M. R. Posner

An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck.

This study examines the role of combination chemotherapy with surgery and/or radiotherapy in the initial treatment of patients with advanced stage III and IV squamous-cell carcinoma of the head and neck (SCCHN). Two courses of initial (induction) cisplatin, bleomycin, and methotrexate with oral calcium leucovorin (PBM) were used with the principal intent of increasing the effectiveness of subsequent surgery and/or radiotherapy. Following induction chemotherapy and local treatment, disease-free patients who had responded to initial chemotherapy were entered into a randomized trial of adjuvant PBM. The response rates to induction PBM chemotherapy were a complete response (CR) rate of 26% and a partial response (PR) rate of 52%, for an overall response rate of 78%. A response to induction PBM was highly correlated with failure-free survival (P less than .0001). A Cox multistep regression analysis of potential prognostic factors was performed. After adjusting for the significant prognostic factors of performance status, initial tumor size, and primary tumor site, a response to induction chemotherapy remained independently associated with improved survival (P = .0002). The randomized trial of adjuvant chemotherapy demonstrated that such treatment significantly improved failure-free survival by decreasing local-regional failures. The benefit of adjuvant chemotherapy was particularly evident in patients who had a PR to induction chemotherapy (P = .01). The toxicity of this multidisciplinary approach was predictable and acceptable. Surgery and radiotherapy were not compromised by induction or adjuvant chemotherapy. Definitive evidence that chemotherapy can favorably influence survival awaits confirmation of these results by a randomized trial using a control arm of patients treated with conventional surgery and/or radiotherapy alone.

Cyclophosphamide, doxorubicin, and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin

Thirteen patients with carcinomas of major and minor salivary gland origin (nine adenoid cystic carcinomas and four adenocarcinomas) were treated with cyclophosphamide (500 mg/m2), doxorubicin (50 mg/m2), and cisplatin (50 mg/m2) (CAP) by intravenous injections on the first day of a 28‐day regimen. Sixty‐one cycles of CAP were administered (mean, 4.7 cycles per patient). Eleven patients were treated for palliation of recurrent disease (locoregional, ten; lung, ten; liver, three; and bone, three). Two patients untreated previously, one with extensive local disease involving the base of the skull and one with a solitary lung metastasis (resected with a positive margin) and an initially unappreciated base of tongue primary, received two cycles of CAP followed by local treatment and adjuvant CAP. Previous therapy for the 11 patients with recurrent disease included surgery (ten), radiotherapy [RT(11)], chemotherapy (three), or hormonal therapy (two). Three complete and three partial responses to chemotherapy were noted for an overall response rate of 46%. The median duration of response in palliative patients was 5 months (range, 2 to 9). Of the two patients receiving induction CAP, one relapsed with distant disease 26 months after treatment, and the other remains disease‐free after 60 months of follow‐up examination. Chemotherapy was well tolerated generally, and no chemotherapy‐related deaths occurred. One hypertensive patient suffered a stroke after 3 cycles of therapy. CAP is an active regimen against salivary gland carcinomas and deserves further study. Also, it may be of value as induction or adjuvant treatment for patients with advanced disease untreated previously.

Preoperative chemotherapy and radiation therapy for stage IIIa carcinoma of the lung

Thirty-six patients with stage IIIa histologically proven non-small cell carcinoma (T3 N2 or T2 N2) underwent concomitant radiation therapy and chemotherapy before pulmonary resection. The therapy consisted of two cycles of continuous infusion of cis-platinum, 25 mg.m-2.day-1 (days 1 through 4) every 4 weeks and concomitant irradiation, 55 Gy, of the tumor and mediastinum. Two to 3 weeks after treatment, the patients were reevaluated for thoracotomy and pulmonary resection. Five patients were found to have unresectable lesions. Thirty-one patients had complete resection, 27 by radical pneumonectomy and 4 by radical lobectomy, giving a resectability rate of 86%. Complete sterilization of lung tumor and mediastinal nodes proven histologically was achieved in 10 patients (28%) and 17 patients (47%). The 3-year survival rate is 61.7% for patients who had resection. Median follow-up is 27 months (range, 6 to 61 months). The preliminary study indicates that preoperative cis-platinum and concomitant radiation therapy is tolerated, appears to increase resectability, and may improve survival in patients with stage IIIa lung cancer.

Hyperphosphatemia in multiple myeloma due to a phosphate‐binding immunoglobulin

Hyperphosphatemia (HP) is usually seen in patients with hypoparathyroidism, renal failure, and tumor lysis. The authors described a patient with HP due to a phosphate‐binding immunoglobulin (Ig). An 86‐year‐old woman had serum phosphate levels as high as 4.75 mmol/l, (normal, 0.77 to 1.45 mmol/l). Serum ionized calcium, blood urea nitrogen (BUN), creatinine, and N‐terminal parathyroid hormone (PTH) levels were normal, but serum 1,25‐dihydroxyvitamin D level was subnormal at less than 12 pmol/l (normal, 36 to 146 pmol/l). Serum total protein was elevated at 105 g/l (normal, 60 to 80 g/l), and additional studies confirmed a diagnosis of immunoglobulin G (IgG) multiple myeloma. Results of in vitro studies using anti‐human IgG antibodies showed that the IgG of the patient bound inorganic phosphate. Several isolated case reports have documented spurious HP due to interference of the paraprotein in the routine serum phosphate assay. In only one patient, however, has actual binding of phosphate to a myeloma protein been documented. The studies of the authors document phosphate binding by an IgG paraprotein and suggest that in this setting HP may be of physiologic significance as evidenced by depressed serum levels of 1,25‐dihydroxyvitamin D.

