Unplanned Treatment Interruptions Research Articles

532P Hypomagnesemia induced by cetuximab and panitumumab

Background Anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been widely used as a standard care for Ras wild-type mCRC. Besides skin toxicity and mucosal damage, hypomagnesemia is also well known as its specific adverse effects. Hypomagnesemia can be a cause of malaise, appetite loss and arrhythmia, and result in unplanned treatment interruptions including dose reduction or treatment delay in severe cases. To investigate the occurrence and severity of hypomagnesemia in the use of anti-EGFR antibody drugs, we concluded a retrospective analysis. Methods Serum magnesium tests along with other blood tests at each treatment were performed. The incidence of hypomagnesemia, administration period and association with other adverse effects were analyzed. Collection of magnesium was started when grade 2 or higher level was identified according to CTCAE-Ver4. Results From January 2011 to January 2016, 93 patients were treated with cetuximab or panitumumab in our hospital. The overall occurrence of hypomagnesemia was observed in 66 patients (71%); grade 1, 2, 3 were 39.8%, 23.7%, and 7.5%, respectively. The median period until the onset of hypomagnesemia in grade 2-3 was earlier than grade 1{43 days (14-439) v.s. 63 days (14-491)}. The median treatment duration was 174 days (35-719) in grade 2-3 and 107.5 days (13-559) in grade 0-1; thus, the administration period was longer in the severe cases. Acne-like skin rash was observed more frequently with hypomagnesemia than without hypomagnesemia (45.5% v.s. 14.8%). Any other association was not observed in terms of adverse events. Conclusions Our data revealed incidence of hypomagnesemia was frequent. There was a correlation between severity of hypomagesemia and treatment duration, hypomanesemia may be a predictive marker of anti-EGFR monoclonal antibody. Monitoring and adjustment of hypomanesemia should be performed. Legal entity responsible for the study Aizawa Hospital Funding Aizawa Hospital Disclosure T. Onikubo, M. Nakamura, M. Furukawa, A. Miura: There is no interest should be disclosed. K. Nakamura, K. Tauchi: There is no interest should be disclosed

Oral Epigallocatechin-3-Gallate Treats Acute Radiation-Induced Esophagitis in Patients With Esophageal Cancer Receiving Chemoradiation Therapy/Radiation Therapy

Patients with esophageal cancer receiving definitive chemo-radiation therapy/radiation therapy often develop acute radiation-induced esophagitis (ARIE) that may interference with quality of life and lead to unplanned treatment interruptions. Our previous trials preliminarily showed that EGCG could be a promising strategy in the treatment of ARIE when esophagus received low dose radiation (mean dose, 14.9Gy) in lung cancer. We hypothesize that EGCG is safe and effective in treating ARIE in esophageal cancer patients with higher mean esophagus dose. All the patients underwent three dimensional conformal or intensity modulation radiated therapy (total dose, 50.4-60Gy). Eligible patients were also required to have met the following criteria: age≥18 years; ECOG PS 0-1; no prior radiation to the thorax; concurrent chemo-radiotherapy or radiotherapy only. EGCG was administrated once ARIE appeared. EGCG was given with the concentration of 440μmol/L during radiotherapy and additionally 2 weeks after radiotherapy. RTOG score, dysphasia and pain related to esophagitis were recorded every week. Thirty-seven patients with stage IIB and III esophageal cancer were enrolled in this study. 81.1% patients received concurrent chemotherapy. Two cases stopped the radiotherapy because of arrest of bone marrow or infection, thus EGCG treatment was also stopped. Other 4 cases also stopped EGCG treatment because of their personal reasons. The median dose of the appearance of ARIE was 28Gy (range, 12–48 Gy). In comparison to the original, the RTOG score in the 1st, 2nd, 3rd, 4th, 5th week after EGCG prescription and the 1st, 2nd week after radiotherapy decreased significantly (P = 0.161, 0.012, 0.022, 0.042, 0.076, 0.000, 0.000, respectively). The pain score of each week was significantly lower than the baseline (P = 0.000, 0.000, 0.000, 0.000, 0.012, 0.000, 0.000, respectively). The EGCG solution was generally well-tolerated, but most patients complained of its nauseating taste. Complete response after chemoradiotherapy/radiotherapy for esophageal cancer obtained in 4 patients, partial response in thirteen, stable disease in thirteen, and progression in one. This study confirmed that the oral administration of EGCG is an effective and safe method to deal with ARIE, even when the esophagus received more than 50.4 Gy radiation. A phase III randomized controlled trial is expected to further corroborate the consequence of EGCG in ARIE treatment in patients with esophageal cancer.

