Purpose: Cancer and Leukemia Group B (CALGB) 9720 evaluated subcutaneous low-dose recombinant interleukin-2 (rIL-2) maintenance immunotherapy as a strategy for prolonging remission in older patients with acute myeloid leukemia (AML).

Patients and Methods: AML patients age 60 years and older in first complete remission after induction and consolidation chemotherapy were randomly assigned to no further therapy or a 90-day regimen of 14-day cycles of low-dose rIL-2, aimed at expanding natural killer (NK) cells, followed by 3-day higher doses aimed at activating cytotoxicity of expanded NK cells to lyse residual AML cells. All randomly assigned patients were included in an intention-to-treat analysis.

Results: A total of 163 (64%) of 254 patients who completed induction and consolidation chemotherapy on CALGB 9720 were randomly assigned to rIL-2 (n = 81) or no further therapy (n = 82); the most common reasons for lack of random assignment were patient refusal and relapse. Fifteen patients randomly assigned to rIL-2 never initiated it because of refusal, intercurrent medical problems, or relapse, and 24 patients initiated rIL-2 but stopped early because of toxicity or relapse. Grade 4 toxicities during rIL-2 therapy included thrombocytopenia (65%) and neutropenia (64%), and grade 3 toxicities included anemia (33%), infection (24%) and malaise/fatigue (14%). Forty-two patients (52%) randomly assigned to rIL-2 completed the full 90-day course. Patients in both arms had similar distributions of both disease-free (combined median = 6.1 months; P = .47) and overall survival (combined median = 14.7 months; P = .61) after random assignment. Moreover, the 42 patients who completed all planned therapy did not show prolongation of disease-free or overall survival.

Conclusion: Low-dose rIL-2 maintenance immunotherapy is not a successful strategy in older AML patients.

Despite the impact of combination antiretroviral therapy (cART) on HIV-related mortality, malignancy remains an important cause of death in the current era. Although the advent of cART has resulted in reductions in the incidence of Kaposi's sarcoma and non-Hodgkin's lymphoma, non–AIDS-defining malignancies present an increased risk for HIV-infected patients, characterized by some common clinical features, generally with a more aggressive behavior and a more advanced disease at diagnosis, which is responsible for poorer patient outcomes. Specific therapeutic recommendations are lacking for these new nonopportunistic malignancies, such as Hodgkin's lymphoma, anal cancer, lung cancer, hepatocarcinoma, and many others. Antiretroviral agents have a propensity for causing drug interactions as a result of their ability to either inhibit or induce the cytochrome P450 (CYP) enzyme system. Because many antineoplastic drugs are also metabolized by the CYP system, coadministration with cART could result in either drug accumulation with increased toxicity, or decreased efficacy of one or both classes of drugs. Further research delineating the combined safety and pharmacokinetics of antiretrovirals and antineoplastic therapy is necessary. Special considerations of these AIDS-related and non–AIDS-related malignancies and their clinical and therapeutic aspects constitute the subject of this review.

Cancer cells frequently harbor defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis but also provides a weakness in the tumor that can be exploited therapeutically. Tumors with compromised ability to repair double-strand DNA breaks by homologous recombination, including those with defects in BRCA1 and BRCA2, are highly sensitive to blockade of the repair of DNA single-strand breaks via the inhibition of the enzyme poly(ADP) ribose polymerase. This provides the basis for a novel synthetic lethal approach to cancer therapy.

Purpose: To determine the clinical relevance of Wilms' tumor 1 (WT1) gene mutations in acute myeloid leukemia (AML) with normal karyotype (NK).

Patients and Methods: Exons 7 and 9 of WT1 were screened in samples from 470 young adult NK AMLs using a combination of direct sequencing and high-resolution capillary electrophoresis.

Results: Overall, 51 mutations were detected in 47 cases (10%): 46 frameshift mutations with insertion/deletion of one to 28 base pairs in exon 7 (n = 45) or exon 9 (n = 1), with a median mutant level of 45% (range, 8% to 86%), and five substitutions in exon 9: D396N (n = 3), H397Y (n = 1) and H397Q (n = 1). Patients with WT1 mutations had an inferior response to induction chemotherapy compared with wild-type cases (complete remission rate, 79% v 90%, odds ratio [OR] = 3.02; 95% CI, 1.17 to 7.82; P = .02), a higher rate of resistant disease (15% v 4%; OR = 9.33; 95% CI, 2.38 to 36.6; P = .001), an increased cumulative incidence of relapse (67% v 43%, hazard ratio [HR] = 3.02; 95% CI, 1.69 to 5.38; P = .0008), with a reduction in both relapse-free survival (22% v 44%; HR = 2.16; 95% CI, 1.32 to 3.55; P = .005) and overall survival (26% v 47%; HR = 1.91; 95% CI, 1.23 to 2.95; P = .007) at 5 years. In multivariate analysis, which included FLT3 internal tandem duplication and NPM1 mutation status, the presence of a WT1 mutation remained an independent adverse prognostic factor.

