Adherence with oral chemotherapy: results from a qualitative study of the behaviour and representations of patients and oncologists

REGNIER DENOIS V., POIRSON J., NOURISSAT A., JACQUIN J.‐P., GUASTALLA J. P. & CHAUVIN F. (2010) European Journal of Cancer Care
Adherence with oral chemotherapy: results from a qualitative study of the behaviour and representations of patients and oncologists Oral chemotherapy is increasingly used in oncology. Poor adherence, that is, non‐respect of medical advice about taking the therapy and surveillance of adverse effects, is the main risk associated with this administration route. Poor adherence may be explained by non‐adherence by the patient to the treatment, misunderstanding the advice or it could also reflect the poor adaptation of the healthcare team to a new administration route. Here we report the results from a qualitative study that aimed to describe and understand existing practice for capecitabine, an oral chemotherapy, which is used for the treatment of metastatic breast and colon cancer. We interviewed 42 patients who were receiving oral capecitabine in groups and individually as well as 10 prescribers. This study was carried out in two specialist cancer centres. The results showed a wide diversity in the prescribers' practices, who make decisions based on their experience of practice guidelines for intravenous chemotherapies. Although the results for the patients do not suggest deliberate non‐adherence, they show poor observance of the dose schedule. The most important result of this study is the patient's inability to identify and to report important signs of harmful toxicity.     

Adherence to oral antineoplastic agents by cancer patients: definition and literature review

Since the 1990s, oral chemotherapy has been gaining ground as cancer treatment. This therapy seems to have few toxic effects and offers patients good quality of life. However, in addition to the fears the therapy might generate in patients, oral treatment raises a new issue, which, until now, has been marginal in this field: therapeutic observance or adherence. We investigated the research into adherence to oral chemotherapy among cancer patients published between 1990 and July 2013. Studies showed considerable diversity in terms of both the definition and measurement of adherence. As well, adherence to antineoplastic therapy is affected by the patient's understanding of the treatment and ability to remember information provided by the physician, treatment length and psychological distress. Our review of the few studies on adherence to anticancer drug treatment raises some questions that could be pursued in future research. In light of our findings, patients should receive ‘therapy education’ to help them and their support groups better understand the disease and its treatment and to achieve optimal health management and improved treatment effectiveness.     

Effective oral chemotherapy for breast cancer: pillars of strength.

Traditionally, anticancer therapy has been dominated by intravenous drug therapy. However, oral agents provide an attractive approach to chemotherapy and use of oral treatments is increasing. We discuss the benefits and challenges of oral chemotherapy from the perspectives of patients, healthcare providers and healthcare funders. Important issues include patient preference, efficacy, compliance, bioavailability, reimbursement, use in special patient populations, financial and staff time savings and flexibility of dosing. We review data for traditional oral agents (e.g. cyclophosphamide, methotrexate), newer oral chemotherapies (e.g. capecitabine), oral formulations of traditionally intravenous agents (e.g. vinorelbine, idarubicin) and new biologic agents under evaluation in breast cancer (e.g. tyrosine kinase inhibitors). Lastly, we review studies of all-oral combination regimens. The wealth of data available and the increasing use of oral agents in breast cancer suggest that many of the concerns and perceptions about oral therapy, including efficacy and bioavailability, have been overcome, and that oral therapy will play a major role in breast cancer management in the future in both the metastatic and adjuvant settings.     

Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial

BackgroundFirst-line treatment of isolated resectable colorectal peritoneal metastases remains unclear. This study (the Swedish peritoneal study) compares cytoreductive surgery and intraperitoneal chemotherapy (surgery arm) with systemic chemotherapy (chemotherapy arm).MethodsPatients deemed resectable preoperatively were randomised to surgery and intraperitoneal 5-fluorouracil 550 mg/m²/d for 6 d with repeated courses every month or to systemic oxaliplatin and 5-fluorouracil regimen every second week. Both treatments continued for 6 months. Primary end-point was overall survival (OS) and secondary end-points were progression-free survival (PFS), and morbidity.ResultsThe study terminated prematurely when 48 eligible patients (24/arm) were included due to recruitment difficulties. Two-year OS was 54% in the surgery arm and 38% in the chemotherapy arm (p = 0.04). After 5 years, 8 versus 1 patient were alive, respectively (p = 0.02). Median OS was 25 months versus 18 months, respectively, hazard ratio 0.51 (95% confidence interval: 0.27–0.96, p = 0.04). PFS in the surgery arm was 12 months versus 11 months in the chemotherapy arm (p = 0.16) with 17% versus 0% 5-year PFS. Grade III–IV morbidity was seen in 42% and 50% of the patients, respectively. No mortalities.ConclusionsCytoreductive surgery with intraperitoneal chemotherapy may be superior to systemic oxaliplatin-based treatment of colorectal cancer with resectable isolated peritoneal metastases.(ClinicalTrials.gov nr:NCT01524094).     

Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial

Patients with high-risk endometrial carcinoma (stage IcG3, IIG3 with myometrial invasion >50%, and III) receive adjuvant therapy after surgery but it is not clear whether radiotherapy (RT) or chemotherapy (CT) is better. We randomly assigned 345 patients with high-risk endometrial carcinoma to adjuvant CT (cisplatin (50 mg m(-2)), doxorubicin (45 mg m(-2)), cyclophosphamide (600 mg m(-2)) every 28 days for five cycles, or external RT (45-50 Gy on a 5 days week(-1) schedule). The primary end points were overall and progression-free survival. After a median follow-up of 95.5 months women in the CT group as compared with the RT group, had a no significant hazard ratio (HR) for death of 0.95 (95% confidence interval (CI), 0.66-1.36; P = 0.77) and a nonsignificant HR for event of 0.88 (95% CI, 0.63-1.23; P = 0.45). The 3, 5 and 7-year overall survivals were 78, 69 and 62% in the RT group and 76, 66 and 62% in the CT group. The 3, 5 and 7-year progression-free survivals were, respectively, 69, 63 and 56 and 68, 63 and 60%. Radiotherapy delayed local relapses and CT delayed metastases but these trends did not achieve statistical significance. Overall, both treatments were well tolerated. This trial failed to show any improvement in survival of patients treated with CT or the standard adjuvant radiation therapy. Randomised trials of pelvic RT combined with adjuvant cytotoxic therapy compared with RT alone are eagerly awaited.     

A randomised trial comparing preoperative to perioperative chemotherapy in early-stage non-small-cell lung cancer (IFCT 0002 trial)

HypothesisThere will be a detectable increase in overall survival (OS) using preoperative (PRE) as opposed to perioperative (PERI) chemotherapy in resectable Stage I–II non-small-cell lung cancer (NSCLC).MethodsThis multicenter, open-label, randomised trial with a 2 × 2 factorial design first compared two chemotherapy strategies (PRE versus PERI), then two chemotherapy regimens (gemcitabine–cisplatin [GP] versus paclitaxel–carboplatin [TC]). The PRE group received two preoperative cycles followed by two additional preoperative cycles, while the PERI group underwent two preoperative cycles followed by two postoperative cycles, the 3rd and 4th cycles being given only to responders in both cases.ResultsA total of 528 patients were randomised, 267 of which were assigned to the PRE group and 261 to the PERI group. Three-year OS did not differ between the two groups (67.4% and 67.7%, respectively; hazard ratio (HR) = 1.01 [0.79–1.30], p = 0.92), nor did 3-year disease-free survival, response rates, toxicity, or postoperative mortality. Pathological complete response was observed in 22 (8.2%) and 16 patients (6.1%), respectively. Although quality of life did not differ significantly, chemotherapy compliance was significantly higher in the PRE group. The proportion of responders who received Cycles 3 and 4 was significantly higher in the PRE group (90.4% versus 75.2%, p = 0.001). In responders, the dose intensity of Cycles 3 and 4 was higher in the PRE group than in the PERI group (mean relative dose intensity of 90.4% versus 82.6%, respectively; p = 0.0007). There was no difference between GP and TC in 3-year OS (HR = 0.97 [95% confidence interval (CI): 0.76–1.25], p = 0.80) or response rates. However, the regimens’ toxicity profiles differed.ConclusionsThis study failed to demonstrate any difference in survival between patients receiving preoperative and perioperative chemotherapy in early-stage NSCLC. The increase from two to four preoperative chemotherapy cycles did not increase the pathological response rate.     