1008P - Effect of protracted radiotherapy treatment on outcome of head and neck SCC patients (NEMROCK experience)

Patients with head and neck cancer receiving radiation therapy alone or with concurrent chemotherapy often develop mucositis that may lead to unplanned treatment interruptions, these decreases in treatment intensity may reduce rates of loco-regional tumor control and survival. A total number of one hundred twenty head and neck cancer patients included in this retrospective study presented to NEMROCK between January 2005 and December 2010 after they underwent surgery and received their post operative adjuvant radiotherapy with or without concomitant chemotherapy. The impact of both overall treatment time of radiation and treatment gaps on loco regional tumor control and overall survival were studied. Radiation treatment gaps lasting 5 days or less did not influence LC (86%) at 3-years, which may suggest that the average dose intensity (>9 Gy/week), appeared high enough to compensate for few days of treatment break meanwhile patients received low DI (<9 Gy/week) had three times risk of recurrence (HR = 3.13; 95% CI, 1.47-6.64; p = 0.003). However prolongation of treatment gaps more than 10 days are related to a decrease in 3-years LCR to 40% (from 86% to 46% p = 0.001). Similar statistically significant difference in 3 years OAS was also observed among the patients with no or up to 5 days treatment gap and the patients experienced > 10 days gap (87.8% vs. 61%, p = 0.001). An increased OTT (> 60 days) and low DI (9 Gy/week) are seem to be related to a decreased OAS among our patients in multivariate analysis. In this retrospective study, patients with head-and-neck cancer, who have unplanned interruptions in radiotherapy have an increased risk of death and tumor recurrence. This analysis have several limitations. It is impossible to fully remove the effect of unmeasured factors that are associated both with presence of treatment interruptions and risk of death like mucositis, xerostomia, dysphagia, and aspiration, each of which may also be associated with decreased survival time. Thus, the observed increased risk of death associated with interruptions in radiotherapy may not be entirely attributable to the interruptions themselves.

Effects of unplanned treatment interruptions on HIV treatment failure - results from TAHOD.

Treatment interruptions (TIs) of combination antiretroviral therapy (cART) are known to lead to unfavourable treatment outcomes but do still occur in resource-limited settings. We investigated the effects of TI associated with adverse events (AEs) and non-AE-related reasons, including their durations, on treatment failure after cART resumption in HIV-infected individuals in Asia. Patients initiating cART between 2006 and 2013 were included. TI was defined as stopping cART for >1 day. Treatment failure was defined as confirmed virological, immunological or clinical failure. Time to treatment failure during cART was analysed using Cox regression, not including periods off treatment. Covariables with P < 0.10 in univariable analyses were included in multivariable analyses, where P < 0.05 was considered statistically significant. Of 4549 patients from 13 countries in Asia, 3176 (69.8%) were male and the median age was 34 years. A total of 111 (2.4%) had TIs due to AEs and 135 (3.0%) had TIs for other reasons. Median interruption times were 22 days for AE and 148 days for non-AE TIs. In multivariable analyses, interruptions >30 days were associated with failure (31-180 days HR = 2.66, 95%CI (1.70-4.16); 181-365 days HR = 6.22, 95%CI (3.26-11.86); and >365 days HR = 9.10, 95% CI (4.27-19.38), all P < 0.001, compared to 0-14 days). Reasons for previous TI were not statistically significant (P = 0.158). Duration of interruptions of more than 30 days was the key factor associated with large increases in subsequent risk of treatment failure. If TI is unavoidable, its duration should be minimised to reduce the risk of failure after treatment resumption.

Abstract C80: Compliance with head and neck radiotherapy in medically insured and uninsured cancer patient populations

