Managing Chemotherapy Toxicities for Improved Patient Outcomes

The proper management of chemotherapy-induced toxicities can have a significant impact on quality-of-life and outcomes for patients. Any adverse events (AEs), if it is severe enough, may lead to emergency department visits, hospital admissions, dose reduction and potentially even discontinuation of treatment. It is therefore critical to stay up to date on how to manage chemotherapy-induced AEs. For many AEs associated with chemotherapy, prevention and treatment strategies have been developed, while unmet needs remain for others.

Chemotherapy-induced AEs can be grouped in a number of ways including by the affected organ. These AEs, include gastrointestinal toxicity, hematologic AEs, and peripheral neuropathy.

Gastrointestinal Toxicities

Gastrointestinal (GI) AEs of chemotherapy include nausea, vomiting and diarrhea. These tend to appear relatively early in the treatment course.

Chemotherapy-related diarrhea (CRD) is a common AEs of chemotherapy that tends to occur relatively early on during treatment and resolve over time. It is most commonly seen with fluoropyrimidines and irinotecan among intravenous cytotoxic chemotherapy but is also common with targeted therapies such as tyrosine kinase inhibitors and other oral oncolytics. The pathophysiology behind CRD includes GI epithelial damage leading to secretory diarrhea, increased intraluminal osmotic concentration leading to osmotic diarrhea or a change in gastrointestinal motility. Depending on the severity of the CRD, patients can have acute kidney injury, electrolyte abnormalities such as hyponatremia and even infection, if there is a disruption of the intestinal mucosa.

A number of strategies work moderately well to manage CRD depending on its severity, including oral hydration and following the BRAT diet (bananas, rice, applesauce and toast). Patients can also be given anti-motility agents such as loperamide and diphenoxylate-atropine. No specific preventive stategy has emerged to date for CRD, but titrating oral drugs at initiation up to full dose may reduce the incidence of CRD.¹

Chemotherapy-induced nausea and vomiting (CINV) is another common GI side effect that can cause significant distress in cancer patients. Importantly, there are certain factors that make CINV more likely to occur, including the type of chemotherapy and patient characteristics. For example, there is a high risk of CINV (>90%) with IV cisplatin whereas there is a low risk (<10%) with IV rituximab. Patient factors that increase the risk of CINV include prior CINV, sex (with higher incidence in women) and age (where younger patients have higher rates).^2,3

There are currently a number of effective prophylactic strategies for CINV. In a large majority of patients, even when treating with chemotherapy that is highly emetogenic, nausea and vomiting can be prevented. Options include 5-HT3 receptor antagonists (such as ondansetron), NK-1 receptor antagonists (such as aprepitant), glucocorticoids (such as dexamethasone), and olanzapine, a second-generation antipsychotic. Of note, there is a need for more trials studying antiemetic treatment for patients receiving oral chemotherapy since most of the prior trials have been in patients receiving IV chemotherapy. While these strategies have largely mitigated the vomiting associated with chemotherapy, there is a small subset of patients who experience chronic nausea after chemotherapy, where a residual unmet need exists.^4,5

The goal of managing CINV and CRD is to find the right management strategy so that patients experience minimal discomfort and can continue to receive treatment with minimal adjustments or delays.

Hematologic Toxicities

The more severe and consequential AEs of chemotherapy involve the hematologic system. This is in part because many chemotherapy agents target rapidly proliferating cells, including cells of the hematopoietic system that are frequently recycling. Therefore, it is common to see patients with decreased white blood cell count, red blood cell count or platelet count as a consequence of chemotherapy treatment.

Chemotherapy-induced anemia can cause fatigue, dyspnea, and cardiac events. If severe and/or symptomatic enough, red blood cell transfusions may be indicated. However, even when transfusions are not required, chronic fatigue can be a significant symptom for patients.Besides transfusions, patients can be given erythropoiesis-stimulating agents (ESAs), but this is restricted to the palliative setting due to their interactions with the chemotherapy treatment itself. Chemotherapy-induced thrombocytopenia, which can cause significant bleeding if severe enough, may be caused by drugs such as carboplatin and gemcitabine. It is typically managed by dose delays and reductions, but occasionally can be severe enough to require platelet transfusions or TPO agonists.^6-8

