ABSTRACT
BACKGROUND: Enthusiasm for precision oncology may obscure the psychosocial and ethical considerations associated with the implementation of tumor genetic sequencing. METHODS: Patients with advanced cancer undergoing tumor-only genetic sequencing in the National Cancer Institute Molecular Analysis for Therapy Choice (MATCH) trial were randomized to a web-based genetic education intervention or usual care. The primary outcomes were knowledge, anxiety, depression, and cancer-specific distress collected at baseline (T0), posteducation (T1) and after results (T2). Two-sided, 2-sample t tests and univariate and multivariable generalized linear models were used. RESULTS: Five hundred ninety-four patients (80% from NCI Community Oncology Research Program sites) were randomized to the web intervention (n = 293) or usual care (n = 301) before the receipt of results. Patients in the intervention arm had greater increases in knowledge (P for T1-T0 < .0001; P for T2-T0 = .003), but there were no significant differences in distress outcomes. In unadjusted moderator analyses, there was a decrease in cancer-specific distress among women (T0-T1) in the intervention arm but not among men. Patients with lower health literacy in the intervention arm had greater increases in cancer-specific distress and less decline in general anxiety (T0-T1) and greater increases in depression (T0-T2) in comparison with those receiving usual care. CONCLUSIONS: Web-based genetic education before tumor-only sequencing results increases patient understanding and reduces distress in women. Refinements to the intervention could benefit low-literacy groups and men.
Subject(s)
Neoplasms , Anxiety , Female , Humans , Male , Medical Oncology , Neoplasms/genetics , Neoplasms/therapy , Precision Medicine , Quality of LifeABSTRACT
BACKGROUND: This North Central Cancer Treatment Group (NCCTG) N064A (Alliance) phase II trial evaluated upfront chemoradiotherapy incorporating the EGFR inhibitor panitumumab, followed by gemcitabine and panitumumab for unresectable, non-metastatic pancreatic cancer. METHODS: The treatment consisted of fluoropyrimidine and panitumumab given concurrently with radiotherapy followed by gemcitabine and panitumumab for 3 cycles followed by maintenance panitumumab. The primary endpoint was the 12-month overall survival (OS) rate and secondary endpoints included confirmed response rate (RR), OS, progression-free survival (PFS), and adverse events. Enrollment of 50 patients was planned and the study fully accrued. RESULTS: Fifty-two patients were enrolled, but only 51 were treated and included in the analysis. The median age of patients was 65 years and 54.9% were women. Twenty-two patients received at least 1 cycle of systemic therapy following radiotherapy, but 29 patients received chemoradiotherapy only without receiving subsequent chemotherapy after completion of chemoradiotherapy. The overall RR was 5.9% (95% CI: 1.2%-16.2%). The 12-month OS rate was 50% (95% CI: 38%-67%) which fell short of the per-protocol goal for success (51.1%). The median PFS was 7.4 months (95% CI: 4.5-8.6) and the median OS was 12.1 months (95% CI 7.9-15.9). Grade 3 or higher adverse events were reported by 88%. CONCLUSION: The combination of panitumumab, chemotherapy, and external beam radiation therapy was associated with very high rates of grades 3-4 toxicities and survival results did not meet the trial's goal for success. This regimen is not recommended for further study (ClinicalTrials.gov Identifier NCT00601627).
