Diane Hershock

Organ Preservation Therapy Using Induction Plus Concurrent Chemoradiation for Advanced Resectable Oropharyngeal Carcinoma: A University of Pennsylvania Phase II Trial

PURPOSE To determine the efficacy, feasibility, and toxicity of a new regimen for locally advanced oropharyngeal carcinoma. PATIENTS AND METHODS Patients had technically resectable stage III/IV squamous cell carcinoma of the oropharynx, exclusive of T1-2N1. Induction chemotherapy consisted of carboplatin (area under the curve formula equal to 6) and paclitaxel 200 mg/m(2) for two cycles, followed by re-evaluation. Patients with major response continued to definitive radiotherapy (70 Gy over 7 weeks) plus concurrent once-weekly paclitaxel (30 mg/m(2)/wk). Patients with advanced neck disease also underwent post-radiation therapy neck dissection and two more chemotherapy cycles. RESULTS Fifty-three patients were enrolled. Median follow-up was 31 months (minimum follow-up for survivors was 18 months). The major response rate to induction chemotherapy was 89%; 90% of patients had a complete response after concurrent chemoradiation. Actuarial survival at 3 years was 70%, and 3-year event-free survival was 59%. The 3-year actuarial locoregional control was 82% and the 3-year actuarial rate of distant metastases was 19%. Organ preservation was achieved in 77% of all patients. One patient (2%) died during therapy. Late grade 3 toxicity occurred in 24% of patients, consisting mainly of chronic dysphagia/aspiration and/or radiation soft tissue ulceration. The treatment-related mortality rate was 4% (two patients died from respiratory failure). CONCLUSION Response to induction chemotherapy as studied in this trial was not useful as a predictive marker for ultimate outcome or organ conservation. Overall, however, this regimen offers good disease control and survival for patients with locally advanced oropharyngeal carcinoma, comparable with other concurrent chemoradiation programs. Further study of similar protocols is indicated.

Interaction of platelet factor 4 with human platelets.

Human washed resting platelets bound 125I-labeled platelet factor 4 in a reaction which was saturable and approached equilibrium within 15-30 min. Scatchard plot analysis of the binding isotherms suggested a single class of specific binding sites. Excess of unlabeled protein and low- and high-affinity heparin competed for platelet factor 4 binding sites on the platelet surface and caused a partial displacement of this molecule. Anti-platelet factor 4 Fab fragments caused inhibition of binding of 125I-platelet factor 4 to platelets. Most of the labeled platelet factor 4 which was bound to intact platelets was recovered in the Triton X-100-insoluble cytoskeletal fraction prepared from the same platelets after their stimulation by thrombin. The association with the cytoskeleton was inhibited by anti-platelet factor 4 Fab fragments and by low-affinity heparin. Anti-platelet factor 4 125I-labeled Fab fragments bound to resting platelets, and this binding was greatly increased following platelet stimulation with thrombin. This suggested that endogenously secreted platelet factor 4 also binds to the platelet surface. No significant binding to platelets of 125I-labeled beta-thromboglobulin and 125I-labeled anti-beta-thromboglobulin Fab fragments was observed. Fab fragments of monospecific anti-human platelet factor 4 antibody raised in rabbits inhibited platelet aggregation and secretion induced by low concentrations of thrombin. Fab fragments of anti-beta-thromboglobulin antibody had no inhibitory effect. We suggest that the binding of alpha-granule-derived platelet factor 4 to the specific sites on the surface of platelets may modulate platelet aggregation and secretion induced by low levels of platelet agonists.

The effects of immobilization stress on serum triglycerides, nonesterified fatty acids, and total cholesterol in male rats after dietary modifications

The effects of acute immobilization stress on triglycerides, nonesterified fatty acids (NEFA) and total cholesterol were determined in serum samples obtained by indwelling jugular catheters from male Sprague-Dawley rats. Stress was evaluated in three groups of rats: (1) those maintained on a regular Purina Chow diet and then fasted for 24 hours; (2) those maintained on this same diet but not fasted (nonfasted) before experimentation; and (3) those maintained on a Purina Chow diet supplemented with cholesterol (1%) and fat (10%) for 6 weeks and nonfasted prior to experimentation. Samples were taken by catheter in the home cage prior to, four times during a one hour stress/nonstress period and thirty minutes after being returned to the home cage for recovery. Nonstressed rats remained in the home cage during the entire 90 minute period. In each dietary state studied, stress affected serum triglycerides and NEFA but not total cholesterol levels. Triglyceride levels in fasted rats increased during the stress period. On the other hand, triglycerides decreased in response to stress in nonfasted rats. In stressed, nonfasted high cholesterol-fed animals, triglycerides were elevated in comparison to their nonstressed counterparts. In both fasted, regular diet-fed and nonfasted, cholesterol-fed rats, NEFA sharply declined from baseline after 5 minutes of stress; NEFA did however increase after fifteen minutes. NEFA levels in both stressed and nonstressed, nonfasted rats also rapidly decreased from baseline and never recovered throughout the session. Total cholesterol did not change in response to stress or dietary modifications. The rats maintained on a high cholesterol diet showed only a diet-induced increase in total cholesterol. Thus, acute immobilization stress affected serum triglyceride and NEFA values and these effects were diet- and time-dependent. Total cholesterol levels were unaffected by stress.

