Survival of patients in a Phase 1 clinic

BACKGROUND:

Patients with advanced malignancies for whom standard therapy is ineffective may participate in phase 1 trials. To gain a better understanding of the clinical features that could influence benefit versus risk, the authors of this report assessed prognostic factors and survival for patients who were referred to a phase 1 clinic focused primarily on targeted agents.

METHODS:

The medical records of 200 sequential patients who presented to the Phase 1 Clinic at The University of Texas M. D. Anderson Cancer Center were reviewed, and their characteristics and survival were analyzed.

RESULTS:

The median patient age was 58 years (range, 12‐85 years), and 57% of patients were men. The median number of prior therapies was 4. Of 200 patients, 182 were treated on at least 1 phase 1 clinical trial. The median follow‐up of surviving patients was 21 months, and the median overall survival was 9 months (95% confidence interval [CI], 7.4‐10.8). In univariate analysis, the factors that predicted shorter survival were primary tumor in the gastrointestinal tract; a history of thrombosis, liver metastases, and elevated levels of serum lactate dehydrogenase; platelet count; carbohydrate antigen 9 (Ca19‐9) and Ca‐125 levels; aspartate aminotransferase levels, and alkaline phosphatase levels (P < .05 for each). In multivariate analysis, independent factors that predicted shorter survival were a history of thromboembolism (hazard ratio [HR], 2.38; 95% CI, 1.29‐4.39; P = .005), platelets ≥440 × 10⁹/L (HR, 1.72; 95% CI, 1.12‐2.65; P = .014), and the presence of liver metastases (HR, 1.51; 95% CI, 1.09‐2.09; P = .013).

CONCLUSIONS:

Patients who were referred to phase 1 studies had a short median survival (9 months). Patients with thrombocytosis, liver metastases, and a history of thromboembolism had worse outcomes. A prognostic score is proposed. Cancer 2009. © 2009 American Cancer Society.     

Phase 1 clinical trials in 83 patients with pancreatic cancer

BACKGROUND:

The outcomes of patients with pancreatic cancer treated on early phase clinical trials have not been systematically analyzed. The purpose of this study was to report the presenting characteristics and outcomes of patients with locally advanced or metastatic pancreatic cancer treated on phase 1 clinical trials at a single institution.

METHODS:

The authors reviewed the records of consecutive patients with metastatic pancreatic cancer who were treated in the Phase I Clinical Trials Program at The University of Texas M. D. Anderson Cancer Center from November 2004 to March 2009. Data recorded and analyzed included survival, response, and disease characteristics.

RESULTS:

Eighty‐three patients were identified. The median age was 62 years (range, 39‐81 years). Of 78 patients evaluable for response, 2 (3%) had a partial response (PR), and 10 (13%) had stable disease (SD) for ≥4 months. With a median follow‐up for survivors of 3.7 months, the median survival from presentation in the phase 1 clinic was 5.0 months (95% confidence interval [CI], 3.3‐6.2). The median overall survival from diagnosis was 22.1 months (95% CI, 17.9‐26.5). The median time to treatment failure was 1.5 months (95% CI, 1.3‐1.8). Independent factors associated with lower rates of PR/SD were liver metastases (P = .001) and performance status >0 (P = .01). Independent factors associated with shorter survival were liver metastases (P = .007), low calcium level (P = .015), and elevated CEA level (>6 ng/mL) (P = .005).

CONCLUSIONS:

Our results suggest that phase 1 clinical trials offer a reasonable therapeutic approach for patients with advanced pancreatic cancer. Cancer 2011. © 2010 American Cancer Society.     

Low immunogenicity of seasonal trivalent influenza vaccine among patients receiving docetaxel for a solid tumour: results of a prospective pilot study

Background:

Patients receiving cytotoxic therapy for solid tumours are at risk of severe influenza. However, few data are available regarding the immunogenical efficacy of influenza vaccine in these patients.

Methods:

In this prospective study, 25 patients with breast (n=13) or prostate (n=12) cancer received a trivalent inactivated influenza vaccine along with docetaxel (Taxotere) administration. The influenza virus type A and B antibody titres were measured using haemagglutinin inhibition (Garten et al, 2009) before and 21 days after the vaccination. Seroconversion rate was defined as the percentage of patients with an increase in the serum titres ⩾4 after vaccination.

