Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase I/II trial.

PURPOSE: A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed. RESULTS: Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor. CONCLUSION: TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: long-term results.

PURPOSE: A phase II trial of cisplatin, fluorouracil, and leucovorin (PFL) induction chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck region (HNCA). PATIENTS AND METHODS: One hundred two patients (stage III/IV, previously untreated) were treated with induction PFL. Patients with resectable primary tumor site lesions and clinical complete response (CR) were offered radiotherapy (RT) without surgery to the primary tumor site. Response, toxicity, local-regional therapy, survival, and preservation of the primary tumor site were assessed. RESULTS: Among 279 courses, the overall response rate was 81%. Nineteen (19%) failed to respond, including three who died during therapy. Sixty-seven (69%) of 97 with assessable primary lesions had a clinical CR at the primary tumor site. Pathologic CR was recorded in 46 of 55 (84%) clinical CR patients who had biopsies performed on the primary tumor site. Toxicities resulted in unexpected hospitalizations in 19% of cases. After definitive local-regional therapy, 84 (82%) were disease-free including 71 (69%) with preserved primary tumor site anatomy. With a median follow-up time of 63 months, the cause-specific, overall (OS), and failure-free survival (FFS) rates at 5 years are 58%, 52%, and 51%. Local failure occurred in 29 of 102 (29%) and the local control rate at 5 years was 68%. CONCLUSION: PFL has significant activity with acceptable toxicity in patients with advanced disease who have a good performance status. Preservation of the primary tumor site could be achieved without apparent loss of local control or survival. Management of neck disease by surgery or RT must be individualized and separate from management of primary tumor. Survival compares favorably with similar trials of induction chemotherapy or chemoradiotherapy.

Docetaxel: an active drug for squamous cell carcinoma of the head and neck.

PURPOSE: We conducted a phase II study designed to evaluate the activity, safety, and tolerability of docetaxel (Taxotere: Rhône-Poulenc Rorer Pharmaceuticals Inc, Collegeville, PA) in patients with advanced, incurable, or recurrent squamous cell carcinoma of the head and neck (SCCHN) who had not received prior palliative chemotherapy. PATIENTS AND METHODS: Thirty-one patients with measurable, locoregional, or metastatic SCCHN were treated with docetaxel, administered at a dose of 100 mg/m2 as a 1-hour intravenous (i.v.) infusion once every 21 days on an outpatient basis. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic administration of growth factors or antiemetics was not permitted. RESULTS: Thirty-one patients were treated. Twenty-nine patients were assessable for response and 30 for toxicity. Four of 31 patients (13%) achieved complete response (CR), nine (29%) achieved partial response had stable disease (SD) and seven (23%) experienced progression of disease (PD). The major response rate was 42% (95% confidence interval [CI], 24% to 60%). The median duration of responses was 5 months (range, 2 to 14). The principal toxicity was leukopenia, which occurred with rapid onset and brief duration. Sixteen patients (53%) experienced nadir fever, and 13 required dose reduction. Hypersensitivity reactions occurred in four patients. Grade 3 peripheral neuropathy occurred in two patients; grade 2 or 3 fatigue occurred in six (20%) and 10 (33%), respectively. Minimal edema (grade 1) occurred in five patients (17%). Clinically significant mucositis, diarrhea, or dermatitis were not observed. CONCLUSION: Docetaxel has major activity against SCCHN. It appears to be well tolerated in this group of patients and can be safely administered on an outpatient basis. Premedication with dexamethasone, cimetidine, and diphenhydramine is associated with a reduced incidence of significant edema, hypersensitivity reactions, and dermatologic toxicities.

Primary site management following induction chemotherapy with cis-platinum, 5-fluorouracil, and leucovorin.