Conclusion: WT1 mutations are a negative prognostic indicator in NK AML and may be suitable for the development of targeted therapy.

Purpose: Epidermal growth factor receptor (EGFR) overexpression is common in endometrial cancers and may have a major role in tumor growth and progression. Erlotinib is an orally active, selective inhibitor of EGFR tyrosine kinase activity.

Patients and Methods: A multinomial design two-stage phase II study was performed to evaluate single-agent activity of erlotinib in women with advanced endometrial cancer with recurrent or metastatic disease who were chemotherapy naïve and had received up to one line of prior hormonal therapy. Erlotinib was administered at daily dose of 150 mg. Archival tumor tissue was analyzed for EGFR expression by immunohistochemistry (IHC) and gene amplification by fluorescence in situ hybridization (FISH). Mutational status of EGFR was determined in responders.

Results: Thirty-two of 34 entered patients are assessable for response. Treatment was well tolerated and severe toxicity infrequent, with the only grade 4 toxicity being an elevation of transaminases (AST). There were four confirmed partial responses (PRs; 12.5%; 95% CI, 3.5% to 29%) lasting 2 to 36 months. Fifteen patients had stable disease (SD), with median duration of 3.7 months (range, 2 to 12 months). EGFR expression was analyzed in thirty patients; 19 were positive, nine were negative, and two were not assessable. Of the 19 patients who were EGFR positive, three had PR (16%), seven SD, and eight progressive disease, and one was not assessable. No mutations were identified in responders. FISH showed no correlation of response with gene amplification.

Conclusion: Erlotinib is well tolerated with an overall objective response rate of 12.5%. Molecular analysis did not identify EGFR mutations in responders or correlation of response with gene amplification.

Purpose: Little is known of the onset of breast cancer in high-risk populations. We investigated the risk of breast cancer in twin sisters and in the contralateral breast taking family history into consideration.

Patients and Methods: We analyzed a Scandinavian population-based cohort of 2,499 female twin pairs, in which at least one had a diagnosis of breast cancer and estimated the risk of breast cancer in the sister. Using a total of 11 million individuals in Sweden with complete family links, we identified 93,448 women with breast cancer and estimated the risk of a bilateral breast cancer.

Results: The incidence of breast cancer in twin sisters of breast cancer patients was 0.64% per year and 0.42% per year in mono- and dizygotic twin sisters, respectively. In comparison, the risk of familial (affected first-degree relative) and nonfamilial bilateral breast cancer was 1.03% per year and 0.68% per year, respectively. Contrary to the risk of unilateral disease, the risk of cancer in the nonaffected twin and the opposite breast was not affected by age or time since first event. The relative risk of familial bilateral cancer was 52% higher (incidence rate ratio [IRR] = 1.52; 95% CI, 1.42 to 1.64) and the relative risk in the dizygotic twin sister was 25% lower (IRR = 0.75; 95% CI, 0.61 to 0.91) compared with the risk of nonfamilial bilateral cancer.

Conclusion: The elevated risk of breast cancer in high-risk groups is little affected by age and time since diagnosis. Our findings suggest that susceptible groups of women might have already aggregated genetic prerequisites for breast cancer.

Purpose: Persistent insomnia is a common complaint in cancer survivors, but is seldom satisfactorily addressed. The adaptation to cancer care of a validated, cost-effective intervention may offer a practicable solution. The aim of this study was to investigate the clinical effectiveness of protocol-driven cognitive behavior therapy (CBT) for insomnia, delivered by oncology nurses.

Patients and Methods: Randomized, controlled, pragmatic, two-center trial of CBT versus treatment as usual (TAU) in 150 patients (103 females; mean age, 61 years.) who had completed active therapy for breast, prostate, colorectal, or gynaecological cancer. The study conformed to CONSORT guidelines. Primary outcomes were sleep diary measures at baseline, post-treatment, and 6-month follow-up. Actigraphic sleep, health-related quality of life (QOL), psychopathology, and fatigue were secondary measures. CBT comprised five, small group sessions across consecutive weeks, following a manualized protocol. TAU represented normal clinical practice; the appropriate control for a clinical effectiveness study.

Results: CBT was associated with mean reductions in wakefulness of 55 minutes per night compared with no change in TAU. These outcomes were sustained 6 months after treatment. Standardized relative effect sizes were large for complaints of difficulty initiating sleep, waking from sleep during the night, and for sleep efficiency (percentage of time in bed spent asleep). CBT was associated with moderate to large effect sizes for five of seven QOL outcomes, including significant reduction in daytime fatigue. There was no significant interaction effect between any of these outcomes and baseline demographic, clinical, or sleep characteristics.

