Fecal energy (FE) loss was measured using bomb calorimetry in 30 patients; 14 had a history of malabsorption, while 16 had no history of intestinal dysfunction. Average digestibility (and range) of energy and FE loss were 73% (48 to 91%) and 493 kcal/day (177 to 927 kcal/day) in the group with malabsorption, compared to 96% (89 to 99%) and 74 kcal/day (8 to 146 kcal/day) in the group without malabsorption, respectively. Metabolizable energy supplied by the diet (intake kcal -- (fecal kcal + urinary kcal) was below the calculated daily energy requirement in five of seven patients with malabsorption; in three of these five subjects the combination of decreased energy intake and increased FE loss produced negative energy balance, while in the remaining two patients malabsorption alone caused negative energy balance. Inadequate metabolizable energy in these five patients was associated with weight loss and protein-energy malnutrition. The usual clinical laboratory tests applied to the study of malabsorption, including fecal fat, fecal nitrogen, and stool weight, were poor predictors of FE loss. These tests were also of limited value in assessing the effects of dietary modification on energy malabsorption. Contrastingly, bomb calorimetry provided a simple and accurate alternative in quantitatively assessing FE loss in the patient with malabsorption.

Purpose Triple negative breast cancers (TNBC) frequently have high epidermal growth factor receptor (EGFR) expression and are sensitive to DNA-damaging agents. Improved therapies are needed for this aggressive malignancy. Patients and methods We performed a phase I trial of bendamustine and erlotinib, an EGFR tyrosine kinase inhibitor, in patients with metastatic TNBC, ECOG performance status ≤2, and ≤1 prior chemotherapy for metastatic disease. Each 28-day cycle included intravenous bendamustine on days 1, 2 and oral erlotinib on days 5–21 with dose escalation according to a 3 + 3 phase I study design. Dose-limiting toxicity (DLT) was determined by toxicities related to study therapy observed during cycle 1. Results Eleven patients were treated, 5 on dose level 1 and 6 on dose level 2. One patient had DLT on dose level 2. However, cumulative toxicities were observed, including grade 3/4 lymphopenia in 91 % (95 % CI 0.59–0.998) with progressively decreased CD4 counts and grade ≥3 infections in 36 % (95 % CI 0.11–0.69) of patients. Conclusions Combination therapy with bendamustine and erlotinib causes excessive toxicity with severe, prolonged lymphopenia, depressed CD4 counts, and opportunistic infections and should not be pursued further. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative lymphocyte toxicity necessitating patient monitoring during and after treatment.

From June 1988 to July 1991, 20 patients with locally advanced rectal or rectosigmoid cancer were treated prospectively with a strategy of combining preoperative irradiation and fluorouracil chemotherapy before surgical resection. The preoperative radiation dose was 5,000 cGy, and fluorouracil chemotherapy was administered on the first and last 3 days of irradiation in an intravenous bolus dose of 500 mg/m2. In a median follow-up of 25 months, the local regional failure rate was 10%. The 3-year actuarial overall survival and disease-free survival were 92% and 82%, respectively. Twenty percent of the surgical specimens showed no residual tumor, and only 10% showed positive lymph nodes. Significant leukopenia occurred in 10% of patients. Preoperative irradiation and fluorouracil chemotherapy increased surgical downstaging and improved local regional control. The overall toxicity was acceptable. The results of this particular multimodality approach was encouraging and warrant further investigation in phase III trials.

1739 Background: Triple negative breast cancers (TNBC) are sensitive to agents that cause DNA crosslinking and strand breaks and have high epidermal growth factor receptor (EGFR) expression and amplification. Therefore, we sought to determine the safety and efficacy of sequential combination therapy with bendamustine (B) and erlotinib (E). While lymphopenia was an expected toxicity, ≥ grade (gr) 3 infections were not anticipated and overall hematologic toxicity and infection rates were expected to be lower than that observed in treatment of hematologic malignancies. Methods: A phase I/II trial of B and E was performed in patients (pts) with metastatic TNBC with ECOG performance status ≤ 2 and ≤ 1 prior chemotherapy (CTX) for metastasis. Pts were required to have adequate bone marrow function and could not have active infection or history of HIV on anti-retroviral therapy. Pts received B on days 1, 2 and E on days 5 – 21 of a 28 day cycle. Phase I consisted of dose escalation of 2 sequential 3 patient cohorts: dose level 1, B 120 mg/m2 intravenous (IV) and E 100 mg oral (po), and dose level 2, B 120 mg/m2 IV and E 150 mg po. Dose limiting toxicity (DLT) was defined on toxicities related to the study therapy observed during cycle 1, including: absolute neutrophil count < 1 × 109/L for > 7 days despite use of white blood cell growth factor support, platelet count < 25 × 109/L for > 7 days, associated with bleeding, or < 10 × 109/L at any time, gr 4 rash, gr 3 diarrhea uncontrolled medically, gr 4 diarrhea, or other non-hematologic toxicity ≥ gr 3. Response was assessed every 2 cycles. Results: 11 pts were treated, 5 on dose level 1 and 6 on dose level 2. One pt had DLT on dose level 2. However, infection-related serious adverse events (SAE) were observed in 4/11 (36%) pts during or after treatment was completed and possibly associated with prolonged lymphopenia (see Table). Within 1 month (mo) of completing 6 cycles Pt 1 was hospitalized for Pneumocystis carinii (PCP) pneumonia (PNA). Pt 5 completed 4 cycles, but received no further CTX; 2 mo later, she developed brain metastases treated with whole brain radiation and dexamethasone. At 3 mos after treatment she was hospitalized for dyspnea, hypoxia and PNA and received empiric PCP treatment, broad spectrum antibiotics and anti-fungal therapy. No diagnostic procedure was done. Within 1 mo of completion of 6 cycles, Pt 6 was hospitalized with PNA concerning for opportunistic pathogen. Pt 8 received 1 cycle, stopped study therapy for DLT (gr 3 fatigue, gr 3 dyspnea), and was hospitalized for progressive disease. She had persistent gr 4 lymphopenia when transitioned to hospice. Conclusion: Combination therapy with B and E causes excessive toxicity with severe and prolonged lymphopenia resulting in clinically significant depressed CD4 counts and opportunistic infections. The extent of lymphopenia is more severe than that observed in prior published clinical trials of B. We hypothesize that E may potentiate B-related lymphopenia. Since toxicity observed is potentially life threatening this combination should not be pursued further. Pts treated on the trial with persistent lymphopenia will have serial lymphocyte and CD4 counts performed and will be placed on prophylaxis for opportunistic infections. We suggest that future trials of B combinations in TNBC patients should take into account the potential for cumulative toxicity to lymphocytes and the need for monitoring patients during and after treatment. Updated results will be presented. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Cephalon, Inc. Disclosures: No relevant conflicts of interest to declare.