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Outcomes and Logistics of Cancer Treatment in the Intensive Care Setting

Bryan Do, PharmD BCOP
Clinical Pharmacy Specialist, Lymphoma/Myeloma
The University of Texas MD Anderson Cancer Center
Houston, TX

Shilpa Paul, PharmD BCOP
Clinical Pharmacy Specialist, Leukemia
The University of Texas MD Anderson Cancer Center
Houston, TX

Jeff Bruno, PharmD BCPS BCNSP BCCCP FCCM
Director, PGY-2 Critical Care Pharmacy Residency
Clinical Pharmacy Specialist, Critical Care/Nutrition Support
The University of Texas MD Anderson Cancer Center
Houston, TX


The prevalence of cancer was an estimated 14,738,719 cases in the United States in 2014, with 1,688,780 new cancer diagnoses in 2017.1 Up to 10% of patients with cancer may develop a severe or life-threatening complication requiring intensive care, and approximately 5% will receive cancer treatment in the intensive care unit (ICU).2,3 Advances in the management of hematologic malignancies and solid tumors and improvements in comprehensive critical care for patients with cancer have been shown to improve survival.4-6 This review discusses the outcomes and logistical considerations of cancer treatment in critically ill patients.

Cancer and Critical Illness
In general, in-hospital mortality is high (up to 60%) among cancer patients admitted to the ICU for medical complications (e.g., respiratory failure requiring mechanical ventilation).5,7,8 Recent studies suggest that the short-term prognosis (ICU mortality or hospital mortality) of critically ill cancer patients may be more strongly associated with severity of illness and extent of organ dysfunction present upon ICU admission and developing during ICU stay than with the malignancy itself.7,9-12 In addition, mortality appears to be influenced by time to intervention following the patient’s deterioration. Retrospective analyses revealed that time to patient intervention by a medical emergency team was independently associated with in-hospital mortality (adjusted odds ratio [OR], 1.445; 95% confidence interval [CI], 1.217–1.717, per 1-hour delay) and crude 1-year mortality (adjusted hazard ratio [HR], 1.027; 95% CI, 1.017–1.037, per 1-hour delay).13,14 Similarly, ICU admission within 24 hours of the patient’s deterioration has been associated with improved in-hospital survival.5

Allocation of ICU resources for critically ill cancer patients has recently been revisited in the 2016 Society of Critical Care Medicine (SCCM) guidelines for ICU admission, discharge, and triage (ADT).15 The SCCM ADT guideline task force suggests that “ICU access of cancer patients be decided on the basis established for all critical care patients, with careful consideration of their long-term prognosis” (ungraded recommendation/best-practice statement). Essentially, ICU resources should be afforded on the basis of severity of illness (is the patient sick enough to benefit?) and long-term prognosis (i.e., lower priority for ICU admission would be given in the setting of terminal illness with no further oncologic treatment options), rather than solely on the basis of having malignancy with or without metastatic disease. A 2005 publication revealed that metastatic cancer was independently associated with critical care providers’ refusal of ICU admission (OR, 5.82; 95% CI, 2.22–15.28).16 The SCCM ADT guidelines also suggest that the status of all critically ill patients, “in particular, cancer patients with advanced disease,” be reassessed and discussed with all major stakeholders, including the patient, at regular intervals (ungraded recommendation/best-practice statement). This statement is in line with ICU time trials suggested in the literature. Based on their 2007 investigation, Lecuyer and colleagues recommended a 6-day full-code ICU treatment trial for critically ill cancer patients who have stable disease, are not bedridden, and have options for lifespan-extending cancer treatment.10 A more recent investigation revealed that the optimal ICU trial duration may be as short as 1–4 days in patients with poor-prognosis solid tumors, but as long as 10 or more days in patients with hematologic malignancy or low severity of illness (sequential organ failure assessment score less than 5) regardless of malignancy type.17 Such findings appear to be in line with perceived prognosis (i.e., good short-term prognosis associated with a low severity of illness or good long-term prognosis in hematologic malignancy with perceived curability) and the provision of aggressive and sustained interventions in an attempt to overcome the acute insult.

