Chemotherapy basics for family physicians

Overview

All chemotherapy drugs work by decreasing cellular growth and proliferation. The mechanisms of these drugs vary from competitively inhibiting cross-linking DNA, to blocking enzymes involved in DNA replication (eg, topoisomerases) and impairing spindle microtubule formation (Figure 1).^2,3 BC Cancer’s drug manual is an excellent resource for more information about chemotherapy drugs (http://www.bccancer.bc.ca/health-professionals/clinical-resources/cancer-drug-manual).

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Figure 1.

Mechanisms of action of various chemotherapy drugs

Chemotherapy intent

The term adjuvant is commonly used in oncology and means in addition to definitive treatment (ie, surgery, radiation). In the curative setting, neoadjuvant treatment is used to downstage (ie, reduce cancers to an earlier and more treatable stage) or improve operability of cancers before definitive therapy. Concurrent treatment is given as a radiosensitizer during radiation therapy. Adjuvant therapy is employed to eradicate microscopic disease after definitive treatment.²

Palliative chemotherapy is a noncurative treatment, aiming to decrease tumour burden and improve quantity and quality of life. Palliative chemotherapy differs from curative chemotherapy in that the number of cycles is not fixed.⁴ Efficacy of palliative chemotherapy is assessed using computed tomography scans to periodically restage the cancer, in concert with monitoring clinical status and biochemical markers when applicable. An unexplained decline in clinical status should prompt restaging investigations to assess for progression. Patients may remain on therapy for months or years, changing regimens when there is disease progression and stopping when they are too unwell or have decided not to pursue further treatment, or when there are no further treatment options. The toxicity of treatment must reflect the goals of therapy: for example, a higher toxicity with increased efficacy may be acceptable in a curative setting, but unacceptable in the palliative setting where quality of life is paramount.

Practical considerations

Chemotherapy efficacy is increased at higher doses; however, because these drugs affect all rapidly dividing cells, doses are limited by the amount of damage to normal tissues, especially to hematologic cells. By delivering chemotherapy in cycles, dose intensity can be maintained, allowing bone marrow time to recover between treatments. Cycle lengths generally range from 14 to 28 days, with the expected nadir in neutrophil counts occurring at 7 to 14 days posttreatment.⁵ The combination of chemotherapy drugs with differing mechanisms of action is synergistic and can allow lower doses of drugs to be given, with decreased development of resistance by cancer cells (Table 1).^6,7

Although many chemotherapies are delivered via bolus intravenous infusion, 5-fluorouracil (5-FU) can also be administered via continuous infusion over 48 hours. Several chemotherapy agents, such as capecitabine (which is metabolized to 5-FU) and etoposide, are given orally.⁷ Consideration must be given to use of central venous access devices such as a port or a peripherally inserted central catheter if the chemotherapy is a vesicant (eg, doxorubicin, epirubicin, vinorelbine, and vincristine).⁸

Bloodwork is monitored before each cycle of chemotherapy, and treatment proceeds if blood counts are appropriate. If patients tolerate treatment poorly, or if their blood counts do not recover before the next cycle of treatment, dose reductions or cycle delays can be considered, depending on the urgency of treating at optimal dose. In the curative setting, where it is critical to maintain dose intensity and remain on schedule, granulocyte colony-stimulating factor can be administered after each cycle to stimulate the bone marrow to increase neutrophil production and prevent febrile neutropenia.⁹ Patients must have a reasonable performance status to tolerate chemotherapy, which in practical terms equates with being well enough to be out of bed at least 50% of the time, or Eastern Cooperative Oncology Group grade 2 (Table 2).¹⁰

Caregivers and patients should treat bodily fluids as cytotoxic and wear gloves if handling emesis, stool, or urine for the first 48 hours after treatment. During this time period, patients should sit down to urinate and close the toilet lid before flushing to avoid splashing bodily fluids.¹¹ Contraception should always be employed. As it is unclear whether chemotherapy drugs can be passed through semen, oral, or vaginal secretions during sexual activity, barrier methods are advised until 7 days after the last chemotherapy treatment.¹²

Management of acute toxicities

Myelosuppression occurs with most chemotherapy drugs and manifests clinically as fatigue, dyspnea, bleeding, and infections. Other acute toxicities are drug specific (Table 3, Figure 2).^2,13 Chemotherapy toxicities are graded from 1 (mild) to 5 (related to death).¹⁴ Patients who require admission to hospital generally have grade 3 or 4 reactions.

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Figure 2.

Schematic of the most common locations of toxicities of selected chemotherapy drugs

Chemotherapy agents are classified as having high to low emetogenic potential, and are known to cause anticipatory, acute, and delayed (day 2 to 5 posttreatment) nausea.¹⁵ Antiemetics target neurotransmitter receptors that are involved in provoking emesis. An effective 4-drug prophylactic antiemetic regimen is recommended for patients who receive highly emetogenic drugs: a neurokinin-1 receptor antagonist (eg, aprepitant), a 5-HT₃ receptor antagonist (eg, ondansetron), a dopamine antagonist (eg, olanzapine), and dexamethasone.^16,17 Intravenous hydration is a helpful adjunct for patients with breakthrough nausea. Delayed nausea may be improved by lengthening the course of dexamethasone, and anxiolytics are effective for anticipatory nausea. Practitioners should be aware that 5-HT₃ receptor antagonists will cause substantial constipation.

Chemotherapy-induced peripheral neuropathy (CIPN) occurs with oxaliplatin, docetaxel, and paclitaxel, which are common treatments for colon and breast cancer.¹⁸ Chemotherapy-induced peripheral neuropathy manifests in a stocking and glove distribution with sensory symptoms, causing impairment of fine motor tasks and gait stability. Early recognition of CIPN and dose adjustment of chemotherapy are key, as once present, neuropathy is only partially reversible. The only treatment with any evidence of benefit for CIPN is duloxetine, although gabapentinoids and tricyclic antidepressants may be trialed.^19,20

Capecitabine or 5-FU can cause inflammation and ulceration throughout the gastrointestinal system. In the mouth, this presents as mucositis, causing pain and decreased oral intake with potential for dehydration and increased risk of bacteremia.²¹ Enteritis, or inflammation of the small bowel, results in watery diarrhea, depleting fluids and electrolytes. Irinotecan also causes diarrhea because of direct mucosal damage. Once alternate causes such as infection, laxatives, and partial bowel obstruction have been ruled out, symptomatic therapies can be employed. Management of mucositis and diarrhea based on cancer agency guidelines is presented in Table 4.^21-25