Conclusion: CBT for insomnia may be both clinically effective and feasible to deliver in real world practice.

Purpose: Survival of patients with multiple myeloma is highly heterogeneous, from periods of a few weeks to more than 10 years. We used gene expression profiles of myeloma cells obtained at diagnosis to identify broadly applicable prognostic markers.

Patients and Methods: In a training set of 182 patients, we used supervised methods to identify individual genes associated with length of survival. A survival model was built from these genes. The validity of our model was assessed in our test set of 68 patients and in three independent cohorts comprising 853 patients with multiple myeloma.

Results: The 15 strongest genes associated with the length of survival were used to calculate a risk score and to stratify patients into low-risk and high-risk groups. The survival-predictor score was significantly associated with survival in both the training and test sets and in the external validation cohorts. The Kaplan-Meier estimates of rates of survival at 3 years were 90.5% (95% CI, 85.6% to 95.3%) and 47.4% (95% CI, 33.5% to 60.1%), respectively, in our patients having a low risk or high risk independently of traditional prognostic factors. High-risk patients constituted a homogeneous biologic entity characterized by the overexpression of genes involved in cell cycle progression and its surveillance, whereas low-risk patients were heterogeneous and displayed hyperdiploid signatures.

Conclusion: Gene expression–based survival prediction and molecular features associated with high-risk patients may be useful for developing prognostic markers and may provide basis to treat these patients with new targeted antimitotics.

Purpose: Two nonoperative approaches (one without fluorouracil) using induction chemotherapy and then definitive chemoradiotherapy developed at two centers were compared in patients with localized esophageal cancer (LEC). The primary end point was to assess whether any approach would achieve a ≥ 77.5% 1-year survival rate, surpassing the historical 66% rate from the Radiation Therapy Oncology Group (RTOG) protocol 9405.

Patients and Methods: In a multi-institutional cooperative group setting, patients with LEC who had unresectable cancer, were unwilling to undergo surgery, or were medically unfit for surgery were randomly assigned to receive either induction with fluorouracil, cisplatin, and paclitaxel and then fluorouracil plus paclitaxel with 50.4 Gy of radiation (arm A) or induction with paclitaxel plus cisplatin and then the same chemotherapy with 50.4 Gy of radiation (arm B). Safety and survival rates were assessed.

Results: A total of 84 patients were randomly assigned (arm A, n = 41; arm B, n = 43), and 72 were assessable (arm A, n = 37; arm B, n = 35). The median survival time was 28.7 months for patients in arm A and 14.9 months for patients in arm B (18.8 months for patients in RTOG 9405). The 1-year survival rate of 75.7% in arm A was close to, but did not meet or surpass, the 77.5% goal. The 2-year survival rate was 56% for arm A and 37% for arm B. Grade 3 (arm A = 54%, arm B = 43%) and grade 4 toxicities (arm A = 27%, arm B = 40%) were frequent. Treatment-related death occurred in 3% of patients in arm A and 6% of patients in arm B.

Conclusion: Both arms of RTOG 0113 were associated with high morbidity, and the study did not meet its 1-year survival end point.

Purpose: Osteonecrosis of the jaws (ONJ) was initially described in 2001 in patients receiving intravenous bisphosphonate (BP) treatment. The objective of the present study was to determine whether routine dental procedures can be considered as possible risk factors for the development of ONJ in breast cancer patients receiving BP.

Patients and Methods: Twenty breast cancer patients who developed ONJ receiving BP treatment were included in group A, whereas group B consisted of 40 matched controls (breast cancer patients who did not progress to ONJ receiving BP treatment). Routine dental care, smoking habits, history of tooth extraction, use of dentures, and root canal therapy were recorded.

Results: Our results indicate that history of tooth extraction during zoledronic acid treatment (adjusted odds ratio [OR] = 16.4; 95% CI, 3.4 to 79.6) and the use of dentures (adjusted OR = 4.9; 95% CI, 1.2 to 20.1) increase the risk of developing ONJ.

Conclusion: The outcome of the present study suggests early referral by oncologists for dental evaluation for every patient to be treated with BP. These results raise the current American Society of Clinical Oncology Level of Evidence linking certain dental procedures with ONJ from V to III. Further studies are needed to assess other possible risk factors and also to highlight the etiopathogenesis mechanism of ONJ.

Purpose: Quality-improvement initiatives are being developed to decrease volume-based variability in surgical outcomes. Resources for national and hospital quality-improvement initiatives are limited. It is unclear whether quality initiatives in surgical oncology should focus on factors affecting perioperative mortality or long-term survival. Our objective was to determine whether differences in hospital surgical volume have a larger effect on perioperative mortality or long-term survival using two methods.

