When patients with stage IV breast cancer experience progression of the cancer during treatment or recurrence of the cancer after an initial treatment induced remission, doctors say the cancer is refractory. Patients may elect to be treated with salvage therapy, which is sometimes referred to as second-line therapy. Second-line therapy means that the patient has already failed treatment with first-line or initial therapy for metastatic cancer.
A variety of factors ultimately influence a patient's decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient's chance of cure, or prolong a patient's survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.
The following is a general overview of the treatment of recurrent breast cancer. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.
Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.
When patients experience a cancer recurrence that is confined to the breast or area immediately surrounding the breast, it is referred to as a local-regional recurrence. Patients who experience a breast cancer recurrence elsewhere in the body have a systemic recurrence. Although breast cancer may recur almost anywhere in the body, common locations include the liver, bones, lungs, brain and skin. A systemic recurrence is typically treated with chemotherapy, hormonal therapy or combinations of therapy. Local-regional recurrences may require surgery, radiation and/or systemic therapy.
Local-Regional Recurrence of Breast Cancer: Following primary surgical treatment of breast cancer with mastectomy or breast-conserving surgery (lumpectomy plus radiation), patients may experience a local recurrence which is defined as cancer recurring within the previously affected breast, chest wall, or skin over the breast. Patients may also experience a regional recurrence of cancer, which is defined as cancer involving the supraclavicular, internal mammary or axillary lymph nodes.
Local recurrence of breast cancer following initial treatment with mastectomy may be effectively controlled with additional radiation treatment. Surgical treatment of locally recurrent cancer prior to radiation therapy may also be beneficial in selected circumstances. Despite effective local control with surgery and radiation, the large majority of patients experiencing a local recurrence ultimately develop systemic recurrence of their cancer. The size of the cancer, the amount of radiation delivered and the size of the radiation field all influence the ability to prevent additional local recurrences.
Because the majority of patients with local recurrence ultimately develop a systemic recurrence of their cancer, many doctors believe additional treatment with chemotherapy or hormonal therapy can be useful. Unfortunately, this has not been well evaluated in controlled clinical trials.
Locally recurrent cancer following initial treatment with breast-conserving surgery (lumpectomy and radiation) is best controlled with mastectomy. Surgical mastectomy results in a 5-year recurrence-free survival of approximately 60-75% in patients with local failure following breast-conserving therapy. Surgery with or without radiation therapy can also effectively provide local control of patients with regional recurrence of breast cancer. Even more so than locally recurrent breast cancer, the majority of patients with regionally recurrent cancer will ultimately relapse systemically.
Chemotherapy Management of Breast Cancer
Both the effectiveness and type of second-line therapy available depends on the type of initial or first-line chemotherapy used. In general, second-line chemotherapy treatment is used to reduce symptoms of recurrent cancer and improve a patient's quality of life. Second-line chemotherapy is typically associated with lower response rates and a shorter duration of remission than first-line therapy except in instances where initial treatment may have been inadequate. The following are general principles that may apply to the use of second-line chemotherapy treatment of breast cancer.
Patients not previously treated with doxorubicin: The chemotherapy drug doxorubicin is one of the most active chemotherapy agents used for the treatment of breast cancer. Most patients, however, receive doxorubicin as part of their initial chemotherapy treatment of breast cancer. Doxorubicin can only be used for a limited amount of time because increased exposure to doxorubicin causes damage to the heart.
If patients have not previously been treated with a doxorubicin-containing chemotherapy regimen, doxorubicin administered alone or in combination with a taxane would constitute appropriate second-line chemotherapy treatment of metastatic breast cancer. Patients who have been previously treated with doxorubicin can receive additional doxorubicin treatment in selected circumstances, depending upon how much prior doxorubicin therapy was administered. Because of doxorubicin's known toxicity to the heart, patients may want their doctor to evaluate their heart function before electing to receive continued doxorubicin therapy.
Patients not previously treated with taxane-based therapy: For patients not previously treated with Taxotere® or paclitaxel, clinical studies suggest that treatment with either chemotherapy drug as a single agent or in combination with other chemotherapy drugs can reduce symptoms from cancer and prolong a patient's survival compared to other treatments. Both Taxotere® and paclitaxel have been approved by the Food and Drug Administration as second-line treatment for stage IV breast cancer.
Gemzar®: Several clinical trials have been conducted to evaluate the safety and efficacy of Gemzar® in breast cancer patients previously treated with chemotherapy (mostly taxanes and/or anthracyclines). In these trials, the anti-cancer response rates varied between 25% to 37% and the median overall survivals ranged from 12 to 18 months. Treatment has been generally well tolerated, with side effects including low levels of blood cells and flu-like symptoms. Clinical studies indicate that Gemzar® has significant anti-cancer activity in patients with recurrent metastatic breast cancer and represents an effective treatment option.