While all of the chemotherapy-induced hematologic AEs have the potential to be life-threatening, chemotherapy-induced neutropenia is arguably the most dangerous due to the potential risk of developing life-threatening infection. Neutropenia is defined by an absolute neutrophil count (ANC) of <1500 cells/μL, and severe neutropenia is defined by an ANC of <500 cells/μL. When patients develop fever associated with neutropenia, infection is assumed, and some patients progress to requiring hospitalization and treatment with broad-spectrum IV antibiotics. In severe cases, sepsis and death can occur. CIN remains the number 1 reason for ER visits, hospitalization, sepsis, mortality, and chemotherapy disruption.⁹

Due to the severity of potential downstream complications, the presence of a fever in a cancer patient should always be an alarm for clinicians to do a thorough workup. But even before symptoms ever develop, understanding which patients are more likely to develop neutropenic fever is critical. The risk of severe neutropenia and febrile neutropenia is largely based on the intensity of the chemotherapy regimen. Examples of high-risk regimens include topotecan for small cell lung cancer, docetaxel, and cyclophosphamide for breast cancer, and brentuximab vedotin + AVD for Hodgkin lymphoma among many others. Patient risk factors can also affect the risk of severe/febrile neutropenia. They include age greater than 65 years, female patients, patients with comorbidities (cardiovascular, renal, etc.), prior radiation, prior chemotherapy, and patients with poor nutritional status.¹⁰

Keeping these risk factors in mind, patients beginning a new chemotherapy regimen should be evaluated for prophylactic treatment with myeloid growth factors. If the predicted risk of neutropenic fever is greater than 20% with a particular regimen, patients should be given granulocyte colony-stimulating factor (G-CSFs) as primary prophylaxis. If the risk is between 10-20%, the decision is made on an individual basis with patient risk factors in mind. It is important to note that the COVID-19 pandemic has influenced guidance on whether or not to give G-CSFs, with updated guidelines given by NCCN and ASCO. Guidelines now state that G-CSFs should also be given with chemotherapy regimens which have a risk of 10-20%, which includes all of the intermediate-risk regimens. In addition, G-CSFs can also be given as secondary prophylaxis in patients who developed neutropenic fever in prior cycles with demonstrated reduction of risk by about 50%. In some clinical scenarios, patients can be given antimicrobial prophylaxis against bacteria (such as gram-negative bacilli), antifungal prophylaxis and antiviral prophylaxis.¹¹

In terms of therapeutic use, it is not recommended to administer G-CSFs in patients with afebrile neutropenia. For patients who have febrile neutropenia, the data are mixed with guidelines from ASCO stating that they can be used for patients who are at high risk for infection-related complications or who have factors that may result in poor clinical outcomes. Lastly, antimicrobials are a significant part of treating febrile neutropenia, but they come with their own individual adverse effects that must be taken into consideration when deciding on regimens.^12-15

While the introduction of G-CSFs led to a significant advancement in the management of CIN, this side effect remains the primary cause of reductions in dose or duration of treatment. Therefore, it is critically important that we do further studies to parse out how to best prevent and treat CIN in patients receiving chemotherapy in order to attain the best cancer outcomes.

Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is another side effect that can cause significant distress, but while other AEs are usually short-term, CIPN can be a chronic and debilitating symptom. Platinum therapies such as cisplatin and oxaliplatin, taxanes and vinca alkaloids are usually the main culprits. CIPN is dose-dependent and can be characterized by a “stocking and glove” distribution that is symmetric and distal. It also primarily results in sensory rather than motor symptoms with thalidomide and paclitaxel being exceptions. These symptoms can recede over time, but when they don’t, patients can be left with significant functional impairment that may include chronic pain and issues with proprioception that can lead to falls.^16,17

Unfortunately, there are currently no well-established ways of preventing CIPN. Therefore, it’s recommended that oncologists do a thorough assessment of whether a particular agent that has the potential to cause significant neuropathy should be used, particularly in patients who already have underlying neuropathy. Methods that have shown some potential include exercise, cryotherapy, acupuncture and compression therapy while anticonvulsants, metformin and vitamins have not shown a benefit. In terms of symptomatic relief, physical therapy and duloxetine have shown modest benefit with agents like topical menthol and topical capsaicin still in need of further research.¹⁸

Communicating With Patients

As physicians, we are always balancing the benefits and risks of a particular treatment, but this is especially true for the treatment of cancer because the stakes can be particularly high. Both the cancer itself and the AEs of chemotherapy can be potentially life-threatening so it’s critical that we communicate with our patients about what is recommended based on their individual needs. There must be a shared decision-making process from start to finish from deciding which chemotherapy to use to changes in dose to pausing treatment. Establishing a rapport is also critical in establishing trust so that patients feel comfortable enough to bring up any AEs and any alternative remedies that they may be using that could potentially interfere with their treatment. At times, we must be fairly directive – if a patient experiences a life-threatening AE, given the risk, a change to the regimen must be discussed. As our patients are going through the hardest times of their lives while in treatment, it is our duty and privilege to listen, educate and care for them during that process.