Results:

Median age was 65 years (range: 33–87 years); 52% were females. Seroconversion rates were low: 28% (95% CI: 23.1–33.3) for H1N1, 8% (95% CI: 7.7–8.3) for H3N2 and 16% (95% CI: 7.7–25) for the B strain. The geometric mean titres ratios were 2.16 (H1N1), 1.3 (H3N2) and 1.58 (B). No serious adverse event (AE) related to the vaccine was reported. All the reported AE were from mild-to-moderate intensity.

Conclusion:

In the patients receiving docetaxel for solid tumours, influenza vaccine triggers an immune response in only one third. Strategies using more immunogenic influenza vaccines must be evaluated in such patients.     

Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients

BACKGROUND:

Metastatic colorectal cancer is frequently treated with irinotecan, a topoisomerase‐I inhibitor. The UGT1A1 gene encodes for an enzyme that metabolizes irinotecan, and its genetic variants were shown to be associated with increased drug toxicity. We evaluated clinical outcomes associated with the UGT1A1*28 variant.

METHODS:

The study included 329 colorectal cancer patients from the Israeli population‐based Molecular Epidemiology of Colorectal Cancer study who were treated with a chemotherapy regimen that included irinotecan. Patients with metastases or disease recurrence were followed up for a median period of 2 years after occurrence of the event. Study end points were appearance of grade 3‐4 hematological and gastroenterological toxicity, hospitalization due to toxic events (mostly neutropenia, fever, diarrhea, or vomiting), length of hospitalization, and overall survival. UGT1A1*28 was genotyped from peripheral blood DNA by fragment analysis and reported as number of TATA sequence repeats in the promoter of the gene.

RESULTS:

The 7/7 variant of UGT1A1*28 was detected in 11.9% of the 329 participants. Grade 3‐4 hematological toxicity was significantly higher in 7/7 carriers compared with 6/7 and 6/6 carriers (48.0%,10.2%, and 7.7% respectively; P < .001), as was the risk of toxicity‐related hospitalization (45.8%, 25.3%, and 14.4% respectively; P = .001). Both short‐term death within 2 months of treatment start (12.8%, 5.2%, and 2.9%, respectively) and median overall survival (1.6, 2.0, and 2.4 years, respectively; P = .01) were significantly worse in the 7/7 carriers. The age/stage‐adjusted hazard ratio for patients with the 7/7 genotype compared with 6/6 was 1.7 (95% confidence interval, 1.1‐2.3).

CONCLUSIONS:

The UGT1A1*28 7/7 genotype is strongly associated with severe hematological toxicity and higher hospitalization rate and predicts lower survival of colorectal cancer in users of irinotecan. Cancer 2011. © 2011 American Cancer Society.     

Microsatellite instability,MLH1 promoter methylation,and BRAF mutation analysis in sporadic colorectal cancers of different ethnic groups in Israel

BACKGROUND:

The molecular mechanisms that underlie colorectal cancer (CRC) include microsatellite instability (MSI), chromosomal instability, and the CpG island methylator phenotype. There is evidence to suggest that CRC incidence varies among different ethnic populations worldwide. The authors of this report hypothesized that environmental factors and lifestyle differences among various ethnic groups may differentially influence the epigenetic regulation of tumor suppressor genes in CRC.

METHODS:

In the current study, microdissection and DNA extraction were performed on 128 samples of CRC from Israeli patients (85 Jews and 43 Arabs). MSI analysis, mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) protein expression levels, and MLH1 promoter methylation were investigated by combined bisulfite restriction analysis. The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) valine‐to‐glutamic acid mutation at residue 600 was investigated by direct DNA sequencing.

