Updated: August 2006
A guide for people with advanced breast cancer.
1) Surgery for Recurrent Disease
There are a few well defined indications for surgery.
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a) |
Investigation of a lesion which may be metastatic but may alternatively be a new primary disease, e.g., a solitary lung lesion. |
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b) |
Treatment of a complication or impending complication of metastatic disease. |
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i) |
Orthopedic procedures for pathological fractures. |
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ii) |
Surgical decompression for spinal cord compression is sometimes indicated. |
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iii) |
Where there is a single brain metastasis, or a small number of brain metastases, if surgical resection is reasonably safe and feasible, survival is improved compared to palliative brain radiation alone. |
2) Radiation Therapy
Locally troublesome areas can be treated with radiation therapy. Metastatic breast cancer is usually moderately radiosensitive and worthwhile symptomatic relief can be expected. Radiation is commonly used in the treatment of:
- Bony metastatic lesions
- Cord compression in conjunction with steroids with or without surgical decompression
- Symptomatic endobronchial lesions
- Superior vena cava obstruction
- Cerebral metastatic disease in conjunction with steroids unless it is a terminal event.
3) Hormone Therapy
First-line hormone therapy is indicated under the following circumstances:
- Patients with positive estrogen or progesterone receptors
- Metastatic disease confined to non-visceral sites
- Relatively indolent metastatic disease not considered likely to produce a life threatening situation in the next twelve weeks (e.g., one or two solitary pulmonary nodules or chest wall recurrence).
Chance of response is highest when there has been a long disease-free interval predating relapse. Therapy should also be offered after response to first-line therapy with chemotherapy, if hormone-receptor positive, to try to maintain longer remission.
TREATMENT OPTIONS IN ORDER OF USE
Treatment should be continued to progression unless there is significant toxicity. Response to one hormonal agent often predicts for responses to other agents.
Premenopausal Women
- Tamoxifen 20 mg/day or ovarian ablation (BRAVTAM)
- Ovarian ablation if tamoxifen used as first line therapy. Ovarian ablation can be surgical oophorectomy, radiation or in some cases Zoladex 10.8 mg IM q 3 months or 3.6 mg IM q month..
- Megace 160 mg/d (BRAVMEG)
Combination therapy with Zoladex and Tamoxifen has been used and reported as effective. (BRAVBT).
Postmenopausal Women
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1. |
Tamoxifen 20 mg/d (BRAVTAM)
Or
Aromatase inhibitors either Anastrozole (Arimidex® ) 1 mg/d (BRAVANAS) or Letrozole (Femara® ) 2.5 mg/d (BRAVLET) |
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2. |
Exemestane (Aromasin® ) 25 mg/d (BRAVEXE) after Anastrozole or Letrozole
Or |
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Tamoxifen if Anastrozole or Letrozole was used as first-line |
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3. |
Exemestane after Tamoxifen and Anastrozole, or Letrozole |
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Megestrol (Megace®) 160 mg/d (BRAVMEG) |
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Testosterone enanthate (Delatestryl®) IM 400 mg every 4 weeks (BRAVTEST) Or Fluoxymesterone (if available) 5 mg bid or tid as tolerated |
Anastrozole (Arimidex®), letrozole (Femara®) and exemestane (Aromasin®) are selective aromatase inhibitors which have been shown to be more effective and less toxic than megestrol (Megace®) as second line therapy in phase III studies. Anastrazole and letrozole are competitive inhibitors of aromatase, so decrease estrogen levels markedly in post-menopausal women. Phase III studies comparing either anastrozole or letrozole to tamoxifen have established that they may also have an important role as first- line therapy. Either letrozole or anastrozole can be used alone as first-line or second-line therapy, but should not be used in sequence, as they have the same mechanism of action and very similar chemistry. A switch between letrozole and anastrazole can be considered if there is a toxicity issue, as sometimes there is a preference between agents in individual patients. Tamoxifen remains a first-line option, especially for those not previously exposed to it as an adjuvant therapy, or can be used as second-line or third-line. Exemestane is an irreversible aromatase inactivator that has shown some activity after previous therapy with reversible aromatase inhibitors, and can be justified as second line or third-line.
Fulvestrant (Faslodex®) is a pure anti-estrogen that is given by monthly intramuscular injection. It has recently been compared to anastrozole and appears equivalent as second line therapy. It is not currently funded by BCCA, but can be purchased by individual patients at a non-BCCA pharmacy. Megestrol acetate or testosterone are appropriate in selected patients likely to respond to further hormone therapy, but should be used only after a response to other more active and less toxic hormonal agents. The choice of agent for optimal hormonal therapy in a given situation should reflect the best available evidence showing patient benefit, the likelihood of response and the associated side-effects.