Oral fluoropyramidines: Several new oral chemotherapy drugs have been developed for the treatment of breast cancer. Xeloda® is a well-tolerated, oral chemotherapy drug that can be taken at home for treatment of breast cancer. Research indicates that 20-30% of patients experience a measurable shrinkage of their cancer following treatment with Xeloda®. The average duration of survival of patients treated with Xeloda® is almost 13 months and the therapy is well tolerated. Xeloda® will continue to undergo evaluation in clinical trials in combination with other chemotherapy drugs and as treatment for earlier stage breast cancer.
Herceptin®: Monoclonal antibodies are a treatment that can locate cancer cells and kill them directly. Herceptin® is the first monoclonal antibody approved for the treatment of advanced breast cancer. Herceptin® recognizes and binds to a protein called HER2, which is found on the surface of some breast cancer cells and plays a role in regulating cell growth. Herceptin® attaches to the HER2 protein to slow growth of breast cancer cells and possibly stimulate the immune system to more effectively attack the cancer. Herceptin® can be administered as a single agent or in combination with some but not all chemotherapy drugs. Herceptin® in combination with Platinol® chemotherapy increases response rates and prolongs survival when compared to treatment with either Herceptin® or chemotherapy alone. More recent studies suggest that Herceptin® may be combined with newer chemotherapy drugs, including Gemzar®.
Hormonal Therapy Management of Breast Cancer
Treatment of cancers that have estrogen or progesterone receptors with hormonal therapy can delay cancer progression and prolong survival, especially in patients with small amounts of cancer not involving the lung or liver. Estrogen is a female hormone produced mainly by the ovaries. Many organs in the body are composed of cells that respond to or are regulated by exposure to estrogen. Cells in the breast, uterus, and other female organs have estrogen receptors and when exposed to estrogen, are stimulated to grow. When cells that have estrogen receptors become cancerous, the growth of these cancer cells can be increased by exposure to estrogen.
The basis of hormonal therapy as a treatment for breast cancer is to block or prevent the cancer cells from being exposed to estrogen. Removal of the ovaries, the organ chiefly responsible for producing estrogen, is one effective approach to eliminating estrogen production and is commonly used in many countries. Another approach is to utilize drugs that can accomplish a similar effect without removing the ovaries. Currently, many women with estrogen receptor-positive breast cancer are initially treated with a drug called Nolvadex® (tamoxifen), which blocks the growth stimulatory effects of estrogen. However, a newer group of drugs, called anti-aromatase agents, have recently been developed and approved by the FDA for the treatment of estrogen-positive breast cancer in post-menopausal women. Clinical trials are ongoing to determine the exact role anti-aromatase agents will play in the treatment of breast cancer.
Selective Estrogen Receptor Modulators (SERM): SERMs block the estrogen receptors of cancer cells, thereby preventing the growth stimulatory effects of estrogen. Blocking the effects of estrogen on the cell removes the growth stimulus of ER-positive cancer cells. Currently, Nolvadex® (tamoxifen) is the most common SERM used for the hormonal treatment of breast cancer. However, Nolvadex® is associated with side effects, including an increased risk of uterine cancer. In response to these side effects, a new class of SERMS has emerged which are believed to have positive effects on bones as well as anti-estrogen effects on breast cancer without increasing the risk of uterine cancer.
Anti-Aromatase Agents: Anti-aromatase agents are a class of hormonal agents that work by inhibiting the formation of estrogen in the body. Aromatase is the enzyme (protein) that initiates the process through which hormones in the body are converted to estrogen. Anti-aromatase agents work by inhibiting aromatase. By inhibiting aromatase, the conversion process that is responsible for creating the active form of estrogen is blocked. This reduces levels of the active form of estrogen in the body so cancer cells are depleted of necessary growth stimulant. This is in contrast to Nolvadex®, which blocks the growth stimulatory effects of estrogen by directly binding to estrogen receptors. Anti-aromatase agents are classified into two groups: aromatase inhibitors and aromatase inactivators. Aromatase inhibitors transiently bind to aromatase, whereas aromatase inactivators permanently bind to the enzyme. Currently, two aromatase inhibitors, Femara® and Arimidex® and an aromatase inactivator, Aromasin®, are approved for treatment of postmenopausal women with various stages of breast cancer.
