Quality of life with first-line pembrolizumab for PD-L1-positive advanced gastric/gastroesophageal junction adenocarcinoma: results from the randomised phase III KEYNOTE-062 study.

BACKGROUND: In the randomised phase III KEYNOTE-062 study, pembrolizumab was non-inferior to chemotherapy for overall survival in patients with programmed death-ligand 1 (PD-L1)-positive [combined positive score (CPS) ≥1] advanced gastric/gastroesophageal junction (GEJ) cancer. We present findings of prespecified health-related quality-of-life (HRQOL) analyses for pembrolizumab versus chemotherapy in this population. MATERIALS AND METHODS: HRQOL, a secondary endpoint, was measured in patients who received ≥1 dose of study treatment and completed ≥1 HRQOL questionnaire [European Organisation for the Research and Treatment of Cancer (EORTC) 30-question quality-of-life (QLQ-C30), EORTC 22-question quality-of-life gastric-cancer-specific module (QLQ-STO22)]. Least squares mean (LSM) change (baseline to week 18) in global health status/quality of life (GHS/QOL; EORTC QLQ-C30) and time to deterioration (TTD) in GHS/QOL, nausea/vomiting and appetite loss scores (EORTC QLQ-C30) and abdominal pain/discomfort scores (EORTC QLQ-STO22) were evaluated. RESULTS: The HRQOL population comprised 495 patients with CPS ≥1 (pembrolizumab, 252; chemotherapy, 243). Compliance rates at week 18 were similar for pembrolizumab and chemotherapy (EORTC QLQ-C30, 87.9% and 81.9%; EORTC QLQ-STO22, 87.9% and 81.3%, respectively). There was no between-arm difference in LSM score change in GHS/QOL [-0.16; 95% confidence interval (CI) -5.01 to 4.69; P = 0.948]. The LSM score change for most subscales showed comparable worsening in both arms. TTD for GHS/QOL [hazard ratio (HR), 0.96; 95% CI, 0.67-1.38; P = 0.826], appetite loss (HR, 0.83; 95% CI, 0.58-1.20; P = 0.314) and pain (HR, 1.22; 95% CI, 0.78-1.91; P = 0.381) were similar between arms. Longer TTD was observed for pembrolizumab versus chemotherapy for nausea/vomiting (HR, 0.61; 95% CI, 0.44-0.85; P = 0.003). CONCLUSIONS: HRQOL was maintained with first-line treatment with pembrolizumab in patients with PD-L1-positive advanced gastric/GEJ cancer and was similar between pembrolizumab and chemotherapy in this population.

The impact of measurement error on the comparison of two treatments using a responder analysis.

Investigators often report results of studies comparing the proportions of subjects who have clinically meaningful responses to various therapeutic regimens. When the outcome variable is a continuous measure this involves dichotomizing the observed response based on a predefined threshold value. The effect of this strategy is examined, paying particular attention to the impact of measurement error on the resulting estimates of treatment effect (difference in the proportion responding). Expressions are obtained for quantifying the magnitude and direction of the resulting bias, and these are illustrated in a study evaluating a pharmaceutical treatment for osteoporosis.

Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis.

OBJECTIVE: Oral alendronate sodium is a potent, specific inhibitor of osteoclast-mediated bone resorption. To assess its efficacy and safety, a 3-year, randomized, double-blind, multicenter study of 478 postmenopausal women with osteoporosis was conducted. PATIENTS AND METHODS: Subjects received either placebo, alendronate 5 or 10 mg/day for 3 years, or 20 mg/day for 2 years followed by 5 mg/day for 1 year (20/5 mg). All subjects received 500 mg/day of supplemental calcium. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DXA). RESULTS: After 3 years, alendronate 10 mg induced marked increases in BMD of the lumbar spine (9.6 +/- 0.4%), femoral neck (4.7 +/- 0.7%) and trochanter (7.4 +/- 0.6%) (mean +/- SE; each P < or = 0.001) versus decreases of 0.8 to 1.6% with placebo. Progressive increases at these sites in the alendoronate 10 mg group were significant during both the second and third years. Alendronate 10 mg increased total body BMD (1.6 +/- 0.3%, P < or = 0.001), and prevented loss but did not increase BMD at the 1/3 forearm site. Alendronate 20/5 mg was no more effective, whereas alendronate 5 mg was significantly less effective than 10 mg at all sites. Bone turnover decreased to a stable nadir over 3 months for resorption markers (urine deoxypyridinoline) and over 6 months for formation markers (alkaline phosphatase and osteocalcin). Mean loss of stature was reduced by 41% in alendronate treated subjects (P = 0.01). CONCLUSION: The safety profile of alendronate was similar to that of placebo. At 10 mg, there were no trends toward increased frequency of any adverse experience except for abdominal pain, which was usually mild, transient, and resolved with continued treatment. Thus, alendronate appears to be an important advance in the treatment of osteoporosis in postmenopausal women.

