Neoadjuvant chemotherapy and radiotherapy in larynx preservation.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
I W Dimery
Publications and source records attributed to I W Dimery.
Recombinant interferon-gamma in the treatment of recurrent nasopharyngeal carcinoma.
The etiologic relationship of the Epstein-Barr virus (EBV) to nasopharyngeal carcinoma prompted this study of the efficacy of interferon-gamma (IFN-gamma), which possesses antiviral and antitumor activity, in the treatment of recurrent carcinoma. Fourteen patients received recombinant IFN-gamma in daily intramuscular doses of 5-10 X 10(6) U/m2. Of 13 patients evaluable for response, five had a minor response; disease was stable in two and had progressed in six. EBV serology for immunoglobin (Ig) G, IgA-VCA, and early antigen was measured in six patients. In four of these, titers rose consistently with disease progression and in one patient, titers decreased with minor response.
Adult↗
Association of the Epstein-Barr virus with lymphoepithelioma of the thymus.
A 30-year-old woman with the histologic diagnosis of lymphoepithelioma of the thymus is reported on. Investigation of Epstein-Barr serology showed evidence of infection, and Southern blot analysis showed the presence of the viral genome in the tumor specimen. The patient achieved complete remission after treatment with combination chemotherapy, autologous bone marrow transplant, and radiotherapy. These findings suggest that lymphoepithelioma of the thymus may have a viral pathogenesis similar to that of nasopharyngeal carcinoma.
Adult↗
Continuous cisplatin (24-hour) and 5-fluorouracil (120-hour) infusion in recurrent head and neck squamous cell carcinoma.
Cisplatin and 5-fluorouracil (5-FU) has been reported to be one of the most active chemotherapeutic regimens in recurrent head and neck squamous cell carcinoma. In this study, 21 patients with recurrent head and neck squamous cell carcinoma received a combination of cisplatin given as a 100 mg/m2 continuous infusion over 24 hours and 5-FU given as a 1000 mg/m2 24-hour continuous infusion for 120 hours. Toxicity was evaluated in all patients, and response and survival were evaluated 20 patients. There were two complete remissions (10%) and three partial remissions (15%) for a major response of 25%. Overall survival for the complete responders was 79+ and 61+ weeks, respectively. Median survival for all patients was 36 weeks. Toxicity consisted of moderate to severe nausea and vomiting in 14 patients (66%), mucositis in 14 patients (66%), granulocytopenia of less than 1000/microliter in 11 patients (52%), objective peripheral neuropathy in one patient (4.7%), and nephrotoxocity in one patient (4.7%). We conclude that the efficacy of 24-hour cisplatin infusion and 120-hour 5-FU infusion in the treatment of recurrent head and neck squamous carcinoma is not superior to the efficacy of single agent trials reported in the literature.
Adult↗
Acute and late toxicity associated with sequential bleomycin-containing chemotherapy regimens and radiation therapy in the treatment of carcinoma of the nasopharynx.
Between 1975 and 1984, 33 patients with squamous cell carcinoma of the nasopharynx received adjuvant chemotherapy before and/or after definitive radiotherapy at UT M. D. Anderson Hospital. The favored chemotherapy regimens during this time were BCMF (bleomycin, cyclophosphamide, methotrexate, and 5-FU) and PMB (cisplatinum, methotrexate, and bleomycin). Total radiation doses to the primary site averaged 65 Gy for T1 and T2 lesions and 70 Gy for T3 and T4 lesions. Neck nodes were given boost treatments to a maximum of 70 Gy, depending on the extent of the disease. The outcome of treatment in these patients was compared to that of a stage-matched group of 71 patients treated during the same time period with radiotherapy alone. However, the groups were not matched with regard to histologic subtypes: 45% of the radiation-only group had prognostically unfavorable keratinizing squamous carcinomas (WHO 1) compared with 18% of the combined modality group. Overall disease-free survival at 5 years was 63% in the combined modality group and 44% in the radiation only group (p = 0.15). Both acute reactions and late treatment complications were much more frequent and severe in patients receiving combined modality treatment. In patients treated with chemotherapy prior to radiation therapy, 10/20 (50%) experienced severe acute toxicity (RTOG Grade 3 or 4) versus 9/71 (13%) in the radiotherapy-only group. Severe late normal tissue injury occurred in 15/33 (45%) of the combined modality group versus 5/71 (7.0%) in the control group. The majority of the late complications in the adjuvant chemotherapy group consisted of severe soft tissue and muscle fibrosis. The average total bleomycin dose in the patients with severe late soft tissue and muscle fibrosis was 336 mg. The actuarial risk of developing a severe late complication by 2 years after treatment was 68% in the combined modality group versus 8% in the radiation-therapy-only group (p = .001). The probability of remaining both disease-free and complication-free at 5 years was 40% in the radiation-only group and 22% in the combined-modality group (p = 0.08). Comparison of these results with other published reports emphasizes the importance of late toxicity data in assessing the ultimate value of combined modality therapy.