Outcomes of Administering Chemotherapy in the ICU
Historically, little was known about the impact of administering chemotherapy to cancer patients in the ICU, but recent studies have shed some light on this topic. In a retrospective observational study, outcomes of intravenous chemotherapy administration in ICU patients with hematologic malignancies were evaluated.18 This tertiary referral center was staffed by three full-time intensivists, of which two had hematology/oncology training. Of the 345 patients evaluated, 54 required chemotherapy, but only 37 went on to receive treatment. Intracranial bleeding, severe uncontrolled infection, septic shock with and without multiple organ failure, and pregnancy constituted reasons for withholding chemotherapy in 17 patients. Extensive disease resulting in upper airway obstruction and tracheal compression, leukostasis or leukemic infiltration of organs, severe disseminated intravascular coagulation (DIC), severe diseases with associated hemolysis, and acute promyelocytic leukemia were reasons provided for chemotherapy initiation. The majority of patients who received chemotherapy (86%) had high-grade malignancy identified as acute myeloid and lymphoblastic leukemia or non-Hodgkin lymphoma, 30% of patients had relapsing disease, and 41% had concomitant infection. Patients with lower severity of illness and lower rate of relapses were more likely to receive chemotherapy than those with severe illness and higher number of relapses (acute physiology and chronic health evaluation II [APACHE II] score, 23±7 vs. 29±5, p = .007; 30% vs. 76%, p = .002, respectively). The only association with in-hospital mortality was mechanical ventilation (OR, 9.3; 95% CI, 1.7–52, p = .007). The 6-month mortality of mechanically ventilated and nonventilated ICU patients was 48% and 7%, respectively (p = .013). Overall, 16 patients died, and of the 21 that survived, a few continued to require renal replacement therapy or vasopressor support or both. This study concluded that initiating chemotherapy early can save lives of those in critical condition; however, it is important to assess each patient individually for the severity of their illness and disease status and to have an agreement between the intensivist and hematologist/oncologist.

Darmon and colleagues conducted a prospective observational study of 100 patients who had organ failure due to newly diagnosed, untreated cancer and required ICU admission and immediate treatment.19 Patients were assessed for overall survival at 30 and 180 days. The majority of the patients had acute leukemia (48) and lymphoma (37). Patients were managed by a multidisciplinary team consisting of a hematologist/oncologist and intensivists. Median age was 47 years (range 32–61 years), and 84 patients had advanced disease (leukocytosis, stage 3/4 lymphoma, or metastatic or locally extensive solid tumor). Fifty patients had documented infection at time of admission, 5 patients had superior vena cava syndrome, and 5 patients had leukemic pulmonary infiltrates or leukostasis. Anticancer treatment was given within 1 day of initial diagnosis (range 0–11.5 days). Chemotherapy dose adjustment for organ failure occurred only in nonleukemic patients. Thirty patients needed to be dialyzed, 42 patients required vasopressors, and 23 patients required both interventions. The overall survival rate after 30 days and 180 days was 60% and 49%, respectively. The independent factors that negatively impacted 30-day outcomes were need for mechanical ventilation (OR, 6.36; 95% CI, 1.76–22.94), need for vasopressors (OR, 6.01; 95% CI, 1.86–19.4), and hepatic failure (OR, 7.76; 95% CI, 1.25–48.27). The study also found that outcomes were directly correlated to number of organ failures, rather than the malignancy itself.