Patients and Methods: From the National Cancer Data Base, 243,103 patients who underwent surgery for nonmetastatic colon, esophageal, gastric, liver, lung, pancreatic, or rectal cancer were identified. Multivariable modeling was used to evaluate 60-day mortality and 5-year conditional survival (excluding perioperative deaths) across hospital volume strata. The number of potentially avoidable perioperative and long-term deaths were calculated if outcomes at low-volume hospitals were improved to those of the highest-volume hospitals.

Results: Risk-adjusted perioperative mortality and long-term conditional survival worsened as hospital surgical volume decreased for all cancer sites, except for liver resections where there was no difference in survival. When comparing low- with high-volume hospitals, the hazard ratios for perioperative mortality were substantially larger than for long-term survival. However, the number of potentially avoidable deaths each year in the United States if outcomes at low-volume hospitals were improved to the level of highest-volume centers was significantly larger for long-term survival.

Conclusion: Although the magnitude of the hazard ratios implies that quality-improvement efforts should focus on perioperative mortality, a larger number of deaths could be avoided by focusing quality initiatives on factors associated with long-term survival.

Purpose: The treatment of patients with follicular lymphoma has changed with the introduction of high-dose therapy (HDT) with autologous stem-cell transplant then with rituximab. The effect of these two strategies on the outcome of relapsing patients with follicular lymphoma has never been compared.

Patients and Methods: We analyzed two cohorts of patients treated in two successive randomized studies with the same treatment, cyclophosphamide, doxorubicin, teniposide, and prednisolone plus interferon, to evaluate the role of rituximab and HDT in salvage therapy after first disease progression or relapse.

Results: Of the 364 patients included in these two studies, 254 progressed or relapsed and constitute the population of this analysis. Among them, 98 had been treated with HDT, including 33 of them after rituximab-containing salvage regimen, and 69 with rituximab alone or combined with chemotherapy but without HDT. Patients' characteristics at diagnosis were similar in all subgroups. If event-free survival was identical for patients treated within Groupe d'Etude des Lymphomes Folliculaires (GELF) -86 or GELF-94 studies, overall survival was longer in GELF-94 study. HDT was associated with a statistically significant benefit in terms of event-free survival from relapse and survival after relapse (SAR). Rituximab was associated with a greater benefit than HDT for these two end points. When both treatments were combined, patients treated with rituximab-containing salvage regimen followed by HDT had 5-year SAR more than 90%.

Conclusion: In follicular lymphoma, for patients treated with first-line chemotherapy the combination of a salvage regimen containing rituximab with or without HDT leads to a dramatic improvement of long-term outcome.

Purpose: To assess the effect of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) treatment on survival and leukemic transformation in myelodysplastic syndrome (MDS).

Patients and Methods: We compared the long-term outcome of patients with MDS treated with EPO plus G-CSF (n = 121) with untreated patients (n = 237) with MDS using multivariate Cox regression with delayed entry, for the first time adjusting for all major prognostic variables (WHO classification, karyotype, cytopenias, level of transfusion-need, age, and sex).

Results: The erythroid response rate to EPO plus G-CSF was 39%, and the median response duration 23 months (range, 3 to 116+). In the multivariate analysis, treatment was associated with improved overall survival (hazard ratio, 0.61; 95% CI, 0.44 to 0.83; P = .002). Interestingly, this positive association was primarily observed in patients requiring fewer than 2 units of RBCs per month. Treatment was not linked to the rate of acute myeloid leukemia in any defined subgroup, including patients with an increase of marrow blasts or an unfavorable karyotype.

Conclusion: The inherent risk of leukemic evolution in MDS makes the current investigation highly relevant, in light of the recent reports of potential negative effects of EPO treatment on outcome in patients with cancer. We conclude that treatment of anemia in MDS with EPO plus G-CSF may have a positive impact on outcome in patients with no or low transfusion need, while not affecting the risk of leukemic transformation.

Purpose: To analyze the prognostic impact of Wilms tumor 1 (WT1) gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML).

Patients and Methods: We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML, who were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 and 19808, for WT1 mutations in exons 7 and 9. The patients also were assessed for the presence of FLT3 internal tandem duplications (FLT3-ITD), FLT3 tyrosine kinase domain mutations (FLT3-TKD), MLL partial tandem duplications (MLL-PTD), NPM1 and CEBPA mutations, and for the expression levels of ERG and BAALC.

Results: Twenty-one patients (10.7%) harbored WT1 mutations. Complete remission rates were not significantly different between patients with WT1 mutations and those with unmutated WT1 (P = .36; 76% v 84%). Patients with WT1 mutations had worse disease-free survival (DFS; P < .001; 3-year rates, 13% v 50%) and overall survival (OS; P < .001; 3-year rates, 10% v 56%) than patients with unmutated WT1. In multivariable analyses, WT1 mutations independently predicted worse DFS (P = .009; hazard ratio [HR] = 2.7) when controlling for CEBPA mutational status, ERG expression level, and FLT3-ITD/NPM1 molecular-risk group (ie, FLT3-ITD^negative/NPM1^mutated as low risk v FLT3-ITD^positive and/or NPM1^wild-type as high risk). WT1 mutations also independently predicted worse OS (P < .001; HR = 3.2) when controlling for CEBPA mutational status, FLT3-ITD/NPM1 molecular-risk group, and white blood cell count.

