Speakers at this international workshop, which was held in Lisbon, Portugal, on June 28, 1997, addressed the integration of new treatment strategies, including paclitaxel (Taxol), into the management of women with breast cancer.
They examined the role of these new strategies in the following settings:
adjuvant and neoadjuvant therapy
first-line metastatic breast cancer patients previously treated with an anthracycline
initial chemotherapy in women with metastatic breast cancer
second-line (or so-called salvage) chemotherapy
The articles in this supplement have been developed from this program.
The importance of developing new treatment strategies has been clearly established. Studies show that there is a significant margin for improving the treatment of metastatic breast cancer in order to better the prognosis for thousands of women newly diagnosed each year as well as for those in whom disease progresses.
The management of metastatic breast cancer is based on a series of discrete events beginning with the diagnosis of the disease. Each of these time points presents an opportunity for intervention and improved care.
In the area of diagnosis, significant changes are taking place, particularly with the advent of molecular diagnostic techniques. This is an exciting sphere as we are constantly learning more about the molecular biology of breast cancer. These findings will create the opportunity for earlier diagnosis, and consequently, earlier treatment than currently being achieved with mammography.
Similarly, improvements in diagnostic tests will enable more accurate staging. In addition, increasing knowledge about the histology of tumors is likely to have a greater impact on their management. For example, there is increasing evidence that a better understanding of a tumors characteristics may allow us to predict response to chemotherapeutic agents, such as paclitaxel, and to plan more effective treatment, accordingly.
Therapy for primary breast cancer is twofold: (1) local therapy, total mastectomy plus axillary dissection or breast-conserving surgery with axillary dissection and (2) radiotherapy. Although there has been significant interest in the United States in axillary dissection, this procedure does not seem to be appropriate in all cases. Research has now demonstrated that the so-called sentinel lymph node biopsy can determine the probability of axillary lymph node involvement. Sentinel nodes can be identified by the use of radioisotopes or dyes. If such a node is found to be negative, there is a greater than 90% chance that other lymph nodes will be negative. Advances like these will significantly alter diagnostic strategies, including axillary resection, over the next few years.
If we turn our attention to systemic treatment, one of the most important questions facing us today is, For whom is adjuvant chemotherapy indicated? This is still a very real question. Our definition changes as our understanding of the biology of the disease increases and the agents available for adjuvant therapy also improve. As adjuvant therapies become more effective, we can treat more patients. Indeed, it is likely that women with a good prognosis will be afforded an even better one with the use of high-quality adjuvant therapy.
Has the Effectiveness of Chemotherapy in Metastatic Breast Cancer Improved Over the Last Five Years?
During this symposium, we had the opportunity to use an audience response system to evaluate the views of the participants. Their response to this question probably reflects the views of many, if not most, oncologists today.
A significant minority believed that chemotherapy has not resulted in some improvement in survival, whereas the majority of respondents felt that the efficacy of chemotherapy has indeed increased. This reflects the use of new agents, like the taxanes, which are the most promising new agents we have seen over the last few years.
There was also a consensus that the tolerability of chemotherapy has improved significantly, probably reflecting the addition of drugs to manage side effects like nausea. Similarly, it was agreed that this improvement in tolerability has been accompanied by an improvement in quality of life, amplified further by better response and a reduction in cancer symptoms.
Prolonged Survival Effect of Chemotherapy Questioned
Perhaps the most controversial area concerned whether we have been able to improve survival. The audience at this symposium was evenly split on this issue. Improved survival has been difficult to demonstrate in prospective, randomized trials. In contrast, we can all think of individual cases where survival has been significantly prolonged in patients rapidly approaching death. Therefore, it is probably true that survival has been improved in individual patients, but it is less certain whether this benefit achieves statistical significance in a population of women with metastatic breast cancer.
However, work undertaken by the Early Breast Cancer Trialists Collaborative Group in Oxford (Peto) may answer this question. Data show that for patients receiving adjuvant chemotherapy, the odds of being alive are significantly greater than for those who do not receive the treatment. Nor has this benefit been offset by excessive mortality from other causes, eg, leukemia. Therefore, for the first time we may be able to confirm that chemotherapy has a significant, positive impact on survival.
However, the total effect on a population basis is relatively modest. Therefore, if a major improvement in survival will require significant, real advances in chemotherapy, we need to realize that currently, chemotherapy is not curing patients but it is, in fact, reducing the rate of disease recurrence. Therefore, the effectiveness of treatment depends on the actual risk of recurrence. So, if we identify and treat patients with the highest risk of recurrence, adjuvant chemotherapy will have its greatest impact on survival.
Taking a More Aggressive Approach
The doses of chemotherapy and the spacing of treatment cycles are also significant factors in the potential effectiveness of treatment. At present, the conventional model of treatment is that a combination chemotherapy regimen is administered to kill all cells that are resistant to one agent but not to another. Equally spaced cycles are used with a flat dose to achieve the same mg/m² with each dose. At the same time, we assume that there is a link between the efficacy and tolerability of the agents we prescribe, ie, a drug that causes more side effects kills more tumor cells than a better-tolerated agent.
There is an urgent need to challenge this philosophy. For example, the concept of equally spaced cycles is a dogma that should be challenged by experimentation. It is now clear that the growth of tumors in breast cancer does not accelerate at a constant rate. Like everything else in biology, growth of these tumors tails off and eventually approaches a plateau. From a clinical viewpoint, this is an important consideration. If we can increase the aggressiveness of our treatment when growth is minimal, we may be in a position to improve survival significantly.
This leads us to the concept of improving therapy by increasing dose intensity, ie, the amount of drug we give divided by the time over which it is administered. When dosage is increased but the administration time remains the same, the strategy is known as dose escalation. Today, there is growing recognition of the potential importance of dose density, ie, the total dose may remain the same, but the duration of administration is significantly decreased. Given the pattern of growth of the tumor, a dose-dense schedule can prevent regrowth of the tumor between cycles. Studies with paclitaxel suggest that dose-dense scheduleswhere the total dose of one agent is given first to eradicate a particular subset of tumor cells, followed by the total dose of another agent to eradicate another groupmay increase the regimens effectiveness.
The future of chemotherapy for metastatic breast cancer is encouraging. As data presented at this symposium demonstrate, the development of the taxanes and their integration into combination regimens with anthracyclines and other drugs have demonstrated that they represent important new opportunities for improving treatment. At the same time, we are seeing the evolution of sequential regimens containing paclitaxel that hold promise in the adjuvant setting. All of these developments reflect the fact that paclitaxel is a very active drug, which can be combined with a number of other active agents to provide new and potentially effective treatment alternatives.
As we move forward in our thinking about breast cancer and about paclitaxel over the next few years, I hope we will begin to be able to develop curative therapeutic regimens for breast cancer, using the right combinations of drugs, with the right chemical manipulations, in patients most likely to respond to the therapy we administer.
Larry Norton, MD