A phase I trial of continuous infusion cisplatin.

Treatment with continuous infusions of cisplatin results in increased filterable drug exposures as measured by the area under the curve (AUC) of nonprotein‐bound plasma platinum levels. To determine the dose‐limiting toxicity and optimal method of administration, 24 patients were treated with continuous infusions of cisplatin at a dose rate of 25 mg/M2/day in a limited Phase I trial. A total of 47 courses were given. Nine patients received 13 courses of 4 days duration, 19 received 29 courses of 5 days duration, and five received courses of 6 or 7 days duration. Dose‐limiting toxicity was found to be leukopenia: 42% of patients receiving the 5‐day treatment developed a nadir count of less than 3000 cells/mm3. Nausea and vomiting were easily controlled. Minimal nephrotoxicity occurred in five patients and was associated with daily volume expansion with 2 l of 0.9% NaCl solution in four patients. All other patients were given 3 l of daily volume expansion during treatment. Responses were seen in 6 of 22 evaluable patients (27%). It is concluded that continuous infusion cisplatin at a dose rate of 25 mg/M2/day can be given safely for 5 days as a single agent if concomitant volume expansion with at least 3 l of 0.9% NaCl solution is given daily. Phase III comparative trials with a conventional bolus and newer high‐dose regimens for response and toxicity are indicated. Cancer 59:15–18, 1987.

Lymphocytes cytotoxic to uveal and skin melanoma cells from peripheral blood of ocular melanoma patients

SummaryTo study antitumor immunity in patients with choroidal melanoma, T cells were generated from the peripheral blood of choroidal melanoma patients by mixed lymphocyte/tumor cell culture (MLTC). Because autologous tumors are generally unavailable, an allogeneic choroidal melanoma cell line, OCM-1, was used as the specific stimulus. Lymphocyte cultures from 27 patients were characterized by cell-surface phenotypes, patterns of reactivity towards cells of the melanocytic origin and T-cell-receptor gene usage. Antimelanoma reactivity was found in cell-sorter-purified CD4+ and CD8+ T cell subsets. To analyze this reactivity, sorter-purified CD4+ and CD8+ cells from a MLTC were cloned by limiting dilution in the presence of exogenous interleukin-2 and interleukin-4 as well as irradiated OCM-1. Under these conditions, CD4+ T cells did not proliferate, perhaps because of the absence of antigen-presenting cells. However, CD8+ grew vigorously and 29 cytolytic CD8+ T cell clones were isolated. On the basis of their pattern of lysis of OCM-1, a skin melanoma cell line M-7 and its autologous lymphoblastoid cell line LCL-7, the clones were categorized into three groups. Group 1, representing 52% of the clones, lysed all three target cells, and are alloreactive. However, since OCM-1 and M-7 did not share class I antigens, these clones recognized cross-reactive epitope(s) of the histocompatibility locus antigen (HLA) molecule. Group 2, constituting 28% of the clones, lysed both the ocular and skin melanoma cell lines but not LCL-7, and were apparently melanoma-specific. Unlike classical HLA-restricted cytolytic T lymphocytes, these T cells might mediate the lysis of melanoma cells via other ligands or a more degenerate type of HLA restriction. For the latter, the HLA-A2 and -A28 alleles would have to act interchangeably as the restriction element for shared melanoma-associated antigen(s). Group 3, representing only 10% of the T cell clones, was cytotoxic only to OCM-1, but not to M-7 or LCL-7. These clones may recognize antigens unique to ocular melanoma cells. Our data suggest that choroidal melanoma patients can recognize melanoma-associated antigens common to both ocular and cutaneous melanoma cells, and presumbly their autologous tumor. Thus, choroidal melanoma, like its skin counterpart, may be responsive to immunotherapeutic regimens such as active specific or adoptive cellular immunotherapy.

