The literature examining obesity as a barrier to screening for breast, cervical, and colorectal cancer has not been evaluated systematically. With the increasing prevalence of obesity and its impact on cancer incidence and mortality, it is important to determine whether obesity is a barrier to screening so that cancers among women at increased risk because of their body size can be detected early or prevented entirely. On the basis of 32 relevant published studies (10 breast cancer studies, 14 cervical cancer studies, and 8 colorectal cancer studies), the authors reviewed the literature regarding associations between obesity and recommended screening tests for these cancer sites among women in the U.S. The most consistent associations between obesity and screening behavior were observed for cervical cancer. Most studies reported an inverse relation between decreased cervical cancer screening and increasing body size, and several studies reported that the association was more consistent among white women than among black women. For breast cancer, obesity was associated with decreased screening behavior among white women but not among black women. The literature regarding obesity and colorectal cancer screening adherence was mixed, with some studies reporting an inverse effect of body size on screening behavior and others reporting no effect. Overall, the results indicated that obesity most likely is a barrier to screening for breast and cervical cancers, particularly among white women; the evidence for colorectal cancer screening was inconclusive. Thus, efforts to identify barriers and increase screening for breast and cervical cancers may be targeted toward obese women, whereas outreach to all women should remain the objective for colorectal cancer screening programs.
The long term effects of initial therapy are a combined consequence of the effects of treatment on the cancer and on the host. Local tumor control, whatever its impact on the occurrence of metastasis, is an achievable and worthwhile goal of therapy and the methods for attaining it may have significantly different effects on quality of life. These considerations are grossly illustrated for renal cell, bladder and prostatic cancers.
The term quality of life (QL) is a global characterization usually consisting of the following factors: physical function, symptoms from disease and/or treatment, occupational and social interactions, and psychological parameters, including mood with some overall assessment of well-being, such as happiness or satisfaction. For the purposes of individual patient management, the physician often assesses many of these in the process of making decisions about cancer care. The aggregate assessment of QL in groups of patients is more difficult. The increasing subjectivity and difficulty in measurement as medical observers move from the physical (objective parameters) to the psychosocial (subjective parameters) has hindered our ability to study QL. The changing status of the patient from initial symptomatic disease, to the incapacitation related to the treatment and/or the ongoing course of the disease often leading to death makes the measurement of QL a moving target. One must be very specific as to the malignancy, the status of disease, the treatments with their side effects and sequela, and the time of measurement in this dynamic spectrum, if the data is to be comparable and to permit generalizations. For the purposes of clinical trials the emphasis remains with the physical factors: function and symptom control. Even these factors are difficult to assess consistently, making the aggregation of such data from similarly treated groups of patients sometimes suspect. The ability to determine the impact of disease and treatment on these factors in a reliable manner could make possible, with aggregated data from many patients, more objective assessment of the advantages and disadvantages of a particular therapy. Late sequelae of treatment may also be important. When cure or prolonged survival are not likely or possible then the ability to determine the probable effects, physical and psychosocial, of a specific treatment on an individual patient is valuable. Treatment then can be guided to some extent by QL considerations.
Concentrations of methotrexate have been determined in the serum and cerebrospinal fluid after 406 infusions of methotrexate to 58 children with acute lymphoblastic leukemia. The dose of methotrexate varied between 500 mg/m2 and 33,600 mg/m2. Pharmacokinetic analysis of the data has been carried out. The effect of dose, age, and number of treatments on steady-state concentration, serum half-life, cerebrospinal fluid (CSF) serum distribution ratio, volume of distribution, systemic clearance of methotrexate was examined. The elevation of dose resulted in a nonproportional increase of the steady-state concentrations both in serum and CSF. The great inpatient and interpatient variations of steady-state concentrations caused only statistically not significant differences in the parameters of different subgroups of dosages. Correlation was found between concentrations of methotrexate in serum and CSF. One to 4 years old children were found to have lower steady-state concentrations of methotrexate in the serum and CSF, greater volume of distribution and faster clearance of the drug. Dose-dependency and age-dependency of methotrexate pharmacokinetics has been concluded.
Large, prospective, randomized trials with long term follow-up are required to obtain an unbiased evaluation of the significance of resection margins in patients with cutaneous melanoma.
The Swedish Melanoma Study Group performed a prospective, randomized, multicenter study of patients with primary melanoma located on trunk or extremities and with a tumor thickness > 0.8 mm and </= 2 mm. Patients were allocated randomly to a 2-cm excision margin or a 5-cm excision margin. In total, 989 patients were recruited during the period 1982-1991. The median follow-up was 11 years (range, 7-17 years) for estimation of survival and 8 years (range, 0-17 years) for evaluation of recurrent disease.
The crude rate of local recurrence, defined as a recurrence in the scar or transplant, was < 1% (8 of 989 patients). Twenty percent of the patients (194 of 989 patients) experienced any disease recurrence, and 15% (146 of 989 patients) died of melanoma. There were no statistically significant differences between the two treatment arms. In a multivariate Cox analysis with patients allocated to wide excision as the reference group, the estimated relative hazards for overall survival and recurrence free survival among those allocated to a 2-cm resection margin were 0.96 (95% confidence interval, 0.75-1.24), and 1.02 (95% confidence interval, 0.80-1.30), respectively.
In this long term follow-up study, local recurrences were found to be rare among patients with tumors > 0.8 mm thick and </= 2.0 mm thick. No difference in recurrence rate or survival between the two treatment groups was found. Patients in this category can be treated with a resection margin of 2 cm as safely as with a resection margin of 5 cm.
The traditional surgical treatment for primary malignant melanoma has often been a wide excision with a margin of about 5 cm. Since the risk of local recurrences is dependent on tumor thickness, thin tumors (<1 mm) have routinely been excised with a narrow margin. For thick tumors, the optimal resection margin is controversial, and can be determined only by prospective, randomized trials.
The Swedish Melanoma Study Group performed a prospective, randomized multicenter study to evaluate an excision margin of 2 versus 5 cm for patients with cutaneous malignant melanoma with tumor thickness > 0.8 and < or = 2.0 mm. The trial includes 769 patients. Patients with melanomas of the skin of the head, neck, hands, feet, or vulva were not included in the trial. In the event of an excision biopsy for diagnosis, radical surgery was completed within 6 weeks. The median follow-up time was 5.8 years for estimation of survival and 4.0 years for diagnosis of recurrent disease.
No significant differences have been observed between the treatment groups regarding local or regional recurrences or survival.
We recommend an excision with a margin of 2 cm for cutaneous malignant melanoma with a tumor thickness > 0.8 and < or = 2.0 mm.
Previous data from an institutional pilot study in patients with advanced or recurrent squamous cell carcinoma of the head and neck (SCCHN) who received treated a combined chemotherapy regimen of paclitaxel, cisplatin, and 5-fluorouracil indicated an overall response rate of 60% and a median survival of 6 months. To validate these results and to determine the feasibility of this combination, a Phase II study was conducted by the Southwest Oncology Group (SWOG S0007).
Patients with advanced or recurrent SCCHN were eligible if they had received 1 previous regimen of induction/adjuvant chemotherapy or no prior systemic therapy. Patients received treatment with paclitaxel (135 mg/m(2) on Day 1), followed by cisplatin (75 mg/m(2) on Day 1), and 5-fluorouracil (1000 mg/m(2)per day as a 96-hour continuous infusion on Days 1-4) every 21 days.
Seventy-six patients received a combined total of 286 cycles of chemotherapy. Sixty-nine patients were evaluable for response. There were 5 complete responses (7%) and 23 partial responses (33%) partial responses, for an overall response rate of 41%. The median progression-free survival was 4 months, and the median overall survival was 10 months. Six treatment-related deaths were documented, including deaths in 2 patients who had a Zubrod PS of 2. Grade 3 or 4 neutropenia (according to National Cancer Institute Common Toxicity Criteria [version 2.0]) was observed in 47% of patients. Other Grade 3 or 4 adverse events included mucositis (34% of patients), nausea (20% of patients), anemia (9% of patients), and neuropathy (8% of patients).
The combination of paclitaxel, cisplatin, and 5-fluorouracil had efficacy similar to that of standard treatment regimens in patients with advanced or recurrent SCCHN but with increased toxicity.
Osteoprotegerin (OPG) is a decoy receptor for OPG ligand (OPGL), or receptor activator of NF-kappaB ligand (RANKL). RANKL/RANK interaction is important in terminal differentiation and activation of osteoclasts. In binding to RANKL, OPG blocks differentiation and activation of osteoclasts. AMGN-0007 is a recombinant OPG construct developed as a potential therapeutic agent in the treatment of bone disease.
