Prasanth Ganesan

Target-Based Therapeutic Matching in Early-Phase Clinical Trials in Patients with Advanced Colorectal Cancer and PIK3CA Mutations

Target-matched treatment with PI3K/AKT/mTOR pathway inhibitors in patients with diverse advanced cancers with PIK3CA mutations have shown promise. Tumors from patients with colorectal cancer were analyzed for PIK3CA, KRAS, and BRAF mutations. PIK3CA-mutated tumors were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Of 194 patients analyzed, 31 (16%) had PIK3CA mutations and 189 (97%) were assessed for KRAS mutations. Patients with PIK3CA mutations had a higher prevalence of simultaneous KRAS mutations than patients with wild-type PIK3CA (71%, 22/31 vs. 43%, 68/158; P = 0.006). Of 31 patients with PIK3CA mutations, 17 (55%) were treated with protocols containing PI3K/AKT/mTOR pathway inhibitors [median age, 57 years; median number of prior therapies, 4; mTORC1 inhibitors (11), phosphoinositide 3-kinase (PI3K) inhibitors (5), or an AKT inhibitor (1)]. None (0/17) had a partial or complete response (PR/CR) and only 1 [6%, 95% confidence interval (CI), 0.01–0.27] had stable disease 6 months or more, which was not significantly different from a stable disease ≥6 month/PR/CR rate of 16% (11/67; 95% CI, 0.09–0.27) in patients with colorectal cancer without PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors (P = 0.44). Median progression-free survival was 1.9 months (95% CI, 1.5–2.3). In conclusion, our data provide preliminary evidence that in heavily pretreated patients with PIK3CA-mutant advanced colorectal cancer, protocols incorporating PI3K/AKT/mTOR inhibitors have minimal activity. PIK3CA mutations are associated with simultaneous KRAS mutations, possibly accounting for therapeutic resistance. Mol Cancer Ther; 12(12); 2857–63. ©2013 AACR.

Evaluation of 122 advanced-stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies

The authors hypothesized that comprehensive genomic profiling of advanced‐stage cutaneous squamous cell carcinoma (cSCC) could identify genomic‐derived drug targets of therapy for patients with conventional therapy‐resistant disease.

Triple-Negative Breast Cancer Patients Treated at MD Anderson Cancer Center in Phase I Trials: Improved Outcomes with Combination Chemotherapy and Targeted Agents

Patients with metastatic triple-negative breast cancer (TNBC) have poor treatment outcomes. We reviewed the electronic records of consecutive patients with metastatic TNBC treated in phase I clinic at MD Anderson Cancer Center (Houston, TX) between Augu st 2005 and May 2012. One hundred and six patients received at least 1 phase I trial. Twelve of 98 evaluable patients (12%) had either complete response (CR; n = 1), partial response (PR; n = 7), or stable disease ≥6 months (SD; n = 4). Patients treated on matched therapy (n = 16) compared with those on nonmatched therapy (n = 90) had improved SD ≥ 6 months/PR/CR (33% vs. 8%; P = 0.018) and longer progression-free survival (PFS; median, 6.4 vs. 1.9 months; P = 0.001). Eleven of 57 evaluable patients (19%) treated with combination chemotherapy and targeted therapy had SD ≥ 6 months/PR/CR versus 1 of 41 evaluable patients (2%) treated on other phase I trials (P = 0.013), and longer PFS (3.0 vs. 1.6 months; P < 0.0001). Patients with molecular alterations in the PI3K/AKT/mTOR pathway treated on matched therapy (n = 16) had improved PFS compared with those with and without molecular alterations treated on nonmatched therapy (n = 27; 6.4 vs. 3.2 months; P = 0.036). On multivariate analysis, improved PFS was associated with treatment with combined chemotherapy and targeted agents (P = 0.0002), ≤2 metastatic sites (P = 0.003), therapy with PI3K/AKT/mTOR inhibitors for those with cognate pathway abnormalities (P = 0.018), and treatment with antiangiogenic agents (P = 0.023). In summary, combinations of chemotherapy and angiogenesis and/or PI3K/AKT/mTOR inhibitors demonstrated improved outcomes in patients with metastatic TNBC. Mol Cancer Ther; 13(12); 3175–84. ©2014 AACR.

