Drug-treatment
Adjuvant Treatment
Systemic adjuvant treatment is given to patients, after primarytreatment i.e. surgery/ radiotherapy for local control of disease, inorder to minimise the risk of metastatic disease.
Thetreatment modality selected will depend upon the stage and nature ofthe primary lesion and the age and condition of the patient.
There are two major types of adjuvant treatment - chemotherapy and endocrine.
1) Chemotherapy
Schedules based on combination chemotherapy have been most widely usedin patients with more aggressive disease, a greater tumour burden atsurgery and younger patients.
Schedules such as 6 cycles ofCMF (cyclophosphamide; methotrexate; fluorouracil) or FEC(fluorouracil; epirubicin; cyclophosphamide) have given rise to a delayin recurrence and, in pre-menopausal patients, a significantprolongation of survival.*
Chemotherapy produces a significantsurvival benefit up to age 70. However above 50 this advantage issmaller and needs discussion with the patient by an oncologist.Anthracycline (epirubicin or doxorubicin) containing regimens may beslightly more effective than CMF but this requires confirmation byfurther clinical trials.
However, these treatment schedules are associated with significant side-effects including bone marrow suppression, mucositis, gastro-intestinal symptoms, hair loss, fatigue and lethargy, induction of menopause, nausea and vomiting.
These latter two can, to some extent, be controlled by the use of anti-emeticregimens. There are a number of studies underway to evaluate thepotential benefits of higher doses of chemotherapy on disease freeinterval (DFI), disease free survival, (DFS) and survival. Theseschedules will be associated with more severe side-effects and the needfor more extensive supportive treatment.
2) Endocrine treatment
Choice of treatment will depend on the age of the patient, tumour characteristics and hormone receptor status.
In breast cancer, endocrine treatment is principally directed to theblocking of oestrogen action or reducing its availability.
In pre-menopausal women, this can be achieved by ovarian ablation, ovarian suppression with GnRH (LHRH) agonists or tamoxifen.
In post-menopausalwomen, the most common endocrine adjuvant agent used is tamoxifen. 5years treatment with tamoxifen has been shown to reduce the risk ofrecurrence and death in pre- and post-menopausal women.
Othermore recent endocrine treatments include aromatase inhibitors(anastrozole/letrozole) and more recently another anti-oestrogen(fulrestrant). The overall effect of tamoxifen in patients with low orzero levels of ER in their primary tumour is low or absent.
In general, endocrine treatment is associated with fewer and less severe side-effects than chemotherapy.
Chemotherapy is given under controlled conditions, with appropriatemonitoring whereas endocrine treatment can be maintained under GPsupervision.
A number of clinical trials, in early disease, using newer endocrine agents (aromatase inhibitors, anti-oestrogens etc.), chemotherapeutic agents (taxoids etc.) and combinations of agents are underway.
*Data from meta analysis of "Early Breast Cancer Trialist's Collaborative Group" Lancet 351 pp1451-1467 (1998)
Treatment v Nil, Total reduction% (SD) in annual odds of:-
* Prior death means death before recurrence
Bone pain / bony metastases
Symptomatic disease of the skeleton is present in about one half ofpatients with metastatic breast cancer. Metastases may be present butsub-clinical at diagnosis. Sites of possible metastases may beidentified as "hot spots" on radio-isotope bone scans and diagnosisconfirmed by plain X-ray.
Magnetic Resonance Imaging (MRI)is probably the most sensitive technique to investigate bony metastasesand may be used in difficult diagnostic situations. However, it isoften (but not invariably) of limited access.
Diseasemanagement includes radiotherapy and general systemic treatment formetastatic breast cancer and for selected patients treatment with bisphosphonates.Follow up of bone metastases is made, as indicated, by X rays tomonitor response and to give early warning of progression.
Isolated bone metastases may be controlled by local radiotherapy and inmore widespread disease radiotherapy often provides palliation ofsymptoms.
Bony metastases are often (but not invariably) susceptible to endocrine treatment.