Two large clinical trials directly comparing Arimidex® to Nolvadex® have been conducted in over 1,000 post-menopausal women with ER-positive or ER status unknown, advanced breast cancer. An average of 18.2 months following treatment, the time to cancer progression was 8.5 months for patients receiving Arimidex®, compared to only 7 months for patients receiving Nolvadex®. In the subgroup of patients with ER-positive breast cancer, the time to cancer progression was 10.7 months for patients receiving Arimidex®, compared to only 6.4 months for patients receiving Nolvadex®. An anti-cancer response was achieved in 57.2% of patients receiving Arimidex® and 52% of patients receiving Nolvadex®. Both treatments were generally well tolerated; however, patients receiving Arimidex® reported fewer blood clotting events and less vaginal bleeding.
Another clinical trial was recently conducted to compare Femara® to Nolvadex® as initial hormonal therapy in postmenopausal patients with ER-positive, metastatic breast cancer. At an average of approximately 2.5 years following therapy, the time to cancer progression was 9.4 months in the patients treated with Femara®, compared to 6 months for patients treated with Nolvadex®. The clinical benefit was achieved in 51% of patients treated with Femara®, compared to 38% of patients treated with Nolvadex®. Patients were allowed to “cross-over”, or receive treatment with the other agent if their cancer progressed while being treated with the initial agent. Therefore, true values for overall survival could not be determined, as half of the patients crossed-over and received both agents during their time of treatment. However, patients who initially received Femara® still had a four-month survival advantage over those who initially received Nolvadex®.
Aromasin® is currently approved for the treatment of ER-positive or receptor status unknown metastatic breast cancer in patients who have stopped responding to Nolvadex®. Several clinical trials have demonstrated an improved survival when Aromasin® was compared to Megace® for treatment in postmenopausal women with ER-positive or receptor unknown status advanced breast cancer who had stopped responding to Nolvadex®. Clinical trials have also indicated an improvement in response rates and survival when Aromasin® was compared to Nolvadex® as initial therapy in postmenopausal patients with metastatic, ER-positive breast cancer.
Managing Bone Complications
Breast cancer commonly spreads to the bone. Cancer cells in the bone, called bone metastases, can cause pain, bone loss, increase the risk of fractures, and lead to a life-threatening condition characterized by a high-level of calcium in the blood
Bisphosphonate drugs can effectively prevent loss of bone that occurs from metastatic lesions, reduce the risk of fractures, and decrease pain. Bisphosphonate drugs work by inhibiting bone resorption, or breakdown. Bone is constantly being “remodeled” by two types of cells: osteoclasts, which break down bone; and osteoblasts, which rebuild bone. Although the exact process by which bisphosphonates work is not completely understood, it is thought that bisphosphonates inhibit osteoclasts and induce apoptosis (cell death) in these cells, thereby reducing bone loss. There is also evidence that these drugs bind to bone, thereby blocking osteoclasts from breaking down bone. Cancer cells release various factors that stimulate osteoclastic activity, causing increased breakdown of bone. By inhibiting osteoclasts, bisphosphonate drugs effectively reduce the detrimental impact that cancer cells have on bone density.
Bisphosphonate therapy has been shown to prevent or delay bone destruction and related pain in women with breast cancer that has spread to the bone. In a large clinical trial, a total of 751 women with metastatic breast cancer were randomly assigned to receive the bisphosphonate drug, Aredia®, or placebo (inactive substitute). The results showed that 64% of women who received the placebo had significant bone damage, compared with only 51% of those who received the bisphosphonate. The average time to the occurrence of the first bone complication was 13 months in the bisphosphonate group, compared to only 7 months in the placebo group. Furthermore, women who did not receive the bisphosphonate experienced significantly more pain and received more pain medications. 1
Bisphosphonate drugs that are FDA-approved for the treatment of cancer-related skeletal complications include Zometa® (zoledronic acid) and Aredia® (pamidronate). Zometa® appears to demonstrate the strongest activity of these two drugs. An added benefit of Zometa® is that it is administered in a dose ten times lower than Aredia®. This considerably reduces administration time from several hours to 15 minutes, resulting in a more convenient regimen for patients.
Strategies to Improve Treatment
The progress that has been made in the treatment of breast cancer has resulted from improved development of adjuvant chemotherapy treatments and doctor and patient participation in clinical studies. Future progress in the treatment of breast cancer will result from continued participation in appropriate studies. Currently, there are several areas of active exploration aimed at improving the treatment of breast cancer.