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Adenocarcinoma/drug therapy , Adenocarcinoma/radiotherapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Humans , Male , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Panitumumab/therapeutic use , Pancreatic NeoplasmsABSTRACT
BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of taxane and platinum-based chemotherapy. Several studies have supported the potential benefit of glutathione for the prevention of platinum-induced CIPN. The current trial was designed to determine whether glutathione would prevent CIPN as a result of carboplatin/paclitaxel therapy. METHODS: In total, 185 patients who received treatment with paclitaxel and carboplatin were accrued between December 4, 2009 and December 19, 2011. Patients were randomized to receive either placebo (n = 91) or 1.5 g/m(2) glutathione (n = 94) over 15 minutes immediately before chemotherapy. CIPN was assessed using the European Organization for Research and Treatment of Cancer Quality-of-Life (EORTC-QLQ) 20-item, CIPN-specific (CIPN20) sensory subscale and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. RESULTS: There were no statistically significant differences between the 2 study arms with regard to: 1) peripheral neurotoxicity, as assessed using both the EORTC-QLQ-CIPN20 (P = .21) and the CTCAE scales (P = .449 for grade ≥2 neurotoxicity; P = .039 for time to development of grade ≥2 neuropathy, in favor of the placebo); 2) the degree of paclitaxel acute pain syndrome (P = .30 for patients who received paclitaxel every 3-4 weeks and P = .002, in favor of the placebo, for patients who received weekly paclitaxel); 3) the time to disease progression (P = .63); or 4) apparent toxicities. Subgroup analyses did not reveal any evidence of benefit in any particular subgroup. CONCLUSIONS: The results from this study do not support the use of glutathione for the prevention of paclitaxel/carboplatin-induced CIPN.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Glutathione/therapeutic use , Neoplasms/drug therapy , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/prevention & control , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Carboplatin/adverse effects , Double-Blind Method , Female , Humans , Male , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , PlacebosABSTRACT
The Oncotype DX colon cancer assay is a clinically validated predictor of recurrence risk in stage II colon cancer patients. This prospective study evaluated the impact of recurrence score (RS) results on physician recommendations regarding adjuvant chemotherapy in T3, mismatch repair-proficient (MMR-P) stage II colon cancer patients. Patients and Methods. Stage IIA colon cancer patients were enrolled in 17 centers. Patient tumor specimens were assessed by the RS test (quantitative reverse transcription-polymerase chain reaction) and mismatch repair (immunohistochemistry). For each patient, the physician's recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin was recorded before and after the RS and mismatch repair results were provided. Results. Of 221 enrolled patients, 141 patients had T3 MMR-P tumors and were eligible for the primary analysis. Treatment recommendations changed for 63 (45%; 95% confidence interval: 36%-53%) of these 141 T3 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%), following review of RS results by physician and patient. Increased treatment intensity was more often observed at higher RS values, and decreased intensity was observed at lower values (p = .011). Conclusion. Compared with traditional clinicopathological assessment, incorporation of the RS result into clinical decision making was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients in this prospective multicenter study. Use of the RS assay may lead to overall reduction in adjuvant chemotherapy use in this subgroup of stage II colon cancer patients.
Subject(s)
Antineoplastic Protocols , Biological Assay , Colonic Neoplasms/therapy , Decision Making , Decision Support Techniques , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Chemotherapy, Adjuvant/statistics & numerical data , Colonic Neoplasms/diagnosis , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Organoplatinum Compounds/therapeutic use , Oxaliplatin , Prospective Studies , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at >50 %, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient's pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9 %) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6 %) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3 months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9 %, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/radiotherapy , Carcinoma, Intraductal, Noninfiltrating/drug therapy , Carcinoma, Intraductal, Noninfiltrating/metabolism , Carcinoma, Intraductal, Noninfiltrating/radiotherapy , Receptor, ErbB-2/analysis , Breast Neoplasms/surgery , Carcinoma, Intraductal, Noninfiltrating/surgery , Female , Humans , Mastectomy, Segmental , Middle Aged , TrastuzumabABSTRACT
PURPOSE: Pelvic radiotherapy (PRT) is known to adversely affect bowel function (BF) and patient well-being. This study characterized long-term BF and evaluated quality of life (QOL) in patients receiving PRT. METHODS: Data from 252 patients were compiled from two North Central Cancer Treatment Group prospective studies, which included assessment of BF and QOL by the BF questionnaire (BFQ) and Uniscale QOL at baseline and 12 and 24 months after completion of radiotherapy. BFQ scores (sum of symptoms), Uniscale results, adverse-event incidence, and baseline demographic data were compared via t test, χ (2), Fisher exact, Wilcoxon, and correlation methodologies. RESULTS: The total BFQ score was higher than baseline at 12 and 24 months (P < 0.001). More patients had five or more symptoms at 12 months (13 %) and 24 months (10 %) than at baseline (2 %). Symptoms occurring in greater than 20 % of patients at 12 and 24 months were clustering, stool-gas confusion, and urgency. Factors associated with worse BF were female sex, rectal or gynecologic primary tumors, prior anterior resection of the rectum, and 5-fluorouracil chemotherapy. Patients experiencing grade 2 or higher acute toxicity had worse 24-month BF (P values, <.001-.02). Uniscale QOL was not significantly different from baseline at 12 or 24 months, despite worse BFQ scores. CONCLUSIONS: PRT was associated with worse long-term BF. Worse BFQ score was not associated with poorer QOL. Further research to characterize the subset of patients at risk of significant decline in BF is warranted.
