Supportive care in patients with cancer during the COVID-19 pandemic.

Cancer care has been profoundly impacted by the global pandemic of severe acute respiratory syndrome coronavirus 2 disease (coronavirus disease 2019, COVID-19), resulting in unprecedented challenges. Supportive care is an essential component of cancer treatment, seeking to prevent and manage chemotherapy complications such as febrile neutropenia, anaemia, thrombocytopenia/bleeding, thromboembolic events and nausea/vomiting, all of which are common causes of hospitalisation. These adverse events are an essential consideration under routine patient management, but particularly so during a pandemic, a setting in which clinicians aim to minimise patients' risk of infection and need for hospital visits. Professional medical oncology societies have been providing updated guidelines to support health care professionals with the management, treatment and supportive care needs of their patients with cancer under the threat of COVID-19. This paper aims to review the recommendations made by the most prominent medical oncology societies for devising and modifying supportive care strategies during the pandemic.

Overall survival and risk of second malignancies with cancer chemotherapy and G-CSF support.

Background: The use of supportive granulocyte colony-stimulating factor (G-CSF) to reduce the risk of neutropenic complications in high-risk cancer patients is consistently recommended by several clinical practice guidelines. However, in a previous meta-analysis, G-CSF prophylaxis was associated with an increased risk of secondary malignancies while reducing long-term mortality. We present here an updated systematic review and meta-analysis. Materials and methods: A systematic literature search was carried out to identify randomized controlled trials of cancer patients receiving conventional-dose chemotherapy, assigned to primary G-CSF support or a control group without initial G-CSF, with at least 2 years of follow-up. Studies were categorized into one of the four groups, based on the chemotherapy regimen and study design. An updated meta-analysis was carried out; relative risk (RR) and 95% confidence intervals (CIs) for all-cause mortality and secondary malignancies were calculated. Results: Of 2604 articles screened, 14 eligible studies were identified and combined with studies identified in the previous systematic literature searches. The updated meta-analysis included a total of 68 studies presenting 71 separate comparisons. Survival was significantly improved in patients receiving primary G-CSF support, compared with patients without primary G-CSF support (mortality RR=0.92; 95% CI 0.90-0.95; ARD=-3.3%; 95% CI -4.2--2.4; P < 0.0001). The largest improvement in survival was observed with dose-dense chemotherapy regimens with G-CSF support, compared with controls receiving no G-CSF support (mortality RR=0.86; 95% CI 0.80-0.92; P < 0.0001). Patients who received primary G-CSF support experienced a significantly higher risk of secondary malignancies, compared with controls (RR=1.85; 95% CI 1.19-2.88; ARD=0.47; 95% CI 0.21-0.73; P < 0.01). Conclusions: Our findings demonstrate that overall survival is improved in patients receiving intensified chemotherapy with primary G-CSF support, compared with those receiving standard chemotherapy. Primary G-CSF support was also associated with a higher risk of developing secondary malignancies, including secondary acute myeloid leukemia and myelodysplastic syndrome.

Clinical prediction rules for mortality in patients with pulmonary embolism and cancer to guide outpatient management: a meta-analysis.

Essentials Clinical prediction rules (CPRs) can stratify patients with pulmonary embolism (PE) and cancer. A meta-analysis was done to assess prognostic accuracy in CPRs for mortality in these patients. Eight studies evaluating ten CPRs were included in this study. CPRs should continue to be used with other patient factors for mortality risk stratification. SUMMARY: Background Cancer treatment is commonly complicated by pulmonary embolism (PE), which remains a leading cause of morbidity and mortality in these patients. Some guidelines recommend the use of clinical prediction rules (CPRs) to help clinicians identify patients at low risk of mortality and therefore guide care. Objective To determine and compare the accuracy of available CPRs for identifying cancer patients with PE at low risk of mortality. Methods A literature search of Medline and Scopus (January 2000 to August 2017) was performed. Studies deriving/validating ≥ 1 CPR for early post-PE all-cause mortality were included. A bivariate, random-effects model was used to pool sensitivity and specificity estimates for each CPR. Traditional random-effects meta-analysis was performed to estimate the weighted proportion of patients deemed at low risk of early mortality, mortality in low risk patients and odds ratios for death compared with higher-risk patients. Results Eight studies evaluating 10 CPRs were included. The highest sensitivities were observed with Hestia (98.1%, 95% confidence interval [CI] = 75.6-99.9%) and the EPIPHANY index (97.4%, 95% CI = 93.2-99.0%); sensitivities of remaining rules ranged from 59.9 to 96.6%. Of the six CPRs with sensitivities ≥ 95%, none had specificities > 33%. Random-effects meta-analysis suggested that 6.6-51.6% of cancer patients with PE were at low risk of mortality, 0-14.3% of low-risk patients died and low-risk patients had a 43-94% lower odds of death compared with those at higher risk. Conclusions Because of the limited total body of evidence regarding CPRs, their results, in conjunction with other pertinent patient-specific clinical factors, should continue to be used in identifying appropriate management for PE in patients with cancer.