A Phase I Study of SPI-077 (Stealth® Liposomal Cisplatin) Concurrent with Radiation Therapy for Locally Advanced Head and Neck Cancer

AbstractBackground: Liposomal cisplatinpreparations have two potential advantagesover the free drug when combined withradiation therapy (RT): 1) selective tumorlocalization, improving the therapeuticratio, and 2) prolonged half-life, allowingmore radiosensitization. We performed aPhase I study of Stealth® liposomalcisplatin (SPI-077) concurrent with RT forhead and neck squamous cell carcinoma(HNSCC). Methods: Patients with StageIVa/b HNSCC were treated with SPI-077,given intravenously twice two weeks apart,concurrent with RT (60–72 Gy in 6–7 weeks).The SPI-077 dose was escalated in standardphase I design. Results: Twenty patientsreceived 38 doses of SPI-077, escalatedfrom 20–200 mg/m2 in six dose levels.Two of these patients received one dosebecause of reversible Grade 3 livertoxicity or rash. Three patients had aGrade 1, and one had a Grade 2 infusionreaction. Four patients had transientlyelevated transaminases: Grade 1 (n = 1),Grade 2 (n = 1), and Grade 3 (n = 2). Grade 3neutropenia occurred in one patient. Therewas no ototoxicity, neurotoxicity, ornephrotoxicity. In-field radiation skin andmucosal toxicities did not appear to beintensified. Ten of 17 patients (59%)finishing treatment achieved initialcomplete response. Conclusions: Systemic andin-field radiation toxicities of SPI-077were minimal. Infusion reactions wereminimized with a slower and more diluteinitial infusion. Further dose escalationwas stopped in the absence of dose-limitingtoxicity to address the reformulation ofthe liposomally bound cisplatin.Nonetheless, this study shows that highdoses of SPI-077 can be given safely. Thepotentially beneficial therapeutic ratiosuggests that liposomal radiosensitizerpreparations warrant furtherinvestigation.

Preliminary investigation of symptom distress in the head and neck patient population: Validation of a measurement instrument

Objective:Observations indicate that the acute toxicity of chemoradiation for squamous cell carcinoma (SCC) of the head and neck is not the same as that which occurs with radiation therapy alone. Thus, the specific aim of this pilot study was to estimate the reliability and validity of a modified version of a symptom distress scale used to assess the qualitative difference in symptom distress between the 2 populations. Methods:Over a period of 4 months a consecutive sample of 56 patients with head and neck cancer were recruited from the Department of Radiation Oncology to take part in our pilot study. The Cancer Disease and Treatment Concern Scale (CDTCS) was modified by adding 15 additional items and called the Head and Neck Distress Scale (HNDS). All dimensions were interrogated with at least four questions and a domain score was generated. In addition, the Head and Neck Radiotherapy Questionnaire (HNRQ), an established 22-item multidimensional questionnaire was also administered by interview after completion of the HNDS. Results:Fifty-six patients, 32 chemoradiation patients (mean age 64 years) completed the HNDS, taking 8 to 10 minutes to complete. The HNDS scores correlated well with the HNRQ scores (r = 0.835), demonstrating an acceptable level of content and concurrent validity. There was a significant difference in the overall HNDS scores between the chemoradiation group and the radiation therapy group (ANOVA, P = 0.001). Conclusion:The HNDS is a valid measure of acute symptom distress and appears able to discriminate between the chemoradiation and radiation alone patients. There is considerable variation in symptoms that cause these patients distress.

Pilot study of organ preservation multimodality therapy for locally advanced resectable oropharyngeal carcinoma.

The purpose of this study was to determine the early efficacy and toxicity of a new multimodality organ-preservation regimen for locally advanced, resectable oropharyngeal squamous cell carcinoma (SCC). Patients with T3-4N0-3M0 or T2N2-3M0 oropharyngeal SCC were eligible for this Phase II study. Patients needed the physiologic reserve for surgery and technically resectable tumors. Induction carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) × 2 cycles (q21 days) were given. Objective responders received definitive radiotherapy (XRT), 70 Gy/7 weeks with concurrent weekly paclitaxel. Initially, the dose of paclitaxel was 50 mg/m2/week; because of mucosal toxicity it was reduced to 30 mg/m2/week. Patients with N2-3 disease received post-XRT neck dissection and 2 more cycles of “adjuvant” chemotherapy. In the first 22 patients, the neutropenic fever rate was 27%. Although there has been no grade IV-V toxicity from induction therapy, grade II-III toxicity resulted in an unacceptable delay in starting XRT in 14% of patients. The response rate to induction chemotherapy was 91%. Grade III mucositis occurred in all patients during concurrent chemoradiotherapy. One patient died of pneumonia during concurrent chemoradiotherapy after receiving 26 Gy and 3 doses of paclitaxel 50 mg/m2. No dose-limiting toxicity occurred in 15 patients treated with concurrent paclitaxel 30 mg/m2/week. Actuarial overall survival at 18 months is 82%; local–regional control is 86%. To date, distant metastases have not developed in any patients. This regimen has intense but acceptable acute toxicity. The maximum tolerated dosage of weekly paclitaxel during standard continuous-course XRT is confirmed to be 30 mg/m2/week. The treatment efficacy of this regimen (response rate and short-term local–regional and distant control) is encouraging. Accrual continues to obtain long-term toxicity, efficacy, and quality-of-life data.