A randomized, double-blind, double-dummy, active-controlled, single-dose, dose escalation study was conducted to determine the safety and effect on bone resorption of AMGN-0007 in patients with multiple myeloma (n = 28) or breast carcinoma (n = 26) with radiologically confirmed lytic bone lesions. Patients were randomized (3:1 ratio) to receive a single dose of either AMGN-0007 (subcutaneously [SC]) or pamidronate (90 mg intravenously) and were followed for 56 days. Medications or other diseases affecting bone metabolism and chemotherapy within 28 days of dosing were exclusion criteria. Biologic activity of AMGN-0007 was assessed by measurement of the surrogate marker of bone resorption, urinary N-telopeptide of collagen (NTX).
AMGN-0007 caused a rapid, sustained, dose-dependent decrease in NTX/creatinine levels, which was at least comparable to the profile observed with pamidronate. Four serious adverse events were reported, three in breast carcinoma patients: a fracture in the left femur (pamidronate, considered unrelated), extreme fatigue (0.3 mg/kg AMGN-0007, considered unrelated), and congestive heart failure (1.0 mg/kg AMGN-0007, considered by the investigator to be probably related to doxorubicin and radiation therapy); one event occurred in a multiple myeloma patient: Herpes zoster (pamidronate, considered unrelated). Two multiple myeloma patients (1.0 mg/kg AMGN-0007) had albumin-adjusted serum calcium levels of 1.9 mmol/L on Day 8 but without clinical symptoms.
A single SC dose of AMGN-0007 suppressed bone resorption as indicated by a rapid, sustained, and profound decrease of urinary NTX/creatinine in multiple myeloma and breast carcinoma patients. Changes were comparable to those with pamidronate. AMGN-0007 was well tolerated.
For patients with advanced soft tissue sarcoma (STS), no standard treatment is established after previous chemotherapy with anthracyclines and ifosfamide. Bendamustine hydrochloride is a bifunctional alkylating agent that is not cross-resistant to other DNA-interacting substances including anthracyclines and oxazaphosphorines. It has shown single-agent activity in refractory lymphoma, myeloma, and some solid tumors. A phase 2 study was initiated to evaluate the efficacy of bendamustine in previously treated patients.
Thirty-six of 44 screened patients were included and received a total of 101 cycles (median, 2 cycles; range, 1-8 cycles), 21 as second-line treatment and 15 as third-line treatment. The median age was 55 years (range, 18-79 years). Bendamustine was given as an intravenous infusion over 30 minutes at a dose of 100 mg/m(2) on 2 consecutive days and repeated every 28 days. Eighty-eight percent of cycles could be given without dose or schedule modification.
The toxicity profile was mild, consisting of National Cancer Institute Common Toxicity Criteria (CTC) grade 3 neutropenia in 11% and grade 3 anemia in 9% of patients. Nonhematologic toxicities were noticed with CTC grade 3 fever in 3% of patients. No other grade 3 toxicity and no treatment-related toxic deaths were observed. The best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 1 partial remission (3%) and disease stabilizations in 31% of patients. Six of 15 patients (40%) with leiomyosarcoma histology achieved stable disease. The estimated 3-month and 6-month progression-free survival rates were 35.3% and 23.5%, respectively, for all histologic subtypes included.
In patients with refractory STS, bendamustine is well tolerated and appears moderately effective, particularly in patients with leiomyosarcoma histology.
The combination of external-beam radiotherapy and brachytherapy is used commonly to treat men with prostate cancer. In this analysis, the authors examined the rate of biochemical recurrence (BR) and late grade > or =3 genitourinary (GU) and gastrointestinal (GI) toxicity after treatment with external-beam radiotherapy and brachytherapy in a multiinstitutional, cooperative group setting.
All eligible patients received external-beam radiotherapy (45 Gray [Gy] in 25 fractions) followed 2 to 6 weeks later by an interstitial implant using iodine-125 to deliver an additional 108 Gy. BR was defined in 2 ways: according to the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Definition (ACD) and according to the Phoenix definition (PD) (prostate-specific antigen nadir +2 ng/mL). The Radiation Therapy Oncology Group(RTOG)/European Organization for Research and Treatment of Cancer late radiation morbidity scoring system was used to grade all toxicity.
One hundred thirty-eight patients were enrolled, and 130 were eligible for the current analysis. The median follow-up for surviving patients was 49 months (range, 20-60 months). The 48-month estimate of late grade > or =3 GU/GI toxicity was 15% (95% confidence interval [95% CI], 8-21%), and the 48-month estimate of BR was 19% (95% CI, 12-26%) and 14% (95% CI, 8-20%) according to the ACD and PD, respectively.
The morbidity observed in this multiinstitutional, cooperative group study was slightly higher than that reported in recent RTOG studies using brachytherapy alone or high-dose external-beam radiotherapy. The BR rate observed in this report was similar to that observed with high-dose external-beam radiotherapy alone in similar patients.
Southwest Oncology Group protocol 0026 evaluated interferon alpha-2b plus thalidomide in patients with disseminated melanoma. Endpoints were 6-month progression-free survival rate, response rate, and toxicity.
Twenty-six patients with Stage IV melanoma, measurable or nonmeasurable disease, performance status of 0-2, and adequate renal and hepatic functions were registered. One prior systemic therapy for Stage IV disease was required. Interferon was administered subcutaneously (1 million U) twice daily; thalidomide was orally administered (200-400 mg) each evening in a dose-escalating manner. Response evaluations using Response Evaluation Criteria in Solid Tumors were performed every 8 weeks.
After 2 sudden deaths and 1 grade 4 treatment-related pulmonary embolism, this study was temporarily closed. One patient with deep-vein thrombosis and 2 with grade 3 cardiac arrhythmias were reported. The relationship of these events to the treatment was worrisome but not definitive. Grade 3 treatment-related adverse events occurred in 14 of 26 patients. Because of concern for patient safety the study was permanently closed. No treatment responses were seen in the 22 evaluable patients. Estimated 6-month progression-free survival rate was 15% (95% confidence interval [CI], 2%-29%), estimated 6-month overall survival was 58% (95% CI, 39%-77%), and estimated response probability was 0 of 22 (95% CI, 0%-15%).
This regimen demonstrated a lack of response and was associated with multiple severe toxicities. Further investigation of interferon alpha-2b and thalidomide in this dose and schedule is not warranted.
This phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health-related quality of life of dacomitinib (PF-00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild-type non-small cell lung cancer (NSCLC).
Patients with advanced NSCLC, progression on 1 or 2 regimens of chemotherapy and erlotinib, KRAS wild-type or known EGFR-sensitizing mutant tumor, and Eastern Cooperative Oncology Group performance status of 0 to 2 received 45 mg of dacomitinib once daily continuously in 21-day cycles.
A total of 66 patients enrolled (adenocarcinoma, n = 50; those without adenocarcinoma [nonadenocarcinoma], n = 16). The objective response rate (ORR) for patients with adenocarcinoma (primary endpoint) was 5% (2 partial responses; 1-sided P = .372 for null hypothesis [H0 ]: ORR ≤ 5%) and 6% (1 partial response) for patients with nonadenocarcinoma. Responders included: 2 of 25 EGFR mutation-positive tumors; 1 of 3 EGFR wild-type with HER2 amplification. Median progression-free survival was 12 weeks overall (n = 66) and 18 weeks (n = 26) for patients with EGFR mutation-positive tumors. Common treatment-related adverse events were of grade 1 or 2 severity, manageable with standard supportive care, and included diarrhea (grade 3 [G3], 12%), acneiform dermatitis (G3, 6%), exfoliative rash (G3, 3%), dry skin (G3, 0%), fatigue (G3, 3%), and stomatitis (G3, 2%). Six patients (9%) discontinued due to treatment-related adverse events. By patient report, NSCLC symptoms of dyspnea, cough, and pain (chest, arm/shoulder) showed improvement first observed after 3 weeks on therapy.
Dacomitinib demonstrated preliminary activity and acceptable tolerability in heavily pretreated patients, and may offer benefit in molecularly defined patient subsets.
Between 30% and 50% of women who have high-grade uterine leiomyosarcoma (uLMS) limited to the uterus at diagnosis remain progression-free at 2 years. Adjuvant pelvic radiation does not improve outcome. The objective of the current study was to determine the 2-year and 3-year progression-free survival (PFS) among a prospective cohort of women who received adjuvant gemcitabine plus docetaxel followed by doxorubicin.
Women with uterus-limited, high-grade uLMS and adequate organ function were eligible. Within 12 weeks of complete resection and after confirmation that they had no evidence of disease on computed tomography (CT) images, the patients received 4 cycles of fixed-dose-rate gemcitabine plus docetaxel. Those who were confirmed disease-free on CT scans after cycle 4 received 4 cycles of doxorubicin. CT imaging for recurrence was performed every 3 months for 2 years, then every 6 months for 3 years.