The effect of filgrastim or pegfilgrastim on survival outcomes of patients with cancer receiving myelosuppressive chemotherapy.

BACKGROUND: Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is associated with higher chemotherapy relative dose intensity, which may lead to improved outcomes; however, the association between G-CSF primary prophylaxis and overall survival (OS) is not well characterized. This study assessed the effect of G-CSF primary prophylaxis on patient outcomes in randomized, controlled, registrational clinical trials of filgrastim and pegfilgrastim. PATIENTS AND METHODS: Three placebo-controlled and two non-inferiority clinical trials of filgrastim and/or pegfilgrastim in patients receiving myelosuppressive chemotherapy for lung, breast, or colorectal cancer were included. The median OS, 6- and 12-month survival rates, and hazard ratios [HRs; unadjusted Cox model with 95% confidence intervals (CIs)] were estimated for patients receiving ≥1 dose of filgrastim, pegfilgrastim, or placebo. Comparisons were based on a log-rank test. A fixed-effect meta-analysis assessed the effect of primary prophylaxis with filgrastim/pegfilgrastim on OS in the placebo-controlled trials. RESULTS: In patients with lung cancer receiving filgrastim versus placebo, the median OS was 14.1 versus 11.1 months (HR, 0.81; 95% CI 0.48-1.35; P = 0.412); in patients who crossed over to filgrastim from placebo after cycle 1, the median OS was 16.9 months (HR, 0.75; 95% CI 0.43-1.28; P = 0.286). The median OS was inestimable in at least one treatment arm in the other studies because of the small number of OS events. Where estimable, 6- and 12-month survival rates were generally greater among patients receiving filgrastim/pegfilgrastim versus placebo. In the meta-analysis of placebo-controlled studies comparing G-CSF primary prophylaxis with placebo in the as-treated analysis sets, the HR (95% CI) for OS was 0.77 (0.58-1.03). CONCLUSIONS: In this retrospective analysis, OS point estimates were greater among patients receiving filgrastim versus placebo, but the differences were not statistically significant. Further studies evaluating patient outcomes with G-CSF prophylaxis are warranted. CLINICAL TRIAL REGISTRATION: NCT00035594, NCT00094809.

An exponential growth in incidence of thyroid cancer: trends and impact of CT imaging.

BACKGROUND AND PURPOSE: Workup of incidental thyroid nodules detected on CT imaging could be contributing to the increased diagnosis of small thyroid cancers. The purpose of this study was to evaluate recent trends in the incidence of thyroid cancer, and to determine the relationship between annual CT imaging volume and rate of thyroid cancer diagnosis. MATERIALS AND METHODS: This retrospective cohort study used data bases for thyroid cancer and CT imaging volume. Thyroid cancer data from 1983-2009 were obtained from the Surveillance, Epidemiology, and End Results data base. National Council of Radiation Protection and Measurements Report No. 160 provided data on hospital and nonhospital CT imaging volume for 1993-2006. Trends in thyroid cancer were modeled for overall incidence on the basis of patient age, tumor histologic features, and tumor size and stage. Linear regression analysis was performed to evaluate the strength of the relationship between annual CT scan volume and the incidence of thyroid cancer by tumor size and histologic type. RESULTS: In 2009, the incidence of thyroid cancer was 14 per 100,000, which represented a 1.9-fold increase compared with 2000. The growth in incidence was exponential compared with a minimal linear increase in thyroid cancer mortality rate. The subgroup with the greatest change was subcentimeter papillary carcinoma, with doubling in incidence approximately every 6.2 years. The linear relationship between annual CT scan volume and the incidence of subcentimeter papillary carcinoma was very strong (R(2) = 0.98; P < .0001). CONCLUSIONS: The incidence of subcentimeter papillary carcinoma is growing at an exponential rate without significant change in mortality rate. The strong linear relationship between new cases of subcentimeter papillary carcinomas and the number of CT scans per year suggests that an increase in CT scans may increase the detection of incidental thyroid cancers.

