Targeting the right chemotherapy for the right patient

In the past few years breast cancer mortality has been declining in most Western countries as a consequence of better education, implementation of screening programs and more effective therapies. However, a small proportion of patients are metastatic at initial diagnosis (about 5–7%), and 25–30% of patients develop metastases following primary treatment. At this stage, the disease is considered incurable, the median survival ranges from 2 to 4 years, and a limited proportion of patients (about 20%) survive more than 5 years. In this scenario, it is important to identify the aims of treatment on the basis of individual patient needs. Data from clinical trials, meta-analyses, databases of large institutions, and cancer registries indicate that chemotherapy can prolong survival, and survival prolongation is associated with the activity of drugs [1–5]. Moreover, those patients who achieve a complete response have about 20% chance of surviving beyond 5 years [6]. Finally, although there are few trials specifically addressing symptomatic control and quality of life, it is generally agreed that tumor shrinkage is associated with better control of symptoms, and that quality of life results from the balance between activity and tolerability of treatments.

Metastatic breast cancer patients represent a very heterogeneous population, and several factors are important in determining prognosis: patient characteristics such as motivation, compliance with treatment, age, performance status and comorbidities; tumor characteristics such as hormonal receptor status and expression of HER2-neu; prior adjuvant therapies and disease-free interval; and site and extension of metastatic spread.

Treatment options include locoregional treatments, endocrine agents, monoclonal antibodies, bisphosphonates and cytotoxic agents. The aims of these treatments include symptomatic control, maintenance of quality of life, tumor shrinkage, prolonging time to progression, and survival prolongation.

Although the role of radiation therapy in controlling locoregional relapses, and of endocrine therapy in the upfront treatment of endocrine-sensitive tumors is undebatable, the optimal use of cytotoxic chemotherapy remains controversial. The main reasons for the lack of general consensus are the heterogeneity of the patient population and the availability of several effective options. In the following paragraphs we discuss the different treatment options in the most common clinical scenarios.

Treatment options based on patient characteristics

The majority of metastatic breast cancer patients are over 65 years of age, and therefore a significant proportion are affected by comorbidities such as hypertension, diabetes and respiratory disease [7]. Tolerability of chemotherapy can be profoundly influenced by these comorbidities as well as by their specific treatments.

In the case of elderly patients with significant comorbidities and declining general condition, the aim of treatment is symptomatic control with improvement in quality of life (QoL). To date, the availability of oral agents such as capecitabine and navelbine allows for a good balance between activity, tolerability, compliance and dosage flexibility. Furthermore, weekly administration allows maintenance of the activity of important cytotoxic agents such as taxanes and platinum salts with substantial decrease in toxicity. Finally, new antimetabolites (gemcitabine) or new formulations of old drugs (liposome-encapsulated doxorubicin) are generally associated with reduced toxicity. For these patients it is clear that the best choice is the use of single agents that can be sequentially administered on the basis of tolerability and disease control.

About 20% of patients present with locoregional relapses (regional lymph nodes, skin metastases). Moreover more sensitive imaging techniques (Multislice computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET] scan) and the development of methods to detect micrometastatic disease (i.e. circulating tumor cells) permit diagnosis of an increasing proportion of patients with oligometastatic disease. A reasonable percentage of these patients can be cured or at least rendered disease free for prolonged period of time; a chemotherapy regimen to induce rapid and important tumor shrinkage followed by locoregional treatments (radiotherapy, surgery, radiofrequency ablation) is necessary to achieve this goal. In this setting, it is clear that combination regimens should be the preferred option.

Another clinical scenario is represented by younger patients, without comorbid conditions, and massive visceral involvement. Here again, rapid tumor shrinkage is important in preventing life-threatening organ failure. In this setting, combination regimens ensure a higher percentage of objective responses [8, 9] and a shorter time to response [10].

Treatment options based on tumor characteristics

Breast cancer tumors are at least as heterogeneous as breast cancer patients. However, the only tumor-related parameters currently utilized in the decision making process are the disease course in the individual patient, hormone receptor status, and HER2-neu overexpression.

In the case of patients with slowly-growing hormone receptor-negative tumors and predominant bone disease, main aims of treatment are maintenance of QoL and prolonging time to progression. In these cases, single-agent chemotherapy provides a better balance between activity and tolerability. More frequently, patients with hormone-sensitive tumors receive several lines of endocrine therapy until development of hormone resistance. Here again, when chemotherapy is required, the preferred choice is the sequential administration of single agents.

Another important tumor characteristic is the HER2-neu status; HER2-neu is overexpressed in 25–30% of breast cancers. As a single agent trastuzumab, a monoclonal antibody directed against the extra-membrane portion of HER2 receptor, can induce a 30% response rate in HER2-overexpressing tumors. The addition of trastuzumab to chemotherapy as compared with chemotherapy alone is associated with a significant improvement in objective response rate, duration of response and overall survival [11].

Several cytotoxic agents showed synergism or additive effect when combined with trastuzumab; clinical trials have shown that trastuzumab can successfully be combined with both single agent and combination chemotherapy.

Treatment options based on prior adjuvant therapy

Anthracyclines represent the most active agents, and anthracycline-containing regimens are more effective in terms of response rates, complete remission rates, remission duration and survival. However, anthracycline regimens are increasingly used in the adjuvant setting, and therefore retreatment with anthracyclines, even if effective, is limited to patients exposed to low cumulative anthracycline doses and with a relapse-free survival after adjuvant chemotherapy longer than 12 months. The main limitation to anthracyclines is their dose-dependent cardiac toxicity; patients should not exceed the cumulative dose of 450–550 mg/m² for doxorubicin and 800–900 mg/m² for epirubicin. However, few data are available on the efficacy of anthracycline rechallenge after prior exposure to adjuvant anthracycline. A recent report from our group [12] has shown that anthracycline-taxane combinations as first-line treatment for metastatic breast cancer are effective, regardless of previous adjuvant chemotherapy.

As more and more patients are receiving taxanes as a component of their adjuvant program, it will be important also to have data on the efficacy of taxane rechallenge in metastatic patients.

Conclusion

Survival prolongation must be the primary goal of treatment, and this aim can be achieved with the incorporation of new active agents in the treatment strategy. Both combined and sequential single agents are acceptable options; however, if not contraindicated by the conditions of the patient and if feasible with an acceptable toxicity profile, there is no reason to delay the upfront use of active agents.