Alendronate stimulation of nocturnal parathyroid hormone secretion: a mechanism to explain the continued improvement in bone mineral density accompanying alendronate therapy.

The major effect of currently available antiresorptive therapy for osteoporosis is to slow or arrest bone loss. Although antiresorptive therapies demonstrate increases in bone mineral density, the effect is usually transient, and a plateau in bone mineral density usually emerges at 1 year. A unique and unexplained feature of treatment with the antiresorptive agent alendronate is continued, and steady improvement in bone mineral density occurs in years 2 and 3. We postulated that a potential mechanism for this unanticipated effect might be an exaggerated nocturnal increase in parathyroid hormone (PTH), which can act as an anabolic agent. We examined day-night levels and diurnal variation of PTH, serum calcium, ionized calcium, and markers of bone formation (osteocalcin) and resorption (N-telopeptide cross-links) over 24 hours in a randomly selected subset of 38 women (placebo: N = 13; mean age +/- SD, 69 +/- 3 years; alendronate: N = 25; mean age +/- SD, 69 +/- 3 years) who had completed 12 to 15 months of a larger (N = 120), randomized, double-blind, placebo-controlled trial with alendronate, 5 mg/day. By month 12, increases in the bone density of the spine (4.6%) and femoral neck (2.7%) were observed in the group treated with alendronate compared with placebo, (spine, 2.2%, p = .05; femoral neck, -0.2%, p < or = .05). Mean nocturnal PTH (10 PM-8 AM) was 21% higher (39 versus 32 pg/ml), and nocturnal serum calcium averaged 3% lower (8.7 versus 9.0 mg/dL) in the alendronate-versus-placebo group (both p < or = .05). Daytime levels (8 AM-10 PM) of PTH did not differ significantly between groups. We observed accompanying decreases in coupled markers of bone formation (osteocalcin, 38% lower, p < or = .01) and resorption (N-telopeptide cross-links, 50% lower, p < or = .01) in the alendronate group. Significant diurnal variations of PTH, serum calcium, and osteocalcin were present in both groups. We conclude that following 1 year of alendronate therapy, women have significant increases in bone mineral density and in nocturnal PTH levels, associated with decreases in nocturnal serum calcium and markers of bone turnover with maintenance of the diurnal variation. The nocturnal increase in PTH may mimic the anabolic effect of low-dose intermittent PTH administration to stimulate bone formation. Therefore, the increase might be a potential mechanism to explain the continued improvement in bone density following more than 1 year of alendronate therapy.

High-dose chemotherapy with autologous marrow rescue for malignant brain tumors: analysis of the impact of prior chemotherapy and cranio-spinal irradiation on hematopoietic recovery.