In total, 47 women were enrolled (46 evaluable) in 3 years. Characteristics included a median age of 53 years; 1988 International Federation of Gynecology and Obstetrics stage I disease in 81% of patients, stage II disease in 15%, and serosa-only stage IIIA disease in 4%; American Joint Committee on Cancer stage II disease in 13% of patients and stage III disease in 87%; a median tumor size of 8 cm (range, 2.5-30 cm); and a median mitotic rate of 18 mitoses per 10 high-power fields (range, 5-83 mitoses per 10 high-power fields). At a median follow-up of 39.8 months, 21 of 46 patients developed recurrent disease (45.7%). The median time to recurrence was 27.4 months (range, 3-40 months). Seventy-eight percent of patients (95% confidence interval, 67%-91%) were progression-free at 2 years, and 57% (95% confidence interval, 44%-74%) were progression-free at 3 years. The median PFS was not reached and exceeded 36 months.
Among women with high-grade, uterus-limited uLMS who received treatment with adjuvant gemcitabine plus docetaxel followed by doxorubicin, 78% remained progression-free at 2 years, and 57% remained progression-free at 3 years. A randomized trial of adjuvant chemotherapy versus observation to determine whether adjuvant chemotherapy can improve survival in women with uterus-limited uLMS is underway.
This study was designed to determine the feasibility, maximum tolerated dose, and toxicities of intraarterial administration of paclitaxel-albumin nanoparticles in patients with advanced head and neck and recurrent anal canal squamous cell carcinoma. Antitumor activity also was assessed.
Forty-three patients (31 with advanced head and neck and 12 with recurrent anal canal squamous cell carcinoma) were treated intraarterially with ABI-007 every 4 weeks for 3 cycles. In total, 120 treatment cycles were completed, 86 in patients with head and neck carcinoma (median, 3 cycles; range, 1-4) and 34 in patients with anal canal carcinoma (median, 3 cycles; range, 1-4). ABI-007 was compared preliminarily with Taxol for in vitro cytostatic activity. Increasing dose levels from 120 to 300 mg/m2 were studied in 18 patients. Pharmacokinetic profiles after intraarterial administration were obtained in a restricted number of patients.
The dose-limiting toxicity of ABI-007 was myelosuppression consisting of Grade 4 neutropenia in 3 patients. Nonhematologic toxicities included total alopecia (30 patients), gastrointestinal toxicity (3 patients, Grade 2), skin toxicity (5 patients, Grade 2), neurologic toxicity (4 patients, Grade 2) ocular toxicity (1 patient, Grade 2), flu-like syndrome (7 patients, Grade 2; 1 patient, Grade 3). In total, 120 transfemoral, percutaneous catheterization procedure-related complications occurred only during catheterization of the neck vessels in 3 patients (2 TIA, 1 hemiparesis) and resolved spontaneously.
Intraarterial administration of ABI-007 by percutaneous catheterization does not require premedication, is easy and reproducible, and has acceptable toxicity. The maximum tolerated dose in a single administration was 270 mg/m2. Most dose levels showed considerable antitumor activity (42 assessable patients with 80.9% complete response and partial response). The recommended Phase II dose is 230 mg/m2 every 3 weeks.
There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). ABI-007 is an albumin-bound formulation of paclitaxel that has demonstrated single-agent activity against metastatic melanoma.
A parallel phase II trial was conducted in patients with unresectable stage IV melanoma who were either chemotherapy naive (CN) or previously treated (PT). The treatment regimen consisted of ABI-007 (100 mg/m(2) ) and carboplatin area under the curve (AUC2) administered on days 1, 8, and 15 every 28 days. The primary aim of this study was objective response rate (RECIST).
Seventy-six patients (41 CN and 35 PT) were enrolled between November 2006 and July 2007. Three patients withdrew consent prior to starting treatment. The median number of treatment cycles was 4. There were 10 (25.6%) responses (1 complete response [CR] and 9 partial responses [PRs]) in the CN cohort (90% CI, 16.7%-42.3%) and 3 (8.8%) responses (3 PRs) in the PT cohort (90% CI, 2.5%-21.3%). Median progression-free survival was 4.5 months in the CN cohort and 4.1 months in the PT cohort. Median overall survival (OS) was 11.1 months in the CN group and 10.9 months in the PT group. Severe toxicities in both groups (Common Terminology Criteria for Adverse Effects v.3.0 ≥grade 3) included neutropenia, thrombocytopenia, neurosensory problems, fatigue, nausea, and vomiting.
The weekly combination of ABI-007 and carboplatin appears to be moderately well tolerated, with promising clinical activity as therapy in patients who are chemotherapy naive and with modest antitumor activity in those previously treated.
Elderly patients comprise a significant portion of patients with limited stage small cell lung carcinoma. However, the prognostic importance of age has been controversial, and concern for toxicity often hinders enthusiasm for offering full dose therapy.
In this retrospective analysis of Intergroup Trial 0096, the authors compared the outcome of patients 70 years or older to those younger than 70 years. Patients received cisplatin 60 mg/m(2), Day 1 and etoposide 120 mg/m(2), Days 1-3 for 4 cycles and either once or twice daily concurrent thoracic radiotherapy to 45 grays.
Of 381 patients, 50 (13%) were age 70 years or older. The elderly group did not differ significantly from those younger than 70 years with respect to gender distribution, performance status, or weight loss. Severe hematologic toxicity (Grade 4-5: 61% vs. 84%; P < 0.01) and fatal toxicity (1% vs. 10%; P = 0.01) occurred more often among older patients. There were no differences in the frequency of nonhematologic toxicities. Response rate (88% vs. 80%; P = 0.11), event free survival rate (5 year, 19% vs. 16%; P = 0.18), time to local failure, and duration of response did not differ between groups. Overall survival rates (5 year, 22% vs. 16%; P = 0.05) favored those younger than 70 years. Much of the difference in overall survival rates between age groups occurred within the first 6 months on study.
Elderly patients had similar response and survival rates compared with those younger than 70 years. However, toxicity, particularly hematologic, was greater among the elderly. Selected older patients, such as those with a good performance status, should be considered for optimum treatment approaches.
Gefitinib was compared with pemetrexed as second-line therapy in a clinically selected population previously treated with platinum-based chemotherapy.
A phase 3 trial of gefitinib (250 mg/day) versus pemetrexed (500 mg/m(2) on day 1, every 3 weeks) was conducted in patients who had never smoked and who had advanced pulmonary adenocarcinoma treated with 1 previous platinum-based regimen. The primary endpoint was progression-free survival (PFS).
A total of 135 patients were analyzed. The gefitinib group had significantly longer PFS compared with the pemetrexed group, with a median PFS time of 9.0 versus 3.0 months (P = .0006). The objective response rates were 58.8% and 22.4% for gefitinib and pemetrexed, respectively (P < .001). However, there was no statistically significant difference in overall survival between the 2 groups (22.2 vs 18.9 months; P = .37). The difference of PFS was increased in a subgroup analysis of 33 patients with activating epidermal growth factor receptor mutation (15.7 vs 2.9 months; hazard ratio, 0.3; 95% confidence interval, 0.13-0.72; P = .005), with numerical superiority of gefitinib in the 38 patients testing negative for epidermal growth factor receptor mutation (5.9 vs 2.7 months; P = .099). Both regimens were well tolerated. There were no significantly different changes in quality of life between the 2 groups, except that symptom scores for dyspnea and diarrhea favored the gefitinib and pemetrexed arms, respectively.
Gefitinib showed superior efficacy to pemetrexed as second-line therapy in Korean never-smokers with pulmonary adenocarcinoma.
The most common causes of malignant pleural effusions in women are metastatic lung carcinomas and breast carcinomas. It is often very difficult to distinguish between breast carcinomas and other metastatic carcinomas when they share a similar morphology and a similar cytokeratin profile (CK7-positive/CK20-negative [CK7+/CK20−]). To better differentiate between metastatic mammary carcinomas and other metastatic carcinomas in pleural effusion cytology, the authors studied the potential use of a novel antibody, CRxA-01, which was identified by a cDNA subtraction library, together with a well characterized antibody against mammaglobin.
The authors are conducting clinical trials of the HER-2/neu E75-peptide vaccine in clinically disease-free breast cancer (BC) patients. Their phase 1-2 trials revealed that the E75 + granulocyte-macrophage colony-stimulating factor (GM-CSF) vaccine is safe and effective in stimulating clonal expansion of E75-specific CD8(+) T cells. They assessed the need for and response to a booster after completion of primary vaccination series.
BC patients enrolled in the E75 vaccine trials who were ≥6 months from completion of their primary vaccination series were offered boosters with E75 + GM-CSF. Patients were monitored for toxicity. E75-specific CD8(+) T cells were quantified using the human leukocyte antigen-A2:immunoglobulin G dimer before and after boosting.
Fifty-three patients received the vaccine booster. Median time from primary vaccination series was 9 months (range, 6-35 months), and median residual E75-specific immunity was 0.70% (range, 0-3.49%) CD8(+) lymphocytes. Elevated residual immunity (ERI) (CD8(+) E75-specific T cells >0.5%) was seen in 94.4% of patients at 6 months from primary vaccination series versus 48% of patients at >6 months (P = .002). The booster was well tolerated, with only grade 1 and 2 toxicity observed. Local reactions were more robust in patients receiving the booster at 6 months from primary vaccination series compared with those at >6 months (99.4 ± 6.1 mm vs 81.8 ± 4.1 mm, P = .01). In patients lacking ERI, 85% had increased ERI after vaccination (P = .0014).