Localised bone pain may be managed by external beam radiotherapy, NSAIDs and analgesics(including opiates). More widespread bone pain may be controlled bywide field radiotherapy. Bone pain may increase sharply on rapidprogression of disease and may precede pathological fracture.
Treatment options for fracture include internal fixation of the affected regions and irradiation. Prophylactic internal fixation should be considered for those patients with a large lytic metastasis in a long bone.
Bisphosphonates are now available for the management of bone pain andthe prevention of skeletal lesions. (See prescription rationale).
Neo-adjuvant Treatment
There is some debate on the potential utility of systemic anti-tumourtreatment to precede primary treatment (surgery/radiotherapy) andclinical studies to address this question are being undertaken.
The most obvious utility of neo-adjuvant treatment is in thedown-staging of large primary tumours prior to surgery. This may allowconservative management to be an option and can be done using endocrineand chemotherapy treatment with similar schedules to conventionaladjuvant therapy.
Patient Information Leaflets: Drug Treatment
Options for treatment of recurrence
Loco-regional recurrence may be treated locally by further surgery orradiotherapy or a combination of both. This may be supplemented orreplaced by systemic treatment with endocrine or chemotherapeuticagents.
The choice of agent and schedule will be made on thebasis of the tumour characteristics, disease free interval (DFI) andeffectiveness of former treatment.
It is important to realisethat recurrence may represent the onset of advanced disease andtreatment options are at that point essentially palliative in intent,however 50% may be curable by local measures (this is particularly sofollowing breast conserving treatment).
Distant recurrencewill be treated according to the site and nature of disease and mayrequire a combination of local and systemic treatment. Radiotherapy isof particular value in the management of symptoms arising from bone andCNS lesions.
In general, visceralmetastases are less responsive to endocrine agents than tochemotherapy, however newer endocrine agents have shown good control inpatients with significant visceral involvement.
Response toendocrine therapy is less dramatic in terms of the percentage ofpatients achieving a complete or partial response. However, significantnumbers of patients also achieve disease stabilisation on endocrinetreatment.
The response to chemotherapy is more pronounced buttreatment is generally associated with significant toxicity. Ingeneral, patients who show a response to endocrine therapy enjoy alonger disease remission than patients treated with chemotherapy.
Newer agents currently under evaluation offer opportunities for moreeffective control and the possibility of sequential treatment onrelapse. Some of these agents may offer the chance of prolongation ofsurvival in responding patients.
Clinical trials are currentlyunderway to evaluate the effect of dose intensification ofchemotherapy, with bone marrow support, to achieve greater remissionand a more durable response.
Treatment of elderly patients
Breast cancer in the elderly may be as aggressive as that found inyounger women and since about 40% of all breast cancers occur inpatients over 70 (who could have an average life expectancy of 14years), treatment must be as equally effective as that used in youngerpatients.
For patients unable to tolerate general anaesthesia,surgery such as wide local excision and even mastectomy can beundertaken using local anaesthesia and sedation. Furthermore,radiotherapy treatment is well tolerated by this age group and may beradical.
It is a feature of tumours in elderly patients that alarger proportion are oestrogen/progesterone receptor rich and hence alarger proportion will benefit from endocrine treatment.
Theoestrogen receptor status of the tumour should be assessed on thecytology specimens prior to starting treatment. However, the onlypatients who may receive tamoxifen,as sole primary therapy, are the small number of very elderly andinfirm patients who are unfit for other treatments (or do not wantsurgery) and who are oestrogen receptor positive (ER +ve).
Prophylactic treatment
Patients with a strong family history of breast cancer in first degreerelatives may be offered counselling by the "Breast Unit" onprophylactic options available to reduce the risk of developing breastcancer. There are a few possible approaches :-
- Advice on diet and life style.
- Options and potential benefits of prophylactic mastectomy.
- Genetic assessment.
- Drug intervention.
- Screening.
(There are a number of clinical trials evaluating hormonal or other treatments (e.g. retinoids,tamoxifen) for the potential in delaying the onset of breast cancer inhigh risk patients. These are not yet complete and no long term dataare available to support or reject this approach.)
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