Intra-arterial induction high-dose chemotherapy with cisplatin for oral and oropharyngeal cancer: long-term results

Intra-arterial (IA) chemotherapy for curative treatment of head and neck cancer experienced a revival in the last decade. Mainly, it was used in concurrent combination with radiation in organ-preserving settings. The modern method of transfemoral approach for catheterisation, superselective perfusion of the tumour-feeding vessel, and high-dose (150 mg x m(-2)) administration of cisplatin with parallel systemic neutralisation with sodium thiosulphate (9 g x m(-2)) made preoperative usage feasible. The present paper presents the results of a pilot study on a population of 52 patients with resectable stage 1-4 carcinomas of the oral cavity and the oropharynx, who were treated with one cycle of preoperative IA chemotherapy executed as mentioned above and radical surgery. There have been no interventional complications of IA chemotherapy, and acute side effects have been low. One tracheotomy had to be carried out due to swelling. The overall clinical local response has been 69%. There was no interference with surgery, which was carried out 3-4 weeks later. Pathological complete remission was assessed in 25%. The mean observation time was 3 years. A 3-year overall and disease-free survival was 82 and 69%, respectively, and at 5 years 77 and 59%, respectively. Survival results were compared to a treatment-dependent prognosis index for the same population. As a conclusion, it can be stated that IA high-dose chemotherapy with cisplatin and systemic neutralisation in a neoadjuvant setting should be considered a feasible, safe, and effective treatment modality for resectable oral and oropharyngeal cancer. The low toxicity of this local chemotherapy recommends usage especially in stage 1-2 patients. The potential of survival benefit as indicated by the comparison to the prognosis index should be controlled in a randomised study.     

Randomized, placebo-controlled trial of Saforis for prevention and treatment of oral mucositis in breast cancer patients receiving anthracycline-based chemotherapy

BACKGROUND: Oral mucositis (OM) is a frequent complication of mucotoxic cancer therapy, causing significant oral pain, increased infection risk, and impaired functioning. The efficacy and safety of Saforis (glutamine) powder in UpTec for oral suspension was evaluated for the prevention and treatment of OM. METHODS: Three hundred twenty-six patients developing World Health Organization (WHO) grade >or=2 OM during a chemotherapy screening cycle were randomized to Saforis (n = 163) or placebo (n = 163) 3 times/day during their next chemotherapy cycle (Treatment Cycle 1). Patients were crossed over to the alternate treatment during Treatment Cycle 2. As prespecified in the statistical plan, because of a carryover effect in Treatment Cycle 2 the primary efficacy analysis was based on Treatment Cycle 1 only. RESULTS: Compared with placebo, Saforis significantly reduced the incidence of clinically significant WHO grade >or=2 OM (38.7% vs. 49.7%; P = .026) and severe WHO grade >or=3 OM (1.2% vs. 6.7%; P = .005) in Treatment Cycle 1. Saforis also significantly reduced the worst Oral Mucositis Assessment Scale ulceration score in Treatment Cycle 1 compared with placebo (mean, 0.23 +/- 0.39 vs. 0.32 +/- 0.45; P = .013). Patients receiving Saforis in Treatment Cycle 1 had a lower-than-expected OM incidence when crossed over to placebo in Treatment Cycle 2, indicating a significant carryover effect (P = .027). The incidence of treatment-emergent adverse events was similar between groups. CONCLUSIONS: Saforis is safe and effective for preventing and treating OM in patients receiving mucotoxic cancer chemotherapy.     