The impact of the granulocyte colony-stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The granulocyte colony-stimulating factor (G-CSF) is utilized to reduce neutropenic complications in patients receiving cancer chemotherapy. This study represents a systematic review and evidence summary of the impact of G-CSF support on chemotherapy dose intensity and overall mortality. MATERIALS AND METHODS: All randomized controlled trials (RCTs) comparing chemotherapy with or without G-CSF support and reporting all-cause mortality with at least 2 years of follow-up were sought. Dual-blind data abstraction of disease, treatment, patient and outcome study results with conflict resolution by third party was carried out. RESULTS: The search revealed 61 randomized comparisons of chemotherapy with or without initial G-CSF support. Death was reported in 4251 patients randomized to G-CSFs and in 5188 controls. Relative risk (RR) with G-CSF support for all-cause mortality was 0.93 (95% confidence interval: 0.90-0.96; P < 0.001). RR for mortality varied by intended chemotherapy dose and schedule: same dose and schedule (RR = 0.96; P = 0.060), dose dense (RR = 0.89; P < 0.001), dose escalation (RR = 0.92; P = 0.019) and drug substitution or addition (RR = 0.94; P = 0.003). Greater RR reduction was observed among studies with longer follow-up (P = 0.02), where treatment was for curative intent (RR = 0.91; P < 0.001), and where survival was the primary outcome (RR = 0.91; P < 0.001). CONCLUSIONS: All-cause mortality is reduced in patients receiving chemotherapy with primary G-CSF support. The greatest impact was observed in RCTs in patients receiving dose-dense schedules.

Incidental thyroid nodules on CT: evaluation of 2 risk-categorization methods for work-up of nodules.

BACKGROUND AND PURPOSE: Thyroid nodules are common incidental findings on CT, but there are no clear guidelines regarding their further diagnostic work-up. This study compares the performance of 2 risk-categorization methods of selecting CT-detected incidental thyroid nodules for work-up. MATERIALS AND METHODS: The 2 categorization methods were method A, based on nodule size ≥10 mm, and method B, a 3-tiered system based on aggressive imaging features, patient age younger than 35 years or nodule size of ≥15 mm. In part 1, the 2 categorization methods were applied to thyroid cancers in the SEER data base of the National Cancer Institute to compare the cancer capture rates and survival. In part two, 755 CT neck scans at our institution were retrospectively reviewed for the presence of ITNs of ≥5 mm, and the same 2 categorization methods were applied to the CT cases to compare the number of patients who would theoretically meet the criteria for work-up. Comparisons of proportions of subjects captured under methods A and B were made by using the McNemar test. RESULTS: For 84,720 subjects in the SEER data base, methods A and B each captured 74% (62,708/84,720 and 62,586/84,720, respectively) of malignancies. SEER subjects who would not have met the criteria for further work-up by both methods had equally excellent 10-year cause-specific and relative survival of >99%. For part 2, the prevalence of ITNs of ≥5 mm at our institution was 133/755 (18%). The number of ITNs that would be recommended for work-up by method A was 57/133 (43%) compared with 31/133 (23%) for method B (P < .0005). CONCLUSIONS: Compared with using a 10-mm cutoff, the 3-tiered risk-stratification method identified fewer ITNs for work-up but captured the same proportion of cancers in a national data base and showed no difference in missing high-mortality cancers.

2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.

