our survey demonstrates that very few investigators embrace this approach in their clinical practices, although when the case is switched to a woman with a node-negative tumor, more researchers (Figure 21, page 18) start with tamoxifen.

3.  5%

Fraction of investigators who would continue tamoxifen in a 65-year-old postmenopausal woman with an ER/PRpositive tumor with three positive nodes who has been on tamoxifen for two years (Figure 10, page 12).

Our previous survey, conducted earlier this year, demonstrated this same result, but at that time we noted an important gap between investigators and community docs, with 56 percent of community oncologists continuing tamoxifen. In our current survey this fraction has decreased to 24 percent.

Three randomized trials have clearly demonstrated that patients who switch to either exemestane (IES study) or anastrozole (Austrian-German and ITA studies) have about a 40 percent lower risk of relapse and experience fewer serious adverse effects than those who continue tamoxifen.

Clearly, there is a rapidly building consensus that five years of adjuvant tamoxifen is an inferior therapy for postmenopausal women compared to a treatment plan that includes or consists of an AI.

Four years after the first ATAC presentation, with a number of other AI trials also reporting advantages for AIs over tamoxifen, it is clear that an important change in practice has occurred, and the minority of oncologists who still use five years of tamoxifen in postmenopausal women should re-evaluate their positions in fairness to their patients.

If I were a postmenopausal woman with a breast cancer who relapsed after having received tamoxifen for initial upfront therapy without having had the option of switching discussed, I would be very unhappy. Yes, AIs cost more, but if an inferior therapy is being recommended to save money, the patient needs to know that is happening and literally “buy in” to the plan.

4.  5%

Fraction of patients treated by community- based oncologists with AIs who have arthralgias significant enough to consider discontinuation or switching to another therapy (Figure 9, page 12).

A key issue in management of these musculoskeletal symptoms is diagnosis. A recent report from the ATAC trialists noted that about one third of patients on tamoxifen had arthralgias, and while that number is higher with a significant p-value for anastrozole, the absolute increase is only about 5 percent.

These data remind us that arthralgias in a patient on either tamoxifen or an AI may be caused by something other than the endocrine therapy. The ATAC trialists urge that oncologists attempt to make a precise diagnosis in this situation and carefully rule out other important causes of this nonspecific syndrome.

The trialists also urge that physicians utilize an integrated management plan (Figure 1) in an attempt to relieve musculoskeletal complaints before therapy is switched to another agent (tamoxifen) that also has the potential for side effects and toxicities and a greater risk for cancer relapse. Note that intolerable vasomotor symptoms are commonly reported with tamoxifen (25% of patients; see Figure 9, page 12).

5.  53%

Fraction of breast cancer specialists who generally utilize dose-dense AC T in 35-year-old patients with ERpositive, node-positive tumors (Figure 23, page 19).

Our prior surveys also demonstrate that the dose-dense regimen is the one most commonly used in node-positive tumors. However, over the past year, data have begun to emerge from a variety of sources suggesting less benefit from chemotherapy in general, and perhaps dose-dense therapy in particular, in patients with ER-positive tumors. Our survey suggests that to this point, docs have not changed their practices in that regard.

One change that is emerging in the selection of chemotherapy is a switch in the Number 2 spot from AC docetaxel to TAC. While many clinical investigators have proclaimed for several years that TAC and dose-dense ACT are the two adjuvant regimens with the best supporting evidence bases, docs in practice were commonly using ACdocetaxel rather than TAC.

One might guess that the shift this year away from ACdocetaxel to TAC is attributable to the disappointing results with that regimen in NSABP-B- 27, reported in December 2004 at San Antonio.

6.  100%

Fraction of clinical researchers who would recommend trastuzumab as adjuvant therapy in younger women with node-positive tumors (Figure 38, page 28).

Adjuvant trastuzumab has now clearly arrived on the scene. Our CME group has been following emerging clinical cancer research for more than 20 years and has never witnessed such a rapid and complete uptake of a new treatment strategy.

To put this in perspective: With other recent advances in the adjuvant setting — such as the aromatase inhibitors after the ATAC presentation in December 2001 and the first report a year later of the effects of dose-dense chemotherapy in CALGB-9741 — only about a third to a half of oncologists changed their practices in the year following the initial key reports for both of these treatment strategies, and it took about two years in total to hit a “steady state” of utilization.

