Clinically meaningful outcomes in refractory metastatic colorectal cancer: a decade of defining and raising the bar.

Currently, there is no consensus definition for clinically meaningful outcomes in randomized clinical trials (RCTs) designed to evaluate new treatments for patients with refractory metastatic colorectal cancer (mCRC). Since 2014, recommended targets for improvements in overall survival and progression-free survival have been published by several societies, including those from the American Society of Clinical Oncology (ASCO) Clinically Meaningful Outcomes Working Group in 2014, the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) in 2015, and Colorectal Cancer Canada (CCC) consensus statements in 2019. However, evidence from several systematic reviews suggests that in a substantial proportion of RCTs that led to oncology drug approvals, the recommended thresholds of ASCO and ESMO-MCBS were not met. In addition to efficacy and safety, quality of life (QoL) is important to patients with mCRC, especially for those who are receiving later-line therapy or end-of-life care. As such, both ESMO-MCBS and CCC recommend the inclusion of QoL assessments in the design of mCRC clinical trials. Since the publication of the ASCO recommendations in 2014, there has been significant progress in the development of treatment options for patients with refractory mCRC; these include the approvals of trifluridine/tipiracil (FTD/TPI) as a single agent and in combination with bevacizumab, and the approval of fruquintinib. Among the phase III RCTs in third-line mCRC, only the SUNLIGHT trial of FTD/TPI plus bevacizumab met all recommended thresholds for clinically meaningful improvements, while also demonstrating a manageable safety profile and slower deterioration in multiple measures of QoL compared with FTD/TPI alone. The results from the SUNLIGHT study show that incremental gains in several clinically meaningful endpoints are achievable, thus raising the bar in defining clinically meaningful outcomes for emerging therapies in refractory mCRC.

Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

Impact of KRASG12 mutations on survival with trifluridine/tipiracil plus bevacizumab in patients with refractory metastatic colorectal cancer: post hoc analysis of the phase III SUNLIGHT trial.

BACKGROUND: In metastatic colorectal cancer (mCRC), KRAS mutations are often associated with poorer survival; however, the prognostic impact of specific point mutations is unclear. In the phase III SUNLIGHT trial, trifluridine/tipiracil (FTD/TPI) plus bevacizumab significantly improved overall survival (OS) versus FTD/TPI alone. We assessed the impact of KRASG12 mutational status on OS in SUNLIGHT. PATIENTS AND METHODS: In the global, open-label, randomized, phase III SUNLIGHT trial, adults with mCRC who had received no more than two prior chemotherapy regimens were randomized 1 : 1 to receive FTD/TPI alone or FTD/TPI plus bevacizumab. In this post hoc analysis, OS was assessed according to the presence or absence of a KRASG12 mutation in the overall population and in patients with RAS-mutated tumors. RESULTS: Overall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRASG12 mutation and 88 with a non-KRASG12RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRASG12 mutation [median 8.3 and 9.2 months, respectively; hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.87-1.4]. Similar OS outcomes were also observed in the subgroup analysis of patients with a KRASG12 mutation versus those with a non-KRASG12RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRASG12 mutational status. Among patients with a KRASG12 mutation, the median OS was 9.4 months with FTD/TPI plus bevacizumab versus 7.2 months with FTD/TPI alone (HR 0.67, 95% CI 0.48-0.93), and in patients without a KRASG12 mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81). CONCLUSIONS: The presence of a KRASG12 mutation had no detrimental effect on OS among patients treated in SUNLIGHT. The benefit of FTD/TPI plus bevacizumab over FTD/TPI alone was confirmed independently of KRASG12 status.

A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202).

BACKGROUND: Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC. PATIENTS AND METHODS: Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. CONCLUSIONS: Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.

Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines.

BACKGROUND: Colorectal cancer (CRC) is still a leading cause of cancer-related deaths in the United States and worldwide, despite recent improvements in cancer management. CRC, like many malignancies, is a heterogeneous disease, with subtypes characterized by genetic alterations. One common mutation in CRC is in the BRAF gene (most commonly V600E substitution). This occurs in ∼10% of patients with metastatic CRC (mCRC) and is a marker of poor prognosis. DESIGN: Herein, we review the clinical and translational literature on the role of the BRAF V600E mutation in the pathogenesis of mCRC, its mechanisms as a prognostic marker, and its potential utility as a predictive marker of treatment response. We then summarize the current evidence-based recommendations for management of BRAF V600E-mutated mCRC, with a focus on recent clinical research advances in this setting. RESULTS: The current standard therapies for first-line treatment of BRAF-mutated mCRC are chemotherapy with bevacizumab as well as 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab in patients with a good performance status. Combination strategies involving mitogen-activated protein kinase (MAPK) pathway blockade have shown promising results for the treatment of patients with BRAF V600E-mutated mCRC. The Binimetinib, Encorafenib, And Cetuximab cOmbiNed to treat BRAF-mutant ColoRectal Cancer (BEACON CRC) study represents the largest study in this population to date and has given strong clinical evidence to support BRAF and epidermal growth factor receptor inhibition with the combination of encorafenib plus cetuximab. CONCLUSIONS: The treatment of BRAF-mutated mCRC has evolved rapidly over the last several years. Recently, combination strategies involving MAPK pathway blockade have shown promising results in BRAF V600E-mutated mCRC, and other potential targets continue to be explored. In addition, a greater understanding of the role of BRAF V600E mutation in the pathogenesis of CRC should also continue to fuel advances in the management of patients with mCRC harboring this genetic aberration.

Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer.

BACKGROUND: Microsatellite instability (MSI) is a biomarker for response to immune checkpoint inhibitors (ICPIs). PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often <50%, suggesting that additional predictive biomarkers are needed. METHODS: Clinicopathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mb of sequenced DNA and reported as mutations/Mb. Potential biomarkers of response and time to progression were analyzed by univariate and multivariate analyses. Once TMB was confirmed as a predictive biomarker, a larger dataset of 18 140 unique CRC patients was analyzed to define the relevance of the identified TMB cut-point. RESULTS: A total of 22 patients were treated with PD-1/L1 inhibitors including 19 with pembrolizumab monotherapy. Among tested variables, TMB showed the strongest association with objective response (OR; P < 0.001) and PFS, by univariate (P < 0.001) and multivariate analysis (P < 0.01). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37 and 41 mutations/Mb. All 13 TMBhigh cases responded, while 6/9 TMBlow cases had progressive disease. The median PFS for TMBhigh has not been reached (median follow-up >18 months) while the median PFS for TMBlow was 2 months. A TMB of 37.4 mutations/Mb in a large MSI-H mCRC population (821/18, 140 cases; 4.5%) evaluated by NGS corresponded to the 35th percentile cut-point. CONCLUSIONS: TMB appears to be an important independent biomarker within MSI-H mCRC to stratify patients for likelihood of response to ICPIs. If validated in prospective studies, TMB may play an important role in guiding the sequencing and/or combinations of ICPIs in MSI-H mCRC.

Blood culture series benefit may be limited to selected clinical conditions: time to reassess.

Blood cultures are often submitted as series (two to three sets per 24 hours) to maximize sample recovery. We assessed the actual benefit of additional sets. Blood cultures submitted from adults (≥ 18 years old) over 1 year (1 February 2012 to 31 January 2013) were examined. The medical records of patients with positive cultures were reviewed. Cultures with commensal organisms were considered contamination in the absence of a source and clinical findings. The impact of additional sets on antibiotic therapy was estimated. We evaluated 15,394 blood cultures. They were submitted as two to five sets per 24 hours in 12,236 (79.5%) instances. Pathogens were detected in 1227 sets, representing 741 bacteremias, of which 618 (83.4%) were detected in the first set and 123 (16.6%) in the additional sets. Pathogens missed in the first set were recovered from patients receiving antibiotics (n = 72; 58.5%) and after undergoing a procedure (n = 54; 43.9%). The additional sets' results could have influenced antibiotic therapy in 76/6235 (1.2%) instances, including 40 (0.6%) antibiotic switches and 36 (0.6%) possible extensions of therapy. The potential impact of the detection of missed pathogens on antibiotic therapy was not apparent in patients who had an endovascular infection (26/27, 96.3%) and those who lacked an obvious source of pathogens (10/10, 100%). These findings suggest that one blood culture is probably adequate in patients with an obvious source of pathogens. Blood culture series are beneficial in patients without an obvious source of pathogens and in those with endovascular infections. It is time to reassess the benefit of blood culture series, perhaps limiting them to selected conditions.

A prospective clinical trial of cholecalciferol 2000 IU/day in colorectal cancer patients: evidence of a chemotherapy-response interaction.

BACKGROUND: We have previously reported a negative correlation between the effect of chemotherapy and 25-hydroxy vitamin D(3) (25-D(3)) levels in patients with colorectal cancer. Based on this finding, we hypothesized that the response to vitamin D(3) supplementation may be attenuated in patients with colorectal cancer. AIM: To determine 25-D(3) response to 2000 IU/day vitamin D(3) supplementation in patients with colorectal cancer. MATERIALS AND METHODS: Fifty evaluable colorectal cancer patients were treated with vitamin D(3) at 2000 IU/day for 6 months. Serum 25-D(3) levels were measured at baseline, 3, and 6 months of supplementation. RESULTS: The mean 25-D(3) level was 17.5 ng/ml at baseline, 31.6 ng/ml at 3 months, and 33.8 ng/ml at 6 months. The most important factor in determining 25-D(3) response was chemotherapy status. A rise in 25-D(3) of ≥10 ng/ml at the 3-month interval was observed in 92% of chemotherapy-free patients vs. 39% of chemotherapy patients. Similar differences in response were noted at the 6-month interval. CONCLUSION: Depressed 25-D(3) levels are common in patients with colorectal cancer. Active chemotherapy is associated with an attenuated response to 2000 IU of D(3) supplementation in this patient population. Alternative vitamin D(3) dosing schedules need further investigation in colorectal cancer patients undergoing chemotherapy.