Subject(s)
Gastrointestinal Neoplasms/radiotherapy , Radiation Injuries/etiology , Rectum/physiology , Rectum/radiation effects , Adult , Aged , Aged, 80 and over , Clinical Trials, Phase III as Topic , Diarrhea/etiology , Female , Glutamine/administration & dosage , Humans , Male , Middle Aged , Multicenter Studies as Topic , Pelvis/radiation effects , Prospective Studies , Quality of Life , Radiation Injuries/physiopathology , Radiotherapy/adverse effects , Randomized Controlled Trials as Topic , Surveys and QuestionnairesABSTRACT
PURPOSE: Primary prophylactic colony-stimulating factors (PP-CSFs) are prescribed to reduce febrile neutropenia (FN) but their benefit for intermediate FN risk regimens is uncertain. Within a pragmatic, randomized trial of a standing order entry (SOE) PP-CSF intervention, we conducted a substudy to evaluate the effectiveness of SOE for patients receiving intermediate-risk regimens. METHODS: TrACER was a cluster randomized trial where practices were randomized to usual care or a guideline-based SOE intervention. In the primary study, sites were randomized 3:1 to SOE of automated PP-CSF orders for high FN risk regimens and alerts against PP-CSF use for low-risk regimens versus usual care. A secondary 1:1 randomization assigned 24 intervention sites to either SOE to prescribe or an alert to not prescribe PP-CSF for intermediate-risk regimens. Clinicians were allowed to over-ride the SOE. Patients with breast, colorectal, or non-small-cell lung cancer were enrolled. Mixed-effect logistic regression models were used to test differences between randomized sites. RESULTS: Between January 2016 and April 2020, 846 eligible patients receiving intermediate-risk regimens were registered to either SOE to prescribe (12 sites: n = 542) or an alert to not prescribe PP-CSF (12 sites: n = 304). Rates of PP-CSF use were higher among sites randomized to SOE (37.1% v 9.9%, odds ratio, 5.91; 95% CI, 1.77 to 19.70; P = .0038). Rates of FN were low and identical between arms (3.7% v 3.7%). CONCLUSION: Although implementation of a SOE intervention for PP-CSF significantly increased PP-CSF use among patients receiving first-line intermediate-risk regimens, FN rates were low and did not differ between arms. Although this guideline-informed SOE influenced prescribing, the results suggest that neither SOE nor PP-CSF provides sufficient benefit to justify their use for all patients receiving first-line intermediate-risk regimens.
Subject(s)
Breast Neoplasms , Carcinoma, Non-Small-Cell Lung , Febrile Neutropenia , Lung Neoplasms , Standing Orders , Humans , Female , Colony-Stimulating Factors/therapeutic use , Granulocyte Colony-Stimulating Factor/adverse effects , Carcinoma, Non-Small-Cell Lung/etiology , Febrile Neutropenia/chemically induced , Febrile Neutropenia/drug therapy , Febrile Neutropenia/prevention & control , Lung Neoplasms/drug therapy , Logistic Models , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/etiologyABSTRACT
PURPOSE: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 (NF1[S1] or GNA11/Q [S2]) altered tumors. METHODS: Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss. RESULTS: Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common. CONCLUSION: Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.
