Chemotherapy of patients with recurrent head and neck cancer.
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Antineoplastic Agents↗
Biomedical subjects
R H Wheeler
Publications and source records attributed to R H Wheeler.
A phase II trial of murine monoclonal antibody 17-1A and interferon-gamma: clinical and immunological data.
A group of 15 patients with metastatic colorectal adenocarcinoma received a combination of interferon gamma (0.1 mg/m2, days 1-15) and the murine monoclonal antibody 17-1A (400 mg, days 5, 7, 9 and 12). The treatment was tolerated with minimal toxicity. Of the 14 evaluable patients, 13 developed human antibody to murine 17-1A, with 11 patients demonstrating antibody to the variable region of 17-1A (anti-idiotype). Antibody to the variable region was inhibited by 17-1A but not by mouse immunoglobulin. Sera from patients with substantial anti-idiotype reactivity were capable of inhibiting the binding of murine 17-1A to antigen expressing LS174-T cells thus indicating the presence of antibody directed against the 17-1A combining site (mirror-image anti-idiotype). The median survival of the whole group was 56 weeks and there was no correlation between clinical response/survival and the development of anti-idiotype antibody.
Adenocarcinoma↗
Pharmacokinetics of a mouse/human chimeric monoclonal antibody (C-17-1A) in metastatic adenocarcinoma patients.
The pharmacokinetic characteristics of a mouse/human chimeric monoclonal antibody (C-17-1A) were determined in 10 patients with metastatic adenocarcinoma following the administration of either 10-mg or 40-mg infusions as a single or multiple dose. The administration of single 10-mg (n = 5) and 40-mg (n = 5) doses infused over 1 hr resulted in mean apparent steady-state distribution volumes of 4.13 +/- 0.97 and 5.16 +/- 1.92 liters, respectively, indicating that C-17-1A appears to distribute throughout the vascular compartment and into limited extracellular fluid volume. The disposition of C-17-1A was adequately characterized using a two-compartment open model with mean distribution half-lives of 15.8 and 18.5 hr and mean elimination half-lives of 90.0 and 97.6 hr for the 10- and 40-mg groups, respectively. A linear relationship was observed between AUC and dose (micrograms/kg). The clearance of C-17-1A was correlated linearly with total Ig, IgG, and tumor size. Multiple administration of either 10-mg (n = 3) or 40-mg (n = 3) doses of C-17-1A infused over 1 hr every 14 days for a total of three doses resulted in superimposable mean serum concentration versus time data and consistent mean pharmacokinetic characteristics. These data indicate that C-17-1A exhibits linear, nonsaturable distribution and elimination characteristics in man over the dose range studied (i.e., 130 to 880 micrograms/kg). The multiple-dose pharmacokinetics of C-17-1A were predictable, indicating a lack of an antibody response to C-17-1A over a period of 42 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenocarcinoma↗
Mouse/human chimeric monoclonal antibody in man: kinetics and immune response.
A mouse/human chimeric monoclonal antibody (mAb) composed of the variable regions of murine 17-1A mAb and the constant regions of human IgG-1K immunoglobulin was administered to 10 patients with metastatic colon cancer. Four patients received single infusion of 10 mg (n = 2) or 40 mg (n = 2). Six patients received three infusion of 10 mg (n = 3) or 40 mg (n = 3) at 2-week intervals. The pharmacokinetics were similar at both dose levels and at the second and third infusions. The plasma disappearance curves were best fit by a two-compartment model having a mean alpha T1/2 of 17.5 hr (range 13-23 hr) and a mean beta T1/2 of 100.5 hr (range 65-139 hr). One patient who received three 40-mg doses of chimeric IgG-1K 17-1A mAb (day 0, 14, and 28) was the only patient to exhibit a detectable but modest antibody reactivity to chimera on days 63 and 84. The antibody reactivity was inhibited by murine 17-1A mAb, indicating that the antibody response was directed to the murine variable region of the chimera. The patients had no toxic or allergic reactions. This chimeric form of 17-1A mAb has an approximate 6-fold longer circulation time and appears to be substantially less immunogenic than its murine counterpart. These characteristics may provide an advantage in the clinical application of such chimeric molecules in therapeutic trials in humans.
Adenocarcinoma↗
Cisplatin and mitoguazone. An induction chemotherapy regimen in advanced head and neck cancer.