Abstract Background: Head and neck cancer is a curable malignancy. However, treatment is complex, costly, and toxic. Radiotherapy is a cornerstone of treatment, requiring 30-35 daily treatments over 6-7 weeks. Diligent patient compliance is crucial; unplanned treatment interruptions reduce cure rates. Compliance tracks closely with a complex mix of treatment and human factors, including patient trust in providers, effectiveness of toxicity management, and quality of social support. Previous studies suggest that medically underserved populations experience higher rates of radiation non-compliance. We studied compliance rates and potential confounding factors in medically insured and uninsured populations served by a single academic health system. Methods: We retrospectively analyzed electronic medical and billing records of head and neck radiotherapy patients referred from 1) the University of Texas Southwestern (UTSW) Medical Center and 2) Parkland Hospital (PHHS), which provides indigent care to Dallas County, Texas. Eligible diagnoses included cancers of the nasopharynx, base of tongue, salivary, paranasal sinus, tonsil, oropharynx, oral cavity, larynx, or hypopharynx. We identified 564 analyzable cases from a total of 722 treated from January 2011 through December 2014. For initial analysis, patients who missed any scheduled treatment were considered “noncompliant”. Subsequent analysis included number of missed treatment days, reasons for missed treatment, multivariate modeling of patient/ treatment variables, and downstream survival outcomes. Results: Three-hundred sixteen (56%) of study patients missed treatment; 114 missed a single session, while 202 missed multiple treatments. Median number of missed treatments was 2 days (lowest 25% interquartile = 1 missed day, 50% interquartile = 2 days, 75% interquartile = 5 days). One-hundred fifty two (70%) PHHS patients were non-compliant vs. 163 (47%) UTSW patients. Stepwise logistic regression analyses identified patient age (p=0.016), use of chemotherapy (p=0.021), and referral location (p=0.0002) was predictive for patient cancellation of treatment. UTSW patients enjoyed a 53.7% less frequent cancelation rate than PHHS patients after controlling the effect of age and chemotherapy. Age (p=0.026), chemotherapy (p=0.005), and referral location (p&amp;lt;0.0001) were also significantly associated with patient no-shows. Referral location (p=0.0007) was the only significant factor associated with total number of missed visits. PHHS patients suffered 1.72 more interrupted days than UTSW patients. Among non-compliant patients, there was a significant difference in time to local recurrence between UTSW and PHHS patient cohorts (p=0.013 by log-rank test). Conclusions: We demonstrate significant disparity in patient compliance to radiation treatment across privately insured and indigent populations managed within a single academic health system. Poor compliance was tracked with expected factors, such as advanced age and treatment intensity (e.g. combined use of chemotherapy with radiation), but was associated most closely with indigent care. Missed treatment predicted for poor local disease control, but only in the PHHS subgroup, suggesting that disease control tracks with high-risk social/treatment factors impacting uninsured patients, rather than secondary time delays themselves. This retrospective study cannot establish causative mechanisms linking uninsured status with non-compliance or disease outcomes, but confirms a pressing need to design interventions to break social/behavioral cycles corrupting cancer care in disadvantaged populations. Citation Format: Kimberly M. Thomas, Travis Martin, Holly Wilhelm, Ang Gao, Chul Ahn, David L. Schwartz. Compliance with head and neck radiotherapy in medically insured and uninsured cancer patient populations. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C80.

Efficacy of percutaneous endoscopic gastrostomy on unplanned treatment interruption and nutritional status in patients undergoing chemoradiotherapy for advanced head and neck cancer.

Efficacy of percutaneous endoscopic gastrostomy (PEG) on unplanned treatment interruption and nutritional status was examined in patients undergoing chemoradiotherapy (CRT) for advanced head and neck cancer. We retrospectively reviewed hospital charts of 44 patients with advanced head and neck cancer who were treated with CRT. CRT-induced mucositis of grade 3 or worse and inadequate oral intake of less than one third of their usual intake developed in 33 patients who were recommended PEG placement, but not in 11 patients. Thirteen patients accepted PEG placement and then completed CRT (compliant group). However, among 20 patients who refused both PEG and nasogastoric tube (NGT) placements (non-compliant group), 10 required unplanned interruptions of CRT at a radiation dose around 30-40 Gy (UI-CRT group) while 10 others could complete CRT without interruption (C-CRT group) CRT. Total serum protein levels were significantly decreased after CRT in all patients. It is suggested that therapeutic PEG placement is useful for preventing unplanned interruption of CRT in patients with advanced head and neck cancer. After severe mucositis and inadequate oral intake have developed during CRT, PEG placement should be considered before the radiation therapy dose of 30 Gy.

Stock-outs of antiretroviral drugs and coping strategies used to prevent changes in treatment regimens in Kinondoni District, Tanzania: a cross-sectional study.