Subject(s)
Melanoma , Neurofibromatosis 1 , Humans , Neurofibromatosis 1/drug therapy , Neurofibromatosis 1/genetics , Neurofibromatosis 1/chemically induced , Pyrimidinones/therapeutic use , Melanoma/drug therapy , Melanoma/genetics , Pyridones/therapeutic use , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , GTP-Binding Protein alpha Subunits/geneticsABSTRACT
Importance: Colony-stimulating factors are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia. Research suggests that 55% to 95% of colony-stimulating factor prescribing is inconsistent with national guidelines. Objective: To examine whether a guideline-based standing order for primary prophylactic colony-stimulating factors improves use and reduces the incidence of febrile neutropenia. Design, Setting, and Participants: This cluster randomized clinical trial, the Trial Assessing CSF Prescribing Effectiveness and Risk (TrACER), involved 32 community oncology clinics in the US. Participants were adult patients with breast, colorectal, or non-small cell lung cancer initiating cancer therapy and enrolled between January 2016 and April 2020. Data analysis was performed from July to October 2021. Interventions: Sites were randomized 3:1 to implementation of a guideline-based primary prophylactic colony-stimulating factor standing order system or usual care. Automated orders were added for high-risk regimens, and an alert not to prescribe was included for low-risk regimens. Risk was based on National Comprehensive Cancer Network guidelines. Main Outcomes and Measures: The primary outcome was to find an increase in colony-stimulating factor use among high-risk patients from 40% to 75%, a reduction in use among low-risk patients from 17% to 7%, and a 50% reduction in febrile neutropenia rates in the intervention group. Mixed model logistic regression adjusted for correlation of outcomes within a clinic. Results: A total of 2946 patients (median [IQR] age, 59.0 [50.0-67.0] years; 2233 women [77.0%]; 2292 White [79.1%]) were enrolled; 2287 were randomized to the intervention, and 659 were randomized to usual care. Colony-stimulating factor use for patients receiving high-risk regimens was high and not significantly different between groups (847 of 950 patients [89.2%] in the intervention group vs 296 of 309 patients [95.8%] in the usual care group). Among high-risk patients, febrile neutropenia rates for the intervention (58 of 947 patients [6.1%]) and usual care (13 of 308 patients [4.2%]) groups were not significantly different. The febrile neutropenia rate for patients receiving high-risk regimens not receiving colony-stimulating factors was 14.9% (17 of 114 patients). Among the 585 patients receiving low-risk regimens, colony-stimulating factor use was low and did not differ between groups (29 of 457 patients [6.3%] in the intervention group vs 7 of 128 patients [5.5%] in the usual care group). Febrile neutropenia rates did not differ between usual care (1 of 127 patients [0.8%]) and the intervention (7 of 452 patients [1.5%]) groups. Conclusions and Relevance: In this cluster randomized clinical trial, implementation of a guideline-informed standing order did not affect colony-stimulating factor use or febrile neutropenia rates in high-risk and low-risk patients. Overall, use was generally appropriate for the level of risk. Standing order interventions do not appear to be necessary or effective in the setting of prophylactic colony-stimulating factor prescribing. Trial Registration: ClinicalTrials.gov Identifier: NCT02728596.
Subject(s)
Colony-Stimulating Factors , Decision Support Systems, Clinical , Febrile Neutropenia , Neoplasms , Adult , Female , Humans , Middle Aged , Colony-Stimulating Factors/therapeutic use , Febrile Neutropenia/drug therapy , Febrile Neutropenia/prevention & control , Neoplasms/drug therapy , AgedABSTRACT
How do oncologists choose therapy for the elderly? Oncologists assigned patients aged 65 years or older with incurable non-small cell lung cancer to: (a) carboplatin (AUC = 2) + paclitaxel 50 mg/m(2) days 1, 8, 15 (28-day cycle × 4) followed by gefitinib; or (b) gefitinib 250 mg/day. With (a), 12 of 34 were progression-free at 6 months; median time to cancer progression was 3.9 months. With (b), the same occurred in 11 of 28 patients with the latter being 4.9 months. The most common reason for conventional chemotherapy was oncologists' opinion that the cancer was aggressive, and for gefitinib alone, patients' reluctance to receive chemotherapy. Interestingly, age had no influence.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Practice Patterns, Physicians' , Age Factors , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/mortality , Disease-Free Survival , Female , Gefitinib , Humans , Lung Neoplasms/mortality , Male , Paclitaxel/administration & dosage , Patient Selection , Practice Patterns, Physicians'/statistics & numerical data , Quinazolines/administration & dosage , Surveys and Questionnaires , Survival Analysis , Time Factors , Treatment Outcome , United StatesABSTRACT
AIM: report primary results from the first multicentre randomised trial evaluating induction chemotherapy prior to trimodality therapy in patients with oesophageal or gastro-oesophageal junction adenocarcinoma. Notably, recent data from a single-institution randomised trial reported that induction chemotherapy prolonged overall survival (OS) in patients with well/moderately differentiated tumours. METHODS: In this phase 2 trial (28 centres in the U.S. NCI-sponsored North Central Cancer Treatment Group [Alliance]), trimodality-eligible patients (T3-4N0, TanyN+) were randomised to receive induction (docetaxel, oxaliplatin, capecitabine; Arm A) or no induction chemotherapy (Arm B) followed by oxaliplatin/5-fluorouracil/radiation and subsequent surgery. The primary endpoint was the rate of pathologic complete response (pathCR). Secondary/exploratory endpoints were OS and disease-free survival (DFS). RESULTS: Of 55 patients evaluable for the primary endpoint, the pathCR rate was 28.6% (8/28) in A versus 40.7% (11/27) in B (P = .34). Given interim results indicating futility, accrual was terminated, but patients were followed. After a median follow-up of 60.4 months, a longer median OS in Arm A versus B was unexpectedly observed (3-year rates 57.1% versus 41.7%, respectively) driven by longer DFS after margin-free surgery. In posthoc analysis, induction (versus no induction) chemotherapy was associated with significantly longer OS and DFS among patients with well/moderately differentiated tumours, but not among patients with poorly/undifferentiated tumours (Pinteraction = 0.037). CONCLUSIONS: Adding induction chemotherapy prior to trimodality therapy did not improve the primary endpoint, pathCR. However, induction chemotherapy was associated with longer median OS, particularly among patients with well/moderately differentiated tumours. These findings may inform further development of curative-intent trials in this disease.