Conclusion: We report the first evidence that WT1 mutations independently predict extremely poor outcome in intensively treated, younger patients with CN-AML. Future trials should include testing for WT1 mutations as part of molecularly based risk assessment and risk-adapted treatment stratification of patients with CN-AML.

Purpose: Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases both local tumor control and toxicity. This study evaluates clinical factors that are associated with and might predict severe late toxicity after CCRT.

Methods: Patients were analyzed from a subset of three previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3 to 4 pharyngeal/laryngeal toxicity (RTOG/European Organisation for the Research and Treatment of Cancer late toxicity scoring system) and/or requirement for a feeding tube ≥ 2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Case-control analysis was performed, with a multivariable logistic regression model that included pretreatment and treatment potential factors.

Results: A total of 230 patients were assessable for this analysis: 99 patients with severe late toxicities and 131 controls; thus, 43% of assessable patients had a severe late toxicity. On multivariable analysis, significant variables correlated with the development of severe late toxicity were older age (odds ratio 1.05 per year; P = .001); advanced T stage (odds ratio, 3.07; P = .0036); larynx/hypopharynx primary site (odds ratio, 4.17; P = .0041); and neck dissection after CRT (odds ratio, 2.39; P = .018).

Conclusion: Severe late toxicity after CCRT is common. Older age, advanced T-stage, and larynx/hypopharynx primary site were strong independent risk factors. Neck dissection after CCRT was associated with an increased risk of these complications.

Purpose: RAS mutations occur in 12% to 27% of patients with acute myeloid leukemia (AML) and enhance sensitivity to cytarabine in vitro. We examined whether RAS mutations impact response to cytarabine in vivo.

Patients and Methods: One hundred eighty-five patients with AML achieving complete remission on Cancer and Leukemia Group B study 8525 and randomly assigned to one of three doses of cytarabine postremission were screened for RAS mutations. We assessed the impact of cytarabine dose on cumulative incidence of relapse (CIR) of patients with (mutRAS) and without (wild-type; wtRAS) RAS mutations.

Results: Thirty-four patients (18%) had RAS mutations. With 12.9 years median follow-up, the 10-year CIR was similar for mutRAS and wtRAS patients (65% v 73%; P = .31). However, mutRAS patients receiving high-dose cytarabine consolidation (HDAC; 3 g/m² every 12 hours on days 1, 3, and 5 or 400 mg/m²/d x 5 days) had the lowest 10-year CIR, 45%, compared with 68% for wtRAS patients receiving HDAC and 80% and 100%, respectively, for wtRAS and mutRAS patients receiving low-dose cytarabine (LDAC; 100 mg/m²/d x 5 days; overall comparison, P < .001). Multivariable analysis revealed an interaction of cytarabine dose and RAS status (P = .06). After adjusting for this interaction and cytogenetics (core binding factor [CBF] AML v non-CBF AML), wtRAS patients receiving HDAC had lower relapse risk than wtRAS patients receiving LDAC (hazard ratio [HR] = 0.67; P = .04); however, mutRAS patients receiving HDAC had greater reduction in relapse risk (HR = 0.28; P = .002) compared with mutRAS patients treated with LDAC.

Conclusion: AML patients carrying mutRAS benefit from higher cytarabine doses more than wtRAS patients. This seems to be the first example of an activating oncogene mutation favorably modifying response to higher drug doses in AML.

Purpose: Given the molecular pathophysiology of thyroid cancer and the spectrum of kinases inhibited by sorafenib, including Raf kinase, vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and RET tyrosine kinases, we conducted an open-label phase II trial to determine the efficacy of sorafenib in patients with advanced thyroid carcinoma.

Patients and Methods: Eligible patients with metastatic, iodine-refractory thyroid carcinoma received sorafenib 400 mg orally twice daily. Responses were measured radiographically every 2 to 3 months. The study end points included response rate, progression-free survival (PFS), and best response by Response Evaluation Criteria in Solid Tumors.

Results: Thirty patients were entered onto the study and treated for a minimum of 16 weeks. Seven patients (23%; 95% CI, 0.10 to 0.42) had a partial response lasting 18+ to 84 weeks. Sixteen patients (53%; 95% CI, 0.34 to 0.72) had stable disease lasting 14 to 89+ weeks. Seventeen (95%) of 19 patients for whom serial thyroglobulin levels were available showed a marked and rapid response in thyroglobulin levels with a mean decrease of 70%. The median PFS was 79 weeks. Toxicity was consistent with other sorafenib trials, although a single patient died of liver failure that was likely treatment related.