Voriconazole is a safe and effective anti-fungal prophylactic agent during induction therapy of acute myeloid leukemia

Background: Antifungal prophylaxis (AFP) reduces the incidence of invasive fungal infections (IFIs) during induction therapy of acute myeloid leukemia (AML). Posaconazole is considered the standard of care. Voriconazole, a generic cheaper alternative is a newer generation azole with broad anti-fungal activity. There is limited data on the use of voriconazole as a prophylactic drug. Materials and Methods: A single-center, prospective study was performed during which patients with AML undergoing induction chemotherapy received voriconazole as AFP (April 2012 to February 2014). Outcomes were compared with historical patients who received fluconazole as AFP (January 2011-March 2012, n = 66). Results: Seventy-five patients with AML (median age: 17 years [range: 1-75]; male:female 1.6:1) received voriconazole as AFP. The incidence of proven/probable/possible (ppp) IFI was 6.6% (5/75). Voriconazole and fluconazole cohorts were well-matched with respect to baseline characteristics. Voriconazole (when compared to fluconazole) reduced the incidence of pppIFI (5/75, 6.6% vs. 19/66, 29%; P < 0.001), need to start therapeutic (empiric + pppIFI) antifungals (26/75, 34% vs. 51/66, 48%; P < 0.001) and delayed the start of therapeutic antifungals in those who needed it (day 16 vs. day 10; P < 0.001). Mortality due to IFI was also reduced with the use of voriconazole (1/75, 1.3% vs. 6/66, 9%; P = 0.0507), but this was not significant. Three patients discontinued voriconazole due to side-effects. Conclusion: Voriconazole is an effective and safe oral agent for IFI prophylaxis during induction therapy of AML. Availability of generic equivalents makes this a more economical alternative to posaconazole.

Chronic Myeloid Leukemia in India

Background In the last decade, the use of imatinib has brought a paradigm shift in the management of chronic myeloid leukemia (CML). In India, imatinib has been available for more than a decade and has been made accessible to all segments of the population because of patient assistance programs and cheaper generic versions. Despite improvements in survival, there are unique challenges in the Indian context. Methods We reviewed published data pertaining to CML in India for the period of 1990 to 2016, using PubMed advanced search with the terms chronic myeloid leukemia and India, and included studies that reported on epidemiology, monitoring for therapy, treatment outcomes, and resistance. Additionally, the references in retrieved articles were also reviewed. Results Thirty-seven studies were identified. The incidence of CML may be slightly lower in India than in the West, but there was only a single article reporting population-based data. Indian patients presented with more advanced disease. Most centers have access to imatinib as first-line therapy, but there is limited availability of molecular monitoring and second-line therapy. Most of the outcome data were retrospective but seemed comparable with that reported in Western centers. Drug adherence was impaired in at least one third of patients and contributed to poor survival. Conclusion Focused prospective studies and cooperative studies might improve the quality of data available. Future studies should focus on adherence, its effects on outcomes, and methods to address this problem.

Acute lymphoblastic leukemia: A single center experience with Berlin, Frankfurt, and Munster-95 protocol.

Background: There is a paucity of data on the outcome following the treatment for acute lymphoblastic leukemia (ALL) from developing countries. Materials and Methods: Two hundred and thirty-eight consecutive patients with ALL <30 years of age diagnosed between January 2005 and December 2011 were analyzed retrospectively. Patients were treated modified Berlin, Frankfurt, and Munster 95 protocol. Event-free survival (EFS) was calculated using Kaplan-Meier survival analysis and variables were compared using log-rank test. Results: The EFS was 63.4% at a median follow-up was 32.7 months. On univariate analysis National Cancer Institute (NCI) risk stratification, sex, white blood cell count, day 8 blast clearance, and income were significantly associated with EFS. However, on multivariate analysis only female sex (P = 0.01) and day 8 blast clearance (P = 0.006) were significantly associated with EFS. Seventy-four of 238 (31%) patients had recurrent leukemia. The common sites of relapse were bone marrow in 55/74 (75%) patients and central nervous system in 11/74 (20%) patients. Conclusion: Compared to western data, there was an increased proportion of NCI high-risk patients and T-cell immunophenotype in our study. There has been an improvement in outcome of patients with ALL at our center over the last 2 decades. Female sex and clearance of blast in peripheral blood by day 8 of induction was associated with better EFS.