The HER-2/neu E75 peptide vaccine E75 stimulates specific immunity in disease-free BC patients. However, immunity wanes with time. A vaccine booster is safe and effective in stimulating E75-specific immunity in those patients without ERI. These results suggest that the booster may be most effective at 6 months after completion of the primary vaccination series.
The authors conducted exploratory phase 1-2 clinical trials vaccinating breast cancer patients with E75, a human leukocyte antigen (HLA) A2/A3-restricted HER-2/neu (HER2) peptide, and granulocyte-macrophage colony-stimulating factor. The vaccine is given as adjuvant therapy to prevent disease recurrence. They previously reported that the vaccine is safe and effective in stimulating expansion of E75-specific cytotoxic T cells. Here, they report 24-month landmark analyses of disease-free survival (DFS).
These dose escalation/schedule optimization trials enrolled lymph node-positive and high-risk lymph node-negative patients with HER2 (immunohistochemistry [IHC] 1-3(+) ) expressing tumors. HLA-A2/A3(+) patients were vaccinated; others were followed prospectively as controls for recurrence. DFS was analyzed by Kaplan-Meier curves; groups were compared using log-rank tests.
Of 195 enrolled patients, 182 were evaluable: 106 (58.2%) in the vaccinated group and 76 (41.8%) in the control group. The 24-month landmark analysis DFS was 94.3% in the vaccinated group and 86.8% in the control group (P = .08). Importantly, because of trial design, 65% of patients received a lower than optimal vaccine dose. In subset analyses, patients who benefited most from vaccination (vaccinated group vs control group) had lymph node-positive (DFS, 90.2% vs 79.1%; P = .13), HER2 IHC 1+-2+ (DFS, 94.0% vs 79.4%; P = .04), or grade 1 or 2 (DFS, 98.4% vs 86.0%; P = .01) tumors and were optimally dosed (DFS, 97.3% vs 86.8%; P = .08). A booster program has been initiated; no patients receiving booster inoculations have recurred.
The E75 vaccine has clinical efficacy that is more prominent in certain patients. A phase 3 trial enrolling lymph node-positive patients with HER2 low-expressing tumors is warranted.
E75, a HER-2/neu-derived peptide, was administered as a preventive vaccine with granulocyte-macrophage-colony-stimulating factor (GM-CSF) in disease-free lymph node-positive (NP) and lymph node-negative (NN) breast cancer (BCa) patients. The optimal biologic dose (OBD) was determined based on toxicity and immunologic response.
Patients were vaccinated over 6 months (3, 4, or 6 times) with different doses of E75 plus GM-CSF. Toxicities were graded per National Cancer Institute Common Terminology Criteria. GM-CSF was reduced for significant toxicity. Immunologic response was measured by delayed type hypersensitivity test (DTH), and E75-specific CD8+ T-cells were quantified with human leukocyte antigen-A2:immunoglobulin G dimer and flow cytometry.
Ninety-nine patients (48 NP and 51 NN) were vaccinated in 7 dose groups. The OBD was 1000 microg E75 plus 250 microg GM-CSF monthly x 6. The optimal dose group (ODG, n = 29) experienced similar toxicities to the suboptimal dose group (SDG, n = 70), which was comprised of the remaining 6 groups. The ODG demonstrated a trend toward an increase in the average postvaccine dimer (0.87 +/- 0.10% vs 0.67 +/- 0.05%; P = .07), a significantly larger DTH response (21.5 +/- 2.5 mm vs 11.3 +/- 1.3 mm; P = .0002), and a trend toward decreased recurrences (3.4% vs 12.9%; P = .27). Compared with the SDG, the ODG had larger tumors (percentage > or =T2: 55% vs 23%; P = .004), more positive lymph nodes (percentage NP: 76% vs 37%; P = .001), and higher grade tumors (percentage grade 3: 52% vs 30%; P = .07), but a shorter median follow-up time (20 months vs 32 months; P < .001).
Compared with suboptimally dosed patients, the optimally dosed E75 vaccine in disease-free BCa patients had similar toxicity but enhanced HER-2/neu-specific immunity that may lead to decreased recurrences with additional follow-up.
Neurotoxicity from adjuvant treatment with oxaliplatin has been studied in patients with colorectal carcinoma in short-term studies, but, to the authors' knowledge, the current article is the first long-term assessment which reports the National Surgical Adjuvant Breast and Bowel Project (NSABP) investigation of whether excess neurotoxicity persists beyond 4 years.
As part of a colorectal cancer long-term survivor study (LTS-01), long-term neurotoxicity was assessed in 353 patients on NSABP Protocol C-07 (cross-sectional sample). Ninety-two of these patients from LTS-01 also had longitudinal data and were reassessed 5 to 8 years (median, 7 years) after random assignment (longitudinal sample). Contingency tables compared cohorts, a mixed model compared neurotoxicity between treatments over time, and a Wilcoxon rank-sum test compared neurotoxicity between treatments (cross-sectional sample).
In the cross-sectional sample, the increase in mean total neurotoxicity scores of 1.8 with oxaliplatin was statistically significant (P = .005), but not clinically significant (a minimally important difference of 4 was reported at the long-term assessment). Patients who received oxaliplatin had increased odds of numbness and tingling in hands (odds ratio, 2.00; P = .015) and feet (odds ratio, 2.78; P < .001) versus patients who did not receive oxaliplatin. The magnitude of the oxaliplatin effect varied with time (P < .001) in the longitudinal sample, such that the oxaliplatin-treated group did not have significantly greater total neurotoxicity scores by 7 years.
At the long-term endpoint, there was no clinically significant increase in total neurotoxicity scores for patients who received oxaliplatin, but the specific neurotoxicities of numbness and tingling of the hands and feet remained significantly elevated for oxaliplatin-treated patients.
Renal cell carcinoma (RCC) is characterized by von Hippel-Lindau gene inactivation and vascular endothelial growth factor (VEGF) overproduction. The mechanism of VEGF overproduction may involve protein kinase C (PKC) delta and zeta isoforms. UCN-01 (7-hydroxystaurosporine) is a selective inhibitor of PKC. Given the historically low objective response rate in RCC, time to disease progression (TTP) as an alternative endpoint was employed to evaluate the antitumor activity of UCN-01 in RCC.
Patients with progressive, metastatic RCC received UCN-01 intravenously on Day 1 of each 21-day cycle. The initial dose was 90 mg/m(2) and all subsequent doses were 45 mg/m(2) unless modified for toxicity. TTP was the primary endpoint, defined as the period from the first day of treatment until disease progression. Detection of circulating EpCAM-positive renal carcinoma cells was undertaken for predictive or prognostic potential.
Twenty-one patients were enrolled in this Phase II study. Accrual was halted after failure to reach a predetermined efficacy requirement with 7 patients remaining disease progression free after 4 months (6 cycles). The median TTP for all patients was 2.67 months (range, 0.4-7.6 months). There were no objective responses. Therapy was generally well tolerated. Thirteen patients had < 0.6 EpCAM-positive cells/mL (considered negative) at all time points measured. Two patients had detectable EpCAM-positive cells at a single time point with other measurements being negative.
TTP is a novel endpoint for the evaluation of agents in RCC. UCN-01 did not demonstrate significant antitumor activity. No evidence for significant circulating EpCAM-positive cells was found in this study cohort.
This study evaluated the impact on overall survival (OS) of 2 versus 5 years adjuvant tamoxifen in early breast carcinoma patients after 12 years of follow-up.
Women with breast carcinoma T1-3, N0-3, M0, aged 50-70 years, were eligible for this multicenter randomized Phase III trial. Patients event-free after 2 years of tamoxifen therapy (TAM) were randomly assigned to stop or continue TAM (20 mg/day) for an additional 3 years. The primary endpoint was disease-free survival. Secondary endpoints included OS and toxicity.
From 1989 through 1996, 1901 patients were randomly assigned either to stop treatment (n = 958) or to continue TAM (n = 943). Overall, 98% of patients alive at the previous report (n = 1611) had updated information about OS, of whom 549 had died. The median duration of postrandomization follow-up was 115 months (interquartile range, 86-137). No statistically significant differences between the two arms were detected in the whole population (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.86-1.22) and in estrogen receptor (ER)-positive patients (HR, 0.90; 95% CI, 0.72-1.13). In the latter group, survival curves started to diverge after 90 months, showing a trend in favor of the 5-year arm. In younger (age < or =55 yrs) ER-positive patients longer TAM was associated with a 44% decrease in the risk of death (HR, 0.56; 95% CI, 0.31-1.00), while no clear benefit was documented in women older than 55 years of age (HR, 0.98; 95% CI, 0.77-1.25).
The benefits of longer TAM on OS start to emerge only after 9 years from diagnosis and seem to be more relevant in younger ER-positive women.