A phase II clinical trial was initiated in 1987 to evaluate a new induction regimen of cis-platinum, 5-fluorouracil, and leucovorin (PFL) for patients with stages III-IV squamous cell carcinoma of the head and neck. Ninety patients were treated and followed for a median duration of 18 months. The median age was 55 and 87% of the patients had stage IV disease. The rates of complete and overall clinical response following three cycles of PFL were 57% and 80%, respectively; the rate of complete response at the primary site was 72%. Eighty-four percent of patients were treated to the primary site with radiation alone (median dose 68 Gy in daily 1.8-Gy fractions) irrespective of the location of the primary site or initial T-stage. The acute tolerance to full-course radiation following PFL was acceptable. The actuarial rate of primary site control for patients treated with radiation was 67% at 36 months. An important prognostic indicator for primary site control was a complete clinical response to induction PFL. For patients who achieved a complete response, radiation or surgery followed by radiation controlled primary site disease equally well at 70%. Patients with a partial response did less well. For these patients, surgery and radiation appeared slightly better than radiation alone.

Lipid-associated sialic acid, squamous cell carcinoma antigen, carcinoembryonic antigen, and lactic dehydrogenase levels as tumor markers in squamous cell carcinoma of the head and neck.

BACKGROUND: Circulating tumor markers are valuable adjuncts in the management of several malignant lesions, including germ cell tumors and adenocarcinomas of the breast, colon, prostate, and ovary. However (to the authors' knowledge), currently, no serologic markers have been shown to have prognostic value for patients with squamous cell carcinomas of the head and neck (SCCHN). METHODS: Novel and existing markers were evaluated prospectively in patients with SCCHN: The levels of lipid-associated sialic acids (LASA), squamous cell carcinoma circulating antigen (SCC-Ag), carcinoembryonic antigen (CEA), and lactic dehydrogenase (LDH) were evaluated in 52 patients: 42 with active measurable SCCHN and 10 with no clinical evidence of active disease after treatment (NED). RESULTS: In patients with active disease, LASA, SCC-Ag, CEA, and LDH were elevated in 71%, 33%, 27%, and 18%, respectively, and in seven patients with distant metastasis (M1) in 100%, 86%, 57%, and 33%, respectively. None of the markers were elevated in the NED group. The incidence and magnitude of LASA and SCC-Ag elevations correlated with the extent of disease (active disease versus NED, Stage III versus IV, T0-3 versus T4 primary lesions, M0 versus M1). LDH and CEA elevations correlated primarily with the presence of distant metastases. CONCLUSIONS: LASA appears to be a promising sensitive marker of SCCHN, followed in decreasing order of sensitivity by SCC-Ag, CEA, and LDH. Additional study to evaluate the specificity of LASA and its correlation with tumor response to therapy is warranted.

Analysis of prognostic factors in squamous cell carcinomas of the head and neck.

It appears that prognostic factors of proven value in the management of other malignancies have marginal value in the treatment of patients with squamous cell carcinomas of the head and neck (SCCHN). For example, age, sex, and performance status do not correlate with treatment outcome. Similarly, histologic differentiation has little predictive value, with undifferentiated carcinomas of nasopharyngeal origin being a possible exception. On the other hand, primary tumor site may be an important prognostic factor, with tumors arising from the nasopharynx, oral cavity, and possibly the oropharynx having a more favorable outcome, whereas tumors of the hypopharynx appear to be the least favorable. A tumor's TNM stage is also highly predictive of response to treatment and survival. Overall stage of disease is an effective predictor of relapse and survival only for patients with limited disease and only after the primary site is specified. Independent of primary tumor site, an inverse correlation clearly exists between T and N stage and either response to treatment or overall survival. Flow cytometry, a relatively new test, appears to be one of the most significant predictors of response to chemotherapy, relapse, and survival in patients with SCCHN. As a prognostic factor, DNA tumor content may be independent of all other known clinical and pathologic factors. Patients with diploid tumors have a superior relapse-free and overall survival as compared with patients whose tumors are aneuploid. Another parameter of significant value is the patient's response to induction chemotherapy, with responding patients demonstrating a far superior relapse-free and overall survival compared with nonresponders. In summary, the site of the primary tumor, its T stage, N stage, and DNA content, and the magnitude of its response to induction chemotherapy are the most valuable prognostic factors in SCCHN. It is assumed, however, that as new and more effective therapies are developed for patients with SCCHN, previously significant prognostic factors will cease to have clinical or scientific value. Similarly, as new diagnostic tests and staging tools are developed, a new generation of prognostic factors with greater biologic and clinical relevance is likely to emerge. In the evolution of new therapies for patients with SCCHN, prognostic factors such as those mentioned here or ones yet to be evaluated will be central to the design of clinical studies and the identification of specific patients for specific therapies. Once treatment is initiated, treatment-related prognostic factors may further identify patients for whom modifications of the initial therapeutic plan would be appropriate.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of cisplatin in treatment regimens for squamous cell carcinoma of the head and neck.