In a retrospective study conducted by Wohlfarth and colleagues, critically ill cancer patients who received chemotherapy in the ICU were assessed for long-term survival.6,20 Fifty-six patients were identified with mostly acute leukemia (n = 13) and aggressive non-Hodgkin lymphoma (n = 25). The investigators noted that 88% of the patients who started chemotherapy in the ICU continued to receive treatment and that one in three patients was alive at 1 year, of whom 69% are in complete remission.20 The reduction in mortality is primarily a result of better triage, better supportive care, better understanding and acknowledgment of oncologic emergencies, and better identification of high-risk malignancies (e.g., acute promyelocytic leukemia).6 The purpose of providing chemotherapy to cancer patients in the ICU can vary from being curative to being palliative or simply a means to provide for symptom management (e.g., to manage tumor lysis syndrome or to reduce mediastinal tumor mass to improve breathing). With increased awareness and knowledge of this subset of patients among nurses, pharmacists, and physicians in the ICU, safe administration of chemotherapy can lead to improvement in short-term and long-term survival.

Logistical Considerations for Management of Critically Ill Cancer Patients
Comprehensive cancer centers, large academic institutions, and community hospitals face common logistical issues in the care of patients with cancer who require both intensive care and chemotherapy. These patients may be admitted to the ICU prior to, during, or after receiving chemotherapy because of cancer-related complications or treatment-related toxicities.3,19 A multidisciplinary approach, with communication between medical, nursing, and pharmacy staff, is crucial to providing appropriate care to critically ill cancer patients. Although a basic understanding of oncologic emergencies or common disease-related complications is helpful in initial management, an intensivist may not have the specialized training necessary to recognize, diagnose, and treat various hematological malignancies and solid tumors. Likewise, a hematologist or oncologist may not be able to optimally manage a patient exhibiting acute deterioration. ICU nurses and pharmacists may lack familiarity with chemotherapy and its unique monitoring parameters and adverse effects. All team members must therefore work together to define the goals of care in order to stabilize the patient and determine the need for anticancer therapy.3,19,21

Several considerations must be made on an individual basis before chemotherapy is initiated in critically ill patients. The healthcare team should determine whether the patient has a confirmed diagnosis of malignancy, consider patient-specific issues (e.g., prognosis, patient wishes), and determine whether safe administration of chemotherapy in the ICU is feasible.3 Confirmed pathology is important because comparisons of postmortem findings have revealed inaccurate or missed diagnoses in up to 25% of patients. Obtaining a diagnosis in critically ill patients, however, can be challenging because they may not be able to undergo diagnostic testing or may receive medications that either confound or delay the workup. For example, early initiation of corticosteroids may treat and alter an underlying lymphoid malignancy, affecting the ability to establish a precise diagnosis. Recent administration of anticoagulants can cause the postponement of some procedures (e.g., biopsies) because of an increased risk of bleeding. The administration of dextrose-containing intravenous fluids, including antibiotics and heparin, may lead to inaccurate positron emission tomography/computed tomography imaging studies. In addition, patients who present with oncologic emergencies such as tumor lysis syndrome, hypercalcemia, spinal cord compression, or DIC may require immediate intervention without a confirmed diagnosis.19,22,23

Initiating chemotherapy in the ICU is often necessary in patients with extensive disease and major organ involvement or high tumor burden with systemic complications.18 Risk versus benefit of a treatment must be weighed on an individual basis. Patients may have pre-existing comorbidities, impaired organ function, immunodeficiency, or secondary metabolic complications that can make treatment decisions challenging. On the other hand, organ dysfunction and various disease-related complications may improve after anticancer treatment is initiated. Many chemotherapy agents and their metabolites are hepatically or renally eliminated, and doses must be adjusted accordingly because of pharmacokinetic and pharmacodynamic changes.24,25

Patients with end-stage renal disease present an added challenge because of the effects of intermittent hemodialysis and continuous renal replacement therapy on drug clearance, dosing, and timing of chemotherapy.25,26 Available literature is limited; however, antimicrobial and chemotherapy dosing recommendations in patients requiring renal replacement therapies have been summarized.25,27 A comprehensive medication review is especially important in critically ill patients because these patients may be on multiple agents that interfere with the metabolism, elimination, or stability of chemotherapy agents (e.g., sedatives, analgesics, antimicrobials, antiepileptic drugs). Lack of oral access, limited data for enteral tube administration, and concerns regarding impaired enteral absorption may impede the safe administration of oral chemotherapy agents. Safe and effective chemotherapy administration in the critically ill requires careful patient selection, multidisciplinary treatment planning, and close monitoring of toxicities.3

