Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial.

BACKGROUND: This multicentre, randomised, double-blinded, placebo-controlled, phase II/III trial aimed to evaluate an oral THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract for prevention of refractory chemotherapy-induced nausea and vomiting (CINV). Here we report the phase II component results. PATIENTS AND METHODS: Eligible patients experienced CINV during moderate-to-high emetogenic intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Study treatment consisted of one cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) three times daily, from days -1 to 5, and 1 cycle of matching placebo in a crossover design, then blinded patient preference for a third cycle. The primary end point was the proportion of participants with complete response during 0-120 h from chemotherapy. A total of 80 participants provided 80% power to detect a 20% absolute improvement with a two-sided P value of 0.1. RESULTS: A total of 81 participants were randomised; 72 completing two cycles were included in the efficacy analyses and 78 not withdrawing consent were included in safety analyses. Median age was 55 years (range 29-80 years); 78% were female. Complete response was improved with THC:CBD from 14% to 25% (relative risk 1.77, 90% confidence interval 1.12-2.79, P = 0.041), with similar effects on absence of emesis, use of rescue medications, absence of significant nausea, and summary scores for the Functional Living Index-Emesis (FLIE). Thirty-one percent experienced moderate or severe cannabinoid-related adverse events such as sedation, dizziness, or disorientation, but 83% of participants preferred cannabis to placebo. No serious adverse events were attributed to THC:CBD. CONCLUSION: The addition of oral THC:CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC:CBD to placebo. Based on these promising results, we plan to recruit an additional 170 participants to complete accrual for the definitive, phase III, parallel group analysis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001036404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370473&isReview=true.

A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial.

BACKGROUND: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. PATIENTS AND METHODS: Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. RESULTS: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. CONCLUSION: The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.

Optimal management of nausea and vomiting in clinical oncology.

The exact mechanisms involved in chemotherapy-induced nausea and vomiting are not known. Therapies are largely empiric. There is no completely effective single agent or even combination-agent regimen. This paper identifies important factors in selecting antiemetic therapy, particularly the emetogenic potential of the chemotherapy and the fact that antiemetic drugs have differing sites of action. Regarding acute emesis, great strides have been made in the 1980s. Anticipatory and delayed symptoms remain a challenge and are a focus of this article. A key in the timing of pharmacologic intervention is pinpointed in each of these situations.

Evaluation of serum galactomannan detection for diagnosis of feline upper respiratory tract aspergillosis.

Measurement of serum galactomannan (GM), a polysaccharide fungal cell-wall component, is a non-invasive test for early diagnosis of invasive aspergillosis in humans. Feline upper respiratory tract (URT) aspergillosis is an emerging infectious disease in cats. Diagnosis requires biopsy for procurement of tissue specimens for cytological or histological detection of fungal hyphae and for fungal culture. The aim of this study was to evaluate serum GM measurement as a non-invasive diagnostic test for URT aspergillosis in cats. A one-stage, immunoenzymatic sandwich ELISA was used to detect serum GM in 4 groups of cats; Group 1 (URT aspergillosis) - confirmed URT aspergillosis (n=13, sinonasal aspergillosis (SNA) n=6 and sino-orbital aspergillosis (SOA) n=7), Group 2 (URT other) - other URT diseases (n=15), Group 3 (ß-lactam) - cats treated with ß-lactam antibiotics for non-respiratory tract disease (n=14), Group 4a - healthy young cats (≤ 1 y of age, n=28), Group 4b - healthy adult cats (>1 y of age, n=16). One cat with SNA and two cats with SOA caused by an Aspergillus fumigatus-mimetic species, tested positive for serum GM. For a cut-off optical density index of 1.5, the overall sensitivity and specificity of the assay was 23% and 78% respectively. False positive results occurred in 29% of cats in Group 3 and 32% of cats in Group 4a. Specificity increased to 90% when Groups 3 and 4a were excluded from the analysis. Overall, serum GM measurement has a poor sensitivity but is a moderately specific, non-invasive screening test to rule out infection in patients with suspected feline upper respiratory tract aspergillosis.

Histopathological and immunohistochemical evaluation of 53 cases of feline lymphoplasmacytic enteritis and low-grade alimentary lymphoma.

Low-grade alimentary lymphoma (LGAL) is a recently described entity displaying many microscopical features similar to lymphoplasmacytic enteritis (LPE). The aim of this study was to review the histopathological and immunohistochemical features of LPE and LGAL to determine if specific features are useful in distinguishing between these disorders. Fifty-three cases of LPE (n=24) or LGAL (n=29) were recruited retrospectively and prospectively. Of the 24 cases of LPE, 12 were mild, seven were moderate and five were marked in severity. The ileum and jejunum were the most common sites affected for both LGAL and LPE (70-90% of cases). Involvement of the stomach was more common with LPE (29%) than LGAL (7%) (P<0.0001). Twelve cases of LGAL (41%) had evidence of concurrent LPE. Microscopical features significantly associated with LGAL were epitheliotropism, involvement of the muscularis propria and/or serosa, more severe infiltration and more severe changes to the villus and crypt architecture. Plasma cell infiltration within the mucosa, conversely, was a feature of LPE. Twenty-eight of the 29 cases of LGAL were of T-cell phenotype. While many LGAL and most LPE cases had a mixed infiltrate of T and B lymphocytes, LGAL cases had a clear predominance of the T-cell phenotype. Expression of class II molecules of the major histocompatibility complex by enterocytes did not differentiate between LGAL and LPE. In eight of 12 cases of moderate-marked LPE there was disparity in diagnosis by two pathologists regarding differentiation from LGAL, requiring assessment by a third pathologist to reach a consensus diagnosis. This demonstrates the inherent difficulty in differentiating LPE from LGAL on the basis of microscopical and immunohistochemical features alone. Other diagnostic tools such as clonality testing may assist in the definitive diagnosis of such cases.

cis-Dichlorodiammineplatinum(II) and adriamycin treatment of advanced ovarian cancer.

Treatment with a combination of adriamycin (ADM) and cis-dichlorodiammineplatinum(II) (DDP) has been evaluated in 24 patients with advanced ovarian cancer. Twenty patients had received prior chemotherapy and/or radiation therapy. Objective remissions were seen in ten patients. The usual toxic manifestations of ADM and DDP were observed. It is concluded that the combination is effective therapy for ovarian cancer. Further investigation of this combination versus single agents is warranted.

Phase II study of diglycoaldehyde in malignant melanomas and soft tissue sarcomas.

A phase II study of diglycoaldehyde was conducted in 42 patients with malignant melanoma and soft tissue sarcoma. All patients received diglycoaldehyde at a dose of 2 g/m2 iv over 6 hours daily for 3 days. This was repeated every 28 days. Major toxic effects included phlebitis and azotemia, requiring dialysis in one patient. Of the 42 patients, 38 were evaluable for response. One objective response occurred in a patient with malignant melanoma. Diglycoaldehyde at this dose and schedule appears to have no role in the management of malignant melanoma or soft tissue sarcoma.