Conclusion: Sorafenib has clinically relevant antitumor activity in patients with metastatic, iodine-refractory thyroid carcinoma, with an overall clinical benefit rate (partial response + stable disease) of 77%, median PFS of 79 weeks, and an overall acceptable safety profile. These results represent a significant advance over chemotherapy in both response rate and PFS and support further investigation of this agent in these patients.

Purpose: To define the clinical and pathologic characteristics of primary cutaneous small/medium CD4⁺ T-cell lymphoma (PCSM-TCL) and identify parameters of prognostic significance.

Patients and Methods: We have investigated 24 patients with primary cutaneous lymphomas composed of small/medium mature T-cells with a βF1, CD3, CD4⁺ and/or noncytotoxic, CD8^- and CD30^- phenotype. The proliferation index and CD8⁺ infiltrating cells were quantified with an automated image analysis system.

Results: Sixteen patients presenting with solitary or localized plaques or small nodules (< 3 cm) had an indolent course. Only three patients experienced repeated cutaneous relapses, and none of them died as a result of the disease after 1 to 168 months (median, 17 months) of follow-up. The tumors had a low proliferation (median Ki-67, 9% ± 5%) and an intense infiltrate of reactive CD8⁺ (median, 20% ± 11.7%). Five patients presenting with rapidly evolving large tumors or nodules (≥ 5 cm) had an aggressive disease and died with extracutaneous dissemination 18 to 36 months after diagnosis (median, 23 months). These tumors had a significantly higher proliferation (median Ki-67, 22% ± 11.3%; P < .05) and lower number of infiltrating CD8⁺ (median, 1% ± 3%; P < .05) than the previous group. A third group of three patients had a peculiar clinical presentation with multifocal relapsing lesions without extracutaneous dissemination after a long period of follow-up ranging from 41 to 92 months. Histologically, these cases had an intense infiltrate of eosinophils.

Conclusion: PCSM-TCL is a heterogeneous group of tumors with differentiated clinical and pathological characteristics with impact in the outcome of the patients.

Purpose: The purpose of this article is to describe the features, treatment, and risk factors for relapse of children with mature teratoma (MT) and immature teratoma (IT) to assist future treatment plans.

Patients and Methods: Patients were younger than 16 years of age and referred to the UK Children's Cancer Study Group centers with biopsy-proven extracranial MT and IT and no prior chemotherapy. Complete excision, with the coccyx in sacrococcygeal patients, and follow-up, including serum alpha-fetoprotein monitoring for early detection of malignant yolk sac tumor (YST) recurrence, were recommended. Carboplatin, etoposide, and bleomycin (JEB) were given for YST relapse, whereas relapsed MT and IT were treated at clinicians' discretion, usually surgically. Pathology was reviewed and treatments, outcome, and prognostic features assessed.

Results: There were 351 patients, 227 with MT, 124 with IT. Tumor sites were: testis (n = 53), ovary (n = 130), sacrococcygeal region (n = 98), thorax (n = 23), and other (n = 47). Surgical resection was incomplete in 26% of MT and 40% of IT patients; 5-year event-free survival was 92.2% and 85.9%, respectively, and 5-year overall survival was 99% and 95.1%. Poorer outcome occurred with incomplete resection, tumor rupture, nongonadal site (particularly sacrococcygeal), young age, higher stage and grade, and gliomatosis peritonei, but not with cyst fluid aspiration/spillage, tumor enucleation, nodal gliomatosis, or microfoci of YST in the tumor (Heifetz lesions). JEB was effective for YST recurrence, but not for MT or IT.

Conclusion: Treatment remains primarily surgical, with JEB chemotherapy for YST relapse. No definite response followed JEB for pure MT and IT. Adjuvant chemotherapy after surgery for sacrococcygeal patients is not advocated.

Purpose: Patients with advanced, incurable thyroid cancer not amenable to surgery or radioactive iodine (¹³¹I) therapy have few satisfactory therapeutic options. This multi-institutional study assessed the activity and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 in patients with advanced thyroid cancer.

Patients and Methods: Patients with thyroid cancer of any histology that was resistant or not appropriate for ¹³¹I were enrolled onto a single-arm phase II trial to receive axitinib orally (starting dose, 5 mg twice daily). Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors was the primary end point. Secondary end points included duration of response, progression-free survival (PFS), overall survival, safety, and modulation of soluble (s) VEGFR.

Results: Sixty patients were enrolled. Partial responses were observed in 18 patients, yielding an ORR of 30% (95% CI, 18.9 to 43.2). Stable disease lasting ≥ 16 weeks was reported in another 23 patients (38%). Objective responses were noted in all histologic subtypes. Median PFS was 18.1 months (95% CI, 12.1 to not estimable). Axitinib was generally well tolerated, with the most common grade ≥ 3 treatment-related adverse event being hypertension (n = 7; 12%). Eight patients (13%) discontinued treatment because of adverse events. Axitinib selectively decreased sVEGFR-2 and sVEGFR-3 plasma concentrations versus sKIT, demonstrating its targeting of VEGFR.