Antineoplastic Combined Chemotherapy Protocols↗
Prospective randomized trial of high-dose cisplatin and fluorouracil infusion with or without sodium diethyldithiocarbamate in recurrent and/or metastatic squamous cell carcinoma of the head and neck.
Previous studies have indicated that sodium diethyldithiocarbamate (DDTC) can reduce cisplatin's (CP) toxic effects without altering the antitumor activity. DDTC has also been shown to have immunostimulative properties. Sixty patients with objectively measurable recurrent and/or metastatic squamous cell carcinoma (SCC) of the head and neck were randomized to receive either (A) CP at 120 mg/m2 over one hour on day 1, plus fluorouracil (5-FU) at 1,000 mg/m2 over 24 hours as a continuous infusion on days 1 through 5, or (B) CP/5-FU as in A, plus DDTC at 600 mg/m2 over 30 minutes administered intravenously (IV) exactly 30 minutes after CP infusion. Group B also received DDTC at 200 mg/m2 administered IV over 30 minutes on days 8 and 15. Each cycle was repeated at 3-week intervals. Objective responses were achieved in 41% of the CP/5-FU group and in 29% of the CP/5-FU with DDTC group (P = .26). Median survival was 9 months in group A and 10 months in group B. CP-related toxicity between the groups was equivalent with respect to nausea and vomiting, renal impairment, neurotoxicity, ototoxicity, and hematologic toxicity. The pharmacokinetics of reactive platinum species in plasma ultrafiltrate and urine samples obtained from both groups were comparable. The immune status of 48 patients was evaluated before and after completion of therapy. There were no significant differences in mean pretreatment and posttreatment values within or between groups A or B, except for absolute pretreatment OKT4 values (P = .02). We conclude that (1) the present dose and infusion schedule of DDTC did not significantly reduce CP-mediated toxic effects, (2) DDTC did not alter the disposition of ultrafilterable platinum species, (3) DDTC did not affect immune responses, and (4) the addition of DDTC improved neither the clinical response nor the survival of patients with recurrent SCC of the head and neck.
Adult↗
Phase I study of recombinant gamma-interferon (rIFN-gamma).
A Phase I study of recombinant gamma-interferon was conducted in 35 patients with advanced malignancy. The schedule was twice weekly administered intravenously. Patients were assigned to six dose levels. The major toxicities were flu-like symptoms and were unrelated to dose. Other adverse reactions, such as myelosuppression, were dose dependent. The addition of a nonsteroidal anti-inflammatory agent did not ameliorate the symptoms at the highest dose level. Antitumor effects occurred in patients with gastric, duodenal, and breast carcinoma.
Drug Evaluation↗
Adjuvant chemotherapy of head and neck cancer: the past, the present, and the future.
In the past two decades, overall survival of head and neck cancer patients has not improved significantly, despite improvements in surgery and radiotherapy techniques. In the early stages, head and neck cancer can be cured with surgery and/or radiotherapy. However, in patients who present with locally advanced lesions after combined surgery and radiation treatment, local recurrences develop in 50% to 60%, distant metastases in 20% to 30%, and a second primary neoplasm in 10% to 40%. Five-year survival for patients with stages III or IV disease who undergo standard treatment ranges from 0 to 60%. Traditional chemotherapy has been used for those patients with recurrent disease after surgery and/or radiotherapy, but the results have been disappointing. Therefore, chemotherapy as an induction regimen has been incorporated into combined modality treatment. The following specific issues of adjuvant chemotherapy will be addressed: (1) rationale for theoretic advantages of induction chemotherapy in head and neck cancer; (2) critical review of controlled and uncontrolled studies of adjuvant chemotherapy; (3) sequential chemotherapy and radiotherapy; (4) simultaneous chemotherapy and radiotherapy in head and neck cancer; (5) issues of surgical and radiotherapy complications following induction chemotherapy; (6) ongoing clinical trials of chemotherapy in head and neck cancer in the United States; (7) development of effective induction regimens in head and neck cancer; (8) future directions of adjuvant chemotherapy in head and neck cancer.