Chemotherapy-induced neutropenia is a major risk factor for infection-related morbidity and mortality and also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact the success of treatment, particularly when treatment intent is either curative or to prolong survival. In Europe, prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim (including approved biosimilars), lenograstim or pegfilgrastim is available to reduce the risk of chemotherapy-induced neutropenia. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. The need for generally applicable, European-focused guidelines led to the formation of a European Guidelines Working Party by the European Organisation for Research and Treatment of Cancer (EORTC) and the publication in 2006 of guidelines for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. A new systematic literature review has been undertaken to ensure that recommendations are current and provide guidance on clinical practice in Europe. We recommend that patient-related adverse risk factors, such as elderly age (≥65 years) and neutrophil count be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. It is important that after a previous episode of FN, patients receive prophylactic administration of G-CSF in subsequent cycles. We provide an expanded list of common chemotherapy regimens considered to have a high (≥20%) or intermediate (10-20%) risk of FN. Prophylactic G-CSF continues to be recommended in patients receiving a chemotherapy regimen with high risk of FN. When using a chemotherapy regimen associated with FN in 10-20% of patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Clinical evidence shows that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications where indicated. Filgrastim biosimilars are also approved for use in Europe. While other forms of G-CSF, including biosimilars, are administered by a course of daily injections, pegfilgrastim allows once-per-cycle administration. Choice of formulation remains a matter for individual clinical judgement. Evidence from multiple low level studies derived from audit data and clinical practice suggests that some patients receive suboptimal daily G-CSFs; the use of pegfilgrastim may avoid this problem.

Febrile neutropenia and related complications in breast cancer patients receiving pegfilgrastim primary prophylaxis versus current practice neutropaenia management: results from an integrated analysis.

Granulocyte colony-stimulating factors (G-CSFs) reduce febrile neutropaenia (FN) incidence but may be used inconsistently in current practice (CP). This study compared the efficacy of pegfilgrastim primary prophylaxis (PPP) with CP neutropaenia management in breast cancer. Individual patient data (N=2282) from 11 clinical trials and observational studies using chemotherapy regimens with > or =15% FN risk and PPP (6 mg, all cycles) or CP (no G-CSF or any cycle G-CSF/pegfilgrastim) were included in an integrated analysis. Most patients received docetaxel-containing regimens. A generalised linear mixed model was fitted (N=2210). Neutropaenia prophylaxis (PPP versus CP), age and disease stage influenced the incidence of FN. Overall, FN was less frequent with PPP than with CP (odds ratio [OR]: 0.124; 95% confidence interval [CI]: 0.08, 0.194; P<0.0001). Odds for cycle 1 FN, dose reductions > or =15% and FN-related hospitalisation were also significantly lower with PPP. These data support PPP in breast cancer patients receiving chemotherapy with moderately high/high FN risk.

EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours.

Chemotherapy-induced neutropenia is not only a major risk factor for infection-related morbidity and mortality, but is also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact on the success of treatment, particularly when treatment intent is either curative or to prolong survival. The incidence of severe or FN can be reduced by prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim, lenograstim or pegfilgrastim. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. While several academic groups have produced evidence-based clinical practice guidelines in an effort to standardise and optimise the management of FN, there remains a need for generally applicable, European-focused guidelines. To this end, we undertook a systematic literature review and formulated recommendations for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. We recommend that patient-related adverse risk factors such as elderly age (>or=65 years), be evaluated in the overall assessment of FN risk prior to administering each cycle of chemotherapy. In addition, when using a chemotherapy regimen associated with FN in >20% patients, prophylactic G-CSF is recommended. When using a chemotherapy regimen associated with FN in 10-20% patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Finally, studies have shown that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications, where indicated.

Randomized clinical trials for hematopoietic stem cell transplantation: lessons to be learned from the European experience.

We evaluated the number and characteristics of randomized controlled trials (RCTs) addressing hematopoietic stem cell transplantation (HSCT) for patients with hematological malignancies, comparing the productivity of US and Europe. A MEDLINE search was conducted to identify all published RCTs for the management of adult patients with hematological malignancies from January 1992 to December 2003. Eighty-three of the 306 trials identified included HSCT as one of the treatment arms. The US produced 25, Europe 54, and all other countries four. Four European countries, France, Italy, Germany, and UK (FIGU), produced 32 out of the 54 European studies. Significant differences emerged when focus of the study and accrual numbers were analyzed. Trials comparing HSCT to standard dose therapy represented 34.9% of the 83 trials and 59.4% of FIGU trials, but only 4% of US studies (P = 0.001). US trials accrued a mean of 110.2 patients per study, as compared to 222.6 in FIGU studies (P = 0.006) and 205.3 when all non-US countries are considered (P = 0.01). Our conclusions are that US transplant RCT have focused on issues other than the comparison of HSCT to standard therapies. There is serious paucity of US trials defining the role of HSCT in the management of hematological malignancies.

