Anticancer therapy within the last 30 days of life: results of an audit and re-audit cycle from an Australian regional cancer centre.

BACKGROUND: The therapeutic landscape in medical oncology continues to expand significantly. Newer therapies, especially immunotherapy, offer the hope of profound and durable responses with more tolerable side effect profiles. Integrating this information into the decision making process is challenging for patients and oncologists. Systemic anticancer treatment within the last thirty days of life is a key quality of care indicator and is one parameter used in the assessment of aggressiveness of care. METHODS: A retrospective review of medical records of all patients previously treated at Goulburn Valley Health oncology department who died between 1 January 2015 and 30 June 2018 was conducted. Information collected related to patient demographics, diagnosis, treatment, and hospital care within the last 30 days of life. These results were presented to the cancer services meeting and a quality improvement intervention program was instituted. A second retrospective review of medical records of all patients who died between 1 July 2018 and 31 December 2018 was conducted in order to measure the effect of this intervention. RESULTS: The initial audit period comprised 440 patients. 120 patients (27%) received treatment within the last 30 days of life. The re-audit period comprised 75 patients. 19 patients (25%) received treatment within the last 30 days of life. Treatment rates of chemotherapy reduced after the intervention in contrast to treatment rates of immunotherapy which increased. A separate analysis calculated the rate of mortality within 30 days of chemotherapy from the total number of patients who received chemotherapy was initially 8% and 2% in the re-audit period. Treatment within the last 30 days of life was associated with higher use of aggressive care such as emergency department presentation, hospitalisation, ICU admission and late hospice referral. Palliative care referral rates improved after the intervention. CONCLUSION: This audit demonstrated that a quality improvement intervention can impact quality of care indicators with reductions in the use of chemotherapy within the last 30 days of life. However, immunotherapy use increased which may be explained by increased access and a better risk benefit balance.

Chemotherapy and biologic use in the routine management of metastatic colorectal cancer in Australia: is clinical practice following the evidence?

BACKGROUND: Emerging evidence on the optimal use of chemotherapy and biologics in patients with metastatic colorectal cancer should impact management in routine care. Recent studies have demonstrated benefits for initial triplet chemotherapy (5-fluorouracil, oxaliplatin and irinotecan, FOLFOXIRI) and for initial treatment with an epidermal growth factor receptor inhibitor (EGFRi) in patients with a RAS wild-type tumour and a left-sided primary tumour. AIM: To explore evolving pattern of metastatic colorectal cancer care over time in Australia. METHODS: We analysed data from the Treatment of Recurrent and Advanced Colorectal Cancer registry. RESULTS: From July 2009 to December 2017, 2552 metastatic colorectal cancer patients were entered into the Treatment of Recurrent and Advanced Colorectal Cancer registry. Of 1585 patients who initially underwent chemotherapy, treatment was with a doublet in 76%. FOLFOXIRI was given to 22 patients (1.4%), mostly young patients and those with potentially resectable disease. Along with first-line chemotherapy, 61% received bevacizumab, while 3.3% received an EGFRi, predominantly over the last 2 years. Within the KRAS wild-type left-sided tumour cohort, EGFRi use increased from 9% in 2015 to 37% in 2017. Across treatment sites, there was a wide variation in the utilisation of FOLFOXIRI and EGFRi therapy; bevacizumab use was more consistent. A clear impact on survival outcomes from these regimens is not evident, potentially due to multiple confounders. CONCLUSION: Doublet chemotherapy + bevacizumab remains the dominant initial strategy, with limited uptake of triplet chemotherapy and of EGFRi. Potential explanations include uncertainty about the significance of post hoc analyses for EGFRi and concerns regarding adverse events for both strategies.

Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial.

BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. FUNDING: Merck & Co, Inc.

Pembrolizumab Induced Ocular Hypotony With Near Complete Vision Loss, Interstitial Pulmonary Fibrosis and Arthritis.

Clinical outcomes for patients with advanced melanoma have improved significantly with the introduction of immune checkpoint inhibitors. These agents have distinct adverse effects with the potential for heightened host immune responses manifesting as an autoimmune reaction in any organ. We report a unique case who developed pembrolizumab induced arthritis, ocular hypotony with vision loss and pulmonary interstitial fibrosis. A 57-year old gentleman with advanced melanoma was treated with pembrolizumab and attained complete response with no evidence of disease on functional imaging. Treatment was well-tolerated with the only side effect being arthritis controlled with low dose steroids. Following a work related blunt trauma to the right eye, the patient developed bilateral visual impairment secondary to ocular hypotony. The ocular hypotony failed to respond to high-dose glucocorticoid and multiple surgeries. Intraoperatively, ciliary body atrophy was found. Pembrolizumab was ceased after the eye trauma and he remained in complete remission from melanoma. After a further 10 months, the patient developed symptomatic pulmonary fibrosis. There was moderate symptomatic improvement with nintedanib, an antifibrotic agent. This case describes two rare and unique adverse effects. Ocular adverse effects are extremely uncommon and this is the first case to report immune checkpoint inhibitor related ocular hypotony without uveitis to the best of our knowledge. Similarly, the incidence of severe pneumonitis is reported to be low, however limited data is available regarding pulmonary interstitial fibrosis. The occurrence of multiple adverse effects in this case including one occurring several months after cessation of treatment highlights the need for vigilance by clinicians who manage patients treated with immune checkpoint inhibitors. Further research is necessary with regards to rare adverse effects of immune checkpoint inhibitors and the relation of these to treatment administration.