RESULTS:

High MSI (MSI‐H), MLH1 methylation, and BRAF mutations were observed in 11.6%, 9.4%, and 23.5% of Jews, respectively, and in 16.2%, 17.6%, and 20.9% of Arabs, respectively (P value nonsignificant). MLH1 promoter methylation was observed in 22.6% of microsatellite‐stable (MSS) tumors and in 53.8% of MSI‐H tumors (P < .015). Extensive methylation (covering both 5′ and 3′ promoter regions) was present in all MSI‐H tumors with loss of MLH1 expression. BRAF mutation was observed in 15.6% and 46.1% of MSS tumors and MSI‐H tumors, respectively (P < .007). BRAF mutation was observed in 66%, 22.2%, and 14.7% of patients who had tumors with extensive MLH1 promoter methylation, methylation of the 5′ region alone, or without methylation, respectively (P < .006).

CONCLUSIONS:

There was no difference in molecular signatures examined between Jewish and Arab patients with CRC in Israel. Extensive promoter methylation was associated with MLH1 inactivation, MSI, and BRAF mutation. Cancer 2009. © 2009 American Cancer Society.     

Timing of palliative care referral and symptom burden in phase 1 cancer patients

BACKGROUND:

Phase 1 trials offer patients with advanced cancer the opportunity to pursue life‐prolonging cancer treatments. In the current study, the timing of referral and symptom burden between patients referred to palliative care by phase 1 oncologists and those referred by non‐phase 1 oncologists were compared.

METHODS:

All 57 patients with advanced solid tumors who were referred by phase 1 oncologists to the palliative care outpatient clinic at The University of Texas M. D. Anderson Cancer Center (MDACC) between 2007 and 2008 were included. The comparison cohort was comprised of 114 non‐phase 1 patients who were stratified by age, sex, and cancer diagnosis in a 1:2 ratio. Information regarding patient characteristics, Edmonton Symptom Assessment Scale (ESAS), timing of referral, and survival was retrieved.

RESULTS:

Both cohorts had the following matched characteristics: average age of 57 years, with44% of the patients being female and 47% having gastrointestinal cancers. At the time of palliative care consultation, patients referred by phase 1 oncologists were more likely than patients referred by non‐phase 1 oncologists to have a better performance status (Eastern Cooperative Oncology Group 0–1: 61% vs 36% [P = .003). The ESAS was not significantly different with the exception of better well‐being in the phase 1 cohort (mean, 4.5 vs 5.5; P = .03). No difference was found for the duration between registration at MDACC and palliative care consultation (13 months vs 11 months; P = .41) and overall survival from the time of palliative care consultation (5 months vs 4 months; P = .69).

CONCLUSIONS:

Outpatients referred to palliative care by phase 1 oncologists were found to have a better performance status but similar symptom burden compared with patients referred by non‐phase 1 oncologists. Patients with phase 1 involvement did not appear to have delayed palliative care referral compared with non‐phase 1 patients. The results of the current study support the development of a simultaneous care model. Cancer 2010. © 2010 American Cancer Society.     

A phase 1 study of systemic ADH‐1 in combination with melphalan via isolated limb infusion in patients with locally advanced in‐transit malignant melanoma

BACKGROUND:

Isolated limb infusion with melphalan is a well‐tolerated treatment for patients with in‐transit extremity melanoma with an approximately 30% complete response (CR) rate. ADH‐1 is a cyclic pentapeptide that disrupts N‐cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH‐1 in combination with melphalan via isolated limb infusion in patients with in‐transit extremity melanoma was performed.

METHODS:

Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH‐1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N‐cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors.

RESULTS:

Sixteen patients have been treated with no observed dose‐limiting toxicities. Common treatment‐related grade 1 or 2 toxicities included skin/dermatologic (n = 14) and pain (n = 12). Grade 3 toxicities included shortness of breath (n = 1), hypertension (n = 1), serologic toxicities (n = 4), and 1 grade 4 creatine phosphokinase elevation. In‐field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH‐1 concentrations at each dose and minimal variability in melphalan drug levels.

CONCLUSIONS:

Systemic ADH‐1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well‐tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N‐cadherin may be a new strategy for overcoming melanoma chemoresistance. Cancer 2009. © 2009 American Cancer Society.     