Conclusion: Axitinib is a selective inhibitor of VEGFR with compelling antitumor activity in all histologic subtypes of advanced thyroid cancer.

Purpose: Assessment of radiologic response (RR) for brain tumors utilizes the Macdonald criteria 8 to 10 weeks from the start of treatment. Diffusion magnetic resonance imaging (MRI) using a functional diffusion map (fDM) may provide an earlier measure to predict patient survival.

Patients and Methods: Sixty patients with high-grade glioma were enrolled onto a study of intratreatment MRI at 1, 3, and 10 weeks. Receiver operating characteristic curve analysis was used to evaluate imaging parameters as a function of patient survival at 1 year. Both log-rank and Cox proportional hazards models were utilized to assess overall survival.

Results: Greater increases in diffusion in response to therapy over time were observed in those patients alive at 1 year compared with those who died as a result of disease. The volume of tumor with increased diffusion by fDM at 3 weeks was the strongest predictor of patient survival at 1 year, with larger fDM predicting longer median survival (52.6 v 10.9 months; log-rank, P < .003; hazard ratio [HR] = 2.7; 95% CI, 1.5 to 5.9). Radiologic response at 10 weeks had similar prognostic value (median survival, 31.6 v 10.9 months; log-rank P < .0007; HR = 2.9; 95% CI, 1.7 to 7.2). Radiologic response and fDM differed in 25% of cases. A composite index of response including fDM and RR provided a robust predictor of patient survival and may identify patients in whom RR does not correlate with clinical outcome.

Conclusion: Compared with conventional neuroimaging, fDM provided an earlier assessment of equal predictive value, and the combination of fDM and RR provided a more accurate prediction of patient survival than either metric alone.

Purpose: Abdominoperineal excision (APE) of the rectum and anus for rectal cancer continues to have greater local recurrence and poorer survival than that seen following anterior resection. Changing to an extended prone perineal dissection results in a more cylindrical specimen and should improve outcomes.

Patients and Methods: One hundred twenty-eight specimens from patients who underwent APE that was performed for potentially curable primary rectal adenocarcinoma were dissected according to standard protocol in Leeds and Stockholm between 1997 and 2007 and were studied. Tissue morphometry was performed on the cross sectional photographs of 93 patient cases.

Results: The cylindrical technique removed more tissue in the distal rectum and in all slices that contained tumor compared with the standard operation (both P < .0001). Greater distance was observed from the muscularis propria or internal sphincter to the anterior, posterior, and lateral resection margins (all P < .0001). This was associated with lower circumferential resection margin (CRM) involvement (14.8% v 40.6%; P = .013) and intraoperative perforations (3.7% v 22.8%; P = .0255). An increase in the amount of tissue removed in the distal rectum (P < .0001) was demonstrated by a single surgeon who changed from the standard to the cylindrical technique during the study period; the change was associated with a reduction in CRM positivity (from 36.2% to 12.5%) and in perforations (from 12.8% to 0.0%).

Conclusion: Cylindrical APE performed in the prone position for low rectal cancer removes more tissue around the tumor that leads to a reduction in CRM involvement and intraoperative perforations, which should reduce local disease recurrence. The cylindrical technique has the potential to improve patient outcomes substantially if appropriate surgical education programs are developed.

Purpose: Imatinib is remarkably effective in treating newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). To date, most of the available data come from a single multicenter study in which some of the patients were censored for diverse reasons. Here, we report our experience in treating patients at a single institution in a setting where all events were recorded.

Patients and Methods: A total of 204 consecutive adult patients with newly diagnosed CML in CP received imatinib from June 2000 until August 2006. Response (hematologic, cytogenetic, and molecular), progression-free survival (PFS) and survival were evaluated.

Results: At 5 years, cumulative incidences of complete cytogenetic response (CCyR) and major molecular response (MMR) were 82.7% and 50.1%, respectively. Estimated overall survival and PFS were 83.2% and 82.7%, respectively. By 5 years, 25% of patients had discontinued imatinib treatment because of an unsatisfactory response and/or toxicity. The 5-year probability of remaining in major cytogenetic response while still receiving imatinib was 62.7%. Patients achieving a CCyR at 1 year had a better PFS and overall survival than those failing to reach CCyR, but achieving a MMR conferred no further advantage. The identification of a kinase domain mutation was the only factor predicting for loss of CCyR.

Conclusion: Imatinib is highly effective in most patients with CML-CP; patients who respond are likely to live substantially longer than those treated with earlier therapies. Achieving CCyR correlated with PFS and overall survival, but achieving MMR had no further predictive value. However, approximately one third of patients still need better therapy.