Subject(s)
Adenocarcinoma/therapy , Chemoradiotherapy, Adjuvant , Esophageal Neoplasms/therapy , Esophagectomy , Induction Chemotherapy , Neoadjuvant Therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Cell Differentiation , Chemoradiotherapy, Adjuvant/adverse effects , Chemoradiotherapy, Adjuvant/mortality , Disease-Free Survival , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophagectomy/adverse effects , Esophagectomy/mortality , Female , Humans , Induction Chemotherapy/adverse effects , Induction Chemotherapy/mortality , Male , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoadjuvant Therapy/mortality , Time Factors , United StatesABSTRACT
The predisposition of patients to develop polyneuropathy in response to toxic exposure may have a genetic basis. The previous study Alliance N08C1 found an association of the Charcot-Marie-Tooth disease (CMT) gene ARHGEF10 with paclitaxel chemotherapy induced peripheral neuropathy (CIPN) related to the three non-synonymous, recurrent single nucleotide variants (SNV), whereby rs9657362 had the strongest effect, and rs2294039 and rs17683288 contributed only weakly. In the present report, Alliance N08CA was chosen to attempt to replicate the above finding. N08CA was chosen because it is the methodologically most similar study (to N08C1) performed in the CIPN field to date. N08CA enrolled patients receiving the neurotoxic chemotherapy agent paclitaxel. Polyneuropathy was assessed by serial repeat administration of the previously validated patient reported outcome instrument CIPN20. A study-wide, Rasch type model was used to perform extreme phenotyping in n=138 eligible patients from which "cases" and "controls" were selected for genetic analysis of SNV performed by TaqMan PCR. A significant association of ARHGEF10 with CIPN was found under the pre-specified primary endpoint, with a significance level of p=0.024. As in the original study, the strongest association of a single SNV was seen for rs9657362 (odds ratio=3.56, p=0.018). To further compare results across the new and the previous study, a statistical "classifier" was tested, which achieved a ROC area under the curve of 0.60 for N08CA and 0.66 for N08C1, demonstrating good agreement. Retesting of the primary endpoint of N08C1 in the replication study N08CA validated the association of ARHGEF10 with CIPN.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Paclitaxel/adverse effects , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/genetics , Rho Guanine Nucleotide Exchange Factors/genetics , Antineoplastic Agents, Phytogenic/adverse effects , Case-Control Studies , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Middle Aged , Models, Genetic , Mutation , Pharmacogenetics , Polymorphism, Single Nucleotide/geneticsABSTRACT
Most cancer patients experience at least one emergency during the course of the disease. This paper reviews the diagnosis and treatment of tumor lysis syndrome, hypercalcemia of malignancy, superior vena cava syndrome, spinal cord compression, strokes and seizures, and treatment-related emergencies.
