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This article provides a succinct update of the current medical treatment of cancers, and to illustrates some of the treatment principles with an overview of the management of three common cancers.
Modern Cancer Drug Therapies
There are three main classes of cancer drug therapies, namely, hormonal therapy, chemotherapy and the new kid on the block – targeted therapy.
Hormonal (or endocrine) therapy is commonly employed in the treatment of breast, prostate and uterine cancers – cancers that are known to be dependent on extracellular hormonal impetus for growth. Most endocrine therapies come in the form of oral tablets or subcutaneous injections.
Cytotoxic chemotherapy has been around for about 30-40 years, and they are designed to destroy actively dividing cells, both cancers and otherwise. Fast-dividing normal cells – such as bone marrow cells, hair cells, and intestinal mucosal cells – may sometimes become innocent bystanders. Fortunately, we now have very effective drugs to manage the side effects of chemotherapy, such as emesis, leucopaenia and anaemia. Chemotherapy remains the cornerstone of treatment for most advanced cancers. Some of the more chemo-sensitive cancers include: lymphomas and leukemias, breast cancers, colorectal cancers, ovarian cancers, nasopharyngeal cancers, testicular cancers, and some lung cancers. There are only a handful of cancers that are truly chemo-resistant. The past decade had witnessed the advent of a number of new chemotherapy drugs that are both very effective and minimally toxic to the normal tissues. Chemotherapy may be used on its own, or may be combined simultaneously, as radiosensitizers, with radiation therapy. Most chemotherapy drugs are administered intravenously in the outpatient setting, although a few chemotherapeutic agents are available orally. Intravenous chemotherapy is usually given in cycles, repeated at fortnightly or 3-weekly intervals.
The new era of targeted therapy announced its arrival at the beginning of this Millennium. Over the past 7-8 years, we have witnessed the birth of a growing number of molecules that are specifically designed to recognize, bind to, and inactivate specific molecular targets (such as receptor tyrosine kinases) that are located on or within cancer cells. The explosion of molecular genetics has inevitably led to the identification of a large number of cancer-specific or cancer-preferred targets. These targets in turn provide the fodder for the pharmaceutical companies to create new drugs against these cancer targets. There are 2 types of targeted cancer therapies, namely, monoclonal antibodies (given intravenously) and small molecule drugs (given orally). Targeted therapies usually do not have the usual adverse effects of cytotoxic chemotherapy such as alopecia, myelosuppression and mucositis, although a few of these new agents have specific adverse effects such as skin rash, cardiotoxicity and at times, hypersensitivity reactions.
Cancer drug therapies may be employed in one or more of the following settings:
- After potentially curative surgery, to lower the risk of relapse (adjuvant therapy);
- Before potentially curative surgery, to induce a tumour shrinkage pre-operatively and to eradicate existing micro-metastases (neoadjuvant therapy);
- As the main curative treatment of cancer (primary therapy); or
- In patients with advanced cancers, to control symptoms and to prolong life (palliative therapy)
The management of three common cancers is now described to illustrate the application of cancer drug therapies.
Management of Some Common Cancers:
Breast cancers are usually operated on in the first instance, unless the tumours are metastatic at presentation or are locally-advanced. In the case of early breast cancer (i.e. stages I and II), the risk of cancer relapse following surgery is a function of a number of well-characterized risk factors, including: presence of nodal metastases; size, grade, hormone receptor status and HER2 proto-oncogene status of the breast tumour, as well as presence of lymphovascular invasion. Such information is now standard in breast cancer histology reports. Most women with early breast cancers require adjuvant (post-operative) chemotherapy. The exceptions include situations where the tumours are very small (e.g. less than 10 mm) and are of low grade, or in women who are unfit to receive chemotherapy because of advanced age or significant co-morbidities. There are a number of different adjuvant chemotherapy regimes, the choice of which for a particular woman depends primarily on the cancer features and secondarily on the preferences of the treating Medical Oncologist. Adjuvant chemotherapy commonly begins 2-4 weeks after the breast surgery, when the wound is sufficiently healed. Breast cancer adjuvant chemotherapy usually spans over 3 to 6 months. In order to achieve the maximal benefit from the adjuvant chemotherapy, it is important that the chemotherapy is administered at full doses and on-time, patient’s tolerability permitting. Aggressive anti-emetic drugs and growth factor support are commonly employed to make the breast cancer adjuvant chemotherapy safer and better tolerated. Many breast cancer patients are able to continue with their jobs during the chemotherapy period.
After the completion of adjuvant chemotherapy, breast cancer patients will be given 5 years of endocrine therapy if the resected cancer demonstrates the presence of oestrogen and/or progesterone receptors (hormone receptors). Tamoxifen may be given to both pre- and post-menopausal women with hormone receptor-positive breast cancers, whereas aromatase inhibitor (arimidex, anastrazole or exemestane) may be given to only post-menopausal women.
Women who undergo breast-conserving surgery will require adjuvant radiotherapy to the residual breast tissues. Some women who have undergone total mastectomy will also require adjuvant chest wall radiotherapy if their cancers possess certain high-risk features, such as the presence of multiple metastatic axillary lymph nodes, large breast tumour, and presence of lymphovascular invasion. Adjuvant radiotherapy starts after the end of adjuvant chemotherapy. Adjuvant chemotherapy and radiotherapy are not administered simultaneously.