ObjectivesSince 2004, the government of Tanzania has been rolling out antiretroviral treatment programs all over the country. However, the capacity of the health system to cope with the rapid scale-up of these programs is a major concern, and problems may result in drug stock-outs that force changes in treatment regimens. This study aims to explore stock-outs of antiretroviral drugs and further determine the coping strategies employed to prevent changes in treatment regimens in HIV/AIDS care and treatment clinics in Kinondoni District, Dar es Salaam, Tanzania.MethodsA cross-sectional study was conducted in 20 HIV/AIDS care and treatment clinics. Interviews were conducted with the person in charge and a member of the pharmacy staff from each clinic using a pre-tested semi-structured interview guide. Verbal responses were transcribed, coded and analysed by thematic approach. Quantitative data were analysed using Excel spreadsheet (Microsoft Excel®, Microsoft Corporation).ResultsThe total number of clients enrolled in the visited clinics was 32,147, of whom 20,831 (64.8%) had already been initiated onto antiretroviral therapies (ART). Stock-out of antiretroviral drugs was reported in 16 out of the 20 clinics, causing 210 patients to change their ART regimens, during the 12 months preceding the survey. Inefficient supply systems, quantification problems and short expiry duration were cited as the main causes of stock-outs. The coping strategies utilised to prevent changes in ART regimens were: shortening of the refill period, borrowing and moving patients to other clinics.ConclusionChanges in ART regimens due to stock-outs of antiretroviral drugs occurred in a small but significant number of patients. This increases the risk of the emergence of drug-resistant HIV strains. Healthcare workers use various coping strategies to prevent changes in ART regimens but, unfortunately, some of these strategies are likely to increase patient-borne costs, which may discourage them from attending their routine clinics, hence leading to unplanned treatment interruptions.

Unplanned antiretroviral treatment interruptions, genetic barrier, and development of resistance

Unplanned antiretroviral treatment interruptions, genetic barrier, and development of resistance

A phase I study of concurrent chemotherapy and thoracic radiotherapy with oral epigallocatechin-3-gallate protection in patients with locally advanced stage III non-small-cell lung cancer

Background and purposePatients with unresectable stage III non-small-cell lung cancer receiving concurrent chemoradiotherapy often develop esophagitis that may lead to unplanned treatment interruptions, which may severely reduce rates of locoregional tumor control and survival. No effectivetreatment that would reduce the incidence and severity of this complication has been identified up to now. Although acceleration of normal tissue protection using epigallocatechin-3-gallate (EGCG) has been reported, its actual clinical practicability remains obscure. Methods and materialsThis is a phase I study of EGCG in combination with standard chemoradiation in surgically unresectable stage III non-small-cell lung cancer. Chemotherapy (cisplatin and etoposide) was given concurrently with radiation. EGCG solution was swallowed three times a day after the occurrence of grade 2 esophagitis at six concentration levels and dose escalation followed a standard phase I design. Esophageal toxicity and patient-reported pain was recorded weekly. ResultsTwenty-four patients with AJCC stage IIIA (six) and IIIB (eighteen) completed the course of therapy. Twelve had squamous histology, ten adenocarcinoma, and two not specified. Patients were treated in six cohorts at six dose levels of EGCG. RT was not interrupted with a median dose of 64Gy. There were no dose-limiting toxicities reported in all EGCG dosing tiers. Dramatic regression of esophagitis to grade 0/1 was observed in 22 of 24 patients, whereas grade 2 esophagitis persisted in 2 of 24 patients at the end of radiotherapy. The pain score was also reduced from a mean of 4.58 (N=24), 1.29 (N=24), 1.42 (N=24), 0.96 (N=23) to 1.13 (N=16) every week in turn. ConclusionWe conclude that the oral administration of EGCG is feasible, safe and effective. The phase II recommended concentration is 440μmol/L.

Supportive Care Considerations During Concurrent Chemoradiotherapy for Pancreatic Adenocarcinoma

Concurrent chemotherapy and radiotherapy (chemoradiotherapy) for the management of pancreatic adenocarcinoma in either adjuvant or locally regional advanced settings produces predictable acute toxicities that are proportional in severity to the intensity and type of systemic therapy and to the parameters of radiotherapy. In addition, relevant to the adjuvant setting, surgery for pancreatic cancer often produces physiologic alterations that may impact a patient's ability to tolerate chemoradiotherapy. Failures to anticipate, monitor, and proactively manage the effects of surgery and toxicities of chemoradiotherapy can result in the need for unplanned treatment interruptions and/or inability to complete all planned therapy. In this review, complications of pancreatic cancer itself and of pancreatic resection as well as toxicities of chemoradiotherapy are delineated, and approaches to their management before, during, and after chemoradiotherapy are presented. Planning for the treatment of side effects before the anticancer therapy begins facilitates therapy administration and improves patient tolerance.