Antineoplastic Combined Chemotherapy Protocols↗
Adjuvant chemotherapy for advanced nasopharyngeal carcinoma.
The outcome of therapy is reported in 34 previously untreated patients with advanced-stage (AJC IV) nasopharyngeal carcinoma treated with combination chemotherapy (cisplatin and non-cisplatin based) and sequential radiation therapy. Sixty-nine patients treated with radiotherapy alone were used as a control group. The control group was matched for T and N stage grouping but differed in that 45% had keratinizing squamous carcinoma, 14.5% had nonkeratinizing squamous carcinoma, and 40.6% had undifferentiated carcinoma, compared with 18%, 50%, and 32.4%, respectively in the combined-treatment group. Seventeen of 21 patients (81%) who received chemotherapy followed by radiotherapy achieved complete remission (CR), whereas 11 of 13 patients (85%) who received radiotherapy followed by chemotherapy achieved CR (P = NS). Patients treated by radiotherapy alone had a 91% CR rate. The combined treatment yielded a relapse-free rate of 78% versus 44% for the radiotherapy group (P = 0.001). Median survival in the combined-treatment group has not been reached (111+ months), compared with 67 months in the group receiving radiotherapy alone (P = 0.04). The recurrence rate at the primary site and in regional nodes was more frequent in the radiotherapy group (36%), compared with the combined-therapy group (7%) (P = 0.004), but the occurrence of distant metastases was similar in each group (P = 0.41). The acute toxicity of the treatment was well tolerated. The major long-term toxic effect experienced by patients in the combined-therapy group was soft tissue fibrosis. These data suggest that a prospective trial comparing chemotherapy and radiotherapy versus radiotherapy alone is warranted.
Adolescent↗
Estrogen receptors in normal salivary gland and salivary gland carcinoma.
To access for possible hormone dependence, 19 samples of normal salivary gland tissue and 14 samples of salivary gland carcinoma were quantitatively analyzed for estrogen receptor (ER) content. A receptor protein content of greater than or equal to 1 fmol/mg of cytosol protein was considered positive. Ten (77%) of 13 histologically normal samples, and four (80%) of five tumor samples obtained from male patients contained ER by this criterion, as did five (83%) of six normal samples and eight (88%) of nine tumor samples obtained from female patients. Mean ER concentrations plus or minus SE in male-derived samples were 2.02 +/- .42 fmol/mg of cytosol protein for normal tissue and 4.35 +/- 1.5 fmol/mg of cytosol protein for tumor tissue; mean ER concentrations in female-derived samples were 3.48 +/- 1.1 fmol/mg of cytosol protein for normal tissue and 12.64 +/- 6.4 fmol/mg of cytosol protein for tumor tissue. Four of eight tumors in women had levels considered to be "hormonally dependent" in breast carcinoma. These findings indicate that salivary gland carcinomas may be hormone-dependent.
Adenocarcinoma↗
Polyamine metabolism in carcinoma of the oral cavity compared with adjacent and normal oral mucosa.