The combination of cisplatin 100 mg/m2 every 3 weeks and mitoguazone 500 mg/m2 every week with dose escalation was administered as a 9-week induction regimen to 27 patients with previously untreated Stage III or IV squamous cell carcinoma of the head and neck. This was followed by full-course radiation therapy for unresectable patients or surgery and postoperative radiation therapy for those with resectable disease. Sixteen patients had bulky unresectable disease, and ten were candidates for curative resection at study entry. Of 26 patients evaluable for response to chemotherapy, there were seven complete responses (CR) (five of six pathologically confirmed) and ten partial responses (PR) (65% CR + PR). Toxicity was generally mild with Grade 3 or 4 nausea and vomiting occurring in 15% and diarrhea in 12%. Nineteen percent of the patients developed transient nephrotoxicity (serum creatinine greater than 2), 62% anemia (hemoglobin decrease greater than 2 g/dl), 23% leukopenia (leukocyte count less than 3500 cells/microliters) and 8% thrombocytopenia (platelets less than 50,000 cells/microliters). Anorexia, fatigue, and weight loss occurred in nearly all patients. The median survival time of all patients was 17.5 months; complete responders, 43 months; partial responders, 16 months; and nonresponders, 9 months (P = 0.0025). In a multivariate analysis of stage, primary site, resectability status, response to chemotherapy, and local treatment (surgery plus radiation versus radiation), complete response was the only statistically significant covariate for survival. In Phase II single agent trials, mitoguazone has been shown to have a 15% response rate in head and neck cancer and cisplatin, a 30% to 40% response rate (less than 10% CR). Thus, our results, both complete and overall response rates, were higher than would be expected from either drug alone. A possible mechanism for this high response rate may be mitoguazone-induced cell synchronization. In vitro studies demonstrate the accumulation of tumor cells exposed to mitoguazone in S- and G2-phases of the cell cycle. These results would support further evaluation of mitoguazone in combination to explore the theoretical potentiation of antitumor effects by sequencing with cycle-specific agents.
Adult↗
Phase I trial of multiple large doses of murine monoclonal antibody CO17-1A. I. Clinical aspects.
Twenty-five patients with metastatic gastrointestinal adenocarcinoma received one to four infusions (400 mg) of murine monoclonal antibody CO17-1A. Eleven patients had mild gastrointestinal symptoms, and one had a transient flushing episode. Two of five who received three weekly infusions had readily reversible anaphylactic reactions at the time of the third infusion (day 15). There were no other toxic effects. One patient had a complete remission and is surviving at greater than 104 weeks, and four had stable disease. The median survival for the whole group was 57 weeks. In general, the antibody infusions were well tolerated but had modest antitumor effects.
Adenocarcinoma↗
Phase I trial of multiple large doses of murine monoclonal antibody CO17-1A. II. Pharmacokinetics and immune response.
Twenty-five patients with metastatic gastrointestinal adenocarcinoma received one to four infusions of large doses (400 mg) of murine monoclonal antibody CO17-1A (17-1A). The pharmacokinetics of 17-1A at the time of first, second, third, or fourth infusion were not statistically different; plasma half-lives were 15.0 +/- 1.7 hours (n = 5), 15.1 +/- 1.8 (n = 10), 25.3 +/- 6.2 (n = 3), and 14.4 +/- 1.8 (n = 5), respectively. Most patients had an antibody response to 17-1A, with peak levels occurring 15-22 days after infusion. The presence of serum antibody to 17-1A at the time of the second or third infusion did not significantly alter the pharmacokinetics of this large dose of antibody. Four of 25 patients failed to develop an antibody response, but this did not correlate with the amount of 17-1A administered. The administration of four doses of 400 mg over 1 week provided continuously circulating 17-1A for 10 days.
Animals↗
Phase I-II study of cisplatin, VP-16, MGBG, mitomycin, and vinblastine with radiation therapy for non-small-cell lung cancer.
Nineteen patients with locoregional non-small-cell lung cancer (NSCLC) were treated with two courses of cisplatin/VP-16/MGBG, followed by involved field radiotherapy and, subsequently, the same chemotherapy alternating with mitomycin-C/vinblastine. Five of 17 patients obtained a response (CR + PR) after induction chemotherapy. Following radiotherapy, an additional two patients responded. The median survival was 7.5 months, with the two longest survivors at 30 and 32 months. Hematologic toxicity was severe, with two deaths from severe neutropenia. Renal and gastrointestinal toxicities were moderate. This program of aggressive therapy did not increase the response rate or median survival compared with those of comparable patients treated in recent trials using radiotherapy alone or combined radiotherapy plus chemotherapy.
Aged↗
Clinical use of a standard kit-preparation of radiolabeled monoclonal antibody 96.5 in the diagnostic imaging of metastatic melanoma.