Characterization of associations and development of atazanavir resistance after unplanned treatment interruptions

Although current guidelines recommend resistance testing prior to antiretroviral therapy (ART) reinitiation after treatment interruptions, virological failure of first-line ritonavir-boosted, protease-inhibitor (PI/r)-containing ART is associated with low emergent PI resistance. In patients experiencing unscheduled treatment interruptions (UTrIs) on ritonavir-boosted atazanavir (ATV/r) ART regimens, we hypothesized low emergence of PI mutations conferring resistance to ATV/r. In a retrospective assessment of HIV-infected patients initiating ATV/r-containing ART, using logistic regression we determined factors associated with UTrI, the prevalence of emergent resistance mutations and virological response after ART reinitiation. A total of 202 patients [median age 33 years (interquartile range (IQR) 29-40 years); 52% female; median CD4 count 184 cells/μL (IQR 107-280 cells/μL); median HIV RNA 4.6 log10 HIV-1 RNA copies/mL (IQR 3.2-5.1 copies/mL)] initiated ATV/r between 2004 and 2009; 80 (43%) were ART naïve. One hundred and ten patients (55%) underwent 195 UTrIs after a median (IQR) 25 (10-52) weeks on ART, with a median (IQR) UTrI duration of 10 (3-31) weeks. Fifty-four of 110 patients (49%) underwent more than one UTrI. The commonest reasons for UTrI were nonadherence (52.7%) and drug intolerance (20%). Baseline HIV RNA > 100 000 copies\mL [odds ratio (OR) 3.6; 95% confidence interval (CI) 1.3-9.95] and being HCV positive, an injecting drug user or on methadone (OR 2.4; 95% CI 1.3-4.4) were independently associated with UTrI. In 39 patients with at least two resistance assays during UTrIs, 72 new mutations emerged; four nucleoside reverse transcriptase inhibitor (NRTI), two nonnucleoside reverse transcriptase inhibitor (NNRTI) and 66 protease inhibitor (PI) resistance mutations. All emergent PI resistance mutations were minor mutations. At least 65% of patients were re-suppressed on ATV/r reinitiation. In this PI-treated cohort, UTrIs are common. All emergent PI resistance mutations were minor and ATV/r retained activity and efficacy when reintroduced, even after several UTrIs, raising questions regarding the need for routine genotypic resistance assays in PI/r-treated patients prior to ART reinitiation after UTrI.

Feasibility and toxicity of concurrent chemoradiation for elderly patients with head and neck cancer

ObjectivesAlthough concurrrent chemoradiation is increasingly used for patients with locally advanced head and neck cancer, many elderly patients receive radiation alone due to toxicity concerns. We evaluate acute and late toxicity among patients age ≥65 who received concurrent chemoradiation for head and neck cancer. DesignRetrospective review. SettingTertiary care center. ParticipantsBetween 6/2003 and 8/2011, 40 consecutive patients age ≥65 underwent combined chemoradiation for head and neck cancer. Ten patients were treated in the postoperative setting and 30 underwent definitive chemoradiation. Twenty-eight patients received concurrent platinum-based chemotherapy and 12 received concurrent weekly paclitaxel. Treatment plans were designed to provide a dose of 66–72Gy at 2–2.12Gy/fraction to >95% of the gross tumor volume in the definitive setting or for positive margins and 60–66Gy at 2Gy/fraction post-operatively. Median follow-up was 23.2months (range: 0–94.4months). Main outcomes measuresAcute skin and mucosal toxicity, unplanned treatment interruptions, and chronic treatment related toxicity including gastrostomy tube dependence as graded by the CTCAE v3.0. ResultsEight patients (20%) required a radiation treatment break of ≥3days. Thirteen (33%) required unplanned hospitalization during or immediately following treatment. No grade 4+ skin or mucosal toxicity was noted. Five patients remained PEG tube dependent at >1year. One patient developed non-healing mandibular osteoradionecrosis >3years following chemoradiation. The 2-year Kaplan–Meier estimate of overall survival was 55%. ConclusionHigher-than-expected rates of in-patient hospitalization with significant acute toxicity were noted in this cohort with a correspondingly high rate of radiation treatment breaks. Late toxicity rates were similar to those observed in historical controls with younger patients. Careful patient selection criteria should be employed for elderly patients considering concurrent chemoradiation for head and neck cancer.