Risk of febrile neutropenia and early treatment cessation in men receiving standard and dose-reduced 3-weekly docetaxel for metastatic castration-resistant prostate cancer.

BACKGROUND: Docetaxel is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC); however, many patients experience febrile neutropenia (FN) and cease treatment early due to toxicity. It is not known whether lower dose (LD) q3-weekly docetaxel impacts toxicity or efficacy. METHODS: Multicenter retrospective study included 166 patients with mCRPC who received q3-weekly docetaxel between 2010 and 2015. Demographic, disease, chemotherapy (standard dose, SD > 60 mg/m2 vs LD ≤ 60 mg/m2 ) and toxicity data were collected. Univariable and multivariable logistic and competing risk regression models evaluated docetaxel-dose association with FN and early treatment cessation (ETC) due to toxicity. Associations between dose and efficacy end points were also evaluated. Analyses were repeated employing inverse propensity score weights. RESULTS: Patients who received LD docetaxel (28.9%) were older with poorer Eastern Cooperative Oncology Group (ECOG) status. Fifteen percent of patients experienced FN, with a nonsignificant trend to lower incidence in the LD group (multiple adjusted odds ratio [OR] = 0.42; P = 0.21). Neither baseline patient nor prior treatment factors were predictive of FN. ETC due to toxicity occurred in 35%, with risk associated with increasing age, comorbidity count and poorer ECOG. There was no difference between LD and SD with respect to ETC due to toxicity, in unweighted and weighted analyses (LD vs SD, multivariable weighted hazard ratio [HR] = 1.47; P = 0.08). LD was associated with reduced prostate-specific antigen (PSA) response (50% vs 66.1%, multivariable weighted HR = 0.54; P = 0.03) and overall survival (median 7.9 vs 13.8 months, multivariable weighted HR = 2.19; P < 0.0001). CONCLUSIONS: LD docetaxel for mCRPC did not mitigate the risk of FN or ETC due to toxicity. Dose reduction may result in poorer PSA response and survival.

Outcomes for patients with synchronous and metachronous primary lung cancer after diagnosis of head and neck cancer.

BACKGROUND: Not-infrequently patients with head and neck cancer are also diagnosed with synchronous lung cancer or metachronous primary lung cancer, which complicates the treatment decisions and prognosis. METHODS: Patients were identified from a database of patients with head and neck cancer with second primary non-small cell lung cancer (NSCLC). RESULTS: Thirty-four eligible patients (15 with synchronous lung cancer and 19 with metachronous lung cancer) were identified. Thirteen of 15 patients with synchronous lung cancer received curative intent treatment for head and neck cancer first. Six of 15 patients were in complete remission, 5 of 15 patients had died, and 4 were alive with progressive disease. Median time between 2 diagnoses was 47 months in the metachronous lung cancer group. Twelve patients had died, 3 were alive with disease, and 4 were lost to follow-up. Median survival from the time of lung cancer diagnosis was 13 months with a trend to better survival with synchronous lung cancer (15 vs 11 months; p = .11). CONCLUSION: Aggressive multidisciplinary management of second primary lung malignancies in patients with head and neck cancer can result in respectable long-term disease control particularly in patients with synchronous lung cancer. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1544-1549, 2017.

Efficacy and toxicity of PACEBOM chemotherapy in relapsed/refractory aggressive lymphoma in the rituximab era.

AIM: Relapsed/refractory (R/R) aggressive lymphoma outcomes are poor. There is no standard treatment. PACEBOM (prednisolone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine and methotrexate) has shown efficacy for several lymphoma subtypes in published reports. We evaluate PACEBOM+/-rituximab for R/R aggressive lymphomas in this millennium. METHODS: In this retrospective, single-center study, R/R aggressive lymphoma patients who received PACEBOM or its derivatives were identified from the pharmacy database. Demographic, treatment, toxicity and survival data were collected. RESULTS: A total of 37 eligible patients were identified. Histological subtypes included 20 Diffuse Large B-Cell Lymphoma (DLBCL), 10 T-Cell Lymphoma (TCL) and 7 Hodgkin lymphoma. All DLBCL patients had received prior rituximab. Thirty-one (84%) received second-line PACEBOM. Median number of cycles was six (1-6). Eighteen out of 20 B-cell lymphoma patients received R-PACEBOM. Overall response rate was 65%, 70% and 71% in patients with DLBCL, TCL and Hodgkin lymphoma respectively. Thirteen patients underwent autologous stem cell transplant post-PACEBOM. Median follow-up was 49 months (3-201). Most common grade 3-4 toxicities were neutropenia (46%), anemia (24%) and thrombocytopenia (16%). No additional toxicity was seen in patients who received rituximab. CONCLUSION: In this cohort, PACEBOM is active in R/R aggressive lymphoma with manageable toxicity and can be safely combined with rituximab. Outcomes were similar to reports of other salvage regimens. PACEBOM remains a suitable option for R/R aggressive lymphoma, in patients exposed to prior rituximab and those planned for autologous stem cell transplant.