Association of Insulin Resistance and Higher Oncotype DX™ Recurrence Score

Annals of Surgical Oncology - Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX? (ODX) recurrence scores has been...     

Phase II trial of sequential high-dose chemotherapy with paclitaxel,melphalan and cyclophosphamide,thiotepa and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer

A single high-dose cycle of chemotherapy can produce response rates in excess of 50%. However, disease-free survival (DFS) is 15-20% at 5 years. The single most important predictor of prolonged DFS is achieving a complete response (CR). Increasing the proportion of patients who achieve a complete response may improve disease-free survival. Women with metastatic breast cancer and at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and G-CSF. The first intensification was paclitaxel (825 mg/m(2)), the second melphalan (180 mg/m(2)) and the third consisted of cyclophosphamide 6000 mg/m(2) (1500 mg/m(2)/day x 4), thiotepa 500 mg/m(2) (125 mg/m(2)/day x 4) and carboplatin 800 mg/m(2) (200 mg/m(2)/day x 4) (CTCb). Sixty-one women were enrolled and 60 completed all three cycles. Following the paclitaxel infusion most patients developed a reversible, predominantly sensory polyneuropathy. Of the 30 patients with measurable disease, 12 converted to CR, nine converted to a PR*, and five had a further PR, giving an overall response rate of 87%. The toxic death rate was 5%. No patient progressed on study. Thirty percent are progression-free with a median follow-up of 31 months (range 1-43 months) and overall survival is 61%. Three sequential high-dose cycles of chemotherapy are feasible and resulted in a high response rate. The challenge continues to be maintenance of response and provides the opportunity to evaluate strategies for eliminating minimal residual disease.     

Phase I and pharmacokinetic study of veliparib,a PARP inhibitor,and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up

Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients. Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1–14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added. 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID. The RP2D is 200 mg veliparib BID on days 1–14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.     

Ethnic neutropenia and treatment delay in African American women undergoing chemotherapy for early-stage breast cancer

Disparities in breast cancer survival have been observed between African American and white women. There are also known differences in mean baseline white blood cell (WBC) count among racial and ethnic groups. If the WBC count falls below conventionally defined treatment thresholds for patients undergoing adjuvant chemotherapy, reduced doses or treatment delays may occur, which could lead to race-based differences in treatment duration. We used the tumor registry at Columbia-Presbyterian Medical Center to identify 1178 women with newly diagnosed stage I and II breast cancer from whom we collected base-line information for 73 African American women and 126 age- and tumor stage-matched white women. Of these women, 43 African American and 93 white women underwent adjuvant chemotherapy. African American women had statistically significantly lower WBC counts than white women at diagnosis (6.2 x 10(9)/L for African American women versus 7.4 x 10(9)/L for white women, difference = 1.2, 95% confidence interval [CI] = 0.2 to 1.2; P =.02) and after treatment (5.3 x 10(9)/L for African American women versus 6.4 x 10(9)/L for white women, difference = 1.1, 95% CI = 0.2 to 2.5; P =.03). Overall, African American women required a statistically significantly longer duration of treatment than white women (19 weeks versus 15 weeks, respectively, difference = 4 weeks, 95% CI = 0.5 to 7.2 weeks; P =.03). The lower baseline WBC counts and longer duration of treatment for early-stage breast cancer in African American women compared with those in white women result in lower dose intensity of treatment for African American women, possibly contributing to observed racial differences in breast cancer survival.     

The state of quality control: a critique

Quality control of clinical laboratory testing must ultimately assure that test results consist of medically reliable information that is received where needed, when needed. This review shows that, despite the sophistication and complexity of current quality control procedures, numerous problems continue to prevent the achievement of this ideal. Solutions to some of these problems are suggested.     

Acute hypertensive crisis following octreotide administration in a patient with malignant pheochromocytoma

A patient with a known history of resected pheochromocytoma was evaluated for recurrent paroxysmal hypertension. The recurrent tumor was localized by magnetic resonance imaging and by somatostatin receptor scintigraphy. Since this scintigraphy demonstrated the presence of somatostatin receptors, empiric treatment with the somatostatin analogue octreotide was initiated in an attempt to stabilize catecholamine secretion prior to attempted surgical resection. The patient experienced a paradoxical reaction manifested by an acute hypertensive crisis which was rapidly responsive to intravenous nicardipine. Stimulation of such a hypertensive crisis by octreotide has not previously been reported. The etiology of this reaction is unclear. We conclude that octreotide and other somatostatin analogues should be administered with extreme caution to patients with known or suspected pheochromocytomas.     

Reduction of paclitaxel-induced peripheral neuropathy with glutamine.

PURPOSE: Dose-limiting toxicity of many newer chemotherapeutic agents is peripheral neuropathy. Prior attempts to reduce this side effect have been unsuccessful. We report on the possible successful reduction of peripheral neuropathy with glutamine administration after high-dose paclitaxel. EXPERIMENTAL DESIGN: Patients entered a high-dose chemotherapy protocol in which the first high-dose cycle was paclitaxel at 825 mg/m(2) given over 24 h. The first cohort of patients did not receive glutamine, and the second cohort of patients received glutamine at 10 g orally three times a day for 4 days starting 24 h after completion of paclitaxel. Neurological assessment was performed at baseline, and at least 2 weeks after paclitaxel, and consisted of a complete neurological exam and nerve conduction studies. RESULTS: There were paired pre- and post-paclitaxel evaluations on 33 patients who did not receive glutamine and 12 patients who did. The median interval between pre- and post-exams was 32 days. For patients who received glutamine, there was a statistically significant reduction in the severity of peripheral neuropathy as measured by development of moderate to severe dysesthesias and numbness in the fingers and toes (P < 0.05). The degree and incidence of motor weakness was reduced (56 versus 25%; P = 0.04) as well as deterioration in gait (85 versus 45%; P = 0.016) and interference with activities of daily living (85 versus 27%; P = 0.001). Moderate to severe paresthesias in the fingers and toes were also reduced (55 versus 42% and 64 versus 50%, respectively), although this value was not statistically significant. All of these toxicities were reversible over time. CONCLUSIONS: Glutamine may reduce the severity of peripheral neuropathy associated with high-dose paclitaxel; however, results from randomized, placebo-controlled clinical trials will be needed to fully assess its impact, if any. Trials are currently ongoing to assess its efficacy for standard-dose paclitaxel in breast cancer and other tumors for which peripheral neuropathy is the dose-limiting toxicity.