Patients presenting with early breast cancer may never relapse; thus a woman presenting with a small (less than 2 cm) primary breast cancer which is node negative at surgery (i.e. the armpit/axillary node specimens contain no microscopic evidence of cancer, has a five to ten year chance of remaining free of disease of 75%. Conversely, the patient who presents with a heavy 'infestation' /involvement of axillary nodes has a 75% chance of relapse by five years. The most common scenario is that at some time later the cancer arises again in some other organ: this is called metastatic or ‘distant’ relapse; in approximately 10% of cases the relapse is ‘local’ or within the breast region. If the relapse is within a breast that has been previously treated by breast conservation, then a total mastectomy is the therapy of choice and there is still a chance of cure – the one relapse situation in this disease where ‘salvage’ cure is possible.
Where the relapse is distant then systemic therapy (i.e. drug treatment) is the therapy chosen because it goes around the body to every conceivable site affected. In the first instance, if the disease is not life threatening in the short term, the doctor may choose some anti-hormonal (endocrine) therapy based on the principles outlined above - viz. that the tumour may well retain hormone sensitivity based on the possession of hormone receptors. In patients who have not yet achieved a menopause, then this artificially created by one of the means outlined above. In those who have not had tamoxifen, then this is the drug of first choice. If the patient has already been given tamoxifen, then clearly it is not rational to use this again because the tumour has relapsed depite its administration. Therefore other endocrine therapy will be used.
The most common next prescription in the UK is anastrazole followed by a progestogen. Cases of metastatic relapse who are treated by an oral endocrine therapy alone are those with relatively slow growing relapse at non-life threatening places in the short to intermediate term – for these patients there is no prejudice to their overall life expectancy by delaying chemotherapy until the progression continues despite endocrine therapy.
Patients with grumbling bone disease are the commonest group exemplified by this sort of approach; it is not at all uncommon for the relapse to be in bone and no other detectable site and to progress slowly with periods of some considerable remission achieved by endocrine therapies. Indeed, for this type of patient, there is an additional type of therapy which will statistically delay progression: this is bisphosphonate therapy. Bisphosphonates get into the calcified bone matrix and make it more difficult for the cancer cells to get their destructive foothold in the bone. It is now commonplace to partner endocrine therapy with bisphosphonate therapy for those with predominantly bone relapse.
For patients who relapse in other organs, then chemotherapy either more rapidly follows a trial of endocrine therapy or these patients are recommended chemotherapy straight away. Thus, it is rare for the doctor to recommend endocrine therapy alone for those with relapse in their livers, for example.
Chemotherapy (and this applies to adjuvant chemotherapy discussed above) is usually a cocktail of several (usually up to three) drugs which directly interfere with vital cellular processes – often DNA replication, othertimes crucial metabolic functions. They are not specific for the cancer cells and also harm other fast dividing cells in the body. However, whereas the normal cells of the bone marrow and gut lining wall (the two fastest turning over cell sites in the body) are also damaged by the chemotherapy, they recruit new cells by the body’s physiological control mechanisms to repair the defect caused by the chemotherapy.
This regulatory control (recovery) process is not present in a cancer (which, by definition, has lost all the control mechanisms that the body would normally have over it constituent cells) and thereby lies a critical difference that is exploited in the practice of multiple courses of chemotherapy – pulsing the next chemotherapy exposure at a time when the normal tissues (e.g. bone marrow –manifested by the blood count) have recovered from the last insult of chemotherapy and before the tumour has had a chance to regrow. Usually, the bone marrow has recovered from the insult of most chemotherapy agents by day 18-21 after exposure and it is therefore common that chemotherapy is re-pulsed/ cycled every 21 days. By use of this difference and the increased sensitivities of certain tumours to certain types of drugs, so the treating doctor will use chemotherapy to achieve a regression of the cancer and a clinical remission.
For each tumour type, the doctors/oncolgists treating the disease have worked a ‘single agent activity table’ of drugs that are most likely to be effective in creating a remission and they then work out combinations of drugs that have the least overlapping toxicity but cumulatively lethal effects on the cancer. The drug regimens are frequently referred to by acronymns: the first letters of the constituent drugs being put together to create some weird words such as: FEC, CMF, FAC, AC+TAXOL, etc.
The general principle is that of trying one first line chemotherapy regimen for three exposures and then, after nine weeks (3X3 weekly exposures), re-imaging to assess the response is common to many oncology situations. If there is not a satisfactory response, then the doctor will change to another, hopefully non-cross resistant regimen.
By the above means, a remission may be achieved in most patients and then, when the patient relapses again (and this always occurs eventually, unless the patient dies of other causes) a second remission attempt is tried.
Recently, a part humanised mouse antibody directed at the HER-2 receptor on breast cancer cells has produced a ‘magic bullet’ approach to the therapy of this disease. This is the concept that one can find a substance that is toxic to only the cancer cells and does not have the toxicity on the normal body cells that has just been described above for the usual chemotherapy drugs (i.e. a‘penicillin’ for cancer).
In trials, the substance marketed as Herceptin has been shown to add to the chances of orthodox chemotherapy in producing remissions in relapsing patients and this therapy is predicted to have a large future in the therapy of relapsed patients with this condition.
In patients who relapse in the breast and prove inoperable, radiotherapy may have a role at controlling the disease at this site and this may also apply to large lymph node masses in the axilla or neck. Indeed, radiotherapy is useful in the relapse situation for many relapses in troublesome spots – most commonly in bone where painful metastases may be arrested by local radiotherapy to the bone and in the brain where the occurrence of metastatic disease is particularly life threatening and where the chemotherapy and endocrine therapies may be less useful than other sites in the body.
We have not yet mentioned high dose chemotherapy for patients who relapse. The principle of dose intensification in cancer chemotherapy has been a solid principle for some time and there is no doubt that small doses of the chemotherapeutic agents do not achieve the same good responses that are gained by doses that substantially drop the blood count, albeit transiently. This was translated into the use of high doses of chemotherapy (beyond that which the bone marrow would tolerate – i.e. beyond marrow death) and then the rescue of the patient by an autologous infusion of their bone marrow progenitor cells (collected earlier). Unfortunately, this approach, although looking optimistic in the short term, has not delivered the good durable results that were predicted and so is in abeyance at present.
Plowman Oncology London (e-mail: postmaster@pnplowman.demon.co.uk)