Advanced squamous cell carcinoma of the head and neck (SCCHN) is both a local-regional and a systemic disease that is ineffectively managed by conventional surgery and radiotherapy. For patients with advanced but potentially curable (Mo) disease, the morbidity associated with conventional surgery or radiotherapy may be significant whereas the probability of lasting disease control is low. For those with recurrent or metastatic lesions, surgery or radiotherapy are rarely effective options. In this setting, chemotherapy has been evaluated as primary therapy for patients with recurrent or metastatic disease and as an adjunct to surgery or radiotherapy for those with potentially curable lesions. As palliative therapy, methotrexate remains the single agent of choice. Combination chemotherapy has been associated with a higher response rate but not improved survival when compared with methotrexate alone. Cisplatin, both as a single agent and in combination with 5-fluorouracil, is active against SCCHN, and may be superior to methotrexate in antitumor activity. The impact of induction and adjuvant chemotherapy or concurrent chemotherapy and radiotherapy in patients with potentially curable lesions remains controversial. A specific role for chemotherapy has not been confirmed by prospective randomized trial, but effective therapies have been achieved: Regimens with increased activity against squamous carcinomas have been reported, clinical trials with sufficient power to reach significant conclusions have been published, and organ preservation has been confirmed as an appropriate end point for studies of induction chemotherapy or concurrent chemotherapy and radiation. The clinical experience with chemotherapy for patients with recurrent or metastatic SCCHN as well as induction and adjuvant chemotherapy and concurrent chemotherapy and radiotherapy for those with potentially curable disease is reviewed, with particular emphasis given to trials involving cisplatin and to avenues for continued clinical investigation.

Reduced membrane protein associated with resistance of human squamous carcinoma cells to methotrexate and cis-platinum.

A membrane protein recognized by monoclonal antibody SQM1 was identified in human squamous carcinomas, including those originating in the head and neck (SqCHN), lung and cervix. Cell lines derived from SqCHN of previously untreated patients expressed high amounts of this protein. In contrast, many cell lines established from SqCHN of patients previously treated with chemotherapy and/or radiation showed diminished amounts of this SQM1 protein. The expression of SQM1 antigen was determined in several SqCHN cell lines made resistant by exposure to methotrexate (MTX) in vitro. The parent cell lines all exhibited strong binding to SQM1 antibody. The MTX-resistant sublines showed much lower membrane binding of SQM1. The lowest SQM1 reactivity was found in cell lines with high resistance to MTX and with diminished rate of MTX transport. Some highly MTX-resistant cell lines which had high levels of dihydrofolate reductase, but which retained a high rate of MTX transport, also retained high levels of SQM1 binding. Reduced SQM1 protein was also found in SqCHN cells which developed resistance to the alkylating drug cis-latinum (CDDP) and which showed reduced membrane transport of CDDP. Cell growth kinetics and non-specific antigenic shifts were not responsible for the differences in SQM1 binding between the parent cell lines and their drug-resistant sublines. The finding of a novel protein which is reduced in cells resistant to MTX and CDDP could contribute to our understanding of the basic mechanisms of drug resistance. By detecting SQM1 protein in clinical specimens, it may be possible to monitor the development of drug resistance in tumors.

Continuous infusion high-dose leucovorin with 5-fluorouracil and cisplatin for untreated stage IV carcinoma of the head and neck.