The relative prognostic value of the Dukes, Astler, and Coller and TNM staging systems was evaluated for 745 pathologically evaluable patients with rectal cancer enrolled in protocol R-01 of the National Surgical Adjuvant Breast and Bowel Projects. All three methods were found to be highly interrelated. However, the magnitude and consistency of prognostic discrimination among stages was best exhibited by the Dukes' and TNM systems. Survival was comparable among patients with Astler and Coller A and B1 and TNM T1N0M0 and T2N0M0 lesions. Since neither method improved on the predictability noted in Dukes' A cases it is suggested that the use of confusing subscripts is unnecessary. On the other hand, striking prognostic discrimination was observed when Dukes' C cases were subdivided according to depth of tumor penetration as proposed by Astler and Coller and designated as C1 and C2. Multivariate analyses revealed this feature to be independent of number of nodal metastases (1-4 versus 5+ positive), their site (near or far from the growth), or degree of tumor differentiation. The site of nodal metastases appeared to be related to numbers of nodal metastases rather than site per se. Considerations of the findings indicate that the Dukes' staging method is the simplest and most consistent algorithm related to prognosis. The only modification that would enhance its value in this regard would be the subdivision of C cases according to the criteria of Astler and Coller rather than that proposed by Dukes himself.
In 1989, the authors began a randomized trial to determine whether 5-fluorouracil and high dose folinic acid (HD-FUFA) would increase the event free and overall survival of patients with resectable Dukes B and C (AJCC/UICC Stage II and Stage III) colon carcinoma, and to assess the toxicity of the treatment and its impact on selected health-related quality-of-life indicators. Early results were published as a part of an international multicenter pooled analysis (IMPACT) in 1995. The purpose of this report is to update the survival data for patients enrolled in the trial and describe their reported perceptions of their own health and quality of life.
The trial involved multiple treatment centers, with a centralized randomization between surgery alone and surgery with chemotherapy. The HD-FUFA regimen employed consisted of 5-fluorouracil (370 mg/m2) plus folinic acid (200 mg/m2) administered daily for 5 days every 4 weeks for 6 cycles. Patients' perceptions of their own health status were obtained by means of 3 self-administered questionnaires, which were completed by patients at the time of discharge from the treatment center and at 6 and 24 months after randomization.
Overall, 888 patients with resected Dukes B2 and C colon carcinoma were enrolled in the trial. HD-FUFA significantly reduced mortality by 25% (95% confidence interval, 5-41%; P=0.02) and events by 31% (95% confidence interval, 14-45%; P < or = 0.001). Compliance with treatment was good; more than 80% of patients completed the planned therapy. Toxicity was mild, and oral mucositis was the main side effect. None of the health-related quality-of-life parameters investigated (emotional status, worry about the future, changes in social life, impact of the disease, follow-up, and global quality of life) seemed to be affected by the treatment to which patients were allocated. A positive trend in the evolution of patients' psychologic status was observed.
Long term results of this SITAC study confirm that HD-FUFA is a well-tolerated, effective 6-month adjuvant regimen for patients with colon carcinoma that has no detrimental effect on their quality of life.
The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC).
Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival.
Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC(SN-38G) and CL(SN-38G). When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC(SN-38G) (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUC(SN-38) (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1(st) cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 -24TT and 3972TT genotypes were associated with higher response rates (P = .031 and P = .048, [corrected] respectively) and longer progression-free survival (P = .010 and P = .019, [corrected] respectively), which was sustained in haplotype analysis.
Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC.
Combined gemcitabine and carboplatin (GC) and combined gemcitabine and vinorelbine (GV) are active and well tolerated chemotherapeutic regimens for patients with advanced nonsmall cell lung cancer (NSCLC). The authors conducted a randomized Phase II study of GC versus GV to compare them in terms of efficacy and toxicity.
One hundred twenty-eight patients with Stage IIIB or IV NSCLC were randomized to receive either carboplatin at an area under the curve of 5 on Day 1 combined with gemcitabine 1000 mg/m2 on Days 1 and 8 (n = 64 patients) or vinorelbine 25 mg/m2 combined with gemcitabine 1000 mg/m2 on Days 1 and 8 (n = 64 patients) every 3 weeks.
Response rates were 20.3% for the GC patients and 21.0% for the GV patients. In the GC arm, the median survival was 432 days, and the a 1-year survival rate was 57.6%; in the GV arm, the median survival was 385 days, and the 1-year survival rate was 53.3% in the GV arm. The median progression-free survival was 165 days in the GC arm and 137 days in the GV arm. Severe hematologic toxicity (Grade 4) was significantly more frequent in the GC arm (45.3% vs. 25.8% in the GV arm; P = .022). Most notably, the incidence of Grade 3 or 4 thrombocytopenia was significantly higher in the GC arm (81.3% vs. 6.5% in the GV arm; P < .001). Conversely, severe nonhematologic toxicity (Grade 3 or 4) was more common in the GV arm (7.8% vs. 19.4% in the GC arm; P = .057).
Although the GV and GC regimens had different toxicity profiles, there was no significant difference in survival among patients with NSCLC in the current study.
In patients with metastatic colorectal carcinoma (MCC), capecitabine has demonstrated a superior response rate (RR), equivalent disease progression-free (PFS) and overall survival (OS), and an improved overall tolerability profile compared with bolus 5-fluorouracil/leucovorin (5-FU/LV). The FOLFOX4 regimen, combining oxaliplatin with LV and bolus plus infusional 5-FU (LV5FU2), has been shown to improve RR and PFS versus LV5FU2, and it was more effective and less toxic than irinotecan plus bolus 5-FU/LV. Capecitabine (an oral fluoropyrimidine) may be an effective, well tolerated, and more convenient alternative to 5-FU/LV in combination with oxaliplatin, especially in older patients.
Elderly (> or = 70 years) patients with MCC were treated with a 3-weekly regimen of oxaliplatin at an initial dose of 85 mg/m(2) intravenously on Day 1 plus capecitabine 1000 mg/m(2) orally twice daily from Days 2 to 15 (XELOX regimen). In the absence of Grade > or = 2 hematologic toxicity, oxaliplatin was increased to 100 mg/m(2) in the second cycle, and in the absence of Grade > or = 2 nonhematologic adverse events during Cycle 2, capecitabine was increased to 1250 mg/m(2) twice daily in the third and subsequent cycles. After the first 35 patients (first series), the treatment protocol was amended so that only an oxaliplatin increase to 110 mg/m(2) and 130 mg/m(2) during Cycles 2 and 3, respectively, was planned in the remaining 41 patients (second series).
Seventy-six patients with a median age of 75 years (range, 70-82 years) entered the current study. In the first series, the oxaliplatin dose was increased in 18 (51%) patients, and the capecitabine dose was increased in 4 (11%) patients. In the second series, the oxaliplatin dose was increased to 110 mg/m(2) in 26 (63%) patients, and to 130 mg/m(2) in 19 (46%) patients. In all, 2 complete and 29 partial responses were observed, for an overall RR of 41% (95% confidence interval [CI], 30-53%). The median PFS was 8.5 months (95% CI, 6.7-10.3 months), and the median OS was 14.4 months (95% CI, 11.9-16.9 months). In a multivariate analysis, the presence of disease symptoms affected both PFS and OS, whereas OS also was independently affected by male gender and disease spread. Age had no independent effect on PFS or OS. Five percent of patients developed Grade > or = 3 hematologic toxicity during treatment, Grade 3 peripheral neuropathy occurred in 8% of patients, and severe hand-foot syndrome in 13% of patients.
Fit elderly patients with MCC showed a good RR to XELOX with only mild toxicity observed in most patients. XELOX, should, therefore be considered as an important therapeutic option for elderly patients with MCC.
Southwest Oncology Group 0124 was a large North American phase 3 trial that failed to confirm a survival benefit for cisplatin/irinotecan over cisplatin/etoposide in patients with extensive stage small cell lung cancer (SCLC). These results were contrary to Japan Clinical Oncology Group 9511, a phase 3 trial exclusively in Japanese patients. Because 0124 and 9511 used identical treatment regimens and similar eligibility criteria, patient-level data were pooled from both trials, and a common arm analysis was performed to explore potential reasons for the divergent results.
Patients with documented extensive stage SCLC and adequate end-organ function were randomized to intravenously receive either cisplatin 60 mg/m(2) Day 1 + irinotecan 60 mg/m(2) Days 1, 8, and 15 every 4 weeks or cisplatin 80 mg/m(2) Day 1 + etoposide 100 mg/m(2) Days 1-3 every 3 weeks. Demographic and outcome data were compared among 805 patients enrolled in 9511 and 0124 receiving identical treatment using a logistic model adjusted for age, sex, and performance status (PS).
Of 671 patients in 0124, 651 eligible patients were included, as were all 154 patients from 9511. Significant differences in sex and PS distribution as well as toxicity were seen between trials. There were also significant differences in response rates (87% vs 60%, P<.001) and median overall survival (12.8 vs 9.8 months, P<.001) when the cisplatin/irinotecan arms from both trials were compared.