Pediatric Hodgkin Lymphoma Treated at Cancer Institute, Chennai, India: Long-Term Outcome

Purpose Pediatric Hodgkin lymphoma (HL) is a highly curable malignancy. Outcomes for pediatric HL may vary between developed and developing countries for multiple reasons. This study was conducted to ascertain the outcomes of children with HL at our center and to identify risk factors for recurrent disease. Methods We analyzed the outcomes of 172 consecutive, previously untreated patients with pediatric HL presenting at our center from 2001 to 2010. Patients were treated with either adriamycin, bleomycin, vinblastine, and dacarbazine or adriamycin, bleomycin, vinblastine, cyclophosphamide, vincristine, prednisone, and procarbazine chemotherapy initially, and radiation to bulky sites or a single site of residual disease when appropriate. Results The median duration of follow-up was 77 months. The median age of the patients was 10 years; 127 (74%) of the 172 patients were male. The extent of disease was stage I and II in 59% of the patients. B symptoms were present in 32% of the patients, and 27% had bulky disease. The most common histologic subtype was mixed cellularity (45%). The 5-year overall survival (OS) and progression-free survival (PFS) of the entire cohort were 92.9% and 83.1%, respectively. The 5-year OS rates for patients with stage I, II, III, and IV were 96%, 94.7%, 84%, and 69.8%, respectively. On univariate analysis, advanced stage, response on interim radiologic assessment, and presence of B symptoms significantly predicted inferior PFS and OS. On multivariate analysis, only interim radiologic response significantly predicted PFS (P < .001) and OS (P < .001). Conclusion Overall, the outcomes of patients treated at our center are comparable to those observed in other centers in India and globally.

Prevalence of multi-drug resistant organisms in stool of paediatric patients with acute leukaemia and correlation with blood culture positivity: A single institution experience

Multi‐drug resistant (MDR) bacteria are associated with increased morbidity and mortality in children with acute leukaemia. The present study was conducted to assess the prevalence of MDR bacteria in stool cultures of patients with acute leukaemia at presentation to the hospital. The results were then correlated with blood cultures when patients developed septicaemia.

Can Radiotherapy Be Omitted in Children With Hodgkin Lymphoma Who Achieve Metabolic Remission on Interim Positron Emission Tomography? Experience of a Tertiary Care Cancer Referral Center

Purpose Treating pediatric Hodgkin lymphoma (HL) involves a delicate balance between cure and reducing late toxicity. Fluorodeoxyglucose positron emission tomography (PET) combined with computed tomography (CT) identifies patients with early response to chemotherapy, for whom radiotherapy may be avoided. The role of PET-CT in upfront risk stratification and response–adapted treatment is evaluated in this study. Methods Patients with HL, who were younger than 18 years, were included. PET-CT was performed at baseline and after two cycles of chemotherapy. Patients were stratified into three risk groups: group 1 (stage I or II with no unfavorable features); group 2 (stage I or II with bulky disease/B symptoms); and group 3 (stage III/IV). A doxorubicin, bleomycin, vinblastine, dacarbazine–based regimen was used in early disease. A cyclophosphamide, vincristine, prednisolone, procarbazine, doxorubicin, bleomycin, vinblastine–based regimen was used in advanced disease. Results Forty-nine patients were included. Fifteen (31%), seven (14%), and 27 (55%) patients were included in groups 1, 2, and 3, respectively. Among 36 patients who underwent staging by PET-CT at diagnosis, seven (19%) patients were upstaged and one (3%) patient was downstaged by PET compared with CT. On the basis of negative interim PET responses, 39 (80%) patients were treated without radiotherapy. The 3-year event-free survival for the entire cohort was 91% (± 5.2%) and overall survival was 100%. Conclusion PET-CT is an excellent stand-alone staging modality in HL. The omission of radiotherapy can be considered in patients who achieve metabolic remission on interim PET.

An effective anti-emetic regimen for less than

e22194Background: Olanzapine is an effective agent for chemotherapy induced nausea and vomiting (CINV). The usual dose is 10 mg X 4 days when chemotherapy is given in a Q 3-4 weekly schedule. We re...