Epidermal Growth Factor Receptor (EGFR) Inhibitors: Epidermal growth factor receptors (EGFR) are small proteins that are found on the surface of all cells. EGFR binds exclusively to small proteins circulating in the blood called growth factors. The binding action between EGFR and growth factors stimulates biological processes within the cell to promote growth of a cell in a strictly controlled manner. However, in many cancer cells, EGFR is either abundantly overexpressed or the EGFR biological processes that normally stimulate cell growth are constantly active, leading to the uncontrolled and excessive growth of the cancer cell.
EGFR inhibitors block the EGFR pathway, thereby halting excessive cellular growth by inhibiting the EGFR process within a cell. Several EGFR inhibitors have been developed and are currently being evaluated in clinical trials. Iressa® is an EGFR inhibitor that binds to the EGFR, HER1 and renders the receptor inactive. It has shown anti-cancer activity in various cancers and is still in clinical trials as researchers evaluate its full potential. Since the activity of some HER2-positive cell lines is presumably dependent upon other HER receptors, including HER1, researchers decided to evaluate the effects of Iressa® on HER2-positive breast cancer cells that also overexpressed HER1. Laboratory results indicated that Iressa® inhibited cellular growth of the HER2-positive breast cancer cells better than Herceptin® and even very low doses of Iressa® appear to produce significant anti-cancer activity in these cells. These laboratory results have prompted the initiation of clinical trials to evaluate Iressa® plus Herceptin® in HER2-positive breast cancer patients. Although the details of the exact mechanisms through which Iressa® halts HER2-positive cellular growth are still speculative, clinical applications of this agent in breast cancer treatment appear promising.
New Hormonal Agents: Researchers are also evaluating novel hormonal agents for the treatment of breast cancer. Faslodex® (fulvestrant) is a new anti-estrogen agent that has recently completed early phase clinical trials. Faslodex® binds to estrogen receptors on the surface of cancer cells and achieves its anti-estrogen effects through two separate mechanisms. First, when Faslodex® binds to the receptors, estrogen is crowded out and no longer able to bind to these receptors. Second, Faslodex® degrades the estrogen receptors to which it is bound. Both of these mechanisms prevent cancer cells from accessing sufficient amounts of estrogen needed for growth and replication.
A recent clinical trial was performed directly comparing Faslodex® to Arimidex®. In this trial, 400 postmenopausal women had early or advanced breast cancer and all had a cancer recurrence following previous hormonal therapy. The results indicated that 42% of patients receiving Faslodex® achieved an anti-cancer response, compared with 36.1% of patients receiving Arimidex®. The average anti-cancer response for patients receiving fulvestrant was 19.3 months, compared to only 10.5 months for patients receiving Arimidex®. Side effects of Faslodex® were comparable to those of Arimidex®. Further evaluation of Faslodex® in clinical trials will define the role of this new agent for breast cancer.
Management of Bone Metastases: Research indicates that the new bisphosphonate Boniva™ (ibandronate) reduces bone complications and the need for radiation or surgery for bone metastasis in patients with bone metastasis from breast cancer. Researchers from Europe recently pooled data from 2 clinical trials evaluating the oral form of Boniva™. The trials included 287 women with bone metastasis from breast cancer. Patients were treated with either Boniva™ or placebo (inactive substitute) and were evaluated for bone complications including bone fractures and spinal cord compression. 2 Boniva™ is approved for the treatment and prevention of osteoporosis in postmenopausal women.
Photodynamic Therapy: Photodynamic therapy is an emerging type of treatment that is still being evaluated and refined in clinical trials and laboratories. Photodynamic therapy works through the use of a photosensitizing agent and light. The photosensitizing agent is typically comprised of a porphyrin, which is a naturally occurring substance in the body involved in a variety of biological processes. The photosensitizing agent is injected into a patient's vein a couple of hours prior to surgery. During this time, the agent selectively collects in rapidly growing cells such as cancer cells. During surgery, the physician applies a certain wavelength of light through a hand-held wand directly to the site of the cancer and surrounding tissues. The energy from the light activates the photosensitizing agent, causing the production of a toxin that accumulates in the cancer cells and ultimately destroys them.
Researchers from New York recently conducted a clinical trial to evaluate the effects of low-dose photodynamic therapy in women with chest wall progression of breast cancer. All of the patients had failed previous treatment consisting of chemotherapy, radiation and/or hormonal therapy for chest wall progression. Six months following photodynamic therapy, 89% of the treated lesions had been completely eliminated, 8% showed a 50% reduction with no regrowth and only 3% of lesions showed no response. Only one lesion (out of 102) grew despite treatment. All treated lesions healed without medical or surgical intervention with no scarring or fibrosis.
Phase I Trials: New chemotherapy drugs continue to be developed and evaluated in patients with recurrent cancers in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anti-cancer activity in patients. |
