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ObjectiveTo evaluate the effectiveness of remote proactive management of toxicities during chemotherapy for early stage breast cancer.DesignPragmatic, cluster randomised trial.Setting20 cancer centres in Ontario, Canada, allocated by covariate constrained randomisation to remote management of toxicities or routine care.ParticipantsAll patients starting adjuvant or neoadjuvant chemotherapy for early stage breast cancer at each centre. 25 patients from each centre completed patient reported outcome questionnaires.InterventionsProactive, standardised, nurse led telephone management of common toxicities at two time points after each chemotherapy cycle.Main outcome measuresThe primary outcome, cluster level mean number of visits to the emergency department or admissions to hospital per patient during the whole course of chemotherapy treatment, was evaluated with routinely available administrative healthcare data. Secondary patient reported outcomes included toxicity, self-efficacy, and quality of life.ResultsBaseline characteristics of participants were similar in the intervention (n=944) and control arms (n=1214); 22% were older than 65 years. Penetration (that is, the percentage of patients who received the intervention at each centre) was 50-86%. Mean number of visits to the emergency department or admissions to hospital per patient was 0.91 (standard deviation 0.28) in the intervention arm and 0.94 (0.40) in the control arm (P=0.94); 47% (1014 of 2158 patients) had at least one visit to the emergency department or a hospital admission during chemotherapy. Among 580 participants who completed the patient reported outcome questionnaires, at least one grade 3 toxicity was reported by 48% (134 of 278 patients) in the intervention arm and by 58% (163 of 283) in the control arm. No differences in self-efficacy, anxiety, or depression were found. Compared with baseline, the functional assessment of cancer therapy trial outcome index decreased by 6.1 and 9.0 points in the intervention and control participants, respectively.ConclusionsProactive, telephone based management of toxicities during chemotherapy did not result in fewer visits to the emergency department or hospital admissions. With the rapid rise in remote care because of the covid-19 pandemic, identifying scalable strategies for remote management of patients during cancer treatment is particularly relevant.Trial registrationClinicalTrials.govNCT02485678.

Citrus juices have many chemical components, we have shown to have anticancer properties, in vitro and in vivo. The principle agents investigated were the citrus limonoids: limonin, nomilin, and a limonoid glucoside mixture and the bioflavonoids: nobiletin, tangeretin, hesperetin and naringenin. Both sets of compounds were found to be potent inhibitors of cellular proliferation in estrogen receptor-negative (ER-) and -positive (ER+) cell lines. They were also found to act independently of the estrogen receptor. The bioflavonoids were shown to inhibit the growth of xenografted tumours in the nude mouse model. The effect of the limonoids in the treatment of an already established tumour in nude mice was investigated at their maximum tolerated dose. From histological analysis of mouse mammary tumours and cellular proliferation data it appeared that increased cell death was occurring. Therefore, to identify a mechanism of action for these compounds a FACS analysis was performed on cells treated with bioflavonoids and limonoids. Hesperetin, a bioflavonoid found in orange juice, induced apoptosis in MDA-MB 435 ER- cells. Naringenin from grapefruit juice had no effect. A limonoid glucoside mixture was also found to increase cell death, but the mode of action is still yet unclear.

Thirty-seven patients with intracranial primary or metastatic tumors were treated with an intraarterial combination of BCNU, cisplatin, and VM-26 to determine the efficacy, toxicity, and maximal tolerated doses for the combination. A transfemoral fluoroscopic approach was used to catheterize temporarily the internal carotid or vertebral artery. Thirteen of 19 (68%) evaluable primary brain tumors and 9 of 16 (56%) evaluable brain metastases responded. The response rate was lower in patients previously treated with both cranial irradiation and i.v. chemotherapy than in patients less heavily pretreated (54% vs. 82%), although even patients previously treated i.v. with all three of the study drugs responded. All five patients with both extracranial and intracranial evaluable tumor deposits experienced a greater response of their intracranial than of their extracranial tumor. Ipsilateral retinal and neurological toxicity were dose-limiting, with major toxicity (permanent decreased vision or hemiparesis) occurring in five of nine (56%) patients receiving doses of BCNU ≥ 100 mg/m2, plus cisplatin, 60 mg/m2, plus VM-26, 175 mg/m2. Only 9% of the patients treated with a lower VM-26 dose developed permanent severe toxicity, and the doses that we now recommend are: BCNU, 100 mg/m2; cisplatin, 60 mg/m2; and VM-26, 150 mg/m2. The response rate was also dose-related (100% at the highest doses tested vs. 57% at the lower doses). Fully reversible toxicity was also seen, including transient decrease in ipsilateral visual acuity (11%), transient hemiparesis or hemianesthesia (5%), transient increased intracranial pressure (5%), mild ototoxicity (3%), mild to moderate vomiting (80%), severe periorbital pain and erythema during BCNU infusion (94%), and myelosuppression (30%). Vertebral artery infusion must be performed with great caution because infusions of BCNU and VM-26 (but not of cisplatin) were associated with marked but rapidly reversible somnolence and potentially life-threatening cardiac and respiratory depression. No cardiorespiratory depression was seen with carotid artery infusions. The intraarterial infusion of this three-drug regimen is quite effective in reducing the size of the tumor as seen on the computed tomographic scan in this poor prognosis group of patients, but is also potentially quite toxic. We are now initiating other studies adding i.v. drugs to our intracarotid combination.