Clinical significance of large rearrangements in BRCA1 and BRCA2

BACKGROUND:

Current estimates of the contribution of large rearrangement (LR) mutations in the BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 2, early onset) genes responsible for hereditary breast and ovarian cancer are based on limited studies of relatively homogeneous patient populations. The prevalence of BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histories and ancestries, referred for clinical molecular testing for suspicion of hereditary breast and ovarian cancer.

METHODS:

Sanger sequencing analysis was performed for BRCA1/2 and LR testing for deletions and duplications using a quantitative multiplex polymerase chain reaction assay. Prevalence data were analyzed for patients from different risk and ethnic groups between July 2007 and April 2011. Patients were designated as “high‐risk” if their clinical history predicted a high prior probability, wherein LR testing was performed automatically in conjunction with sequencing. “Elective” patients did not meet the high‐risk criteria, but underwent LR testing as ordered by the referring health care provider.

RESULTS:

Overall BRCA1/2 mutation prevalence among high‐risk patients was 23.8% versus 8.2% for the elective group. The mutation profile for high‐risk patients was 90.1% sequencing mutations versus 9.9% LRs, and for elective patients, 94.1% sequencing versus 5.9% LRs. This difference may reflect the bias in high‐risk patients to carry mutations in BRCA1, which has a higher penetrance and frequency of LRs compared with BRCA2. There were significant differences in the prevalence and types of LRs in patients of different ancestries. LR mutations were significantly more common in Latin American/Caribbean patients.

CONCLUSIONS:

Comprehensive LR testing in conjunction with full gene sequencing is an appropriate strategy for clinical BRCA1/2 analysis. Cancer 2012. © 2012 American Cancer Society.     

Phase 1 study of oxaliplatin and irinotecan in pediatric patients with refractory solid tumors

BACKGROUND:

For this report, the authors estimated the maximum tolerated dose (MTD) and investigated the toxicities of oxaliplatin combined with irinotecan in children with refractory solid tumors.

METHODS:

Oxaliplatin was administered on Days 1 and 8 in combination with irinotecan on Days 1 through 5 and Days 8 through 12 of a 21‐day cycle. An oral cephalosporin was administered daily to ameliorate irinotecan‐associated diarrhea. Pharmacokinetic studies of oxaliplatin and uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotyping were performed.

RESULTS:

Thirteen patients were enrolled. Dose‐limiting diarrhea (n = 3), serum lipase elevation (n = 3), serum amylase elevation (n = 2), colitis, abdominal pain, and headache (n = 1 each) occurred at the first dose level (oxaliplatin at a dose of 60 mg/m²; irinotecan at a dose of 20 mg/m²). Only 1 of 7 patients who received reduced doses of both agents (40 mg/m²/dose oxaliplatin; 15 mg/m²/dose irinotecan) experienced a dose‐limiting toxicity (DLT): diarrhea. When the oxaliplatin dose was re‐escalated (60 mg/m²) with irinotecan at a dose of 15 mg/m², 2 of 3 patients had a DLT (1 episode of diarrhea, 1 episode of hypokalemia). Myelosuppression was minimal. One patient had a complete response, and another patient had stable disease for 6 cycles of therapy. The median oxaliplatin area under the concentration versus time curve (AUC_0→∞) was 5.9 μg · hour/mL (range, 1.8‐7.6 μg · hour/mL). The frequency of the 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes was 5 of 10, 4 of 10, and 1 of 10, respectively.

CONCLUSIONS:

The oxaliplatin MTD was 40 mg/m² per dose on Days 1 and 8 in combination with irinotecan 15 mg/m² per dose on Days 1‐5 and Days 8‐12. There was some evidence of antitumor activity; however, severe toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was observed. Cancer 2009. © 2009 American Cancer Society.     

Microtubule‐damaging agents enhance RASSF1A‐induced cell death in lung cancer cell lines

BACKGROUND:

Tumor suppressor gene product RASSF1A has been reported to induce mitotic arrest and apoptosis through its interaction with microtubule and binding to the Ras effector NORE1. Despite this promising antitumor action of microtubule‐targeted drugs, clinical studies demonstrated that paclitaxel (TXL) and vincristine (VCS) have differential antitumor effects, depending on the status of microtubule‐related genes in lung cancer patients. In this study, to provide effective chemotherapeutic treatment for lung cancer patients with the microtubule‐targeted drugs, the authors investigated whether RASSF1A could enhance sensitivity to TXL and VCS, as an intrinsic microtubule modulator, in nonsmall cell lung cancer (NSCLC) cells.