We studied the efficiency of a standard-kit preparation using 1 mg 111In-labeled 96.5 monoclonal antibody in combination with 19 mg of unlabeled antibody in the diagnostic imaging of 27 patients with documented metastatic melanoma. Twenty-three of 26 patients (88%) demonstrated immunoscintigraphic localization of tumor. Of 104 metastatic sites previously documented by conventional studies, 62 (60%) were identified by immunoscintigraphy. A total of 77 sites demonstrated localization of radiolabeled antibody. Fifty-four (70%) corresponded to known sites of disease; eight sites (10%) were "discovered" by immunoscintigraphy and subsequently confirmed by conventional studies; 15 imaged sites (20%) could not be confirmed by conventional studies. Size and location of metastasis appear to be important features that influence imaging efficiency. Tumor size (greater than or equal to 2 cm v less than 2 cm) appears to be the statistical dominant determinant. The feasibility and potential clinical use of radioimmune imaging of tumors is discussed.
Adult↗
A randomized comparison of haloperidol plus dexamethasone versus prochlorperazine plus dexamethasone in preventing nausea and vomiting in patients receiving chemotherapy for breast cancer.
The antiemetic effectiveness of haloperidol plus dexamethasone was compared with that of prochlorperazine plus dexamethasone in a prospective study of patients receiving chemotherapy for breast cancer. Chemotherapy consisted of cyclophosphamide, doxorubicin or methotrexate, and fluorouracil in all patients. Patients who received the doxorubicin-containing combination experience significantly more nausea and vomiting than those who received the chemotherapy combination containing methotrexate. There was no significant difference between the two antiemetic regimens in the overall incidence of post-chemotherapy nausea and vomiting, but patients who received haloperidol and dexamethasone did have a lower incidence of severe vomiting. Neither regimen is highly effective, especially for the combination containing doxorubicin, and cannot be recommended as standard antiemetic therapy for this population of patients.
Antineoplastic Combined Chemotherapy Protocols↗
Cisplatin and dichloromethotrexate: a pharmacologically rational combination.
Dichloromethotrexate (DCM), a dihalogenated analog of methotrexate (MTX), is a potent classic folate antagonist that is metabolized and excreted by the liver. It is not nephrotoxic nor are its pharmacokinetics significantly affected by changes in renal function. Therefore, the feasibility of administering a maximum tolerated dose of DCM in combination with high-dose ciplatin (CDDP) was investigated in patients with head and neck, bladder, or cervical cancer--three epithelial carcinomas known to be responsive to single-agent CDDP and MTX. The overall response rates in 24 evaluable patients with head and neck cancer, 21 evaluable patients with bladder cancer, and 22 evaluable patients with cervical cancer were 54%, 57%, and 50%, respectively. Complete response rates of 25%, 19%, and 36%, respectively, were observed. DCM can be administered on a weekly schedule at a maximum tolerated dose in combination with CDDP with tolerable side effects and without significant nephrotoxicity.
Adult↗
A phase II trial of cisplatin and methylglyoxal bis-guanylhydrazone (MGBG) in recurrent squamous cell carcinoma of the head and neck.
Thirty-one patients with unresectable squamous cell carcinoma of the head and neck, 28 with local or distant recurrences following primary surgery and/or radiation and three with distant metastases at diagnosis, were treated with cisplatin and methylglyoxal bis-guanylhydrazone (MGBG). Cisplatin was given at 60 mg/m2 i.v. every 21 days X 3, followed by 80 mg/m2 every 28 days in responding patients. MGBG 500 mg/m2 i.v. was given weekly X 5, then every 14 days. Each dose of MGBG was to be escalated in the absence of toxicity, but in the majority of patients doses greater than 500 mg/m2 resulted in unacceptable toxicity. Gastrointestinal symptoms were the major side effects of this combined treatment. In 28 evaluable patients there were two complete remissions and nine partial remissions. This 39% response rate is not different from that reported with either drug alone. Combined cisplatin and MGBG as administered in this study had no apparent advantage compared to either agent alone in this group of patients.
Adult↗
Tumor blood flow and systemic shunting in patients receiving intraarterial chemotherapy for head and neck cancer.
Radionuclide techniques have been used to estimate the systemic shunt and to quantitate blood flow to the tumor and a reference normal tissue in nine patients undergoing intraarterial chemotherapy for head and neck cancer. The systemic shunt was calculated as the percentage of pulmonary trapping of intraarterially injected 99mTc-labeled macroaggregated albumin. The mean systemic shunt in the 12 separate arteries studied was 23 +/- 13% (SE) (range 8-43%). Quantitative blood flow was determined from the slope of the washout curve of intraarterially injected 133Xe. The mean tumor blood flow was 13.6 +/- 6.7 ml/100 g/min, while the mean blood flow to the scalp was 4.2 +/- 2.1 ml/100 g/min providing a mean tumor/normal tissue ratio of 3.9 +/- 2.7. An estimate of blood flow distribution was obtained by calculating the ratio of counts/pixel in the tumor mass versus the remainder of the head as determined by single photon emission computed tomography following an intraarterial injection of 99mTc-labeled macroaggregated albumin. The mean ratio of tumor to normal tissue perfusion by this technique was 5.6 +/- 3.7. These techniques have allowed noninvasive determination of the blood flow parameters associated with intraarterial chemotherapy. At least part of the therapeutic advantage of regional chemotherapy in patients with head and neck cancer is due to a tumor/normal tissue blood flow ratio that favors drug delivery to the tumor contained within the infused volume.