放、化疗联合治疗晚期宫颈癌的临床研究

目的探讨放疗与化疗何种联合方式治疗晚期宫颈癌最佳. 方法 86例Ⅲ和Ⅳ期宫颈癌患者用信封法随机分为2组,每组各43例（Ⅲ期各26例,Ⅳ期各17例）一组采用诱导化疗,另一组为同步放化疗,两组放疗方法、时间、剂量和分割均相同.外照射给予50Gy/5周,A点腔内后装治疗36～42 Gy/6～7次.诱导化疗组于放疗前先行PF方案化疗2周期,放疗在化疗结束后2周开始;同步放化疗组在放疗期间共进行PF方案化疗2周期.PF方案：顺铂 （DDP）25～30mg/m2/d,静脉注射,连用3 天;5-氟尿嘧啶（5-Fu）500 mg /m2/d,静脉滴注,连用5 天.结果放射治疗结束后3个月两组肿瘤消退相比有显著性差异（P〈0.05）, 诱导化疗组和同步放化疗组有效率分别为74.42%（32/43）和90.70%（39/43）. 放射治疗结束后3年生存率、局部控制率, 两组相比差异有显著性（P〈0.05）. 诱导化疗组分别为58.14% （25/43）和65.12%（28/43）,同步放化疗组分别为79.07%（34/43）和83 .72%（36/43）.同步放化疗组毒副作用较诱导化疗组重,但未影响放疗进程.结论晚期宫颈癌的放、化疗联合方式中同步放化疗要优于诱导化疗.     

Systematic versus on-demand early palliative care: results from a multicentre,randomised clinical trial

BackgroundEarly palliative care (EPC) in oncology has been shown to have a positive impact on clinical outcome, quality-of-care outcomes, and costs. However, the optimal way for activating EPC has yet to be defined.MethodsThis prospective, multicentre, randomised study was conducted on 207 outpatients with metastatic or locally advanced inoperable pancreatic cancer. Patients were randomised to receive ‘standard cancer care plus on-demand EPC’ (n = 100) or ‘standard cancer care plus systematic EPC’ (n = 107). Primary outcome was change in quality of life (QoL) evaluated through the Functional Assessment of Cancer Therapy – Hepatobiliary questionnaire between baseline (T0) and after 12 weeks (T1), in particular the integration of physical, functional, and Hepatic Cancer Subscale (HCS) combined in the Trial Outcome Index (TOI). Patient mood, survival, relatives' satisfaction with care, and indicators of aggressiveness of care were also evaluated.FindingsThe mean changes in TOI score and HCS score between T0 and T1 were −4.47 and −0.63, with a difference between groups of 3.83 (95% confidence interval [CI] 0.10–7.57) (p = 0.041), and −2.23 and 0.28 (difference between groups of 2.51, 95% CI 0.40–4.61, p = 0.013), in favour of interventional group. QoL scores at T1 of TOI scale and HCS were 84.4 versus 78.1 (p = 0.022) and 52.0 versus 48.2 (p = 0.008), respectively, for interventional and standard arm. Until February 2016, 143 (76.9%) of the 186 evaluable patients had died. There was no difference in overall survival between treatment arms.InterpretationsSystematic EPC in advanced pancreatic cancer patients significantly improved QoL with respect to on-demand EPC.     

Phase II trial of the oral platinum complex JM216 in non-small-cell lung cancer: An EORTC early clinical studies group investigation

Background: JM216 is a new oral platinum complex with dose-limitingtoxicity myelosuppresssion, now undergoing phase II evaluation.Patients and methods: JM216 was evaluated as first line therapy innon-small-cell lung cancer. 17 patients received 120 mg/m²/dayfor five days repeated every three weeks.Results: Toxicity was manageable, the commonest side-effects being nausea,vomiting, diarrhoea, constipation and asthenia. Myelososuppression wasgenerally grade <2 and there were no cases of neutropenic sepsis orbleeding. Thirteen patients were fully evaluable for response. No sustainedobjective responses were reported. One patient was reported as stable diseasehad a partial response after three courses but was progressing again afterfour. An additional five patients had stable disease (46.2%).Conclusions: Although some patients may have had useful palliation, JM216did not appear to have significant antitumour activity in non-small-cell lungcancer.     