In this study, polyamine biosynthesis required for cellular proliferation showed elevated levels in neoplastic cells. Putrescine, spermidine, and spermine, as well as the rate-limiting enzyme ornithine decarboxylase, were measured to evaluate differences in tissue concentration in squamous cell carcinoma of the oral cavity, and in the normal adjacent, buccal, and retromolar trigone tissues. Mean polyamine levels (nanomoles per gram of tissue +/- standard error of the mean) were significantly elevated in tumor tissue at 136 +/- 42 nmol/g for putrescine compared with 41 +/- 9 nmol/g in adjacent, 25 +/- 5 nmol/g in buccal, and 41 +/- 14 nmol/g in retromolar trigone tissues. Tumor spermidine was 415 +/- 41 nmol/g compared with 192 +/- 34 nmol/g in adjacent, 184 +/- 34 nmol/g in buccal, and 214 +/- 63 nmol/g in retromolar trigone tissues. Tumor spermine was 461 +/- 41 nmol/g compared with 236 +/- 30 nmol/g in adjacent, 233 +/- 35 nmol/g in buccal, and 269 +/- 59 nmol/g in retromolar trigone samples. Ornithine decarboxylase activity was highly variable in tumor tissues. High levels of polyamines appear to be specific for this malignancy, whereas ornithine decarboxylase activity is not. Measurement of polyamine content may be useful in evaluating epithelial changes in the oral cavity.
Carcinoma, Squamous Cell↗
Primary oat cell carcinoma of the larynx.
The aggressiveness of small (oat) cell carcinoma of the larynx presents a therapeutic challenge to the oncologist. Since the first description of this type of carcinoma in 1972, 52 patients have been reported in the literature and a variety of treatment regimens have been used. The purpose of this study was to report two new cases and review all previous reports to determine the disease's biological behavior, clinical manifestations, and optimum treatment. Thirty-five percent of the tumors were transglottic, and 27% were supraglottic. Fifty-four percent of patients had regional metastases at initial presentation and 17.6% had distant metastases. The median survival was 10 months for all patients. Patients who were treated with chemotherapy with or without other modalities had the best 2-year survival rates (52.2%). Forty-one percent of patients had regional recurrence only, 12.5% had regional recurrence and distant metastases, and 2% developed distant metastases only. We conclude that patients with oat cell carcinoma of the larynx should be treated with combination chemotherapy and radiation therapy. Surgery is best reserved for persistent and recurrent disease at the primary site and neck.
Adult↗
Phase II trial of tiazofurin in recurrent squamous cell carcinoma of the head and neck.
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Adult↗
Sequential methotrexate, 5-fluorouracil, and cisplatin in the treatment of recurrent squamous-cell carcinoma of the head and neck: failure of hypertonic saline to reduce the nephrotoxicity of cisplatin.
Fifty patients with histologically proven squamous-cell carcinoma of the head and neck, recurrent after surgery and/or radiation therapy, were treated with a triple-drug combination of methotrexate (MTX), 250 mg/m2 intravenously (IV) on day 1, followed by 5-fluorouracil (5-FU), 600 mg/m2 IV on days 1 and 2, followed by cisplatin, 50 to 60 mg/m2 IV on days 3 and 4. Patients were randomly assigned to receive cisplatin either in 300 mL of 3% saline or with standard mannitol diuresis along with appropriate hydration. The courses of treatment were repeated every 3 to 4 weeks. Among 47 evaluable patients, there were four complete responses (CRs) and 17 partial responses (PRs) (9% and 36%, respectively). The median duration of response was 23 weeks and the overall survival was 7 months. The median survival of responders v nonresponders was 12 months and 6 months, respectively. Nausea and vomiting was experienced by all patients and diarrhea was experienced by 36% of patients. Neutropenia occurred in 37 patients (79%) and resulted in fever or infection in 11 patients (23%) and death in two patients. Mild renal failure (persistent serum creatinine greater than 1.5 mg/ dL) was observed in ten patients (21%), six treated with 3% saline and four treated with mannitol. The median cumulative dose of cisplatin that lead to the development of renal impairment was 485 mg/m2 in the hypertonic saline arm and 550 mg/m2 in the mannitol arm (P = .40). The antitumor activity of this regimen was not superior to that of sequential MTX and 5-FU. The use of hypertonic saline was not effective in reducing the renal toxicity of cisplatin.
Adult↗
High-dose cisplatin administration without hypertonic saline: observation of disabling neurotoxicity.