The immediate acceptance and implementation of adjuvant trastuzumab reflects several factors, including the following:

1. Virtually all breast cancer researchers expected the adjuvant trastuzumab trials to show benefit.

2. The magnitude of benefit was impressive.

3. Extremely rapid and efficient methods of disseminating clinical research data and perspectives now exist in the medical oncologist community. (See the next cool number.)

7.  44 %

Fraction of community docs who cited the Breast Cancer Update audio series as a source of information about data from the adjuvant trastuzumab trials presented at ASCO on May 16, 2005 (Figure 2, above).

In August, when this Patterns of Care survey was executed, our CME group had distributed one Breast Cancer Update audio program discussing the adjuvant trastuzumab data presented at ASCO 2005. It is interesting to note that at the time of the survey, this piece — which included interviews with George Sledge and Edward Romond — had already been heard by almost half of the oncologists in this country, and perhaps another 20 to 30 percent are likely to hear this program and others covering trastuzumab in the next few months.

Like all contemporary physicians, medical oncologists learn about emerging clinical research findings in a variety of ways. In addition to live events such as scientific meetings like ASCO and a mélange of tumor boards, grand rounds and CME meetings, docs also keep up to date by the individual use of information delivery vehicles.

I started my medical education career as a video producer, and while this medium was fun and interesting, it requires the user to focus solely on the program, which is a problem because docs are busy as hell and have scarce time to allocate for continuing education.

Our initial attraction to audio for oncology CME in the late 1980s was based on the hypothesis that the ability to multitask (mainly drive a car or exercise) while listening would present an important advantage. Today, we know from more than a dozen external studies of our work over the last five years that about three quarters of oncologists in the United States are regular listeners to our programs and that most of this use occurs in the car.

It’s both awesome and scary to think that our CME group has the opportunity to pass on critical clinical research information such as the adjuvant trastuzumab data, and we take this responsibility very seriously.

8.  98%

Fraction of clinical investigators who start adjuvant trastuzumab concurrently with the taxane portion of chemotherapy (Figure 38, page 28).

This finding has a potentially interesting international twist, and one wonders if investigators in Europe — where the HERA trial was executed — have the same practice pattern as we do in the United States.

Note that HERA demonstrated that the post-chemotherapy use of trastuzumab resulted in an impressive reduction in risk of recurrence of about 50 percent, as in the NSABPNCCTG combined analysis of concurrent trastuzumab (with taxanes).

On the other hand, the NCCTG data presented at ASCO revealed a nonstatistically significant 13 percent reduction in relapse rate following sequential therapy à la HERA, while the concurrent arm of that trial (with paclitaxel) demonstrated a statistically significant reduction in relapse rate of 36 percent.

Many oncologists in practice find these results contradictory, and a third of these docs currently favor a HERAlike strategy. The sequential approach may also lessen the risk of cardiac toxicity, but that is speculation at this point. Perhaps the clinical investigators in our survey are more uniform in their preference for concurrent therapy because they feel more confident in their own data.

9.  About a third

Fraction of clinical investigators and community oncologists who would offer a year of trastuzumab to a 55-year-old woman treated two years previously for HER2-positive disease with 10 positive axillary nodes (Figure 39, page 30).

Most oncologists are considering delayed trastuzumab, probably because the clinical research groups who performed the adjuvant trastuzumab studies offered that therapy to participating patients who were randomly assigned to chemotherapy alone and were less than a year out from the completion of therapy.

I am very concerned about these “missed the window of opportunity” patients, who remind me of the tens of thousands of postmenopausal women who relapsed or had thrombotic events while on tamoxifen in the year or two after the ATAC trial was first presented. When patients and their loved ones face the tragedy of distant recurrence, it is important for them to believe that they did all they could to prevent it, and patients who don’t at least hear about new treatment options like aromatase inhibitors and trastuzumab — initially and at delayed time points — are not receiving state-of-the-art advice.

Click here to see image

10.  38%

Fraction of community-based oncologists who would recommend bevacizumab to a 40-year-old taxane-naïve patient as part of first-line therapy in the metastatic setting (Figure 45, page 34).