The most exciting new development in the adjuvant treatment of breast cancer is the use of adjuvant monoclonal antibody trastuzumab (Herceptin®) in patients with HER2-positive breast cancers, which tend to be aggressive. In this subpopulation, which comprises approximately 25% of all breast cancer patients, intravenous adjuvant trastuzumab was recently shown to reduce the risk of breast cancer relapse by half! Testing the breast tumour for the presence of HER2 is a standard practice today. Trastuzumab therapy is given every 3 weeks for 1 year. The main toxicity of note is the risk of cardiotoxicity.
For advanced breast cancer (stages III and IV), palliative chemotherapy is usually given right from the start of the treatment programme. For patients who have low-volume and slow-growing metastatic cancers, oral endocrine therapy may be appropriate, so long as close monitoring is done. With the judicious use of the various classes of drugs at different stages of the cancer treatment programme, some patients with stage IV breast cancer may derive durable and clinically meaningful benefits from treatment.
One special drug that deserves mention in the treatment of advanced breast cancer is another monoclonal antibody called bevacizumab (Avastin®), which has an anti-angiogenesis function. It targets the tumour-associated neovasculature. The combination of bevacizumab and chemotherapy is an effective option in the treatment of metastatic breast cancers.
Colorectal cancers are usually resected in the first instance. The risks of bleeding and bowel obstruction underpin the usefulness of primary tumour resection. Occasionally, the colon surgery may be omitted if the patient has a small primary colonic tumour but extensive metastases. Colorectal cancers are divided into 4 stages. The management of colon and rectal cancers differ in some aspects. Stage I colon cancers are treated with surgery alone. Stage II colon cancers are treated with surgery, although some stage II patients who have high risk of relapse (e.g. intestinal obstruction or high CEA at diagnosis, or presence of lymphovascular invasion) should be considered for adjuvant chemotherapy for 6 months. Stage III colon cancers are associated with a high risk of relapse. All such patients should receive adjuvant chemotherapy following their surgery. The adjuvant chemotherapy can take the form of either intravenous or oral drugs. The inclusion of an effective drug, oxaliplatin, in the adjuvant setting has been associated with the best outcome.
Stage IV colon cancers are treated with drugs. Chemotherapy forms the backbone of the treatment. The addition of monoclonal antibody as targeted treatment to the chemotherapy backbone significantly enhances the efficacy. Colon cancers are relatively chemo-sensitive. Whereas untreated stage IV patients live for 6 months on average, it is quite common for treated patients to survive for 18-24 months, and sometimes longer.
Rectal cancers are managed slightly differently, with the notable addition of radiotherapy to the chemotherapy for patients with stage II and stage III cancers. Stage IV rectal cancers are managed in the same way as stage IV colon cancers.
Lung cancers are divided into small cell lung cancers (SCLC) and non-small cell lung cancers (NSCLC). NSCLC are commoner. SCLC are highly chemo-sensitive. Limited-stage SCLC are treated with chemotherapy and thoracic radiotherapy. Extensive-stage SCLC are treated with chemotherapy only. SCLC patients often benefit from post-chemotherapy prophylactic cranial irradiation, which significantly reduces the risk of future brain recurrences and also prolongs overall survival.
NSCLC are divided into 4 stages. Stage I NSCLC are usually treated by surgery alone; some patients with stage IB NSCLC are offered adjuvant chemotherapy. Stage II NSCLC are treated by surgery, followed routinely by adjuvant chemotherapy. Treatment of stage III (or locally-advanced) NSCLC, is more complicated, as there are a number of different treatment approaches. The commonest treatment approach to stage III NSCLC is the use of combined chemotherapy and radiotherapy as primary therapy over a 6-7 weeks period.
Stage IV, or metastatic, NSCLC is treated with drugs, either intravenous chemotherapy, or oral targeted therapy. First-line treatment of stage IV NSCLC is chemotherapy, using a combination of 2 drugs, one of which is a platinum compound (either cisplatin or carboplatin). There are about 5 different chemotherapy doublets that may be considered in the selection of a first-line chemotherapy regime; their relative efficacies do not differ very much. When patients do not respond to, or stop responding to, first-line chemotherapy, second-line treatment is given. This can take the form of either another chemotherapy drug, or an oral targeted therapy. Recent studies have shown that oral targeted therapy, either gefitinib (Iressa®) or erlotinib (Tarceva®), may provide clinically meaningful control of NSCLC in the second-line setting.
As in the case of advanced breast and colorectal cancers, the addition of anti-VEGF monoclonal antibody bevacizumab (Avastin®) to the lung cancer chemotherapy backbone has been shown to improve the efficacy. Bevacizumab should not be used in patients with a history of active haemoptysis, brain metastasis, or squamous cell carcinoma histology, as these situations are associated with a higher risk of major haemorrhage when bevacizumab is used.
As the above examples illustrate, modern treatment of cancers necessarily calls for the joint participation of a number of different specialties at appropriate times in the overall treatment programme. The advent of molecular medicine is impacting the day-to-day management of cancer patients in a fundamental way. The net result is the availability of more and better treatment options for our patients as they fight their malignant nemeses.
The article was written by Dr. Kong for a Mount Alvernia Hospital newsletter Oct-Dec 2007
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