Effects of adinazolam on plasma catecholamine, heart rate and blood pressure responses in stressed and non-stressed rats.

Adinazolam (ADI) is a new benzodiazepine with anxiolytic and antidepressant properties. To assess its effects on the acute stress response, rats were given a single intraperitoneal injection of 2.5 or 5.0 mg/kg of ADI and stressed for 1 hr by restraint. Neither dose of ADI had any effect on heart rate, blood pressure or norepinephrine (NE) and epinephrine (EP) in plasma in the resting rats. In the stressed animal, 2.5 and 5.0 mg/kg of ADI did not affect stress-induced increases in heart rate or blood pressure but both significantly reduced the stress-induced increases in plasma NE and EP. During certain stressful experiences in patients with abnormally-increased sympathetic drive, ADI may be therapeutically useful in reducing high levels of catecholamines.

Comparison of platelet fibrinogen receptors on intact and proteolytically-treated platelets by use of an antiglycoprotein IIIa monoclonal antibody (MA 123)

A murine monoclonal antibody (MA 123) was selected by screening 153 supernatants of hybridoma cells secreting anti-human platelet antibodies for their ability to inhibit the fibrinogen-induced aggregation of chymotrypsin-treated platelets. MA 123 inhibited the binding of 125I-fibrinogen to ADP-stimulated intact human platelets and to platelets treated with chymotrypsin or pronase. Moreover, it inhibited the fibrinogen-induced aggregation of these platelet suspensions. The degree of inhibition was similar in each of the three types of platelets tested. The interactions of MA 123 with the 125I-labeled surface components of intact and chymotrypsin-treated platelets were studied by immunoprecipitation using Staphylococcus aureus coated with goat anti-mouse IgG, followed by SDS-polyacrylamide gel electrophoresis and autoradiography. MA 123 precipitated the glycoprotein IIb-glycoprotein IIIa (GPIIb-GPIIIa) complex from the surface of detergent solubilized intact human platelets; and it precipitated GPIIIa from the surface of chymotrypsin-treated platelets. Partially purified GPIIIa was also immunoprecipitated by MA 123. Our data suggest that the exposure of fibrinogen receptors by ADP, chymotrypsin or pronase, is associated with alterations of GPIIIa on the platelet surface.

A phase 1 study of fixed dose rate gemcitabine and irinotecan in patients with advanced pancreatic and biliary cancer

The combination of a fixed dose rate (FDR) infusion of gemcitabine and irinotecan may have a synergistic effect in the treatment of patients with advanced and metastatic pancreatic and biliary cancer. The current study was conducted to determine the dose‐limiting toxicity (DLT) and the maximum tolerated dose (MTD) of the combination.

Final report of a pilot trial of accelerated radiotherapy plus concurrent 96-hour infusional paclitaxel for locally advanced head and neck cancer

Recent data show that accelerated radiotherapy (XRT) improves local-regional control (LRC) over standard-fractionation XRT. Concurrent chemoradiotherapy improves LRC and survival over XRT alone. This study assesses the feasibility, toxicity, and preliminary efficacy of concurrent 96-hour paclitaxel infusion with accelerated XRT. Eligible patients had stage IV squamous cell carcinoma of the head and neck, exclusive of nasopharynx cancer. Tumor had to be considered technically unresectable after evaluation by our multidisciplinary head/neck tumor board. XRT was given continuous course using an accelerated regimen with twice a day fractionation for the cone down (70–72 Gy/6 weeks). Chemotherapy consisted of 2 cycles of paclitaxel via 96-hour infusion during weeks 1 and 5 of XRT. The first 10 patients received doses of 40–120 mg/m2/cycle, and the subsequent 13 patients received 100 mg/m2/cycle. Twenty-three patients were studied. Median follow-up was 20.4 months (44.4 months for the 10 long-term survivors). Most (19/23) patients had reversible grade 3 acute mucositis. Median treatment time was 44 days, and all but 1 patient received both cycles of paclitaxel at their planned dose. The 3- and 4-year actuarial survival was 37%. Three- and 4-year LRC was 50%. Four patients (18%) developed distant metastases. Two patients (9%) developed severe esophageal strictures requiring permanent gastrostomy/tracheostomy, and 2 patients developed other late grade 3+ toxicities. Accelerated XRT plus concurrent 96-hour infusional paclitaxel as given in this study has intense but acceptable toxicity and is feasible. LRC and survival compare favorably with other aggressive regimens for this poor-prognosis population. Further study of accelerated XRT with concurrent chemotherapy is indicated.