January 7, 2008

You are a previously healthy 55-year-old woman who was diagnosed several years ago with a 2.1-cm, ER-positive, PR-positive, HER2-negative breast tumor with one positive node. After receiving dose-dense AC paclitaxel, you began treatment with an aromatase inhibitor and have taken the small white pill daily without complications. Your life has been super busy balancing work, family and a full social calendar, and you barely have time to think about cancer, but for a few days just before every follow-up visit with your oncologist, you lie awake at night fearing what could be.

For the past few weeks, you’ve had a persistent backache, and on Christmas Day, you woke up with sore ribs. The NSAID you were taking is no longer effective, and the pain has been bothersome enough to make you pull out an old bottle of oxycodone. Instead of going out on the town as planned, you rang in the New Year with a quiet dinner at home with your family, trying not to think about your appointment for a bone scan in a couple of days and a return visit to see your oncologist.

Today, the news you’ve dreaded is delivered by your compassionate but crestfallen doctor. The bone scan shows multiple suspicious lesions and a CAT scan revealed masses in your liver as well. A subsequent biopsy confirms recurrence. The oncologist expresses concern about the extensive nature of the liver involvement and wishes to begin chemotherapy with the hope of seeing a response, which might then be followed by endocrine treatment. Specifically, a combination of nab paclitaxel and bevacizumab is recommended, and treatment is initiated the Friday of Super Bowl weekend. Previously, when you received adjuvant chemo, there was some numbness and tingling toward the end of the paclitaxel, but when treatment was stopped, this resolved as your hair regrew. The chemo premeds during adjuvant therapy made you agitated and sleepless, and you are grateful that now, with the nab, you can get some rest.

March 11, 2008

Within a few weeks of beginning therapy, the bone pain abates, and although you feel better physically, your soul is crushed. Your teenage children are withdrawn and tense, and you can see the anguish in your spouse’s eyes as he does everything possible to reassure your kids, reminding them of the oncologist’s vision of metastatic breast cancer as a “chronic disease.” Everyone seems cautiously optimistic but also completely uncertain about what to expect next.

The repeat CAT scan — a terrifying experience — reveals major shrinkage of the liver lesions. You receive the news with tearful gratitude, but in spite of your healthcare background, you don’t ask to see the images. Several months pass, and numbness returns in your fingers, followed by paresthesias in your feet. You attend your daughter’s high school graduation and wonder if you will be around to watch your other daughter receive her diploma in the same auditorium next year.

July 22, 2008

The nab paclitaxel is stopped because the neuropathy has worsened, but the bevacizumab is continued. You are back at work, and every other Friday you leave early for your oncologist’s office for the bevacizumab infusion, which causes no noticeable side effects. Every other visit you also receive fulvestrant and zoledronate.

For some years you’ve had mild hypertension, and it gets a bit worse on the bevacizumab. With a few changes to your regular medication, your blood pressure is quickly controlled and you joke about how you wished your cancer responded that well. In August, you join your family on a vacation and wonder if this is the last time you will truly feel well and be able to travel. You have a nice autumn, and things seem to be falling into a consistent pattern.

December 15, 2008

Thanksgiving takes on a new meaning this year, but only a few days after an emotional and festive family gathering, the bone pain returns. A new bone scan and abdominal CT show more osseous and hepatic lesions. You feel apathetic about Christmas for the first time, and after another subdued New Year’s Eve, you begin a series of sequential systemic therapies that have modest or no major benefits.

June 2, 2009

You attend your younger daughter’s graduation, knowing that things are not going well. You begin painful discussions with your husband about a living will, and you enter a Phase I trial of a novel targeted agent, which results in a skin rash and disease progression. On two occasions, you receive radiation therapy to painful bony areas, which slowly results in symptom relief only to be followed by new areas of discomfort.

November 24, 2009

Your oncologist — an extraordinary, compassionate, open physician — tells you and your spouse that further systemic therapy is likely to cause more problems than benefit. A nurse from hospice visits and describes their services. Your family is at your side constantly, and you view yourself from a distance, not really believing what is happening. On New Year’s Eve, you realize this will be the last time you watch the ball descend in Times Square.