The relative impact of age, sex, nucleated cell dose, prior chemotherapy, prior cranio-spinal irradiation (CSI) and bone marrow harvest (BMH) site on hematological recovery after ABMT were analyzed in a multivariate model. The study population comprised 100 patients with a median age of 9 years who underwent ABMT for malignant brain tumors. Two engraftment parameters were evaluated: number of days post ABMT before (1) an absolute neutrophil count (ANC) > or = 0.5 x 10(9)/l and (2) a platelet count > or = 50 x 10(9)/I were achieved for the third consecutive day without transfusions. Increasing cell dose correlated significantly with a more prompt recovery of platelet counts and ANC. Previous chemotherapy significantly delayed both neutrophil and platelet engraftment. The group of patients who also received CSI had a very delayed platelet recovery with a median time to engraftment of 72 days. Neutrophil engraftment was also significantly delayed and occurred at a median of 23 days. This effect of CSI was independent of cell dose or prior chemotherapy. In 20 of these patients, marrow was harvested at least partially from the posterior iliac crests, which might have received significant doses of irradiation. We conclude that engraftment is significantly faster if bone marrow is harvested prior to any chemotherapy administration, and that patients who receive prior CSI may have significant engraftment delay, particularly of the platelet lineage. In this latter group of patients, marrow should not be harvested from the posterior iliac crests. Strategies that might enhance both neutrophil and platelet count recovery should be considered in patients with irradiation damage to a substantial proportion of the total hematopoietic tissue.

Pediatric desmoid tumor: retrospective analysis of 63 cases.

PURPOSE: This study was conducted to evaluate clinical prognostic factors predictive of the probability of recurrence of desmoid tumor (DT). PATIENTS AND METHODS: Sixty-three patients with histologically confirmed diagnosis of DT were retrospectively studied. Median age at diagnosis was 13 years. Patient distribution by site was as follows: 61% extremities, 18% head and neck, 13% trunk (including 5% intraabdominal), and 8% multicentric lesions. All patients had partial or complete resections; 20 patients also received radiotherapy and/or chemotherapy. RESULTS: At a median follow-up time of 6 years since first treatment, the overall actuarial probability of having one or more recurrences was 75%. Age, sex, site, size, or number of previous recurrences had no significant impact on the likelihood of recurrence. The only factor associated with an increased proportion of recurrence-free patients was a negative margin of resection (70% v 15% with positive margins; P = .006). Of the four patients with more than 3 years follow-up since chemotherapy, two recurred, and of the 11 patients with the same follow-up after radiotherapy, four recurred, including two of five patients who received a dose of 50 Gy or more. No deaths directly related to tumor invasion were observed. CONCLUSION: A surgical approach aiming at clear margins is presently the best treatment option. When this cannot be accomplished without severe disfigurement or function impairment, partial resection is an acceptable alternative, but one associated with a high risk of regrowth. Whether adjuvant strategies should be used in this situation remains to be addressed.

Prognostic factors for recurrence and survival in head and neck soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas of the head and neck represent uncommon malignant neoplasms. With the exception of orbital and parameningeal sites, the treatment of sarcomas in the head and neck has not been standardized. The authors used a prospectively collected database of adult soft tissue sarcomas to identify prognostic factors for local control and survival. METHODS: A prospectively collected database of adult soft tissue sarcoma from 1982 to 1989 was analyzed for the impact of prognostic factors on local control and survival. Factors examined included histologic type, tumor grade, size, and resection margins. RESULTS: The overall and disease free survival at 5 years was 71 and 60%, respectively. Local control was 70% at 5 years. On univariate analysis, grade and margin status were predictors for local control. Analysis based on the Cox proportional hazard model revealed that margin status was the only significant factor in predicting local control. Grade and margin status were significant prognostic indicators for survival both on univariate analysis and in the Cox proportional hazard model. CONCLUSION: Patients with head and neck sarcomas should undergo wide excision with the removal of all gross disease and the acquisition of negative, microscopic surgical margins. Patients with positive margins should receive adjuvant radiotherapy for local control. High grade lesions place patients at risk for local recurrence and distant dissemination. Investigational regimens designed to prevent metastatic disease should be performed.

Nativity, complications, and pathology are determinants of surgical results for gastric cancer.