A randomized phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer.

BACKGROUND: Vorinostat is synergistic with 5-FU in vitro and in vivo models. A combination of these two agents was associated with clinical activity in 5-FU refractory colorectal cancer patients in a phase I clinical trial, therefore warranting the conduct of this prospective phase II study. PATIENTS AND METHODS: Patients with refractory metastatic colorectal cancer were randomized in a two-stage design to receive vorinostat at 800 or 1,400 mg/day once a day × 3, every 2 weeks. 5-FU, preceded by leucovorin, was administered as a bolus followed by a 46-h infusion on days 2 and 3 of vorinostat. A pre-specified 2-month progression-free survival (PFS) rate of 27/43 patients per arm was needed to deem an arm interesting for further investigation. RESULTS: The high-dose vorinostat arm did not reach the needed efficacy endpoint at completion of the first stage, with only 8 out of 15 patients being alive and progression free at 2 months. The low-dose vorinostat arm proceeded to accrue 43 patients with a 2-month PFS rate of 53% (23 out 43), including one partial response. The median PFS and overall survival on the low-dose arm were 2.4 and 6.5 months, respectively. Both treatment arms were well tolerated. No differences were noted in the pharmacokinetics of vorinostat at the 800- or 1,400-mg dose-levels, suggesting bioavailability saturation. CONCLUSIONS: While the addition of vorinostat to 5-FU resulted in 1 partial response and in some disease stabilizations, the limited activity does not warrant the unselected use of this combination in chemotherapy-refractory colorectal cancer.

Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer.

The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, plays an important role in the control of cell growth and differentiation. Disruption of its signaling leads to neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis.EGFR is overexpressed in a variety of solid tumors, including colorectal cancer (CRC), and its overexpression is associated with poorer prognosis. One class of agents that is currently used to target EGFR in the treatment of metastatic CRC (mCRC) is the monoclonal antibodies. While the monoclonal antibody EGFR inhibitors lack many of the severe side effects commonly observed with cytotoxic chemotherapy, they are associated with a set of unique dermatological toxicities. This paper reviews the safety profile of the anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of mCRC.

Efficacy of the monoclonal antibody EGFR inhibitors for the treatment of metastatic colorectal cancer.

Two anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) have been approved in Canada for the treatment of metastatic colorectal cancer (mCRC) - cetuximab, a mouse-human chimeric MoAb, and panitumumab, a fully human MoAb. This paper reviews the efficacy of the anti-EGFR monoclonal antibodies cetuximab and panitumumab - both as monotherapy and in combination with cytotoxic chemotherapy - in the treatment of mCRC. Both cetuximab and panitumumab have demonstrated clinical efficacy in monotherapy in patients with mCRC, an advantage that has recently been found to be limited largely to those with wild-type KRAS tumors. Advantages of using these agents in monotherapy include reduced cost and toxicity. While the addition of cetuximab to irinotecan has shown superior progression-free survival and response compared with cetuximab monotherapy, there is currently no evidence for a benefit of panitumumab in combination with irinotecan.

A case of curative-intent hepatectomy for colon cancer metastatic to the scapula and liver.

Colon cancer is the second leading cause of cancer death in the United States. Patients with colon cancer metastatic to liver and bone are deemed non-curable and have a poor prognosis. We present a case of recurrent colon cancer with synchronous hepatic and bony metastases treated with radiation, chemotherapy, and curative-intent hepatectomy. The patient is alive and free of disease recurrence, off chemotherapy, more than 2 years post-hepatectomy.

Persistent Staphylococcus aureus bacteremia: incidence and outcome trends over time.