The American Society of Clinical Oncology and the Oncology Nursing Society established four domains for safety standards concerning chemotherapy administration: (1) staffing and general policy; (2) treatment planning, patient consent, and education; (3) ordering, preparing, dispensing, and administering chemotherapy; and (4) monitoring and assessment.28 Although these recommendations serve as the basis for chemotherapy policies and standards at many institutions, barriers still exist because of the lack of appropriate knowledge, training, and experience; the lack of integrated computer systems or electronic health records; and limited staffing or support systems. Critical care providers do not have enough exposure or frequent opportunities to become familiar with various antineoplastic or targeted therapies. Although the decision to treat in the ICU may be the result of an interdisciplinary effort, it is important that the critical care team is able to execute the treatment plan. These limitations may lead to medication errors, including underdosing or overdosing; scheduling, timing, and infusion rate errors; and omission or improper administration of drugs. Moreover, obtaining informed patient consent and conducting education in the ICU are problematic when patients are sedated or intubated and when caregivers are unavailable or have differing perspectives. 

Effective communication between all parties is important to prevent inappropriate care and exclusion in treatment decisions.3 Because of the advent of new therapies that may require ICU admission, the demand for additional resources to help educate and train medical staff and patients and their caregivers regarding safe administration of anticancer therapies and recognition of signs and symptoms of their toxicities is increasing. For example, T-cell engaging therapies such as blinatumomab and chimeric antigen receptor (CAR) T-cells can have severe treatment-related toxicities (e.g., cytokine release syndrome, hemophagocytic lymphohistiocytosis, and neurotoxicity) that require intensive care.29,30 Modalities to optimize continuity of care include formalizing a critical care–oncology collaboration system, developing shared continuing education programs, scheduling periodic reviews to discuss initiatives and improvements, and enhancing training programs.31

Bedside Execution of the Above Principles
The University of Texas MD Anderson Cancer Center (MDACC), a National Cancer Institute–designated comprehensive cancer center with 600-plus beds, houses a 36-bed medical ICU (MICU) and an 18-bed surgical ICU, with a proposed expansion in the near future. In addition, a medical emergency response incident team (MERIT) provides 24/7 prompt, hospital-wide evaluation of patients exhibiting signs of decompensation. MERIT works closely with the ICU triage team to coordinate timely transfer and interventions for patients requiring ICU admission. All ICUs within MDACC are open units, with patients comanaged by critical care teams and the primary hematology/oncology teams (e.g., stem cell transplant, leukemia, and lymphoma/myeloma teams). Teams comprising an attending physician, physician trainees, advanced practice providers (nurse practitioners or physician assistants), and clinical pharmacy specialists with 2 years of postgraduate or equivalent training conduct daily patient care rounds using an academic model. Ancillary care members including respiratory therapists, dietitians, and social workers participate daily in ICU patient care rounds; consultant teams (e.g., from the areas of infectious diseases, cardiology, and nephrology) are available as needed and are used often. Though respective teams may round separately, daily communication occurs between providers to coordinate plans of care and to help optimize achievement of patient-specific goals. Accordingly, the oncology clinical pharmacy specialist and the critical care clinical pharmacy specialist work closely together to address pharmacotherapy-related issues.

Between July 1, 2016, and June 30, 2017, 1,592 patients were admitted to the MICU, and 186 patients (12%) received chemotherapy (excluding investigational agents and CAR T-cell therapy). A total of 1,047 doses of chemotherapy were administered to these 186 patients: 516 oral/enteral, 511 intravenous, and 20 intrathecal doses. Patients with leukemia accounted for the majority (62%) of chemotherapy doses administered (67% oral/enteral, 55% intravenous, 80% intrathecal doses), followed by lymphoma/myeloma (16% of all chemotherapy, 0.2% oral/enteral, 33% of intravenous, 20% of intrathecal doses). Other populations that received chemotherapy in the MICU during this period included genitourinary oncology, gynecologic oncology, melanoma, sarcoma, thoracic medical oncology, and neuro-oncology.