The effectiveness of commonly used mouthwashes for the prevention of chemotherapy-induced oral mucositis: a systematic review

Daily chlorhexidine mouthwash is often recommended for preventing chemotherapy-induced oral mucositis. Povidone-iodine, NaCl 0.9%, water salt soda solution and chamomile mouthwash are also recommended. However, the effectiveness of these mouthwashes is unclear. Therefore, we performed a systematic review to assess the effectiveness of mouthwashes in preventing and ameliorating chemotherapy-induced oral mucositis. Based on study quality, three out of five randomized controlled trials were included in a meta-analysis. The results failed to detect any beneficial effects of chlorhexidine as compared with sterile water, or NaCl 0.9%. Patients complained about negative side-effects of chlorhexidine, including teeth discoloration and alteration of taste in two of the five studies on chlorhexidine. The severity of oral mucositis was shown to be reduced by 30% using a povidone-iodine mouthwash as compared with sterile water in a single randomized controlled trial. These results do not support the use of chlorhexidine mouthwash to prevent oral mucositis.     

A phase III randomised trial comparing sequential chemotherapy using cisplatin-based regimen and paclitaxel to cisplatin-based chemotherapy alone in advanced non-small-cell lung cancer.

BACKGROUND: The purpose of this study is to determine whether in advanced non-small-cell lung cancer (NSCLC), the sequential administration of cisplatin-based chemotherapy and paclitaxel (Taxol) is superior to a cisplatin-based chemotherapy, followed by paclitaxel as salvage treatment. PATIENTS AND METHODS: A total of 485 chemotherapy naive patients with advanced NSCLC were treated with three courses of GIP (gemcitibine + ifosfamide + cisplatin), consisting of cisplatin 50 mg/m(2) on day 1, ifosfamide 3 g/m(2) on day 1 and gemcitabine 1 g/m(2) on days 1 and 8. Patients with nonprogressive disease were then randomised to further similar courses of GIP or courses of paclitaxel (225 mg/m(2) over 3 h every 3 weeks). RESULTS: Objective response or nonprogression after induction GIP occurred in 174 and 115 patients, respectively. After randomisation, there were 140 patients in the GIP arm and 141 in the paclitaxel arm. In terms of postrandomisation survival, there was no statistically significant difference (P = 0.17) between the two arms. Median times were 9.7 [95% confidence interval (CI) 7.8-11.6] and 11.9 (95% CI 9.4-14.3) months for paclitaxel and GIP, respectively. Multivariate analysis demonstrated that sex and haemoglobin were independent prognostic factors. After adjustment for these factors, the observed hazard ratio was 0.81 (95% CI 0.63-1.04) in favour of GIP (P = 0.10). Toxicity was tolerable; there was a significantly higher rate of grades III/IV thrombocytopenia with GIP and more alopecia with paclitaxel. CONCLUSION: Sequential chemotherapy using cisplatin-based regimen followed by paclitaxel does not result in better outcome than cisplatin-based chemotherapy using taxane as salvage treatment.     

Participants' uptake of clinical trial results: a randomised experiment

Background:

It is unknown whether breast cancer (BC) characteristics among young women treated with radiotherapy (RT) for Hodgkin''s lymphoma (HL) differ from sporadic BC.

Methods:

Using population-based data, we calculated BC risk following HL according to clinicopathologic features.

Results:

Compared with BC in the general population, risks of oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive and ER-negative/PR-negative BC in young, irradiated HL survivors were increased five-fold (95% confidence interval (CI)=3.81–6.35) and nine-fold (95% CI=6.93–12.25), respectively. Among 15-year survivors, relative risk of ER-negative/PR-negative BC exceeded by two-fold (P=0.002) than that of ER-positive/PR-positive BC.

Conclusion:

Radiotherapy may disproportionately contribute to the development of BC with adverse prognostic features among young HL survivors.     

A three-arm phase III randomised trial assessing, in patients with extensive-disease small-cell lung cancer, accelerated chemotherapy with support of haematological growth factor or oral antibiotics.