METHODS:

The growth inhibitory effects of TXL and VCS on RASSF1A‐transfected cells were assessed using clonogenic and flow cytometry–based propidium iodide–labeled assay. The levels of mitosis‐related proteins in RASSF1A‐transfected cells after treatment with TXL or VCS were examined by Western blot analysis and in vitro kinase assay.

RESULTS:

RASSF1A enhanced the growth inhibitory effect of TXL and VCS on NSCLC cells and bronchial epithelial transformed cells (BEAS‐2B) by inducing cell cycle arrest at the G₂/M?phase. Accumulation of cyclin B1, G₂/M‐phase–related protein, was observed when RASSF1A‐transfected H1299 cells were treated with TXL or VCS, accompanied with an increase of cyclin A. Inhibition of the activity of cyclin B1/Cdc2 complex by RASSF1A and TXL or VCS was confirmed by kinase assay and knockdown of RASSF1A expression by using small interfering RNA.

CONCLUSIONS:

RSAAF1A protein has a cooperative growth inhibitory effect with microtubule‐targeted drugs through cyclin B1 accumulation on NSCLC cells, suggesting novel insights for the selection of chemotherapeutic agents. Cancer 2009. © 2009 American Cancer Society.     

Functional regulatory variants of MCL1 contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: implications for context-dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor

BACKGROUND:

Dysfunction of molecules that regulate both apoptosis and proliferation is involved in tumorigenesis. A common insertional polymorphism in promoter of MCL1, a member of BCL2 family gene with the dual regulatory functions, has been shown to be functional in leukemia, but its association with cancer predisposition and prognosis has not been well established. We hypothesized that MCL1 promoter variants may modify risk of solid cancer.

METHODS:

We genotyped ?190 insertional polymorphism and 3 linked single nucleotide polymorphisms (SNPs) (?627A>C, ?298G>C, and ?235C>A) in 320 lung cancer patients and 362 controls, and analyzed their functional significance.

RESULTS:

We confirmed that these regulatory variants correlated with enhanced promoter activity and elevated expression of both mRNA and protein in solid cancer cells and tissues. We further demonstrated that heightened expression of MCL1 resulted in decreased proliferation ability of lung cancer cells. We found a reduced cancer risk (adjusted odds ratio [OR] = 0.47; 95% confidence interval [CI] = 0.25‐0.88) associated with ?190 insertional genotype. Stratification analysis further showed pronounced associations in nonsmokers (OR, 0.25; 95% CI, 0.09‐0.70), in females (OR, 0.22; 95% CI, 0.07‐0.74), and in the histological type of adenocarcinoma (OR, 0.18; 95% CI, 0.05‐0.62). Likewise, homologous diplotype of these polymorhpisms that positively affected gene expression was associated with reduced risk in nonsmokers (OR, 0.19; 95% CI, 0.06‐0.58).

CONCLUSION:

The present study demonstrated that common variants in MCL1 promoter correlated with increased transactivation in solid cancer cells and were associated with reduced risk of lung cancer in nonsmokers, suggesting a dominant antiproliferative function of MCL1 against its antiapoptosis effect in development of solid cancer in nonsmokers. Cancer 2012. © 2011 American Cancer Society.     

Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001‐2007)

BACKGROUND:

The incidence, epidemiology, Candida species distribution, resistance patterns, and outcome of candidemia in high‐risk hematologic malignancy and/or stem cell transplantation patients have not been extensively described since the introduction of new antifungal agents.

METHODS:

In this retrospective study, the authors reviewed the medical records and microbiologic data of hematologic malignancy patients with candidemia at The University of Texas M. D. Anderson Cancer Center from March 2001 to February 2007.