Given the relative infrequency of chemotherapy administration in our MICU, it is imperative that the ICU bedside nursing staff receive adequate training and support. Therefore, all newly hired ICU nurses first participate in a mandatory 3-week didactic lecture series as part of their orientation, which includes general ICU topics (e.g., hemodynamics, renal replacement therapy, end-of-life care) and specific presentations on the principles and general pharmacology of chemotherapy and biotherapy. A second component of the training is a required case study, with simulated chemotherapy administration using our intravenous pumps and respective medication library. Both the didactic portion and the case simulation are facilitated by ICU nurse educators and guest lecturers with expertise on the selected topics. Third, to help solidify training, all ICU nurses spend 1 experiential day on a stem-cell-transplant patient care floor, where they are assigned to an established oncology nurse and must demonstrate proper chemotherapy administration, documentation, and monitoring procedures according to MDACC policies. Finally, the institution’s oncology charge nurses and nurse educators are available to help troubleshoot chemotherapy-related administration concerns; similarly, the oncology clinical pharmacy specialists are available to triage questions regarding chemotherapy treatment plans.

Conclusion
Outcomes of critically ill cancer patients requiring admission to the ICU were once thought to be dismal; however, recent data suggest that hospital survival may be more reflective of severity of illness than the malignancy itself. Accordingly, critically ill cancer patients who have a reasonable prognosis should be considered for ICU admission. Chemotherapy administration in the ICU appears feasible, but treatment should be carefully considered and individualized for each patient. Coordinated efforts among multidisciplinary critical care and hematology/oncology providers are crucial in managing the critically ill cancer patient. Institutions are encouraged to develop an appropriate infrastructure and staff educational plan to facilitate safe and prompt management of cancer patients experiencing acute decompensation. 

References

1.  National Cancer Institute. SEER Cancer Stat Facts: Cancer of Any Site. http://seer.cancer.gov/statfacts/html/all.html

2.  Bos MM, Verburg IW, Dumaij I, et al. Intensive care admission of cancer patients: a comparative analysis. Cancer Med. 2015;4(7):966-976.

3.  Shimabukuro-Vornhagen A, Boll B, Kochanek M, Azoulay E, von Bergwelt-Baildon MS. Critical care of patients with cancer [published online ahead of print on June 27, 2016]. CA Cancer J Clin. doi: 10.3322/caac.21351

4.  Azoulay E, Soares M, Darmon M, Benoit D, Pastores S, Afessa B. Intensive care of the cancer patient: recent achievements and remaining challenges. Ann Intensive Care. 2011;1(1):5.

5.  Azoulay E, Mokart D, Pene F, et al. Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium—a groupe de recherche respiratoire en reanimation onco-hematologique study. J Clin Oncol. 2013;31(22):2810-2818.

6.  Moors I, Pene F, Lengline E, Benoit D. Urgent chemotherapy in hematological patients in the ICU. Curr Opin Crit Care. 2015;21(6):559-568.

7.  Soares M, Caruso P, Silva E, et al. Characteristics and outcomes of patients with cancer requiring admission to intensive care units: a prospective multicenter study. Crit Care Med. 2010;38(1):9-15.

8.  Bos MM, de Keizer NF, Meynaar IA, Bakhshi-Raiez F, de Jonge E. Outcomes of cancer patients after unplanned admission to general intensive care units. Acta Oncol. 2012;51(7):897-905.

9.  Staudinger T, Stoiser B, Mullner M, et al. Outcome and prognostic factors in critically ill cancer patients admitted to the intensive care unit. Crit Care Med. 2000;28(5):1322-8.

10.  Lecuyer L, Chevret S, Thiery G, Darmon M, Schlemmer B, Azoulay E. The ICU trial: a new admission policy for cancer patients requiring mechanical ventilation. Crit Care Med. 2007;35(3):808-814.