The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia.

Healthcare costs continue to rise with hospitalization representing the single largest component of direct medical costs associated with cancer care. Neutropenia and its complications including febrile neutropenia remain the major dose-limiting toxicity associated with systemic cancer chemotherapy. Febrile neutropenia often occurs early in the course of chemotherapy and is associated with substantial morbidity, mortality and cost. The colony-stimulating factors (CSFs) have been used effectively in a variety of clinical settings to prevent or treat febrile neutropenia and to assist patients receiving dose-intensive chemotherapy. A meta-analysis of the available randomized controlled trials (RCTs) has confirmed the efficacy of prophylactic CSFs. Economic models based on measures of resource utilization derived from RCTs have provided estimates of expected treatment costs along with febrile neutropenia risk threshold estimates for the cost saving use of the CSFs. Recent studies have demonstrated the potential value of targeting the CSFs toward patients at greatest risk based on accurate and valid predictive models.

Survival after HLA-identical allogeneic peripheral blood stem cell and bone marrow transplantation for hematologic malignancies: meta-analysis of randomized controlled trials.

The impact of peripheral blood stem cell transplantation (PBSCT) on survival relative to bone marrow transplantation (BMT) remains poorly defined. Several randomized controlled trials (RCTs) comparing HLA-matched related PBSC- and BMT for patients with hematologic malignancies have been published, yielding differing results. We conducted a meta-analysis of published RCTs to more precisely estimate the effect of PBSCT on survival. Seven trials that assessed survival were identified and included in our analysis. Using a fixed effects model, and combining the results of all seven trials, the summary odds ratio for mortality after PBSCT was 0.81 (95% CI, 0.62-1.05) when compared to BMT. Subgroup analysis revealed no association between the median PBSCT 34+ cell dose and relative risk for morality after PBSCT. However, there was an association between the proportion of patients enrolled with advanced-stage disease and the summary odds ratio for mortality. The pooled estimate was 0.64 for studies where patients with intermediate/advanced disease comprised at least 25% of enrollment, and was 1.07 for the studies enrolling a smaller proportion. This finding substantiates results from previously published studies that have demonstrated a survival advantage with PBSCT limited to patients with advanced disease.

Economic analysis of randomized, controlled trials.

To facilitate the comparison of different treatment strategies, measures have been developed that bring together clinical, quality-of-life, and economic outcomes into summary measures such as the quality-adjusted life year, cost-effectiveness, and cost-utility ratios. A number of different types of economic evaluations have been developed, including cost-minimization, cost-effectiveness, and cost-utility analyses. Performance of economic analyses in association with randomized, controlled trials (RCT) has gained increasing enthusiasm in recent years. However, economic measures in RCTs are often outcomes of secondary interest and associated with frequent missing data and inadequate sample size. Variability in the cost measures used and the lack of agreement on clinically meaningful cost differences further limit the conclusions derived from such studies. Economic analyses should be limited to large trials with important trade-offs between efficacy and cost. The strengths and limitations of such analyses are discussed, and guidelines are offered for proper economic analyses in randomized, controlled trials.

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

Hematopoietic growth factors in the older cancer patient.

Aging is associated with a progressive decline in the functional reserve of multiple organ systems, which may lead to enhanced susceptibility to stress such as that caused by cancer chemotherapy. Myelodepression is the most common and the most commonly fatal complication of antineoplastic drug therapy and may represent a serious hindrance to the management of cancer in older individuals. This is already a common and pervasive problem and promises to become more so. Currently 60% of all neoplasms occur in persons aged 65 years and older, and this percentage is expected to increase as the population ages. This well-known phenomenon, sometimes referred to as squaring or the age pyramid, is caused by the combination of an increasing life expectancy and a decreasing birth rate. This article explores the use of hematopoietic growth factors in the older cancer patient after reviewing the influence of age on hemopoiesis and chemotherapy-related complications. The issue is examined in terms of effectiveness and cost. An outline of the assessment of the older cancer patient is provided at the end of the chapter as a frame of reference for clinical decisions.