Subject(s)
Emergencies , Neoplasms/complications , Humans , Hypercalcemia/diagnosis , Hypercalcemia/etiology , Hypercalcemia/therapy , Risk Factors , Seizures/diagnosis , Seizures/etiology , Seizures/therapy , Spinal Cord Compression/diagnosis , Spinal Cord Compression/etiology , Spinal Cord Compression/therapy , Stroke/diagnosis , Stroke/etiology , Stroke/therapy , Superior Vena Cava Syndrome/diagnosis , Superior Vena Cava Syndrome/etiology , Superior Vena Cava Syndrome/therapy , Tumor Lysis Syndrome/diagnosis , Tumor Lysis Syndrome/etiology , Tumor Lysis Syndrome/therapyABSTRACT
BACKGROUND: Prior economic analysis that compared the 12-gene assay to published patterns of care predicted the assay would improve outcomes while lowering medical costs for stage II, T3, mismatch-repair-proficient (MMR-P) colon cancer patients. This study assessed the validity of those findings with real-world adjuvant chemotherapy (aCT) recommendations from the US third-party payer perspective. METHODS: Costs and quality-adjusted life-years (QALYs) were estimated for stage II, T3, MMR-P colon cancer patients using guideline-compliant, state-transition probability estimation methods in a Markov model. A study of 141 patients from 17 sites in the Mayo Clinic Cancer Research Consortium provided aCT recommendations before and after knowledge of the 12-gene assay results. Progression and adverse events data with aCT regimens were based on published literature. Drug and administration costs for aCT were obtained from 2014 Medicare Fee Schedule. Sensitivity analyses evaluated the drivers and robustness of the primary outcomes. RESULTS: After receiving the 12-gene assay results, physician recommendations in favor of aCT decreased 22 %; fluoropyrimidine monotherapy and FOLFOX recommendations each declined 11 %. Average per-patient drugs, administration, and adverse events costs decreased $US2,339, $US733, and $US3,211, respectively. Average total direct medical costs decreased $US991. Average patient well-being improved by 0.114 QALYs. Savings are expected to persist even if the cost of oxaliplatin drops by >75 % due to generic substitution. CONCLUSIONS: This study provides evidence that real-world changes in aCT recommendations due to the 12-gene assay are likely to reduce direct medical costs and improve well-being for stage II, T3, MMR-P colon cancer patients.
Subject(s)
Colonic Neoplasms/economics , Colonic Neoplasms/genetics , Genetic Predisposition to Disease , Genetic Testing/economics , Neoplasm Recurrence, Local/economics , Neoplasm Recurrence, Local/genetics , Adult , Chemotherapy, Adjuvant/economics , Colonic Neoplasms/drug therapy , Cost-Benefit Analysis , Drug Costs , Female , Health Care Costs , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Quality-Adjusted Life YearsABSTRACT
UNLABELLED: Metastatic carcinoma of unknown primary (CUP) has a very poor prognosis, and no standard first-line therapy currently exists. Here, we report the results of a phase II study utilizing a combination of gemcitabine and irinotecan as first-line therapy. Treatment was with gemcitabine 1000 mg/m(2) and irinotecan 75 mg/m(2) weekly times four on a six week cycle (Cohort I). Due to excessive toxicity, the dose and schedule were modified as follows: gemcitabine 750 mg/m(2) and irinotecan 75 mg/m(2) given weekly times three on a four week cycle (Cohort II). The primary endpoint was the confirmed response rate (CR + PR). Secondary endpoints consisted of adverse events based upon the presence or absence of the UDP glucuronosyltransferase 1 family, polypeptide A1*28 (UGT1A1*28) polymorphism, time to progression, and overall survival. Thirty-one patients were enrolled with a median age of 63 (range: 38-94), and 26 patients were evaluable for efficacy. Significant toxicity was observed in Cohort 1, characterized by 50% (7/14) patients experiencing a grade 4+ adverse event, but not in cohort II. The confirmed response rate including patients from both cohorts was 12% (95% CI: 2-30%), which did not meet the criteria for continued enrollment. Overall median survival was 7.2 months (95% CI: 4.0 to 11.6) for the entire cohort but notably longer in cohort II than in cohort I (9.3 months (95% CI: 4.1 to 12.1) versus 4.0 months (95% CI: 2.2 to 15.6)). Gemcitabine and irinotecan is not an active combination when used as first line therapy in patients with metastatic carcinoma of unknown primary. Efforts into developing novel diagnostic and therapeutic approaches remain important for improving the outlook for this heterogeneous group of patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00066781.