RESULTS:

The authors analyzed 173 episodes of candidemia (170 patients), 125 (72%) of which were breakthrough cases after prior antifungal agents, mainly fluconazole (28 [22%]), caspofungin (25 [20%]), and voriconazole (18 [14%]). The incidence of candidemia (per 100,000 inpatient days) remained relatively stable, from 13.9 in 2001 to 19.2 in 2006. However, compared with the findings of previous studies at the authors' institution, the frequency of Candida glabrata and C. krusei infection decreased (to 5% and 17%, respectively) and C. parapsilosis (24%) and C. tropicalis (21%) increased. C. parapsilosis fungemia was associated with prior caspofungin use (P < .001). The overall 30‐day crude mortality rate was 38%, and the attributable mortality rate was 19%, similar to previous findings at the authors' institution. The Candida species associated with the highest mortality rate was C. glabrata.

CONCLUSIONS:

Despite the widespread use of antifungal prophylaxis and the introduction of new antifungal agents, the incidence and associated mortality rates of candidemia remained stable in high‐risk hematologic malignancy patients. However, its epidemiological characteristics have shifted, with C. parapsilosis and C. tropicalis becoming more common. Cancer 2009. © 2009 American Cancer Society.     

Herpes simplex virus lower respiratory tract infection in patients with solid tumors

BACKGROUND:

The clinical significance of herpes simplex virus (HSV) isolated in lower respiratory tract specimens (LRTS) of patients with solid tumors (ST) is unknown. In the current study, the authors attempted to determine the clinical relevance of this finding among ST patients.

METHODS:

The authors reviewed records of ST patients admitted to the study institution between April 2000 and April 2004 with clinical and radiologic evidence of pneumonia, and HSV identified in LRTS by culture alone or culture and cytology. Patients were categorized as having proven (HSV identified by culture and cytology from the LRTS), probable (HSV as the sole pathogen by culture alone), and possible (HSV along with copathogens identified by culture) HSV pneumonia.

RESULTS:

Forty‐five ST patients with either proven (6 patients), probable (25 patients), or possible (14 patients) HSV pneumonia were identified. When compared with patients with probable or possible HSV pneumonia, more patients with proven infection were on mechanical ventilation (40% vs 50% vs 100%, respectively; P = .03), and had longer length of stay in the intensive care unit (12 days vs 13 days vs 26 days, respectively; P = .05). The overall mortality rate was 22% (10 patients). Four of 25 (16%) patients who received HSV‐directed antiviral therapy died during their hospital stay versus 6 of 20 (30%) who were not treated (P = .3). None of the 6 patients with proven HSV pneumonia who were treated with acyclovir died. On univariate analysis, risk factors for mortality included underlying breast cancer, an Acute Physiology and Chronic Health Evaluation (APACHE) II score >15, admission to the intensive care unit, and use of mechanical ventilation and vasopressors (all P ≤ .05), with underlying breast cancer and APACHE II score >15 being found to be independent predictors of death by multiple logistic regression analysis (all P ≤ .05).

CONCLUSIONS:

Having a proven HSV pneumonia appears to be associated with high morbidity and with no increase in mortality in ST patients. This subset of patients appears to benefit from acyclovir therapy. Cancer 2009. © 2008 American Cancer Society.     

Preliminary indication of survival benefit from ERCC1 and RRM1-tailored chemotherapy in patients with advanced nonsmall cell lung cancer: evidence from an individual patient analysis

BACKGROUND:

Excision repair cross complementing 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) are molecular determinants that predict sensitivity or resistance to platinum agents and gemcitabine, respectively. Tailored therapy using these molecular determinants suggested patient benefit in a previously reported phase 2 trial. Here, we report an individual patient analysis of prospectively accrued patients who were treated with the “personalized therapy” approach versus other “standard,” noncustomized approaches.