Managing Chemotherapy Toxicities: Where We Are Today

When it comes to managing chemotherapy AEs, our best approaches are preventative.

Many supportive care advances have transformed our ability to give full doses of chemotherapy, which is critically important for agents to achieve their full efficacy, especially in the curative setting such as for cytotoxic agents in breast and colon cancer. However, significant unmet needs remain in a few areas, including chemotherapy-induced neutropenia, patients with chronic nausea or diarrhea after chemotherapy and chemotherapy-induced peripheral neuropathy. Better management of these residual unmet needs will improve patient quality of life during and after treatment, reduce risk associated with serious complications and ultimately improve chemotherapy outcomes.

_References:

_{1. O'Brien BE, Kaklamani VG, Benson AB 3rd. The assessment and management of cancer treatment-related diarrhea. Clin Colorectal Cancer. 2005; 4(6):375-381.doi: 10.3816/CCC.2005.n.009}

_{2. Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--state of the art. Support Care Cancer. 2011; 19 (suppl 1:S43). doi: 10.1007/s00520-010-1003-x}

_{3. Pollera CF, Giannarelli D. Prognostic factors influencing cisplatin-induced emesis. Definition and validation of a predictive logistic model. Cancer. 1989; 64:1117. doi: 10.1002/1097-0142(19890901)64:5<1117}

_{4. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020; 38:2782. doi: 10.1200/JCO.20.01296}

_{5. Sutherland A, Naessens K, Plugge E, et al. Olanzapine for the prevention and treatment of cancer-related nausea and vomiting in adults. Cochrane Database Syst Rev. 2018; 9:CD012555. doi: 10.1002/14651858.CD012555.pub2}

_{6. Wood PA, Hrushesky WJ. Cisplatin-associated anemia: an erythropoietin deficiency syndrome. J Clin Invest. 1995; 95:1650. doi: 10.1172/JCI117840}

_{7. Leyland-Jones B, Bondarenko I, Nemsadze G, et al. A randomized, open-Label, multicenter, phase III study of epoetin alfa versus best standard of care in anemic patients with metastatic breast cancer receiving standard chemotherapy. J Clin Oncol. 2016; 34:1197. doi: 10.1200/JCO.2015.63.5649}

_{8. Kuter DJ. Managing thrombocytopenia associated with cancer chemotherapy. Oncology (Williston Park) 2015; 29:282.}

_{9. Lalami, Yassine, and Jean Klastersky. Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: an overview about well-established and recently emerging clinical data. Crit Rev Oncol Hematol. 2017;120:163-179. doi: 10.1016/j.critrevonc.2017.11.005}

_{10. Bow EJ. The diagnostic approach to the febrile neutropaenic patient: Clinical considerations. In: Infections in Hematology, Maschmeyer G, Rolston K (Eds), Springer-Verlag, Heidelberg 2011. doi: 10.1007/978-3-662-44000-1_6}

_{11. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011; 52:e56. doi: 10.1093/cid/cir073.}

_{12. Crawford J, Ozer H, Stoller R, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991; 325:164. doi: 10.1056/NEJM199107183250305.}

_{13. Hartmann LC, Tschetter LK, Habermann TM, et al. Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia. N Engl J Med. 1997; 336:1776. doi: 10.1056/NEJM199706193362502}

_{14. Mhaskar R, Clark OA, Lyman G, et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database Syst Rev. 2014; :CD003039. doi: 10.1002/14651858.CD003039.pub2}

_{15. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015; 33:3199. doi: 10.1200/JCO.2015.62.3488}

_{16. Mols F, Beijers T, Vreugdenhil G, van de Poll-Franse L. Chemotherapy-induced peripheral neuropathy and its association with quality of life: a systematic review. Support Care Cancer 2014; 22:2261. doi: 10.1007/s00520-014-2255-7}

_{17. Winters-Stone KM, Horak F, Jacobs PG, et al. Falls, functioning, and disability among women with persistent symptoms of chemotherapy-induced peripheral neuropathy. J Clin Oncol. 2017; 35:2604. doi: 10.1200/JCO.2016.71.3552}

_{18. Loprinzi CL, Lacchetti C, Bleeker J, et al. Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. J Clin Oncol. 2020; 38:3325. doi: 10.1200/JCO.20.01399}