BACKGROUND: About half the patients involved in the current study were born outside of the United States. Epidemiologic and histologic features and survival estimates were compared with persons born in the United States. Results of gastrectomy with lymph node dissection were studied. METHODS: Records of 187 patients with adenocarcinoma of the stomach were reviewed. Seventy-six with a curative gastrectomy were staged retrospectively. Univariate and multivariate analyses were done. RESULTS: Seventy-six percent of histologically reviewed curative resections had the intestinal subtype with the same frequency in U.S.-born and foreign-born patients. Fewer patients with proximal third lesions were foreign born. Thirty-six percent had complications. The overall 5-year Kaplan-Meier survival estimate was 46%: 77% for patients with negative nodes and 33% for patients with positive nodes. N1 survival estimate was 44%; N2, 25%; N3(M1), 0%. All six patients with early gastric cancer are alive 50-147 months after surgery. Other stage I patients had estimated survival of 65%; Stage II, 52%; Stage III, 40%; and Stage IV, 0%. Multivariate analysis revealed four significant prognostic variables: nativity, histologic subgroup, presence of complications, and number of positive nodes. CONCLUSIONS: Proximal gastric cancer was more common in U.S.-born persons. Gastric cancer may be more malignant in U.S.-born persons than in foreign-born persons because their survival was significantly poorer. Complications, a significant adverse factor, were more common in U.S. series. Pancreatectomy with gastrectomy is rarely indicated, because microscopic involvement is rare and complications frequent. The prognostic advantage of a regional lymphadenectomy remains unclear.

Tolbutamide inhibits gluconeogenesis in the tumor-influenced hepatocyte.

The tumor-bearing state is associated with an increase in gluconeogenesis which may contribute to the development of cancer cachexia. The purpose of this study was to determine if tolbutamide, a drug known to decrease gluconeogenesis in diabetes, could decrease gluconeogenesis in hepatocytes isolated from tumor-bearing rats. Hepatocytes from 24-hr fasted normal and methylcholanthrene-induced sarcoma-bearing rats (5-10% tumor burden) were isolated by in situ collagenase liver perfusion. Hepatocytes (n = 12 samples) from non-tumor-bearing (NTB) controls and tumor-bearing (TB) rats were incubated with lactate (10 mM) and alanine (10 mM) with and without 1 mM tolbutamide. Supernatant glucose concentration was measured at 30-min intervals for 2 hr. Rates of gluconeogenesis (+/- standard error) were calculated by linear regression and are expressed as nmole glucose/10(6) cells/min. Comparisons were made by two-way analysis of variance and significance defined as P < 0.05. TB hepatocytes had an increased rate of gluconeogenesis (P < 0.0001) from alanine and lactate (3.8 +/- 0.30 and 2.2 +/- 0.10, respectively) compared with NTB hepatocytes (0.66 +/- 0.10 and 1.2 +/- 0.04, respectively). TB hepatocytes treated with tolbutamide had a decreased (P < 0.0001) rate of gluconeogenesis from alanine and lactate (3.1 +/- 0.10 and 1.1 +/- 0.10, respectively) compared with untreated TB hepatocytes (5.3 +/- 0.10 and 2.1 +/- 0.10, respectively). Tolbutamide inhibits gluconeogenesis from lactate and alanine in tumor-influenced hepatocytes.

Combined modality therapy for primary CNS lymphoma.

PURPOSE: Primary CNS lymphoma (PCNSL), formerly rare, is being seen with increased frequency among apparently immunocompetent patients. Conventional treatment has consisted of whole-brain radiotherapy (RT) and corticosteroids, with a median survival of 15 to 18 months and a 3% to 4% 5-year survival. Chemotherapy has been useful in the treatment of recurrent PCNSL. In 1985 we began a treatment protocol using chemotherapy and cranial irradiation for the initial therapy of non-AIDS PCNSL. PATIENTS AND METHODS: Thirty-one patients (group A) completed the combined modality regimen. All had placement of an Ommaya reservoir and received pre-RT systemic methotrexate, 1 g/m2, plus six doses of intra-Ommaya methotrexate at 12 mg per dose. A full course of cranial RT (4,000-cGy whole-brain RT plus a 1,440-cGy boost) was followed by two cycles of high-dose cytarabine (ara-C), with each course consisting of two doses of 3 g/m2 ara-C separated by 24 hours and infused over 3 hours. During this period, 16 additional patients (group R) were treated with RT alone, either because patients refused chemotherapy or RT was initiated before our consultation; all would have been eligible to participate in the protocol. Follow-up extended through April 1, 1991. RESULTS: Group A had a significantly prolonged time to recurrence (median, 41 months) compared with group R (median, 10 months; P = .003). Although median survival was doubled from 21.7 months for group R to 42.5 months for group A, this was not statistically significant because of small sample size. More importantly, group R patients received systemic chemotherapy for recurrent PCNSL, which improved survival. CONCLUSION: The addition of chemotherapy to cranial RT for initial treatment of PCNSL significantly improved disease-free survival and contributed to overall survival; all non-AIDS patients with newly diagnosed PCNSL should be considered for combined modality therapy.