STUDY OBJECTIVE: To study the activity of continuous infusion cisplatin, 5-fluorouracil, and high-dose leucovorin (PFL) as induction chemotherapy in patients with previously untreated, advanced squamous cell carcinoma of the head and neck. DESIGN: Nonrandomized, prospective trial. SETTING: A comprehensive cancer center. PATIENTS: Thirty-five patients (4 patients [11%], stage III; 31 patients [89%], stage IV [MO]), all evaluable for response and toxicity. INTERVENTIONS: Two to three cycles of PFL before definitive, local-regional therapy (surgery and radiation therapy or radiation therapy alone). Chemotherapy included continuous intravenous infusion of cisplatin (25 mg/m2 body surface area daily, days 1 through 5); 5-fluorouracil (800 mg/m2 body surface area daily, days 2 through 6); and leucovorin (500 mg/m2 body surface area daily, days 1 through 6) administered once every 28 days. Pathologic response was evaluated by surgical resection or biopsy. Serum-reduced folates were measured before and 18 hours after the initiation of chemotherapy. RESULTS: A clinical response to PFL was achieved in 28 of 35 (80%) patients: 23 (66%) patients had a complete response (90% CI, 50% to 79%) and 5 (14%) patients, a partial response. A complete response was confirmed pathologically in 14 of 19 (74%) patients. The most common toxicity was mucositis (grade 2 to 3; 94% of patients). Dose reduction for toxicity was necessary in 11 (31%) patients. There were no treatment-related deaths. Serum levels of leucovorin and (6S)5-methyltetrahydrofolate were measured in 7 patients. After 18 hours, the mean leucovorin level (+/- SD) was 34.3 +/- 1.5 mumol/L, of which only 8.0 +/- 0.5% was the active 6S isomer. The mean serum (6S)5-methyltetrahydrofolate was 9.2 +/- 0.6 mumol/L. CONCLUSIONS: Continuous infusion cisplatin, 5-fluorouracil, and high-dose leucovorin is a new and highly active chemotherapy regimen that can achieve clinical and pathologically confirmed complete responses in a substantial proportion of patients with advanced, local-regional squamous cell carcinoma of the head and neck. Further studies are needed to confirm the activity of PFL and to determine its potential impact on local tumor control and disease-free and overall survival.

Selective expansion of 5,10-methylenetetrahydrofolate pools and modulation of 5-fluorouracil antitumor activity by leucovorin in vivo.

Expansion of CH2THF pools in tissues of BALB/c mice bearing s.c.-implanted EMT6 mammary adenocarcinomas was measured after leucovorin administration. Twenty-four mice were treated with leucovorin at doses of 0, 45, 90, or 180 mg/kg/injection x 8 injections spaced over 48 h. Tumor and bone marrow cytosols were assayed for CH2THF by forming ternary complexes with thymidylate synthase and [3H]FdUMP. Tumor CH2THF pools were expanded significantly at the two higher doses. Marrow levels were not different from controls. Groups of tumor bearing mice were treated with saline, leucovorin, 5-fluorouracil or 5-fluourouracil plus leucovorin on an optimal dosage schedule. Measured plus leucovorin on an optimal dosage schedule. Measured from the last day of treatment, these tumors grew to 10 mm root-mean-square diameters in 3.5 +/- 1.4, 5.0 +/- 1.2, 6.5 +/- 1.5, and 9.3 +/- 1.2 days, respectively. Growth rates were significantly different from controls only in the latter two groups.

Chemotherapeutic strategies in the multidisciplinary treatment of head and neck cancer.