METHODS:

Patients who had nonsmall cell lung cancer (NSCLC) with extranodal metastatic disease and an Eastern Cooperative Oncology Group performance status of 0/1 were accrued to 4 phase 2 clinical trials conducted at the H. Lee Moffitt Cancer Center: Trial A (first‐line carboplatin/gemcitabine followed by docetaxel), Trial B (docetaxel and gefitinib in patients aged ≥70 years), Trial C (combination therapy with carboplatin/paclitaxel/atrasentan), and Trial D (personalized therapy based on ERCC1 and RRM1 expression). Patients with low RRM1/low ERCC1 expression received gemcitabine/carboplatin, patients with low RRM1/high ERCC1 expression received gemcitabine/docetaxel, patients with high RRM1/low ERCC1 expression received docetaxel/carboplatin, and patients with high RRM1/high ERCC1 expression received vinorelbine/docetaxel. Patients who were treated on Trials A, B, and C were pooled together and analyzed as the “standard therapy” group. Patients accrued to Trial D were called the “personalized therapy” group. Individual patient data were updated as of February 8, 2011. Overall survival (OS) and progression‐free survival (PFS) were estimated using the Kaplan‐Meier method.

RESULTS:

There were statistically significant improvements between the personalized therapy group versus the standard therapy group in response (44% vs 22%; P = .002), OS (median: 13.3 months vs 8.9 months; P = .016), and PFS (median: 7.0 months vs 4.3 months; P = .03).

CONCLUSIONS:

The results from individual patient analyses suggest that ERCC1 and RRM1/tailored selection of first‐line therapy improved survival over standard treatment‐selection approaches. Cancer 2012. © 2011 American Cancer Society.     

Gender disparity in the rate of partner abandonment in patients with serious medical illness

BACKGROUND:

Life‐threatening illness creates severe stress that may result in marital discord, separation, or divorce and may adversely impact treatment, quality of life, and survival. The few studies that are available to date have suggested that the risk of divorce is not higher in cancer patients, but to the authors' knowledge, no data exist to date that have examined the effect of gender on this rate.

METHODS:

A total of 515 patients were prospectively identified as having either a malignant primary brain tumor (N = 214), a solid tumor with no nervous system involvement (N = 193), or multiple sclerosis (N = 108) who were married at the time of diagnosis. Basic demographic information and data regarding marital status were compiled. Patients were followed prospectively from enrollment until death or study termination.

RESULTS:

Women composed 53% of the patient population. Divorce or separation occurred at a rate similar to that reported in the literature (11.6%). There was, however, a greater than 6‐fold increase in risk after diagnosis when the affected spouse was the woman (20.8% vs 2.9%; P < .001). Female gender was found to be the strongest predictor of separation or divorce in each cohort. Marriage duration at the time of illness was also correlated with separation among brain tumor patients (P = .0001). Patients with brain tumors who were divorced or separated were more likely to be hospitalized, and less likely to participate in a clinical trial, receive multiple treatment regimens, complete cranial irradiation, or die at home (P < .0001).

CONCLUSIONS:

Female gender was found to be a strong predictor of partner abandonment in patients with serious medical illness. When divorce or separation occurred, quality of care and quality of life were adversely affected. Cancer 2009. © 2009 American Cancer Society.     

Association of PAI‐1 gene polymorphism with survival and chemotherapy‐related vascular toxicity in testicular cancer

BACKGROUND:

High Plasminogen‐Activator Inhibitor 1 (PAI‐1) expression by tumors has been associated with poor prognosis in several cancer types, and high systemic PAI‐1 levels with increased thrombosis risk. The authors investigated whether the germline 4G/5G deletion/insertion polymorphism in the PAI‐1 promoter (rs1799889), which may influence PAI‐1 expression, is associated with survival and chemotherapy‐related vascular toxicity in testicular cancer (TC).

METHODS:

Data were collected on PAI‐1 4G/5G polymorphism, survival, venous thromboembolism (VTE), and coronary heart disease (CHD) for 324 non‐seminomatous TC patients treated with platinum‐based chemotherapy. Genotypes were compared regarding survival and disease outcome. VTE and CHD incidence were compared with adjustment for cardiovascular risk factors and prothrombotic gene polymorphisms of coagulation factors II/prothrombin (G20210A) and V (G1691A).