Adult↗
A phase II trial of aclacinomycin-A in advanced squamous cell carcinoma of the head and neck.
Sixteen patients with advanced squamous cell carcinoma of the head and neck were entered into a phase II trial of Aclacinomycin-A (ACM), 100 mg/M2 administered by brief infusion every three weeks. All patients had received prior radiation therapy and prior non-anthracycline containing chemotherapy. No clinically significant disease regression was observed in fourteen patients having adequate trials. The major toxicity was myelosuppression; leukopenia occurred in 93% of patients. Gastro-intestinal toxicity was mild and included two patients with transient liver function test abnormalities. No antitumor activity was observed in this patient population which was heavily pre-treated and had a median Karnofsky performance status of only 60%. The results of other phase II trials of ACM-A have been similarly disappointing suggesting that it is not a clinically useful agent in the treatment of solid tumors.
Aclarubicin↗
The use of a vasoconstrictor to improve tumour blood flow in intra-arterial chemotherapy: preliminary report.
The effectiveness of intra-arterial chemotherapy is dependent on a high tumour to normal blood flow ratio (T/NT). This report demonstrates the use of a vasoconstrictor (NE) to improve the relative blood flow to head and neck tumours by causing vasoconstriction and decreased blood flow to normal soft tissue. Five quantitative planar Tc-MAA perfusion studies were performed on three patients with increasing dose rates of norepinephrine (NE) to determine the optimal dose in each patient that would produce the best T/NT. All patients demonstrated a change in perfusion pattern with increasing dose rates (0.1 to 15 micrograms min-1), although there was considerable variation between patients. Quantitative SPECT was performed on two patients. In one, there was a 35% increase in the T/NT and a 16% decrease in arteriovenous (A-V) shunting to the lung.
Antineoplastic Agents↗
Surgical aspects of intra-arterial chemotherapy of outpatients with head and neck cancer.
We have evaluated the use of the completely implantable infusaid pump in 22 patients with advanced cancer confined to the head and neck. Unilateral head lesions are treated with a single-catheter pump infusing the external carotid artery. A dual-catheter pump is used for midline or bilateral head lesions (both external carotid arteries infused) or unilateral head and neck disease (the second catheter positioned in the thyrocervical trunk). The infused volume of each catheter is determined by nuclear tomography after slow intra-arterial injection of 99mTc-labeled macroaggregated albumin through the pump's auxiliary port. The injection port/infusion chamber configuration of the pump permits long-term, multiple-course, combination-drug intra-arterial therapy on an outpatient basis. To date, 15 patients have been treated longer than 6 months and five longer than 1 year with no bleeding or neurologic complications. Eight of 10 patients treated with cisplatin and fluorodeoxyuridine (FUdR) have responded. The Infusaid pump permits long-term, practical, cost-effective, intra-arterial therapy to the entire tumor volume of ambulatory head and neck cancer patients with a high rate of tumor response.
Ambulatory Care↗
High-dose adriamycin combination chemotherapy for intermediate and high-grade non-Hodgkin's lymphomas.
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Adult↗
Single-agent and combination-drug regional chemotherapy for head and neck cancer using an implantable infusion pump.
Chemotherapy delivered through angiographically placed catheters requires patient hospitalization, and is usually limited to short-term infusions. Treatment given through surgically placed catheters with external portable infusion pumps permits greater patient freedom and longer infusion durations. However, some patient restrictions remain, and thrombotic or infectious complications are common with long-term therapy. A totally implantable pump has allowed long-term intraarterial therapy in an outpatient population. Patient activity was unrestricted, and the complication rate has been low. This system has been used to deliver single-agent therapy with FUdR, dichloromethotrexate or bleomycin, and combination-drug treatment with cisplatin + FUdR or bleomycin + mitomycin C + dichloromethotrexate. The majority of patients have responded to at least one drug program. Seven of 14 patients who had pumps implanted over 1 year ago have received therapy for at least 1 year, and four patients have had functioning system for over 2 years. Systemic toxicity (except for nausea and vomiting with cisplatin) has been uncommon. Further clinical experience with these programs will be necessary to fully establish the objective response rate. However, the Infusaid Pump has proven safe, reliable and has high patient acceptance.
Adolescent↗