A role for chemotherapy in the multidisciplinary treatment of patients with advanced squamous cell carcinoma of the head and neck (SCCHN) is yet to be defined. Results of uncontrolled studies indicate high response rates to induction chemotherapy and an association between a response to chemotherapy and either local-regional control or survival. Unfortunately, results of randomized, controlled trials have not confirmed an overall survival advantage with such treatment. From 1979 to the present, the Dana-Farber Cancer Institute has registered more than 224 patients on two trials of induction and adjuvant chemotherapy for patients with stage III to IV SCCHN. Protocol 80-016 (1979 to 1983) evaluated two cycles of induction cisplatin, bleomycin, and methotrexate/leucovorin (PBM) before local regional treatment in 114 patients. Eighty-nine (78%) patients responded to PBM, with 30 (28%) patients achieving a complete response (CR). After surgery and/or radiotherapy (RT), 46 responders to induction PBM entered a trial of the randomly assigned additional adjuvant PBM. Protocol 83-084 (1983 to present) randomly assigned patients to receive up to four cycles of either induction PBM or cisplatin and infusion 5-fluorouracil before local treatment. Adjuvant chemotherapy was not used in the latter study. Updated results from both trials will be presented, with their implications for future phase II and III multidisciplinary studies. Optimal approaches to the treatment of patients with advanced SCCHN can include planned reductions in the extent of surgery or RT offered to selected patients with a good response to induction chemotherapy but may require adjuvant chemotherapy for patients at high risk for recurrent disease. Until the rate of CR to induction chemotherapy is reproducibly over 50%, documentation of an improved overall survival with multidisciplinary treatment may be difficult.

Localization of radiolabeled SM1 monoclonal antibody to small-cell lung cancer tumors in mice.

Small-cell carcinoma (SCCL) is an aggressive type of lung cancer. Though it is usually responsive to therapy, be it chemotherapy or radiation, the majority of patients eventually relapse and overall prognosis is dismal. New forms of therapy are, therefore, needed. SM1 monoclonal antibody (MAb) was developed in our laboratory and demonstrated to be highly reactive against SCCL. I125 radiolabeled SM1 antibody was administered intravenously to nude mice bearing SCCL tumor xenografts. The mice were sacrificed, different tissues sampled and tested for uptake of radioactivity five days following antibody injection. There was over a 30 fold increase in localization of labeled antibody to the tumor as compared to muscle tissue. All organs tested showed an insignificant amount of MAb (p = 0.01) including the spleen, which had the highest normal tissue uptake in these experiments. These results demonstrate that SM1 MAb can be successfully targeted to SCCL xenografts. Its potential applications for imaging and therapy of SCCL in man are currently under investigation.

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.

Nasopharyngeal carcinoma: the Dana-Farber Cancer Institute experience with 24 patients treated with induction chemotherapy and radiotherapy.

Nasopharyngeal carcinoma traditionally has been treated with radiotherapy alone. Although the probability of cure for patients with stage I and II nasopharyngeal carcinoma is high, the probability of cure for patients with stage III and IV disease is poor because of a higher rate of local-regional and distant failure. Between February 1981 and August 1986, 24 patients with previously untreated, stage IV nasopharyngeal carcinoma were treated with two to four monthly courses of cisplatin-based combination chemotherapy prior to radiotherapy. A response to induction chemotherapy was recorded in 75% of patients (29% complete response and 46% partial) prior to radiotherapy. By actuarial estimate with a median follow-up of 42 months, the 2-year failure-free survival for all patients was 57%. In conclusion, induction chemotherapy has significant activity in nasopharyngeal carcinoma. The toxicity of this approach, as well as the influence of initial histopathology and response to chemotherapy on survival, will be discussed.

Chest wall tenderness as a pitfall in the diagnosis of pulmonary embolism. A report of two cases.

Chest wall tenderness is commonly indicative of chest wall disease. Two patients with angiographically proved pulmonary emboli had clinical presentations dominated by chest wall tenderness. Clinicians should be alert to this mode of presentation and not exclude pulmonary embolism on the basis of such findings.

Protracted epigastric pain and vomiting as a presentation of thyrotoxicosis.

Apathetic thyrotoxicosis is frequently difficult to recognize and can imitate a variety of diseases. A patient with a severe thyrotoxic state is reported, who presented with protracted epigastric pain and vomiting. Hyperthyroidism should be considered in patients with such prolonged and unexplained symptoms.

Hemochromatosis simulating hepatoma by computed tomography.

Computed tomography of the liver in hemochromatosis characteristically demonstrates diffusely increased attenuation. We report a patient with this disorder who presented with such a finding over the right lobe of the liver and a benign, large lower density area occupying the other lobe, closely simulating malignancy. Biopsies of the liver showed prominent fibrosis of the left lobe as compared with the right lobe, which probably accounts for the attenuation difference.