Nephrotoxicity of cisplatin can be ameliorated with intravenous (IV) hydration and forced diuresis with mannitol. Cisplatin has recently been used with hypertonic saline which allows administration of higher doses amounting to 40 mg/m2/d for 5 days, without significant nephrotoxicity. In this report we describe our experience with administration of cisplatin in a dose range of 30 to 40 mg/m2/d for 5 days, administered with IV hydration alone. Thirteen patients with recurrent carcinoma of the head and neck region were treated with high-dose cisplatin along with 5-fluorouracil (5-FU) used as a continuous infusion. Eight patients received a total of 21 courses of cisplatin with the higher dose range (40 mg/m2 for 5 days) and the remainder received 11 courses with the lower dose range. The renal toxicity was minimal but the myelo-suppression was intense, frequently requiring hospitalization for the treatment of infections associated with neutropenia. Furthermore, we encountered severe peripheral neuropathy in five patients, four of whom developed major difficulties with ambulation. Six patients achieved objective regression of their tumor, two had minor response, and five failed to respond to chemotherapy. The study was terminated because of serious nonrenal toxicity from the high-dose cisplatin. Based on our limited experience, we believe that IV hydration alone, without the use of hypertonic saline, allows administration of high-dose cisplatin without significant nephrotoxicity. However, cisplatin used in a dose schedule of 40 mg/m2 for 5 days for more than three courses resulted in a disabling form of peripheral neuropathy.
Adult↗
Phase II study of PCNU in the treatment of head and neck carcinoma.
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Adult↗
Variation amongst K562 cell cultures.
K562 cell cultures were obtained from three laboratories (A, B and C) outside our institution, and were designated according to source as K562A, K562B or K562C. The cultures obtained were constitutive or "wild type" K562 cell cultures, not cloned sublines. These cell cultures were compared with respect to growth kinetics, cell surface protein markers, surface antigens, cytogenetics and hemoglobin production. Morphology, growth kinetics in liquid suspension culture, cloning efficiency in soft agar culture, binding of anti-K562 monoclonal antibodies, and the majority of cell surface proteins were generally similar. In contrast, several important differences were observed: (1) hemoglobin synthesis induced by hemin was significantly different among K562A, B and C, K562A being most sensitive (P less than 0.05); (2) whereas more than 90% of K562A or C cells appeared to be Philadelphia chromosome (Ph1)-positive, less than 15% of K562B cells contained a Ph1; (3) membrane proteins (93 and 85 kilodalton) were identified in K562A, whereas only the 93 kilodalton protein was detected in K562B and neither of the proteins were detected in K562C. Our results indicate that K562 cells maintained in different laboratories can undergo tangible changes which may influence experimental results obtained in studies using these cells.
Autoradiography↗
Laryngeal preservation by induction chemotherapy plus radiotherapy in locally advanced head and neck cancer: the M. D. Anderson Cancer Center experience.
Standard treatment of locally advanced laryngeal, hypopharyngeal, and some oropharyngeal cancers includes total laryngectomy. In an attempt to preserve the larynx through induction chemotherapy, we conducted two consecutive phase II studies. From March 1986 to February 1991, 64 patients with advanced untreated but resectable head and neck cancer who would require total laryngectomy were enrolled on one of two cisplatin-based induction regimens: cisplatin-bleomycin-5-fluorouracil (PBF) in 31 patients and cisplatin-5-fluorouracil (PF) in 33; all received definitive radiotherapy. Surgery was reserved for patients who achieved less than a partial response to chemotherapy and patients with residual or recurrent disease after sequential chemotherapy plus radiotherapy. Overall complete plus partial response rates to both cisplatin-based regimens were comparable. The combined PF and PBF overall response rates were 75% for laryngeal cancer, 78% for hypopharyngeal cancer, and 75% for oropharyngeal cancer. Complete response rates after radiotherapy were 88%, 83%, and 50%, respectively. Neutropenia (< 1,000 cells/mm3) was the most common hematologic toxic effect: it occurred in 44% of patients who received PF and 16% of those who received PBF. Grade > or = 3 mucositis occurred in 50% of patients who received PF and 4% who received PBF. The data suggest that laryngeal preservation was feasible in all three primary-site subgroups. With follow-up of 15+ to 54+ months, 44% of patients with laryngeal cancer, 28% with hypopharyngeal cancer, and 22% with oropharyngeal cancer are alive with laryngeal preservation. The overall 2-year survival rates for patients with cancer of the larynx, hypopharynx, and oropharynx were 71%, 46%, and 38%, respectively.
Adult↗