The European Lung Cancer Working Party (ELCWP) designed a 3-arm phase III randomised trial to determine the role of accelerated chemotherapy in extensive-disease (ED) small-cell lung cancer (SCLC). Eligible patients were randomised between the 3 following arms: (A) Standard chemotherapy with 6 courses of EVI (epirubicin 60 mg m(-2), vindesine 3 mg m(-2), ifosfamide 5 g m(-2); all drugs given on day 1 repeated every three weeks. (B) Accelerated chemotherapy with EVI administered every 2 weeks and GM-CSF support. (C) Accelerated chemotherapy with EVI and oral antibiotics (cotrimoxazole). Primary endpoint was survival. 233 eligible patients were randomised. Chemotherapy could be significantly accelerated in arm B with increased absolute dose-intensity. Best response rates, in the population of evaluable patients, were, respectively for arm A, B and C, 59%, 76% and 70%. The response rate was significantly higher in arm B in comparison to arm A (P = 0.04). There was, however, no survival difference with respective median duration and 2-year rate of 286 days and 5% for arm A, 264 days and 6% for arm B and 264 days and 6% for arm C. Severe thrombopenia occurred more frequently in arm B but without an increased rate of bleeding. Non-severe infections were more frequent in arm B and severe infections were less frequent in arm C. Our trial failed to demonstrate, in ED-SCLC, a survival benefit of chemotherapy acceleration by using GM-CSF support.     

The potential for oral combination chemotherapy of 5'-deoxy-5-fluorouridine, a 5-FU prodrug, and cyclophosphamide for metastatic breast cancer

Preclinical studies have demonstrated the synergistic anti-tumour activity of combination therapy with the oral cytostatics, 5'-deoxy-5-fluorouridine (5'-DFUR) and cyclophosphamide (CPA), in human breast cancer xenograft models. This study was performed to evaluate the efficacy and safety of this oral combination chemotherapy in the treatment of metastatic breast cancer. In all, 101 patients with metastatic breast cancer were enrolled in the study, and the data for 94 eligible patients of these were evaluated. The patients received twice daily oral combinations of 5'-DFUR (1200 mg/body/day) and CPA (100 mg/body/day) for 2 weeks, followed by a 1-week rest period. After a median of 19 treatment cycles (range 1-66 cycles), 16 patients (17.0%) had a complete response, and 40 patients (42.6%) had partial responses. The response rate was 59.6% (95% CI, 49.0-69.6%). The median time to progression and overall survival times were 11.7 and 40.3 months, respectively. The toxicity was mild and tolerable, and the related grade 3/4 clinical adverse effects consisted of haematological toxicity in 21 patients (22%) and nonhaematological toxicity in five patients (5%). These results suggest that the oral combination chemotherapy of 5'-DFUR and CPA has low toxicity and is a novel, very convenient and effective treatment for metastatic breast cancer.     

Oral mucositis and selective elimination of oral flora in head and neck cancer patients receiving radiotherapy: a double-blind randomised clinical trial

Mucositis is an acute inflammation of the oral mucosa because of radiotherapy and/or chemotherapy. All patients receiving radiotherapy in the head and neck region develop oral mucositis. The aim of this study was to analyse the effects of selective oral flora elimination on radiotherapy-induced oral mucositis, in a double-blind, randomised, placebo-controlled trial. Sixty-five patients with a malignant tumour in the head and neck regions to be treated with primary curative or postoperative radiotherapy participated in this study. The patients received either the active lozenges of 1 g containing polymyxin E 2 mg, tobramycin 1.8 mg and amphotericin B 10 mg (PTA) (33 patients) or the placebo lozenges (32 patients), four times daily during the full course of radiotherapy. Mucositis, changes in the oral flora, quality of feeding and changes of total body weight were assessed. Mucositis score did not differ between the groups during the first 5 weeks of radiotherapy. Nasogastric tube feeding was needed in six patients (19%) of the placebo group and two patients (6%) of the PTA group (P=0.08). Mean weight loss after 5 weeks of radiation was less in the PTA group (1.3 kg) (s.d.: 3.0) than in the placebo group (2.8 kg) (s.d.: 2.9) (P=0.05). Colonisation index of Candida species and Gram-negative bacilli was reduced in the PTA group and not in the placebo group (P<0.05). No effect on other microorganisms was detected. In conclusion, selective oral flora elimination in head and neck irradiation patients does not prevent the development of severe mucositis.