11. de Montmollin E, Tandjaoui-Lambiotte Y, Legrand M, et al. Outcomes in critically ill cancer patients with septic shock of pulmonary origin. Shock. 2013;39(3):250-254.

12.  Xia R, Wang D. Intensive care unit prognostic factors in critically ill patients with advanced solid tumors: a 3-year retrospective study. BMC Cancer. 2016;16:188.

13.  Song JU, Suh GY, Park HY, et al. Early intervention on the outcomes in critically ill cancer patients admitted to intensive care units. Intensive Care Med. 2012;38(9):1505-1513.

14.  Lee DS, Suh GY, Ryu JA, et al. Effect of early intervention on long-term outcomes of critically ill cancer patients admitted to ICUs. Crit Care Med. 2015;43(7):1439-1448.

15.  Nates JL, Nunnally M, Kleinpell R, et al. ICU admission, discharge, and triage guidelines: a framework to enhance clinical operations, development of institutional policies, and further research. Crit Care Med. 2016;44(8):1553-1602.

16.  Garrouste-Orgeas M, Montuclard L, Timsit JF, et al. Predictors of intensive care unit refusal in French intensive care units: a multiple-center study. Crit Care Med. 2005;33(4):750-755.

17.  Shrime MG, Ferket BS, Scott DJ, et al. Time-limited trials of intensive care for critically ill patients with cancer: how long is long enough? JAMA Oncol. 2016;2(1):76-83.

18.  Benoit DD, Depuydt PO, Vandewoude KH, et al. Outcome in severely ill patients with hematological malignancies who received intravenous chemotherapy in the intensive care unit. Intensive Care Med. 2006;32(1):93-99.

19.  Darmon M, Thiery G, Ciroldi M, et al. Intensive care in patients with newly diagnosed malignancies and a need for cancer chemotherapy. Crit Care Med. 2005;33(11):2488-2493.

20.  Wohlfarth P, Staudinger T, Sperr WR, et al. Prognostic factors, long-term survival, and outcome of cancer patients receiving chemotherapy in the intensive care unit. Ann Hematol. 2014;93(10):1629-1636.

21.  Schellongowski P, Sperr WR, Wohlfarth P, et al. Critically ill patients with cancer: chances and limitations of intensive care medicine—a narrative review. ESMO Open. 2016;1(5):e000018.

22.  McCurdy MT, Shanholtz CB. Oncologic emergencies. Crit Care Med. 2012;40(7):2212-2222.

23.  Pi J, Kang Y, Smith M, Earl M, Norigian Z, McBride A. A review in the treatment of oncologic emergencies. J Oncol Pharm Pract. 2016;22(4):625-638.

24. Floyd J, Mirza I, Sachs B, Perry MC. Hepatotoxicity of chemotherapy. Semin Oncol. 2006;33(1):50-67.

25.  Niscola P, Vischini G, Tendas A, et al. Management of hematological malignancies in patients affected by renal failure. Expert Rev Anticancer Ther. 2011;11(3):415-432.

26.  Nolin TD, Aronoff GR, Fissell WH, et al. Pharmacokinetic assessment in patients receiving continuous RRT: perspectives from the Kidney Health Initiative. Clin J Am Soc Nephrol. 2015;10(1):159-164.

27.  Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy. 2009;29(5):562-577.

28.  Neuss MN, Gilmore TR, Belderson KM, et al. 2016 Updated American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards, Including Standards for Pediatric Oncology. J Oncol Pract. 2016;12(12):1262-1271.

29.  Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20(2):119-122.

30.  Shank BR, Do B, Sevin A, Chen SE, Neelapu SS, Horowitz SB. Chimeric antigen receptor T cells in hematologic malignancies. Pharmacotherapy. 2017;37(3):334-345.

31.   Hull CS, O’Rourke ME. Oncology-critical care nursing collaboration: recommendations for optimizing continuity of care of critically ill patients with cancer. Clin J Oncol Nurs. 2007;11(6):925-927.

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