Efficacy of rebamipide-gargle for chemotherapy-induced oral mucositis.

9637 Background: Chemotherapy-induced oral mucositis (CIOM) is a severe adverse event resulting from cancer chemotherapy, and causes severe pain which impacts eating, nutrition, infection and overall quality of life. CIOM can result in unplanned treatment interruptions including dose reduction or treatment delay. Toxic free radicals and several pro-inflammatory cytokines produced by anti-cancer drugs have been reported to correlate with CIOM. Rebamipid, an endogenous inducer of prostaglandins, is widely used for gastric ulcers and gastritis in Asia. It has been shown to increase gastric endogenous prostaglandin E2 and I2, to promote gastric epithelial mucin, to behave as an oxygen–free radical scavenger, and to have other anti-inflammatory actions. In this study, we made a rebamipide gargle using rebamipide and ultrahydrogel, which is added for mucosal protection and to sustain the rebamipide on oral mucosa for a long time. Methods: The objective of this study is to evaluate the efficacy of the rebamipide gargle in relieving CIOM. Each 300ml of rebamipide gargle is made by combining rebamipide 600mg, high molecular weight polyethylene oxide 3g, carrageenin 1.2g, pineapple flavor and water. Patients were instructed to use the rebamipide gargle 5-6 times a day. The severity of CIOM was assessed according to the National Cancer Institute Common TerminologyCriteria for Adverse Events (CTCAE version 4.0). Results: From November 2009 to December 2012, 175 patients with CIOM were enrolled in this study (colorectal cancer 95 patients, breast cancer 32, gastric cancer 22, lung cancer 14, and other cancers 12). The patients’ CTCAE grades (3/2/1/0) changed from (n=13/64/98/0) to (0/10/103/62) respectively after initiation of rebamipide gargle (p&lt;.01; paired t test). A decrease in CTCAE was observed in 142 patients (81.1%) including 62 patients (35.4%) achieving grade 0. The mean duration to best response was 14 days (range: 1-49), and rebamipide gargle was continued 42 days (range: 5-970).There were no unexpected safety events. Conclusions: Rebamipide gargle was well tolerated and demonstrated significant therapeutic response for CIOM.

Outcomes after reinitiating antiretroviral therapy in children randomized to planned treatment interruptions

Excess risks for death/opportunistic disease in adults randomized to CD4-driven planned treatment interruption (PTI) in the Strategies for Management of Antiretroviral Therapy (SMART) trial remained after antiretroviral therapy (ART) re-initiation. Risks for children following PTI were evaluated in long-term follow-up of children in the PENTA 11 trial. Children with HIV RNA below 50 copies/ml and CD4 at least 30% (2-6 years) or at least 500 cells/μl (7-15 years) were randomized to continuous ART (cART) or PTI in PENTA 11 (ISRCTN 36694210). After the end of the trial, all were recommended to resume ART. Data were collected annually and analysed up to the second year of visit. One hundred and one (51 cART, 50 PTI; median baseline age 9.2 years) children had median overall follow-up 4.6 (range 3.7-5.0) years. During 2-year post-trial period, there were no deaths or new Centers for Disease Control and Prevention (CDC) stage B/C events. Rate of clinical grade of at least two events was similar between PTI and cART [relative risk (RR) 1.03; 95% confidence interval (CI) 0.43, 2.50; P = 0.94]. At 2 years, difference in absolute CD4% between PTI and cART was -1.6% (-4.5%; 1.3%; P = 0.27), and proportions with HIV RNA below 50 copies/ml were 82 versus 86% (P = 0.57), respectively; no differences in growth or fasting lipids were observed. Key predictors of greater CD4% recovery after re-initiating ART were higher CD4% at baseline (P < 0.001) and longer time since ART re-initiation (P < 0.001). During overall follow-up, 4 (8%) PTI versus 5 (10%) CT children switched ART for failure (P = 0.75) and 9 (18%) versus 1 (2%) (P = 0.008) substituted ART for simplification. No adverse clinical, immunological or virological consequences of PTI were observed 2 years after the end of PENTA 11 trial. Although ART interruption is not generally recommended, it may be an acceptable option for children, particularly when there is high risk of unplanned treatment interruptions.