Persistent Staphylococcus aureus bacteremia (SAB-P) is well known but poorly delineated due to unclear definition. We retrospectively studied 78 patients with SAB-P using a stringent definition (bacteremia for > or = 7 d), in a single teaching hospital, during 1 January 2002 to 30 June 2003 and 1 November 2005 to 31 December 2006 to determine whether the frequency, risk factors and outcome changed over time. SAB was encountered in 354 and 259 instances during the 2 periods, respectively. Patients' characteristics changed with increasing organ dysfunction score (2.9+/-1.7 vs 3.4+/-1.4; p <0.001), patients with invasive devices (27.7% vs 41.3%; p=0.001), hemodialysis dependence (19.2% vs 27.8%; p=0.04), MRSA (50.8% vs 64.5%; p=0.001), and vancomycin treatment (57.9% vs 67.2%; p=0.02). SAB-P frequency increased slightly (11.0% vs 15.1%). Risk (associated) factors for SAB-P (identified by logistic regression) were metastatic infection (OR=5.60; 95% CI 3.00 - 10.47), vancomycin treatment (OR=4.17; 95% CI 2.14 - 8.11), endovascular sources (OR=3.35; 95% CI 1.92 - 5.85) and diabetes (OR=2.14; 95% CI 1.26 - 3.64). SAB- and SAB-P-associated case-fatality did not change (23.2% vs 18.5% and 25.6 vs 30.8%, respectively). All survivors ultimately achieved clearance. These findings suggest that patients with SAB are changing over time. Additionally, SAB-P frequency is higher than previously reported. SAB-P rise is probably due to increasing SAB, MRSA, and patients at risk for complications. Innovative approaches should target novel treatment modalities and risk reduction.

Interinstitutional and intrainstitutional transmission of a strain of Acinetobacter baumannii detected by molecular analysis: comparison of pulsed-field gel electrophoresis and repetitive sequence-based polymerase chain reaction.

Pulsed-field gel electrophoresis and repetitive sequence-based polymerase chain reaction provided comparable strain discrimination with minor discordance in typing Acinetobacter baumannii clinical isolates from patients at our hospital and affiliated institutions. Typing revealed a cluster strain with intrainstitutional and interinstitutional spread during the study period. A long-term acute care facility may have been the reservoir.

Impact of initial antibiotic choice and delayed appropriate treatment on the outcome of Staphylococcus aureus bacteremia.

The study presented here investigated the impact of initial antibiotic choice (beta-lactams vs vancomycin) on the outcome of 342 patients with Staphylococcus aureus bacteremia (50.9% with methicillin-resistant isolates) encountered between 1 January 2002 and 30 June 2003. Initial antibiotics were inappropriate (beta-lactams) in 60 (34.5%) methicillin-resistant cases and suboptimal (vancomycin) in 62 (36.9%) methicillin-susceptible cases. Time to effective antibiotic therapy was longer in methicillin-resistant cases (25.5+/-28.6 vs 9.6+/-16.6 h; p<0.0005). All-cause in-hospital mortality was higher with inappropriate therapy (35.0 vs 20.9%; p=0.02). Initial vancomycin treatment was associated with a higher incidence of delayed clearance (>or=3 days) of methicillin-susceptible bacteremia (56.3 vs 37.0%; p=0.03). The results indicate inappropriate initial therapy is associated with higher in-hospital mortality and initial vancomycin may delay clearance.

Pigtail catheter for the treatment of ascites associated with ovarian hyperstimulation syndrome.

BACKGROUND: Severe ovarian hyperstimulation syndrome (OHSS) is potentially dangerous. The study aim was to evaluate the efficacy and safety of percutaneous pigtail catheter drainage for the management of ascites complicating severe OHSS. METHODS: This was a prospective trial conducted at a private IVF centre and a tertiary teaching medical centre. A total of 26 patients with severe OHSS was recruited. Patients were divided into two groups. Patients in group 1 (n = 13) were hospitalized, while patients in group 2 (n = 13) were managed on an outpatient basis. A pigtail catheter was inserted under transabdominal ultrasound guidance and kept in place until drainage ceased. The main outcome measures were resolution of OHSS as determined by symptomatology and laboratory values, time to removal of catheter, patient tolerance of the procedure and complication rate. RESULTS: The catheter was successfully placed in all patients following one attempt and was kept in place for a mean +/- SD of 12.9 +/- 4.3 days (range 7-24). Average amount of fluid drained was 11.2 +/- 4.3 l (range: 3.35-18.5). An improvement of symptoms and signs was noted 24-48 h after catheter placement in all patients in both groups. Procedure was well tolerated and no complications reported. CONCLUSIONS: Percutaneous placement of a pigtail catheter is a safe and effective treatment modality for severe OHSS. It may represent an attractive alternative to multiple vaginal or abdominal paracentesis.

Intramedullary spinal cord metastasis (ISCM) in renal cell carcinoma: a series of six cases.

Intramedullary spinal cord metastasis (ISCM) has been infrequently diagnosed during the clinical course of renal cell carcinoma (RCC). With the advent of more sensitive diagnostic procedures including magnetic resonance imaging (MRI), more cases of ISCM have been documented. The management of these cases is particularly challenging as lack of prompt intervention often results in irreversible progressive neurological deficits. We describe the management and clinical course in six patients with RCC who developed ISCM. Two of these patients were treated surgically while four were treated with radiation therapy (RT). Although no major improvements in neurological function were noted, stabilizations were common. This prolonged their ability to live independently, a matter of utmost importance in these terminally ill patients.