Significant differences in patient demographics, toxicity, and efficacy were identified in the 9511 and 0124 populations. These results, relevant in the current era of clinical trials globalization, warrant: 1) consideration of differential patient characteristics and outcomes among populations receiving identical therapy; 2) utilization of the common arm model in prospective trials; and 3) inclusion of pharmacogenomic correlates in cancer trials where ethnic/racial differences in drug disposition are expected.
Research has suggested that men with hormone-refractory prostate carcinoma have a lower quality of life (QOL) compared with men who have hormone-sensitive prostate carcinoma and that quality of life (QOL) steadily declines over the last year of life for men with prostate carcinoma. The primary purpose of the current study was to evaluate whether there was evidence of palliative effects associated with suramin at any of the three doses administered in the original clinical trial.
Patients with histologically confirmed advanced hormone-refractory adenocarcinoma of the prostate were randomized to receive suramin at a low dose (n = 129; median age, 69 years), an intermediate dose (n = 129; median age, 71 years), or a high dose (n = 127; median age, 70 years) as part of the Intergroup 0159/Cancer and Leukemia Group B 9480 trial. Patients completed a battery of assessment tools, including the Functional Assessment of Cancer Therapy (FACT)-Prostate, the Center for Epidemiological Studies-Depression Scale (CES-D), the Brief Pain Inventory, and an opioid medication log, at baseline, on Day 1 of the sixth week of active therapy, during the second week after treatment termination, and 3 months after administration of the final suramin dose.
Patients who received low-dose suramin reported improvement in QOL (FACT-General: P < 0.01; FACT-Treatment Outcome Index: P < 0.01) and decreased levels of depression (CES-D: P < 0.0006) during treatment compared with patients in the intermediate- and high-dose arms. After treatment, all groups experienced equal decreases in FACT and CES-D scores.
The pattern of results suggests that the lowest dose of suramin administered had a palliative effect in terms of improvement in QOL and decreased levels of depression and that this effect was lost once suramin was discontinued.
Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy (NCT) for some subsets of patients with invasive breast cancer have prompted interest in whether patients who achieved a pCR can be identified preoperatively and potentially spared the morbidity of surgery. The objective of this multicenter, retrospective study was to estimate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting a pCR in the breast.
MRI studies at baseline and after the completion of NCT plus data regarding pathologic response were collected retrospectively from 746 women who received treatment at 8 institutions between 2002 and 2011. Tumors were characterized by immunohistochemical phenotype into 4 categories based on receptor expression: hormone (estrogen and progesterone) receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 327), HR-positive/HER2-positive, (n = 148), HR-negative/HER2-positive, (n = 101), and triple-negative (HR-negative/HER2 negative; n = 155). In all, 194 of 249 patients (78%) with HER2-positive tumors received trastuzumab. Univariate and multivariate analyses of factors associated with radiographic complete response (rCR) and pCR were performed.
For the total group, the rCR and pCR rates were 182 of 746 patients (24%) and 179 of 746 patients (24%), respectively, and the highest pCR rate was observed for the triple-negative subtype (57 of 155 patients; 37%) and the HER2-positive subtype (38 of 101 patients; 38%). The overall accuracy of MRI for predicting pCR was 74%. The variables sensitivity, negative predictive value, positive predictive value, and accuracy differed significantly among tumor subtypes, and the greatest negative predictive value was observed in the triple-negative (60%) and HER2-positive (62%) subtypes.
The overall accuracy of MRI for predicting pCR in invasive breast cancer patients who were receiving NCT was 74%. The performance of MRI differed between subtypes, possibly influenced by differences in pCR rates between groups. Future studies will determine whether MRI in combination with directed core biopsy improves the predictive value of MRI for pathologic response.
A Phase I/II randomized dose-seeking trial was performed to document the severity, time course, and significance of white matter changes seen on serial imaging scans (magnetic resonance imaging, computed tomography) associated with bis-chlorethyl nitrosourea (BCNU) and hyperfractionated cranial irradiation.
Long term survivors (> or = 18 months) were identified from a prospective randomized dose-escalation Phase I/II trial designed to evaluate twice-daily radiotherapy for supratentorial high grade malignant gliomas. All scans were reviewed by a neuroradiologist who had no information about the prescribed dose and fractionation. In the trial, patients were assigned to receive 64.8 Gy, 72.0 Gy, 76.8 Gy, or 81.4 Gy (all fractionated as 1.2 Gy twice a day [bid]), or 48.0 Gy or 54.4 Gy (both in 1.6-Gy bid fractions). Bis-chlorethyl nitrosourea was administered every 8 weeks for 1 year. Of 747 randomized patients, 177 had analyzable scans. The scans reviewed were those acquired preoperatively, immediately postoperatively, 3, 6, 12, and 18 months after radiotherapy. Radiographic endpoints included no white matter change (Grade 0), minimal patchy white matter foci (Grade 1), start of confluence of white matter disease (Grade 2), large confluent areas (Grade 3), confluence with cortical/subcortical involvement (Grade 4), leukoencephalopathy (Grade 5), and possible necrosis (Grade 6) according to the classification of F. Fazekas et al. The effects were scored relative to the baseline preoperative scans. The dose pairs of 48 Gy and 54.4 Gy, 64.8 Gy and 72 Gy, and 76.8 Gy and 81.4 Gy were grouped together for analysis (low, intermediate, and high dose, respectively). Toxicity was analyzed in three ways: Grade 2 or worse, Grade 3 or worse, and Grade 6.
Grade 2 or worse changes were observed in 26.6, 27.6, and 40.4% of patients in the low, intermediate, and high dose groups, respectively. Grade 3 or worse changes were observed in 8.3, 20.0, and 36.5% of patients in the low, intermediate, and high dose groups, respectively. Grade 6 changes were observed in 1.6, 4.6, and 19.2% of patients in the low, intermediate, and high dose groups, respectively. No statistically significant differences were observed among treatment groups when toxicity was evaluated as Grade 2 or worse. For toxicity of Grade 3 or worse, an chi-square test revealed P values of 0.04 (low vs. intermediate dose), 0.09 (intermediate vs. high dose), and 0.0005 (low vs. high dose). With the endpoint of possible necrosis (Grade 6), P values were 0.21 (low vs. intermediate dose), 0.05 (intermediate vs. high dose), and 0.003 (low vs. high dose). The median time to radiographic appearance of an effect (15 months) was not influenced by total dose or fraction size.
A well described toxicity scale for white matter injury was applied successfully to patients with malignant glioma treated with definitive irradiation. Severe white matter changes continued to increase significantly as the total dose of hyperfractionated cranial irradiation was escalated. The time to onset of the white matter abnormalities appeared to be independent of dose. An ongoing Radiation Therapy Oncology Group study will allow correlation of white matter injury with prospective neuropsychometric testing.
The authors evaluated the long-term efficacy and side effects in patients with nonmetastatic, unilateral, inflammatory breast cancer (IBC) who received homogeneous treatment with intensive induction chemotherapy followed by a maintenance regimen.
One hundred twenty patients were randomized to receive high-dose fluorouracil, epirubicin, and cyclophosphamide (FEC-HD) (fluorouracil 750 mg/m(2) on Days 1 to 4, epirubicin 35 mg/m(2) on Days 2 to 4, and cyclophosphamide 400 mg/m(2) on Days 2 to 4 for 4 cycles every 21 days) with or without lenograstim. Locoregional treatment consisted of surgery and/or radiotherapy. Maintenance chemotherapy was FEC 75 (fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) on Day 1 every 21 days for 4 cycles). No hormone treatment was allowed.
The safety of the FEC-HD regimen was described previously. Among 102 patients who underwent surgery, a pathologic complete response (pCR) was achieved by 23.5% of patients with breast tumors and by 31.4% of patients with involved axillary lymph nodes. The overall pCR rate was 14.7%. One hundred nine patients received FEC 75. After a median 10 years of follow-up, the disease-free survival (DFS) and overall survival (OS) rates were 35.7% and 41.2%, respectively. The median DFS was 39 months (95% confidence interval [95% CI], 25-53 months), and the median survival was 61 months (95% CI, 43-79 months). Five patients developed a temporary decrease in left ventricular ejection fraction without congestive heart failure. In the lenograstim group, 1 patient developed acute myeloblastic leukemia M2, and 1 patient developed myelodysplastic syndrome.
FEC-HD induction chemotherapy followed by FEC 75 maintenance regimen had moderate and acute long-term toxicities and lead to high DFS and OS rates in patients with IBC.
Confounding biologic factors, including histologic grade, may influence the outcome of adult patients with malignant gliomas more than may modifications in therapeutic approach. Any clinical trial design for malignant gliomas in adults must account for such biologic factors, including the accurate identification of the two histologic subgroups astrocytoma with anaplastic foci (AAF) or glioblastoma multiforme (GBM), which are associated with distinctly different survival outcomes. This paper examines the need for a central pathology review before entry of patients in cooperative group clinical trials stratified by histologic grade.