Compensability index for compensation radiotherapy after treatment interruptions

BackgroundThe goal of our work was to develop a simple method to evaluate a compensation treatment after unplanned treatment interruptions with respect to their tumour- and normal tissue effect.MethodsWe developed a software tool in java programming language based on existing recommendations to compensate for treatment interruptions. In order to express and visualize the deviations from the originally planned tumour and normal tissue effects we defined the compensability index.ResultsThe compensability index represents an evaluation of the suitability of compensatory radiotherapy in a single number based on the number of days used for compensation and the preference of preserving the originally planned tumour effect or not exceeding the originally planned normal tissue effect. An automated tool provides a method for quick evaluation of compensation treatments.ConclusionsThe compensability index calculation may serve as a decision support system based on existing and established recommendations.

Virological failure rates and HIV‐1 drug resistance patterns in patients on first‐line antiretroviral treatment in semirural and rural Gabon

IntroductionAs antiretroviral treatment (ART) continues to expand in resource-limited countries, the emergence of HIV drug resistance mutations (DRMs) is challenging in these settings. In Gabon (central Africa), no study has yet reported the virological effectiveness of initial ART given through routine HIV care.MethodsFollowing the World Health Organization (WHO) recommendations, a cross-sectional study with a one-time HIV-1 RNA viral load (VL) measurement was conducted in Gabon to assess virological failure (VF) defined by a VL result ≥1000 copies/ml and DRMs among adult patients living with non-B HIV-1 strains and receiving first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy for at least 12 months. Risk factors associated with VF and DRMs were assessed.ResultsBetween March 2010 and March 2011, a total of 375 patients were consecutively enrolled from two decentralized (one semirural and one rural) HIV care centres. Median time on ART was 33.6 months (range, 12–107). Overall, the rate of VF was 41.3% (36.4–46.4). Among viremic patients, 56.7% (80/141) had at least one DRM and 37.6% had dual-class resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and NNRTIs. The most frequent DRMs were K103N/S (46.1%) and M184V/I (37.6%). Thymidine analogue mutations were found in 10.6%. Independent risk factors associated with VF were being followed up at the semirural centre (P=0.033), having experienced unstructured treatment interruptions (P=0.0044), and having low CD4+ counts at enrolment (P<0.0001). A longer time on ART (P=0.0008) and being followed up at the rural centre (P=0.021) were risk factors for DRMs.ConclusionsThis is the first study conducted in Gabon providing VF rates and DRM patterns in adult patients receiving first-line ART. In sub-Saharan Africa, where NNRTI-based regimens are recommended as the standard for first-line ART, strengthening virological monitoring together with preventing unplanned treatment interruptions are a global public health priority.

Continuous 7-Days-A-Week External Beam Irradiation in Locally Advanced Cervical Cancer: Final Results of the Phase I/II Study

To evaluate the feasibility and efficacy of definitive continuous 7-days-a-week pelvic irradiation without breaks between external beam radiotherapy and brachytherapy in locally advanced cervical cancer. Between November 1998 and December 1999, 30 patients with International Federation of Obstetrics and Gynecology Stage IIB or IIIB cervical cancer were included in a prospective Phase I/II study of continuous 7-days-a-week pelvic irradiation, to the total Manchester point B dose of 40.0-57.6 Gy. The first 13 patients (Group A) were given a daily tumor dose of 1.6 Gy, and the remaining 17 patients (Group B) were given 1.8 Gy. One or two immediate brachytherapy applications (point A dose 10-20 Gy, each) were performed in 28 cases. Two patients did not complete the irradiation because of apparent early progression of disease during the irradiation. Eleven of the 28 evaluable patients (39%; 45% and 35% in Groups A and B, respectively) completed their treatment within the prescribed overall treatment time. Acute toxicity (including severe European Organisation for Research and Treatment of Cancer/Radiation Therapy Oncology Group Grade 3 and 4 effects in 40%) was experienced by 83% of patients and resulted in unplanned treatment interruptions in 40% of all patients (31% and 47% of patients in Groups A and B, respectively). Severe intestinal side effects occurred in 31% and 41% of Patients in Groups A and B, respectively (p = 0.71). The 5-year overall survival probability was 33%. Cancer recurrence occurred in 63% of patients: 20% inside and 57% outside the pelvis. Cumulative incidence of late severe bowel and urinary bladder toxicity at 24 months was 15%. Continuous irradiation in locally advanced cervical cancer is associated with a high incidence of severe acute toxicity, resulting in unplanned treatment interruptions. Late severe effects and survival after continuous radiotherapy do not substantially differ from those obtained with conventionally fractionated radiotherapy.