4) Chemotherapy
Chemotherapy in the presence of proven metastatic disease is not curative using the currently available regimens. The aim of treatment is to relieve symptoms and extend survival, without causing unacceptable side effects.
Indications for Chemotherapy
- Rapidly progressive metastatic disease
- Metastatic disease involving the viscera, particularly the liver
- Estrogen receptor negative primary tumours with symptomatic metastasis
- Failure of hormonal maneuvers
- Investigational studies (consult BCCA medical oncologist)
First-line Chemotherapy
First-line chemotherapy for metastatic disease will depend upon whether or not the patient has received prior adjuvant chemotherapy, and on her2/neu status.
It is generally felt that the patient who develops metastatic disease, having previously received adjuvant chemotherapy, has disease that is likely to be resistant to the initial agents and therefore non cross-resistant chemotherapy should be used. The longer the interval from adjuvant therapy until relapse, the better chance that some sensitivity to the same chemotherapy agents may be maintained.
Her 2/neu negative breast cancer:
If no prior chemotherapy:
Consider an anthracycline-containing regimen, such as AC (BRAVAC) or CAF (BRAVCAF), or consider CMF (BRAVCMF).
If anthracyclines are contraindicated (eg. Due to cardiac dysfunction) or if patient has had recent (<1 year) adjuvant therapy with anthracyclines, a taxane regimen would be a frequent alternate choice. Monotherapy with docetaxel (BRAVDOC or BRAVDOC7) or with paclitaxel (BRAVTAX) can be considered. In a fit individual with more aggressive disease relapse, it may be appropriate to consider a combination regimen with a taxane, such as BRAVCAD (docetaxel capecitabine) or BRAVGEMT (paclitaxel gemcitabine).
Phase II or randomized phase III studies are sometimes available to test new agents, particularly in the first- or second-line therapy of relapsed breast cancer,
Second-line Chemotherapy
This is less rewarding than first-line chemotherapy both in terms of probability of tumour response and in terms of toxicity. Therapeutic gain is modest in most circumstances, but chemotherapy may relieve symptoms and therefore is of importance. Taxanes (docetaxel or paclitaxel) are recommended as second-line therapy in patients progressing after anthracycline therapy. Doses may need to be reduced in light of previous tolerance of chemotherapy, performance status, and organ function (especially liver and peripheral nerve function). Please see protocol descriptions for details. Vinorelbine, an iv microtubule inhibitor, (BRAVNAV) or capecitabine, an oral 5-FU prodrug ,(BRAVCAP) are alternative selections, if not used previously in combination. An anthracycline regimen could be used (as listed above), if not used previously in the metastatic setting. If significant prior therapy with anthracyclines has been offered in the adjuvant setting, it may be necessary to use a cardioprotectant agent (eg. Dexrazoxane) after a lifetime total of 6-8 anthracycline cycles. Dexrazoxane is available through the undesignated indication program, in appropriate circumstances.
Third-line Chemotherapy
In responding patients third line chemotherapy may palliate symptoms, and can be considered, particularly if there has been good previous tolerance of and response to chemotherapy. Capecitabine, vinorelbine, or anthracycline may be effective, if not already used. See discussion and protocol names above.
We recommend that third-line chemotherapy be considered for the following patients:
- Metastatic breast cancer that has been previously treated with anthracyclines and taxanes and which has responded to at least one previous therapy in the metastatic setting
- Performance status 0-2
- Anticipated survival >3 months
Response should be evaluated after 2 or 3 cycles and non-responding patients should have treatment discontinued. Responding patients can be treated with six cycles of chemotherapy or for two cycles past best response. Toxicity with capecitabine is usually mild but can be severe if treatment is continued in the face of toxicity. Dose modifications should be adhered to and patients should be advised to report toxicity. Prescribing physicians and pharmacists must be aware of the toxicity profile for the relevant drug.
Her 2/neu positive breast cancer:
First-line therapy:
Studies of patients with her2/neu positive breast cancers have revealed that survival may be improved by earlier use of trastuzumab in combination with chemotherapy, compared to delayed initiation of trastuzumab. The use of trastuzumab is associated with a small risk of cardio-toxicity, and use of this agent may not be feasible if significant cardiac dysfunction exists at baseline, either due to previous anthracycline exposure or other causes. A trastuzumab-containing regimen is therefore recommended as first-line therapy to women with her2/neu over-expressing metastatic breast cancer. Chance of response to therapy is also likely highest with a trastuzumab-containing regimen. Responding patients should be offered continuation of therapy with trastuzumab alone after about 6 cycles of chemotherapy, as some patients may remain free of further relapse for prolonged periods (years) on this therapy. Trastuzumab is an intravenous monoclonal antibody which is generally very well tolerated for prolonged periods, barring the development of clinical symptoms of heart failure.