Potentiation of epidermal growth factor receptor protein-tyrosine kinase activity by sulfate.

The protein-tyrosine kinase activity of the epidermal growth factor (EGF) receptor is critical for EGF-stimulated cell growth, although little is known about the molecular details of its enzymatic activity. Previous studies have found that EGF receptor kinase activity can be stimulated by factors such as ammonium sulfate ((NH4)2SO4), but the manner in which (NH4)2SO4 induces this effect is unclear. Therefore, we have explored the processes by which (NH4)2SO4 potentiated tyrosine kinase activity to better understand not only the molecular events involved in (NH4)2SO4 activation, but also the kinetic properties and mechanism of the EGF receptor. In this study, the addition of an optimum concentration of (NH4)2SO4 (250 mM) resulted in a 5-fold stimulation of kinase activity toward the peptide substrate, angiotensin II. The sulfate group is primarily involved in this action, since other salts containing SO4(2-) increased kinase activity similarly, whereas salts containing Cl- and F- had less of an effect, and divalent salts such as HPO4(2-) and NaVO4(2-) were inhibitory at doses of 1 mM or more. In addition, EGF receptor kinase activation by (NH4)2SO4 did not strictly correlate with changes in the ionic strength or conductivity of the solution. However, several lines of evidence suggest that SO4(2-) directly alters the kinetic properties of the EGF receptor kinase: (1) the maximum velocity (Vmax) and Km (ATP) for EGF receptor phosphorylation of angiotensin II were substantially higher in the presence of (NH4)2SO4. (2) EGF receptor kinase activity in the absence of (NH4)2SO4 required either Mn2+ or Mg2+, yet in the presence of (NH4)2SO4, only Mn2+ supported the increase in kinase activity. (3) Ammonium sulfate addition altered the product inhibition pattern of ADP versus angiotensin II, suggesting that an enzyme-angiotensin II-ADP complex can form in the presence of (NH4)2SO4 but not in its absence. (4) The near-maximal rate of self-phosphorylation was not affected by (NH4)2SO4 but the apparent Km (ATP) was greatly increased. From these results, we propose a model for (NH4)2SO4 stimulation of EGF receptor kinase activity in which SO4(2-) interacts directly with the receptor or receptor-Mn(2+)-ATP complex and alters reactant binding and the catalytic efficiency of the tyrosine kinase.

The importance of clinical staging of minor salivary gland carcinoma.

We reviewed a 45-year experience with 459 patients who had previously untreated minor salivary gland neoplasms, 378 (82%) of which were malignant. Data were adequate for retrospective clinical staging in 353 of the 378 patients with malignant tumors using criteria identical to those for squamous carcinoma in the same sites. Five-, 10-, and 15-year survival rates for the patients with malignant tumors treated after 1966 were 75%, 62%, and 56%, respectively, a significant improvement compared with results reported previously. Multivariate analysis confirms that survival was significantly influenced by the clinical stage and the histologic grade, but the applicability of grading was limited to patients with mucoepidermoid carcinoma or adenocarcinoma. Ten-year overall survival was 83%, 53%, 35%, and 24% for patients with stage I through stage IV, respectively. Results in these patients are similar to those we have recently reported in patients with major salivary gland carcinomas, but we are unable to demonstrate that postoperative radiotherapy improved survival.