Non-adherence to antiretroviral treatment and unplanned treatment interruption among people living with HIV/AIDS in Cameroon: Individual and healthcare supply-related factors

In low-income countries, health system deficiencies may undermine treatment continuity and adherence to antiretroviral therapy (ART) that are crucial for the success of large-scale public ART programs. In addition to examining the effects of individual characteristics, on non-adherence to ART and treatment interruption behaviors – i.e. treatment interruption for more than 2 consecutive days during the previous 4 weeks, this study aims to extend our knowledge on the role played by healthcare supply-related characteristics in shaping these two treatment outcomes. These effects are examined using multilevel logistic models applied to a sub-sample of 2381 ART-treated patients followed-up in 27 treatment centers in Cameroon (ANRS-EVAL survey, 2006–2007).Multivariate models show that factors common to both non-adherence and treatment interruption include binge drinking (at the individual-level) and large hospital size (at the healthcare supply-level). Among the individual factors, financial difficulties of paying for HIV-care are the major correlates of treatment interruption [Adjusted Odds Ratio (AOR) 95% confidence interval (CI) = 11.73(7.24–19.00)]. By contrast, individual factors associated with an increased risk of non-adherence include: having a main partner but not living in a couple compared to patients living in a couple [AOR(95%CI) = 1.51(1.14–2.01)]; experience of discrimination in the family environment [AOR(95%CI) = 1.74(1.14–2.65)]; a lack of regular meals [AOR(95%CI) = 1.93(1.44–2.57)], and switching antiretroviral drugs (ARV) regimen [AOR(95%CI) = 1.36(1.08–1.70)]. At healthcare facility-level, the main correlate of ART interruption was antiretroviral stock-outs [AOR(95%CI) = 1.76(1.01–3.32)] whereas the lack of psychosocial support from specialized staff and lack of task-shifting to nurses in medical follow-up were both associated with a higher-risk of non-adherence [respective AOR (95%CI) = 2.81(1.13–6.95) and 1.51(1.00–3.40)].Results reveal different patterns of factors for non-adherence and treatment interruption behaviors. They also suggest that psychosocial support interventions targeted at the individual patient-level will not be sufficient to achieve favorable treatment outcomes if not combined with interventions focused on strengthening health systems, including appropriate drug supplies and human resources policies, as well as sustainable and equitable financing mechanisms.

Receding Horizon Control of HIV

This paper describes a model of the immunologic response of the human immunodeficiency virus (HIV) in individuals. It then illustrates how a Receding Horizon Control (RHC) methodology can be used to drive the system to a stable equilibrium in which a strong immune response controls the viral load in the absence of drug treatment. We also illustrate how this feedback methodology can overcome unplanned treatment interruptions, inaccurate or incomplete data and imperfect model specification. We consider how ideas from stochastic estimation can be used in conjunction with RHC to create a robust treatment methodology. We then consider the performance of this methodology over random simulations of the previously considered clinical conditions. Copyright © 2010 John Wiley & Sons, Ltd.

Gabapentin for the Treatment of Cancer-Related Pain Syndromes

Gabapentin was initially developed as an antiepileptic drug but was later discovered to be an effective treatment of neuropathic pain. Gabapentin has been successfully used for the treatment of multiple neuropathic pain syndromes such as diabetic neuropathy and postherpetic neuralgia. However, limited data exist about its efficacy for other pain syndromes. The objective of the current review is to describe, from the literature, the role of gabapentin for the treatment of cancer-related pain syndromes. Studies were identified by searching the PubMed electronic databases. Additional review articles and article reference lists were used to identify other studies. Recent studies showed effectiveness of gabapentin in improving the pain control in patients with neuropathic cancer pain, already treated with opiates. Moreover, gabapentin appeared promising in reducing the need for high total doses of opioids and avoiding unplanned treatment interruptions for patients with head and neck malignancies treated with radiotherapy or concurrent chemoradiotherapy. Furthermore, the combination of gabapentin and morphine has been shown to effect better pain relief at lower doses of each drug when compared with gabapentin or morphine alone in patients with painful diabetic neuropathy or postherpetic neuralgia. The combination of both drugs was associated with a beneficial effect on pain-related interference with daily activity, mood, sleep and quality of life. Given the significant benefits of gabapentin and the combination of gabapentin with opioids for the treatment of neuropathic pain, randomized clinical trials are needed to establish the role of these analgesic regimens for the treatment of neuropathic cancer pain.