RESULTS:

The 4G/4G variant of PAI‐1 4G/5G polymorphism shows a higher prevalence of International Germ Cell Cancer Classification (IGCCC) poor prognosis compared with 4G/5G and 5G/5G (24% vs 8% and 15%; chi‐square P = .003). In addition, the 4G/4G variant shows reduced TC‐related survival with a hazard ratio of 2.69 (95% CI, 1.26‐5.73; P = .010) for TC‐related death (adjusted for IGCCC). This is related to an increased risk for refractory disease and early relapses (odds ratio, 3.35; 95% CI, 1.48‐7.59; P = .004). PAI‐1 4G/5G polymorphism is not associated with VTE and CHD risk.

CONCLUSIONS:

The 4G/4G variant of PAI‐1 4G/5G polymorphism may be an unfavorable prognostic as well as predictive factor for response to chemotherapy in TC patients. If confirmed, it may contribute to the identification of patients with increased risk for refractory disease. Cancer 2010. © 2010 American Cancer Society.     

Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors

BACKGROUND:

Preclinical testing suggests the combination of carboplatin and irinotecan has at least additive antitumor activity. The primary objectives of the current study were to determine the maximum tolerated doses (MTDs) and recommended phase 2 doses of carboplatin administered with irinotecan to pediatric patients with refractory solid tumors.

METHODS:

This was a multicenter, open‐label, single‐arm dose escalation study in which subjects with refractory solid tumors received 21‐day treatment cycles of intravenous carboplatin on Day 1 followed by intravenous irinotecan administered daily for 10 days within 2 consecutive weeks. The plasma pharmacokinetics of ultrafiltrable platinum, irinotecan, and 2 irinotecan metabolites were determined during Cycle 1. The interpatient plan for dose escalation at study initiation was to increase irinotecan first followed by increases in carboplatin.

RESULTS:

Twenty‐eight patients with a median age of 8.5 years (range, 1‐21 years) were enrolled with a variety of solid tumors. Two of 6 subjects at the first dose level (carboplatin target area under the curve [AUC], 4.0 mg/mL*min; irinotecan, 18 mg/m²/dose) experienced dose‐limiting gastrointestinal toxicities requiring a dose de‐escalation scheme (carboplatin AUC, 4.0 mg/mL*min; irinotecan, 15 mg/m²/dose). Three of 6 subjects at the second dose level experienced dose‐limiting gastrointestinal complications and bone marrow suppression. A further dose de‐escalation to carboplatin AUC of 4.0 mg/mL*min and irinotecan of 12 mg/m²/dose resulted in dose‐limiting bone marrow suppression in 1 of 13 patients treated at that dose, and therefore was determined to be the MTD. One complete response (in a patient with medulloblastoma) and 3 partial responses (in patients with neuroblastoma, medulloblastoma, and lymphoendothelial carcinoma, respectively) were observed.

CONCLUSIONS:

The recommended phase 2 dose in heavily pretreated pediatric patients is carboplatin (AUC, 4 mg/mL*min on Day 1) and irinotecan (12 mg/m²/ day × 10 days) given every 21 days. Cancer 2009. © 2008 American Cancer Society.     

Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy

BACKGROUND:

The prognosis of patients with myelodysplastic syndrome (MDS) after decitabine failure is not known.

METHODS:

Data from 87 patients with MDS (n = 67) and chronic myelomonocytic leukemia (n = .20) after failure of decitabine regimens were reviewed.

RESULTS:

After a median follow‐up of 21 months from decitabine failure, 13 (15%) patients remained alive; the median survival was 4.3 months, and the estimated 12‐month survival rate was 28%. The estimated 12‐month survival rates were 27%, 33%, and 33%, respectively, for patients with high‐risk, intermediate‐2‐risk, and intermediate‐1‐risk disease (P = .99) by the International Prognostic Scoring System. The estimated 12‐month survival rates were 100%, 54%, 41%, and 18%, respectively, for patients with low‐risk, intermediate‐1‐risk, intermediate‐2‐risk, and high‐risk disease according to The University of Texas M. D. Anderson Cancer Center risk model (P = .01).

CONCLUSIONS:

The outcome of patients after decitabine failure is poor and appears to be predictable after decitabine failure. Cancer 2010. © 2010 American Cancer Society.