Phase I study of gefitinib plus celecoxib in patients with metastatic and/or locally recurrent squamous cell carcinoma of the head and neck (SCCHN)

5540 Background: Treatment options for incurable metastatic and/or locally recurrent SCCHN are limited. Platinum-based therapy yields response rates of approximately 30%, and median survival of 6-7 months. Epidermal growth factor receptor (EGFR) and Cyclooxygenase-2 (COX-2) are both overexpressed and thought to contribute to the malignant phenotype in SCCHN. The EGFR inhibitor, gefitinib, has a single-agent response rate of 11% in this population. Preclinical and pharmacodynamic data suggest that the addition of a COX-2 inhibitor may enhance the antitumor effect of gefitinib.nnnMETHODSnA phase I trial was designed to determine the maximum tolerated doses (MTD) of gefitinib and celecoxib (GC) in patients with incurable SCCHN. Secondary objectives were to describe toxicities of this combination and to study biomarkers of activity, including Ki-67, CD31, activation of EGFR, ERK1/2, and Akt, and serum IL-8 and EGFR. Response will also be determined. MTD was defined as one dose level below which dose-limiting toxicities (DLTs) occurred in 2 or more of 6 patients, or the highest dose level tested. Eligible patients had measurable metastatic and/or locally recurrent SCCHN, at least 1 prior chemotherapy, performance status 2 or better, and adequate end-organ function.nnnRESULTSnThus far, 12 patients have enrolled. Dose escalation and toxicities are outlined in Table 1. The most common toxicities were rash (predominately acneiform), diarrhea and hand-foot syndrome (HFS). To date, no DLTs have occurred. Three of nine evaluable patients achieved a partial response. Additional transient responses were observed. Biomarker analysis is pending.nnnCONCLUSIONSnOverall, GC is very well-tolerated in patients with incurable SCCHN. Preliminary data suggest that celecoxib enhances gefitinib activity. A phase II study is warranted. [Figure: see text] No significant financial relationships to disclose.

Epstein Barr Virus Transformation of Peripheral Blood B Cells Secreting Antibodies Reactive with Cell Surface Antigens

EBV transformable peripheral blood B cells secreting antibodies reactive with cell surface antigens present on two indicator human leukemia cell lines, NALM1 and U937, were studied. Oligoclonal EBV transformants from patients with a variety of diseases were frequently found to produce cell surface reactive antibodies. Antibody secreting transformants could also, although less frequently, be readily cultured from the PBM of normal volunteers, and represented, by limiting dilution, 1 out of 113 transformable B cells. CD8 antibody had no effect on the frequency of antibody producing B cells, but depletion of CD8+ cells by immunomagnetic methods prior to transformation significantly (P less than 0.05) increased the recovery of antibody secreting B cells to 1/33. Readdition of magnetically depleted cells did not significantly inhibit the transformation of these B cells. During the acute and recovery phases of some infections increasing numbers of these transformable antibody producing B cells appear in the circulation. The majority of antibodies produced were of the IgM class, although IgG antibodies were also detected. IgM antibody producing transformants were tested and some were found to react with autologous and allogeneic normal lymphocytes. These results lend support to the notion that B cells capable of secreting cell surface reactive antibodies, a proportion of which are autoreactive, are present in the normal repertoire of healthy adults, and that these cells are under active regulation by CD8+ cells.

Clinical pharmacokinetics of 3-day continuous infusion cisplatin and daily bolus 5-Fluorouracil

In-vitro and animal studies have indicated that the combination of 5-Fluorouracil (5-FU) and cisplatin may have a synergistic antitumor effect [1-3]. The synergism of combination regimens has been shown to occur clinically in the treatment of head and neck cancer [4] and colorectal carcinoma [5, 6]. In this report, we describe the pharmacokinetics of the combination regimen using a 3-day continuous infusion of cisplatin (25mg/m2/day) and bolus doses of 5-FU (400 mg/m 2) at 24, 48 and 72 h after the start of continuous infusion cisplatin. The clinical results of this trial have been reported [6]. A total of 7 patients with gastrointestinal malignancies (5 m, 2 f; ages 48-78 y) participated in the study. Cisplatin blood samples were drawn at times 0, 3, 24, 48, and 72 h during infusion and 10, 30, 60, 120 and 180 min post-infnsion. Four successive 24-h urine samples were collected for measurement of cisplatin excretion. 5-FU blood samples were drawn at times 5, 10, 20, 30, 45 and 60 min after the 24 and 72-h bolus 5-FU. Samples were assayed for total and filterable platinum by the method of Forastirere et al. [7] and for 5-FU by the method of Miller et al. [8]. Cisplatin measurements were made on samples from 6 patients (6 courses) and 5-FU measurements on samples from 5 patients (8 courses). Because of the unexpected result of prolonged elevated filterable platinum levels in plasma after drug administration, an animal study using rats was performed to confirm the clinical data. Sprague-Dawley rats (400600 g) had cisplatin (15 mg/m 2 in 0.5 ml saline) administered by tail vein injection i min before 5-FU (300 mg/m 2 in 0.5 ml saline) or saline (0.5 ml) injections. Rats were sacrified by exsanguination at various times after cisplatin administration (20, 60, 90 and 180 min). The blood was immediately collected for measurement of total and filterable plasma platinum levels [7]. Table 1 presents the results of 5-FU plasma measurements and the pharmacokinetics are in agreement with

Acupuncture for dysphagia after chemoradiation therapy in head and neck cancer: An ongoing pilot, randomized, sham-controlled trial.

TPS270 Background: Dysphagia is a common side effect following chemoradiation therapy (CRT) in patients with head and neck cancer (HNC). Dysphagia and other treatment-related conditions such as asp...