Pathology slides from Radiation Therapy Oncology Group (RTOG) trial 83-02, a randomized Phase II study of hyperfractionated and accelerated hyperfractionated radiation therapy and carmustine for malignant gliomas, provided 747 analyzable cases, with 680 (91%) available for central pathology review. This review was performed by a single pathologist according to RTOG/Eastern Cooperative Oncology Group histopathologic criteria. The kappa statistic was used to measure agreement between the institutional and central classification of AAF and GBM. The influence of misclassification was examined using computer simulation of varying clinical trial sizes (n = 25, 50, or 200). The effect on the statistical power of trials (n = 200) with varying mixtures of AAF and GBM tumors was investigated using computer simulations.
Of 159 tumors classified as AAF by institutional pathology review, only 66% (105) were classified as AAF (AAF/AAF) by central review, and 54 of these cases (34%) were classified as GBM (GBM/AAF), whereas 96% (501) of 521 institutionally classified as GBM (GBM/GBM) were similarly classified by central review. Computer simulations demonstrated a 59% underestimation in the median survival (1.82 vs. 4.49 years) for trials of patients with institutionally defined AAF compared to patients with centrally defined AAF in studies of 200 patients, resulting from the addition of poor prognosis of GBM in the trial. Misclassification can also substantially reduce the statistical power of a clinical trial. In one of the simulation studies, statistical power was reduced from 65% to 14% if 50% of the patients were to receive an inaccurate histologic classification. Even greater losses in power are possible in many plausible clinical settings.
This examination of a central versus an institutional pathology review demonstrates a low level of agreement on AAF classification and a high level of concordance on GBM classification. The results indicate the need to adjust sample size for trials of both AAF and GBM tumors to have adequate statistical power. A central pathology review remains essential for trial entry for patients with AAF and could be omitted for trials enrolling patients with GBM only.
In an effort to identify the site of recurrent colorectal cancer in patients with occult metastasis and increasing serum CEA levels, we conducted two trials using monoclonal antibodies (MoAb) against CEA. The first utilized Indium-111-labeled ZCE-025; an immunoglobulin G1 (IgG1) anticarcinoembryonic antigen (anti-CEA) antibody (Hybritech, San Diego, CA). The second study used Tc-99m-labeled Fab' fragment of IMMU-4 (Immunomedics, Morris Plains, NJ). Eighteen patients were imaged with the ZCE-025 and 14 with the Tc-99m Fab' IMMU-4. True-positive scans, defined as at least one correct correlation of the MoAb scan and surgical/histologic findings, were observed in 12 of 15 patients undergoing exploration or biopsy using the ZCE-025 and 11 of 14 using the IMMU-4. There were no true-negative scans with the ZCE-025 and only 2 of 14 with the IMMU-4. There were 3 false-positive scans with the ZCE-025 and 1 of 14 with IMMU-4. There were no false-negative scans with either ZCE-025 or IMMU-4. Four (31%) of 13 patients undergoing exploration and imaged with ZCE-025 and 5 (36%) of 14 imaged with IMMU-4 had complete tumor resection. Treatment decisions were affected in 3 (16%) of 18 ZCE-025-imaged patients and 3 (21%) of 14 IMMU-4 ones. Two (14%) of 14 patients imaged with IMMU-4 had negative MoAb scans and negative laparotomies. Despite these findings, it is not known whether such early detection and resection will translate into improved survival rates. The authors suggest two randomized studies, one designed to ascertain the role of MoAb added to blind exploratory laparotomy. In that study, patients with increasing CEA levels and a negative workup will be randomized to an exploratory laparotomy preceded by MoAb anti-CEA scans or a straight exploratory laparotomy without the assistance of a MoAb anti-CEA scan. Endpoints will be differences in complete resectability and survival. A second study will examine the merits of blind exploratory laparotomies. In that study, patients with increasing CEA levels and a negative workup would be randomized to MoAb imaging, exploratory laparotomy, and radioimmunoguided surgery, and the other cohort of patients would continue to have conventional radiologic workup. Exploration in this latter group would be performed only when indicated by radiologic or endoscopic studies. The endpoint of the study would compare survival in the two cohorts of patients. These two studies may ultimately settle the debate regarding the correct approach to patients with occult metastatic colorectal cancer and a increasing levels of serum CEA.
A study was undertaken to test whether indium 111 (111In)-labeled anti-carcinoembryonic antigen (CEA) (type ZCE 025) monoclonal intact antibody (MoAb) would concentrate in primary lung cancer enabling its detection and localization by scintigraphy. The scintigraphic results were correlated with chest radiograph, computed tomograph (CT), bronchoscopy, surgical resection, and tumor CEA analysis. Twenty adult male patients with clinical suspicion of primary lung cancer were studied. Each subject was infused with 4 to 5 mCi of 111In anti-CEA ZCE 025 MoAb, and planar and tomographic scintiphotos were obtained on days 3 and 6 or 7 postinfusion. The scintigraphy was true-positive in 12 of 16 patients with primary lung cancer, eight of nine patients with squamous cell carcinoma, and four of seven with adenocarcinoma; it was true-negative in three of four patients with benign lung disease with an overall accuracy of 75%. In seven patients with confirmed primary lung cancer, but with negative bronchoscopic findings, the scintigraphy was true-positive in four. In 11 patients with definitely positive or suspicious malignancy by bronchoscopy the monoclonal scintigraphy was positive in eight. In true-positive cases, the location and size of the lesion by 111In anti-CEA ZCE 025 MoAb imaging correlated well with CT findings and also tumor mass at surgery. Only one of 12 tumors stained positive for CEA had serum CEA levels greater than 10 ng/ml, indicating nonleakage of the tumor antigen into general circulation in early lung cancer. It is concluded that 111In anti-CEA ZCE 025 MoAb planar and tomographic imaging shows potential to serve as a noninvasive diagnostic test in the evaluation of primary lung cancer. The lung lesion is likely to be malignant if it concentrates 111In anti-CEA ZCE 025 MoAb and benign if it does not. Further studies in large number of patients with suspected primary lung cancer are needed to define the ultimate role for MoAb scintigraphy.
It has been hypothesized that people in lower socioeconomic groups have worse outcomes because they present with advanced-stage cancers or receive inadequate treatment. The authors investigated this hypothesis by using education level as a proxy for socioeconomic status in patients treated on Radiation Therapy Oncology Group (RTOG) Protocol 90-03.
RTOG 90-03 was a Phase III randomized trial investigating four different radiation fractionation schedules in the treatment of locally advanced head and neck carcinomas. Overall survival and locoregional control rates were analyzed by education level as measured by patient response on the demographic form at study entry.
A significant difference was observed in the distribution of patients by education level between the standard fractionated radiation treatment arm and the hyperfractionated radiation treatment arm. More patients in the standard fractionated treatment arm had a higher education level (P = 0.018). Patients attending college had highly and significantly better overall survival and locoregional control than the other groups combined (P = 0.0056 and P = 0.025, respectively: from Cox proportional hazards models stratified by assigned treatment with educational level, T classification, N classification, Karnofsky performance status, primary site, and race). Multivariate analysis revealed that education level was significant for predicting both overall survival and locoregional control when comparing attended college/technical school compared with all other education levels.
Patients attending college or technical school had improved overall survival and locoregional control. These differences cannot be explained by differences in tumor stage or treatment. Poorer overall health or lack of support systems contributing to these results needs to be investigated further.
Euoxic and hypoxic BP-8 murine sarcoma cells were exposed for up to 3 hours to various concentrations of three nitroimidazole derivatives (misonidazole, Ro 03-8799, RSU-1164) at normal or elevated incubation temperatures. Cell survival was monitored with the iodine 125 (125I)-iododeoxyuridine prelabeling assay. When cell lethality was evaluated as a function of drug molarity, the three nitroimidazoles displayed widely different toxicities, but when expressed in terms of toxicity ratio between euoxic and hypoxic cells, all three drugs showed nearly identical toxicity differentials of 16 to 18 in 1-hour drug incubation experiments. Prolonging the treatment period to 3 hours did not change the euoxic/hypoxic toxicity ratio for misonidazole and Ro 03-8799, but with RSU-1164 the toxicity ratio was increased significantly from 16 (1 hour) to 73 (3 hours). This increase was attributed to the bifunctional action of RSU-1164 as a combined electron-affinic and alkylating agent, with the alkylation component of cell killing becoming more pronounced after prolonged drug incubation under hypoxic conditions. Combined administration of hyperthermia and nitroimidazoles increased drug-induced cell lethality for all three agents, but did not materially change the relative toxicity differential between euoxic and hypoxic cells. In short, based on cellular toxicity data, Ro 03-8799 appears to offer no advantage over misonidazole as a selective cytocidal agent for hypoxic cells, but RSU-1164 does provide a moderate therapeutic advantage.
