Gender-specific activity of chemotherapy correlates with outcomes in chemosensitive cancers of young adulthood.

Good evidence indicates that adolescents and young adults (AYAs) with cancer do badly compared with children with similar cancers. The reasons are poorly understood. Australian registry data on 14,824 cancers of adolescence and young adulthood seen between 1982 and 2002 were reviewed. A detailed substudy of clinical characteristics was analyzed from 179 AYAs with Hodgkin lymphoma (HL), Ewing sarcoma (ES) or osteosarcomas (OS) treated at a single institution. Despite significant improvements in survival for both groups over the period in question, for acute lymphoblastic leukaemia, rhabdomyosarcoma, ES, OS and HL, survival for AYAs was worse than for children. For ES, OS and HL, the survival gap occurred almost entirely in males (Hazard ratios compared with female AYAs of 1.8 [p < 0.01], 1.4 [p = 0.03] and 1.5 [p < 0.01] respectively). Survival outcomes from ES, OS and HL for female AYAs were not significantly different from children of either sex. For brain tumors and thyroid cancers, which are primarily treated surgically, there were no gender-related differences in outcomes. Although no differences in tumor stage or compliance were identified, male AYAs experienced less toxicity and lower response rates to chemotherapy (p = 0.008). Young males account almost entirely for excess mortality from chemosensitive cancers of adolescence and young adulthood compared to children, which may be due to relative underdosing with current chemotherapy dosing algorithms.

First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma: A Phase 2b Randomized Clinical Trial.

IMPORTANCE: Standard therapy for advanced soft-tissue sarcoma has not changed substantially in decades, and patient prognosis remains poor. Aldoxorubicin, a novel albumin-binding prodrug of doxorubicin, showed clinical activity against advanced soft-tissue sarcoma in phase 1 studies. OBJECTIVE: To evaluate efficacy and safety of aldoxorubicin vs doxorubicin in patients with advanced soft-tissue sarcoma. DESIGN, SETTING, AND PARTICIPANTS: International, multicenter, phase 2b, open-label, randomized study at general community practices, private practices, or institutional practices. Between August 2012 and December 2013, 140 patients with previously untreated locally advanced, unresectable, or metastatic soft-tissue sarcoma were screened. INTERVENTIONS: Randomization (2:1) to aldoxorubicin 350 mg/m2 (dose equivalent to doxorubicin 260 mg/m2) or doxorubicin 75 mg/m2, administered once every 3 weeks for up to 6 cycles. MAIN OUTCOMES AND MEASURES: Primary end point was progression-free survival. Secondary end points were 6-month progression-free survival, overall survival, tumor response rate, and safety. All efficacy end points were evaluated by independent and local review. RESULTS: A total of 126 patients were randomized, and 123 received aldoxorubicin (n = 83) or doxorubicin (n = 40). Median (range) patient age was 54.0 (21-77 years); 42 (34%) had leiomyosarcoma. By independent review, median progression-free survival was significantly improved (5.6 [95% CI, 3.0-8.1] vs 2.7 [95% CI, 1.6-4.3] months; P = .02) with aldoxorubicin compared with doxorubicin, as was the rate of 6-month progression-free survival (46% and 23%; P = .02). Median overall survival was 15.8 (95% CI, 13.0 to not available) months with aldoxorubicin and 14.3 (95% CI, 8.6-20.6) months with doxorubicin (P = .21). Overall tumor response rate (by Response Evaluation Criteria in Solid Tumors, version 1.1) by independent review was higher with aldoxorubicin than with doxorubicin (25% [20 patients, all partial response] vs 0%). Grade 3 or 4 neutropenia was more frequent with aldoxorubicin than with doxorubicin (24 [29%] vs 5 [12%]), but not grade 3 or 4 febrile neutropenia (12 [14%] vs 7 [18%]). No acute cardiotoxic effects were observed with either treatment, although left ventricular ejection fraction less than 50% occurred in 3 of 40 patients receiving doxorubicin. CONCLUSIONS AND RELEVANCE: Single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response. Aldoxorubicin therapy exhibited manageable adverse effects, without unexpected events, and without evidence of acute cardiotoxicity. Further investigation of aldoxorubicin therapy in advanced soft-tissue sarcoma is warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01514188.

The promise of PET in clinical management and as a sensitive test for drug cytotoxicity in sarcomas.

Positron emission tomography (PET) is a noninvasive functional imaging technique that allows assessment of key biological processes important in cancer development and progression. It provides information complementary to conventional anatomic imaging, demonstrating utility in a range of cancer settings from diagnosis, biopsy guidance, tumor stratification and prognostication, and staging and surveillance of disease recurrence. Its ability to evaluate vital processes in tumor biology also makes it a potentially valuable and sensitive tool for assessing therapeutic response. The development of novel PET tracers and improvements in technology will only continue to augment the potential of PET and enhance its attractiveness as an instrument to facilitate drug development. This article will discuss the above issues, using the setting of sarcomas as an example.

Recent developments in the systemic therapy of advanced gastroesophageal malignancies.

Cancers of the upper gastrointestinal tract are a common cause of worldwide morbidity and mortality. The prognosis for patients with these cancers remains poor and only a minority of patients are cured. Systemic therapy has been used to treat patients with advanced disease but outcomes have not improved dramatically in the past few decades. Newer, more effective agents are desperately needed, and agents such as the taxanes (docetaxel and paclitaxel), irinotecan, oxaliplatin and capecitabine have recently shown some promise. In addition, molecularly targeted, non-cytotoxic therapies are being evaluated with the hope of improving the available therapeutic options. This article reviews the current clinical data regarding systemic therapy for patients with advanced upper gastrointestinal malignancies.

Beyond 5-fluorouracil: new horizons in systemic therapy for advanced colorectal cancer.

Worldwide, colorectal cancer is a common cancer and a major cause of morbidity and mortality. Patients frequently present with, or later develop, metastatic disease. Median survival with supportive care alone is approximately 6 - 8 months. However, a number of recent developments have greatly increased the range of therapeutic options, improving median survival to > 20 months. Cytotoxic agents such as capecitabine, irinotecan and oxaliplatin are now established treatment strategies. In parallel, an improved understanding of tumour biology has led to the development of non-cytotoxic targeted therapies. Examples include bevacizumab (targeting tumour angiogenesis) and cetuximab (targeting the epidermal growth factor receptor). These agents have recently been incorporated into standard management. This paper reviews these and other advances in the care of patients with advanced colorectal cancer and discusses a number of agents that are currently under development.