Purpose: To investigate the sensitivity and accuracy of endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) for restaging the mediastinum after induction chemotherapy in patients with non–small-cell lung cancer (NSCLC).

Patients and Methods: One hundred twenty-four consecutive patients with tissue-proven stage IIIA-N2 disease who were treated with induction chemotherapy and who had undergone mediastinal restaging by EBUS-TBNA were reviewed. On the basis of computed tomography, 58 patients were classified as having stable disease and 66 were judged to have had a partial response. All patients subsequently underwent thoracotomy with attempted curative resection and a lymph node dissection regardless of EBUS-TBNA findings.

Results: Persistent nodal metastases were detected by using EBUS-TBNA in 89 patients (72%). Of the 35 patients in whom no metastases were assessed by EBUS-TBNA, 28 were found to have residual stage IIIA-N2 disease at thoracotomy. The majority (91%) of these false negative results were due to nodal sampling error rather than detection error. Overall sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of EBUS-TBNA for mediastinal restaging after induction chemotherapy were 76%, 100%, 100%, 20%, and 77%, respectively.

Conclusion: EBUS-TBNA is a sensitive, specific, accurate, and minimally invasive test for mediastinal restaging of patients with NSCLC. However, because of the low negative predictive value, tumor-negative findings should be confirmed by surgical staging before thoracotomy.

Purpose: Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.

Patients and Methods: This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m² on day 1 and gemcitabine 1,250 mg/m² on days 1 and 8 (n = 863) or cisplatin 75 mg/m² and pemetrexed 500 mg/m² on day 1 (n = 862) every 3 weeks for up to six cycles.

Results: Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.

Conclusion: In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Purpose: Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non–small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy.

Patients and Methods: Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial.

Results: With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin.

Conclusion: Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.

Purpose: The combination of lapatinib and trastuzumab has been observed to have a synergistic, antiproliferative effect against ErbB2-positive breast cancer cells in vitro. This phase I study assessed the safety, clinical feasibility, optimally tolerated regimen (OTR), pharmacokinetics (PK), and preliminary clinical activity of this combination in patients with ErbB2-positive advanced breast cancer.

Patients and Methods: Cohorts of three patients with ErbB2-positive advanced breast cancer were treated with escalating doses of lapatinib (750 to 1,500 mg) administered once daily (continuous) in combination with trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) to determine the OTR. Once the OTR was determined, additional patients were enrolled to provide the PK profile of both agents alone and in combination.

Results: A total of 54 patients were treated: 27 in the dose-escalation group and 27 in the PK group. Overall, adverse events were mild to moderate in severity, with no drug-related grade 4 events. The most frequent drug-related grade 3 events included diarrhea (17%), fatigue (11%), and rash (6%). The OTR was 1,000 mg lapatinib with standard weekly trastuzumab. One patient had a complete response and seven patients had partial responses. The PK parameters (maximum concentration in plasma and area under the curve) of lapatinib and trastuzumab in combination were not significantly different than when either was administered alone.

Conclusion: The OTR of the lapatinib/trastuzumab combination was lapatinib 1,000 mg per day with standard weekly trastuzumab. At these doses, the regimen was well tolerated and clinically active in this heavily pretreated ErbB2-positive breast cancer population.

Purpose: Patients with angioimmunoblastic T-cell lymphoma (AITL) have poor prognoses with current conventional chemotherapy. The aim of this study was to evaluate the effect of high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) on patients with AITL.

Patients and Methods: We report a retrospective, multicenter study of 146 patients with AITL who received ASCT. The source of the stem cells was peripheral blood in 143 patients. The conditioning regimen varied, and 74% of the patients received carmustine and 1,3-bis(2-chloroethyl)-1-nitrosourea; etoposide; ara-C; and melphalan chemotherapy.

Results: After a median follow-up of 31 months (range, 3 to 174 months), 95 patients (65%) remained alive, and 51 patients (35%) died. Forty-two patients died as a result of disease progression, and nine died as a result of regimen-related toxicity. The cumulative incidence of non relapse mortality was 5% and 7% at 12 and 24 months, respectively. The actuarial overall survival (OS) was 67% at 24 months and 59% at 48 months. The cumulative incidence of relapse was estimated at 40% and 51% at 24 and 48 months, respectively. Disease status at transplant was the major factor that impacted outcome. Patients who received a transplant during first complete remission (CR) had significantly superior progression-free survival and OS. The estimated PFS rates for patients who received their transplants in CR were 70% and 56% at 24 and 48 months, respectively; 42% and 30% for patients with chemotherapy-sensitive disease at those time points, respectively; and 23% at both time points for patients with chemotherapy-refractory disease.

Conclusion: This study shows that HDT and ASCT offers the possibility of long-term disease-free survival to patients with AITL. Early transplantation is necessary to achieve optimal results.