March 14, 2010

A little more than two years after the first diagnosis of metastatic breast cancer, your life ends.

The above vignette is written by a clinician/educator and not a patient. I could never presume to understand such an experience from the outside. The main purpose of this fictitious scenario is to put a human face on clinical research data.

This case scenario demonstrates a number of key issues, including the following:

1. The personal side of the risk-benefit equation in the treatment of metastatic breast cancer is very different from the numbers and graphics we see in clinical trial reports.

The 26-month duration of survival in this case matches the outcome of one of the most important breast cancer clinical trials of the last decade, ECOG-E2100, an Eastern Cooperative Oncology Group study that compared paclitaxel alone or with bevacizumab (Figure 1). As in this case, the median time to progression for patients receiving the combination was 11+ months or, in real terms for this patient, most of 2008 (Figure 2).

Based on the ECOG data, had bevacizumab not been used, this hypothetical woman who began treatment in January would have experienced a return of bone pain and progressive disease not in December but in July, about 5 months earlier. Of course, one could argue that the lack of a placebo control in the E2100 study might mean that the PFS advantage really does not exist, but I don’t know one major breast cancer clinical investigator who questions this advantage, and our Patterns of Care surveys consistently demonstrate support from researchers and docs in practice for these cooperative group data. Also based on the E2100 findings, the date of death might have been a couple of months earlier had bev not been utilized, but this assumption is far less certain, and this trial is not different than many other recent studies in metastatic breast cancer (MBC) demonstrating PFS but not survival benefits, perhaps because the downstream events make survival benefits more difficult to document.

Of course, bev is not without its toxicities, and we might have also inserted an arterial event in this case history, although one wonders whether the risk might be lower in a “healthy” 55-year-old woman.

I am not a politician, regulatory expert or economist, but there are also important questions about the cost of healthcare in this case scenario, not restricted solely to bevacizumab but also relating to nab paclitaxel, which may be less toxic and more effective than its Cremophor®-based cousin.

Many other such “costly” agents and regimens exist in contemporary oncology, and a number of vocal investigators and healthcare pundits have expressed legitimate and deep concerns about this trend.

I wonder how these individuals and regulatory bodies would have viewed the E2100 results with the five-month median delay in progression had the therapy in question been an inexpensive elemental agent like calcium or magnesium. Smarter and more experienced people than me can weigh in on the way data, agents and their cost should be carried into practice, but I would ask with all humility, if you were this patient in this first-line situation, what treatment would you want?

2. MBC is a devastating disease.

Another issue this case raises is the disappointing reality of our current treatment tools for MBC. Every day, medical oncologists are asked to do the impossible by providing reassurance to people with incurable and largely uncontrollable clinical situations. It is natural to stretch the truth a bit and talk about MBC as a chronic disease, but despite the fact that thousands of women live many comfortable years with this illness, in toto — as reflected in the E2100 data and in the case scenario — many or most people succumb to MBC within a couple of years, and if reading the above narrative was as painful for you as writing it was for me, we can both begin to understand the apocalyptic nature of this illness and, for that matter, every fatal case of cancer.

Can laboratory and clinical research truly make MBC a chronic controllable disease with minimal morbidity and mortality? After listening to hundreds of investigators day and night for many years, and thinking through these comments critically, my conclusion is a resounding, “Probably!” If a patient in the above scenario can remain asymptomatic with minimal objective signs of tumor growth for one year, can we extend that to 40 years and allow “aging” in the form of cardiovascular and cerebrovascular disease to be the eventual cause of death?

The tragedy of cases like this one is that the dream of eliminating the morbidity and mortality of MBC is not likely to happen in our lifetime unless dramatic changes are made to the cancer research infrastructure. Again, no politics here — I am just a humble reporter of the obvious. See the excerpt below from the interview with Dr Larry Norton in this issue of Breast Cancer Update for more details.

— Neil Love, MD
DrNeilLove@ResearchToPractice.com
January 4, 2008

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EDITOR'S NOTE
Another perspective on metastatic breast cancer
Neil Love, MD
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Larry Norton, MD
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Charles E Geyer Jr, MD
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