The fraction of clinical investigators who would use bevacizumab and, specifically, paclitaxel-bevacizumab is almost double this fraction. At CME meetings and other venues, many communitybased oncologists have noted that they are frankly confused about what to do concerning the data presented at ASCO by Kathy Miller on ECOG-E2100, demonstrating a progression-free and overall survival benefit when bevacizumab was added to paclitaxel.

This is particularly interesting in view of the common utilization of “bev” by community-based oncologists for metastatic colon cancer. Part of the issue with breast cancer is concern about reimbursement for this non-FDA-approved, pricey therapy (Figure 3, above), but perhaps equally important is the skepticism often found in community docs when only one trial demonstrates benefit, particularly in a noncurative situation.

There also is a general belief among oncologists that so many options exist for metastatic breast cancer that the use of bev seems less compelling than, for example, in non-small cell lung cancer, where FDA approval of bev/carbo/ paclitaxel is likely to be followed by a stampede of use similar to what we saw in colon cancer.

11.  53%

Fraction of investigators who recommend capecitabine as first-line therapy for metastatic disease in a 40-year-old patient who is minimally symptomatic and had received prior adjuvant therapy with an anthracycline and a taxane (Figure 47, page 36).

As in our prior surveys, capecitabine is far more commonly utilized by investigators than community docs. What is particularly interesting is that half of the researchers who would utilize capecitabine would add bevacizumab in this situation.

A study in the late-line metastatic setting of this combination — also by Kathy Miller — did not meet its primary endpoint of progression-free survival, although there was an increased response rate in patients treated with bev. Some investigators consider this a positive trial, and others do not. The capecitabine/ bevacizumab regimen was well tolerated, and cited by Eric Winer in his ASCO discussion of Kathy’s paper as one of several considerations for patients who are not good candidates for taxanes.

12.  Greater than 90%

Fraction of oncologists who consider the short infusion time and lack of need for premedication clinically significant benefits for the use of nanoparticle paclitaxel (Figure 53, page 39).

Clinicians are clearly putting their feet in the water gingerly with this new and somewhat costly therapy, but one might expect that as reimbursement issues are resolved and additional research is generated, many more patients will be treated with this interesting agent.

Note that docs are currently split in terms of weekly versus three-weekly use of nab paclitaxel (Figure 52, page 39), with the weekly contingent likely basing their preference on Phase II US Oncology data from Joanne Blum.

13.  About 90%

Fraction of clinical investigators (and community docs) who believe that the efficacy of nab paclitaxel is equal to or greater than both paclitaxel and docetaxel (Figure 54, page 40).

Complementing this somewhat uniform perspective about antitumor efficacy is the perception that nab paclitaxel is also better tolerated than the other two available taxanes. If these oncologists are correct, it seems possible that nab paclitaxel will emerge over the next couple of years as perhaps the dominant taxane utilized in breast and perhaps other cancers.

14.  Greater than 50%

Fraction of investigators and community docs who would use fulvestrant in a postmenopausal patient who relapses on adjuvant anastrozole (Figure 61, page 46).

This choice is interesting, particularly because there are no data comparing tamoxifen to fulvestrant in this situation, although there are data showing essentially equivalent results of these two agents in hormone-naïve patients. Other research has demonstrated at least equivalence between fulvestrant and anastrozole in patients who progress on tamoxifen.

Note also that about half of the investigators use a loading dose of fulvestrant, while this approach is much less commonly utilized in the community setting (Figure 64, page 48).

This is our fifth issue of Patterns of Care devoted exclusively to the management of breast cancer. With each new survey, I eagerly anticipate the opportunity to look at the data because in my mind these findings truly provide a glimpse into what clinical investigators and oncologists in practice consider state-of-the-art patient care. I can’t wait to see what cool numbers emerge in 2006.

— Neil Love, MD

The data in this monograph reflect a series of telephone/fax/email surveys conducted in August/September 2005 of 100 randomly selected US-based medical oncologists who spend more than 50 percent of their time in patient care. Sample sizes of 50 are presented. In addition the survey was completed by 45 clinical investigators who spend more than 80 percent of clinical time caring for breast cancer patients. Survey results were reviewed by Clifford Hudis, MD and Debu Tripathy, MD.

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