Usual first choice regimens incorporating trastuzumab include; trastuzumab plus paclitaxel +/- carboplatin (BRAVTRAP or BRAVTPC) or plus docetaxel (BRAVTRAD). If for some reason a taxane agent is contraindicated, trastuzumab plus vinorelbine could also be considered (BRAVTRNAV). BRAVTPC or BRAVTRAD are preferred choices in this setting, if no contraindications exist.
If the patient is on trastuzumab as an adjuvant therapy at the time of diagnosis with metastatic disease, trastuzumab should not be continued, except in the occasional patient with resectable brain metastasis only (see adjuvant trastuzumab protocol details for further explanation).
If the patient has had trastuzumab as an adjuvant therapy, treatment with trastuzumab and chemotherapy may still be reasonable in some patients, who have had a long treatment-free interval after trastuzumab in the adjuvant setting.
Second-line therapy:
At the time that there is demonstrated progression of disease while on trastuzumab, either in initial combination or as a continuing monotherapy after combination treatment, trastuzumab should be discontinued permanently. There is no clinical evidence that survival is improved by continuing trastuzumab after resistance has developed to it.
Second-line choices could include an anthracycline protocol (if not previously used, and if no cardiac toxicity has developed on trastuzumab); vinorelbine (BRAVNAV), or capecitabine (BRAVCAP). Trastuzumab has a prolonged half-life, so introduction of anthracycline therapy should be conducted cautiously if shortly after trastuzumab discontinuation, as the chance of cardio-toxicity may be enhanced for a period of time.
Clinical trials of other experimental agents targeting her2/neu over-expression may be available for certain clinical circumstances, through BCCA.
Third-line therapy:
The same considerations apply as per the section above for her2/neu negative tumours.
Bisphosphonate Therapy for Patients with Breast Cancer Metastatic to Bone
Bisphosphonates have been studied extensively in breast cancer. There are currently a number of relevant trials available for review. The Ontario Cancer Treatment Practice Guidelines Initiative has developed an evidence-based recommendation regarding the use of bisphosphonates in breast cancer, based on these trial results. The conclusion of these guidelines is that women with bone metastases from breast cancer should be offered treatment with bisphosphonates. This is based on the pooled results of 7 randomized, placebo-controlled clinical trials involving 1476 patients and evaluating both pamidronate and clodronate. In this summary, the risk ratio for treated patients of developing fractures was 0.72 and the risk of requiring radiation was 0.61, compared to the placebo-treated groups. All available randomized, controlled trials studying this issue have demonstrated consistent results; there are no trials with conflicting conclusions.
- Oral clodronate 1600 mg per day should be recommended for all patients presenting with bony metastases from breast cancer. This treatment should be continued until death, intolerance, or obvious rapid deterioration in performance status. Clodronate may be better tolerated if the initial dose is 50%, and the doses are increased over the first 1-3 weeks. The full 1600 mg dose can be taken once daily.
- For the small number of patients (approx 10%) who do not tolerate oral clodronate, pamidronate 90 mg iv by 1-2 hour infusion should be recommended every 4-6 weeks. This also should be continued until intolerance, death, or severe deterioration of the performance status of the patients.
- At this time we are not recommending the use of bisphosphonate immediately upon completing adjuvant therapy in women. Further studies are pending which will be reviewed prior to any recommendation in the adjuvant setting.
- Etidronate and alendronate have not been studied in this setting and are not recommended for treatment use, other than as appropriate for other conditions such as treatment of osteoporosis. Further studies with these agents may be available in the future. Zolendronate has been studied but is not currently funded by BCCA.
- There is as yet insufficient evidence to support the use of bisphosphonates for women with metastatic cancer but without bone metastases except in the treatment of other conditions such as osteoporosis.
ACUTE PAIN SYNDROME
There have been 4 randomized, placebo-controlled double blind studies using bisphosphonates in the treatment of the acute pain syndrome secondary to bony metastases. This pain syndrome is described as severe, acute, rapidly progressive pain not relieved by analgesics or narcotics. The severity of this syndrome usually requires hospital admission. It has been shown that an IV infusion of 90-120 mg of pamidronate can help to relieve this type of pain. The painful bone syndrome may occur with a variety of malignancies including breast, lung, and myeloma, prostate, renal, etc. Studies suggest that iv medication is required for rapid effect.
It is recommended:
- That pamidronate 90-120 mg iv over 2-4 hours be used in the setting of acute pain syndrome secondary to bony metastases from any malignancies.
- That pamidronate should be given one time and then followed by aggressive use of narcotic analgesic and treatment of underlying disease if possible. Repeat us of pamidronate may be considered if after 1 week there is clear but only partial relief of the pain despite aggressive analgesics. If there is not response other maneuvers should be initiated.