Several aromatase inhibitor studies have reported variations in the inhibitory potency of these agents that could lead to differences in clinical outcomes. In the current study, the authors formally evaluated the activity of anastrozole and exemestane in postmenopausal women with hormone-responsive, advanced breast cancer.
Postmenopausal women who had measurable disease according to Response Evaluation Criteria in Solid Tumors and had not received previous endocrine therapy for advanced breast cancer were randomized to receive either oral exemestane 25 mg daily or oral anastrozole 1 mg daily until they had disease progression. The primary endpoint was the objective response rate (ORR), and secondary endpoints included the clinical benefit rate (CBR), time to progression (TTP), overall survival, and safety. Crossover to the other aromatase inhibitor was permitted at the time of disease progression; ORR, CBR, and TTP after second-line treatment also were explored.
In total, 103 patients were enrolled. The median patient age was 71.6 years, 52.4% of patients had visceral disease, and 75.8% of patients had ≥ 2 disease sites. Half of the patients had received previous tamoxifen, and 60% had received previous chemotherapy. The efficacy observed in the exemestane and anastrozole groups was an ORR of 36.2% and 46%, respectively; a CBR of 59.6% and 68%, respectively, and a TTP of 6.1 months and 12.1 months, respectively. At progression, 28 patients crossed over to the other aromatase inhibitor, including 16 patients who switched to exemestane (CBR, 43.7%; TTP, 4.4 months) and 12 patients who switched to anastrozole (CBR, 8.3%; TTP, 2 months). Both drugs were generally well tolerated, and no study drug-related serious adverse events were reported.
In this phase 2 randomized trial, no significant differences in clinical activity were observed in favor of exemestane to justify a superiority phase 3 trial design in the first-line setting.
The European Organization for Research on Treatment of Cancer (EORTC) trial 20781, concerning osteosarcoma of the limbs is reported. After definitive treatment of the primary tumor with amputation or irradiation, adjuvant treatment was given, randomized into either 9 months of chemotherapy according to a modified Rosen schedule, or elective bilateral lung irradiation of 20 Gy, or 3 months of chemotherapy followed by lung irradiation. The 4-year disease-free survival and total survival were 24% and 43%, respectively, with no difference between the treatment arms. In the radiotherapy arms the lung metastases were more frequently suitable for surgical treatment. The survival of patients with either tibia localizations or higher age was somewhat better. Local recurrences occurred in 16% of patients, 50% of them with distant metastases. The trial was executed from 1978 to 1983; 205 patients were evaluable and eligible, and three toxic deaths occurred in the chemotherapy arms. Elective lung irradiation provided the same survival as the adjuvant chemotherapy given in that time.
An association of human leukocyte antigen (HLA)-DQw3 alleles with squamous cell carcinoma (SCC) of the cervix has been reported in some European populations, but the significance of HLA-DQw3 has not been examined in other populations to the authors' knowledge. The interaction between HLA-DQw3 and human papillomavirus (HPV) in SCC remains to be clarified.
To elucidate the association of HLA-DQ alleles with SCC of the cervix, DNA samples extracted from blood lymphocytes of 23 patients with SCC were amplified by the polymerase chain reaction (PCR) using specific primers for the DQB1 genes, and then, each HLA-DQB1 genotype was defined by digestion with restriction enzymes. Human papillomavirus typing also was performed in all cases by PCR, using specific primers for the E6 regions of cancer-associated HPV types (HPV 16, 18 and 33).
Twenty patients (87%) carried a DQB1 gene-encoding HLA-DQw3, compared with 49.4% Japanese control subjects in the International Histocompatibility Workshop panel (P = 0.0003). Human papillomavirus 16 or HPV 18 DNA was detected in 86% of the patients. In 13 of the patients with invasive carcinoma with HPV, a high incidence of not only HLA-DQw3 but also of HLA-DQw1 was observed compared with that in control subjects (P = 0.0019, P = 0.047, respectively). The correlation between DQB1*03 alleles and HPV infection was not statistically significant.
The frequency of HLA-DQw3 alleles was higher in the authors' patient group than in the control group, suggesting that the HLA-DQw3 molecules may influence the development of SCC of the cervix in young Japanese women. In the patients with HPV-positive invasive carcinoma, the association with HLA-DQw1 molecules suggested that it also may influence the progression of SCC.
Melanoma patients who carry the human leukocyte antigen (HLA) Class II allele DQB1*0301 have an increased frequency of metastases at presentation compared with those lacking HLA-DQB1*0301. This study was designed to determine whether HLA-DQB1*0301 is associated with an increased risk of recurrence in melanoma patients presenting with American Joint Committee on Cancer (AJCC) Stage I or II (localized) disease.
Molecular oligotyping of HLA-DQ genes was performed for 259 patients with AJCC Stage I or II melanoma. Rate of disease recurrence was determined by retrospective review and prospective follow-up. Kaplan-Meier analysis, log rank, and proportional hazard (Cox) comparison were performed.
Median follow-up was 24 months. Minimum follow-up was 6 months. Although HLA-DQB1*0301-positive and -negative patients were balanced with regard to standard melanoma prognostic factors (primary tumor thickness, level of invasion, presence of ulceration, anatomic location, and sex), HLA-DQB1*0301-positive patients were more likely to develop locally recurrent, regional, or distant metastatic melanoma during follow-up (actuarial median disease free survival 48 months [DQB1*0301-positive patients] vs. 97 months [DQB1*0301-negative patients]; log rank P = 0.0002). HLA-DQB1*0301 status, in addition to primary tumor thickness, was an independent prognostic indicator in these patients (Cox multivariate P = 0.02).
Patients presenting with localized melanoma who carry HLA-DQB1*0301 are at an increased risk of developing recurrent disease compared with stage-matched patients who lack this allele. HLA-DQB1*0301 is a genomic marker which independently identifies melanoma patients in whom recurrence is more likely, and is potentially useful in selecting those most likely to benefit from adjuvant therapy.
Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing.
In total, 112 patients were accrued. Eighteen patients received standard radiation and temozolomide with cilengitide in a safety run-in phase followed by a randomized phase 2 trial with 94 patients assigned to either a 500 mg dose group or 2000 mg dose group. The trial was designed to estimate overall survival benefit compared with a New Approaches to Brain Tumor Therapy (NABTT) Consortium internal historic control and data from the published European Organization for Research and Treatment of Cancer (EORTC) trial EORTC 26981.
Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for the patients in the 500 mg dose group, 20.8 months for patients in the 2000 mg dose group, 30 months for patients who had methylated O6-methylguanine-DNA methyltransferase (MGMT) status, and 17.4 months for patients who had unmethylated MGMT status. For patients aged ≤70 years, the median survival and survival at 24 months was superior to what was observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27%, respectively; P = .008).
Cilengitide was well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with glioblastoma multiforme regardless of MGMT methylation status. The authors concluded that, from an efficacy and safety standpoint, future trials of this agent in this population should use the 2000 mg dose. Cancer 2012.
HER-2/neu, overexpressed in breast cancer, is a source of immunogenic peptides that include GP2 and E75. Phase 2 testing of E75 as an adjuvant vaccine has suggested a clinical benefit. GP2, derived from the transmembrane portion of HER-2/neu, has differing binding characteristics and may be more immunogenic than E75. Results of the first phase 1 trial of GP2 peptide vaccine are presented.
Disease-free, lymph node-negative, human leukocyte antigen (HLA)-A2(+) breast cancer patients were enrolled. This dose escalation trial included 4 groups to determine safety and optimal GP2 peptide/granulocyte-macrophage colony-stimulating factor (GM-CSF) dose. Toxicities were monitored. Immunologic response was assessed ex vivo via the HLA-A2:immunoglobulin dimer assay to detect GP2-specific CD8(+) T cells (and E75-specific CD8(+) T cells to assess epitope spreading) and in vivo via delayed type hypersensitivity (DTH) reaction (medians/ranges).
Eighteen patients were enrolled. All toxicities were grade < or =2. Eight (88.9%) of 9 patients in the first 3 dose groups required GM-CSF dose reductions for local reactions > or =100 mm or grade > or =2 systemic toxicity. GM-CSF dose was reduced to 125 microg for the final dose group. All patients responded immunologically ex vivo (GP2-specific CD8(+) T cells from prevaccination to maximum, 0.4% [0.0%-2.0%] to 1.1% [0.4%-3.6%], P < .001) and in vivo (GP2 pre- to postvaccination DTH, 0 mm [0.0-19.5 mm] to 27.5 mm [0.0-114.5 mm, P < .001). E75-specific CD8(+) T cells also increased in response to GP2 from prevaccination to maximum (0.8% [0.0%-2.41%] to 1.6% [0.86%-3.72%], P < .001).
The GP2 peptide vaccine appears safe and well tolerated with minimal local/systemic toxicity. GP2 elicited HER-2/neu-specific immune responses, including epitope spreading, in high-risk, lymph node-negative breast cancer patients. These findings support further investigation of the GP2 vaccine for the prevention of breast cancer recurrence.