Subject(s)
Antineoplastic Agents/therapeutic use , Camptothecin/analogs & derivatives , Deoxycytidine/analogs & derivatives , Neoplasms, Unknown Primary/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Camptothecin/adverse effects , Camptothecin/therapeutic use , Cohort Studies , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Dose-Response Relationship, Drug , Female , Humans , Irinotecan , Male , Middle Aged , Treatment Outcome , GemcitabineABSTRACT
INTRODUCTION: Angiogenesis is an established target for the treatment of MBC. Aflibercept (VEGF-Trap) is a humanized fusion protein, which binds VEGF-A, VEGF-B, and PIGF-1 and -2. PATIENTS AND METHODS: A 2-stage phase II study with primary end points of confirmed tumor response and 6-month progression-free survival (PFS). If either end point was promising after the initial 21 patients, an additional 20 patients would be enrolled. Measurable disease, <2 previous chemotherapy treatments, previous anthracycline or taxane therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1 were required. Aflibercept was given at a dose of 4 mg/kg intravenous every 14 days. RESULTS: Twenty-one patients were enrolled; 71% had visceral disease, 57% were estrogen receptor negative, 19% had HER2(+) disease with previous trastuzumab treatment, and 33% had 2 previous chemotherapy regimens. Partial response rate was 4.8% (95% confidence interval [CI], 0.1%-23.8%) and 6-month PFS was 9.5% (95% CI, 1.2%-30.4%). Neither primary end point met efficacy goals and the study was terminated. A median of 3 cycles was given. Median PFS was 2.4 months. Common grade 3 or 4 adverse events were hypertension (33%), fatigue (19%), dyspnea (14%), and headache (14%). Two cases of severe left ventricular dysfunction were noted. CONCLUSIONS: Aflibercept did not meet efficacy goals in patients previously treated with MBC. Toxicity was as expected for anti-VEGF therapy.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Receptors, Vascular Endothelial Growth Factor/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Anthracyclines/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Bridged-Ring Compounds/administration & dosage , Chemotherapy, Adjuvant , Drug Resistance, Neoplasm/drug effects , Female , Humans , Medical Oncology/organization & administration , Middle Aged , Neoplasm Metastasis , Receptors, Vascular Endothelial Growth Factor/adverse effects , Recombinant Fusion Proteins/adverse effects , Societies, Medical , Survival Analysis , Taxoids/administration & dosage , United StatesABSTRACT
PURPOSE: Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM. METHODS AND MATERIALS: Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals. RESULTS: Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2%, which was not statistically different compared with that of historical control population (48.9%, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT (16.7%) was also not significantly different to that of historical controls (30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS. CONCLUSIONS: In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS.
Subject(s)
Antineoplastic Agents/administration & dosage , Brain Neoplasms/drug therapy , ErbB Receptors/antagonists & inhibitors , Glioblastoma/drug therapy , Quinazolines/administration & dosage , Adult , Aged , Antineoplastic Agents/adverse effects , Brain Neoplasms/genetics , Brain Neoplasms/mortality , Brain Neoplasms/radiotherapy , Chemotherapy, Adjuvant/methods , Dexamethasone/administration & dosage , Diarrhea/chemically induced , Disease-Free Survival , Drug Administration Schedule , Enzyme Activators/administration & dosage , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Gefitinib , Gene Amplification/genetics , Genes, erbB-1/genetics , Glioblastoma/genetics , Glioblastoma/mortality , Glioblastoma/radiotherapy , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Quinazolines/adverse effects , Young AdultABSTRACT
The standard therapies of surgery, radiotherapy, and hormonal manipulations often fail to control metastatic prostate cancer (PC). Docetaxel and thalidomide may have activity in refractory PC. We highlight the potential pulmonary toxicity when docetaxel is combined with thalidomide. We reviewed three examples of docetaxel and thalidomide pulmonary toxicity at the National Cancer Institute (NCI) and summarized the published literature regarding docetaxel and thalidomide pulmonary toxicity. Docetaxel and thalidomide pulmonary toxicity has the following four main presentations: (1). symptomatic effusions; (2). dyspnea on exertion without any objective pathologic evidence; (3). interstitial lung disease; and (4). pulmonary embolus. As chemotherapy becomes more common in the treatment of PC, clinicians must consider possible pulmonary toxicities. If pulmonary symptoms or signs develop, clinicians should consider holding chemotherapy pending a complete evaluation.