Treatment of recurrent head and neck cancer with cisplatin and 5-fluorouracil vs. the same plus bleomycin and methotrexate.

A prospective randomized trial of 62 patients with recurrent squamous cell carcinoma of the head and neck was conducted to compare the effectiveness of our standard chemotherapy program with that of our test regimen. The standard chemotherapy regimen consisted of cisplatin 80 mg/M2 on day 1 followed by 5-fluorouracil 800 mg/M2 days 2 through 6. Our test regimen consisted of the same two drugs plus 15 U bleomycin on day 1 and methotrexate 100 mg/M2 on day 16 followed in 24 hours with 15 mg leucovorin every 6 hours for six doses. One patient in each arm of the study was not evaluated. Among 29 patients receiving the two-drug regimen, there was 1 complete response and 10 partial responses (38% response rate). Among 31 patients receiving the four-drug regimen, there were 3 complete responses and 16 partial responses (61% response rate; two vs. four-drug regimen, P = .06). The failure-free survival in the four-drug group was better than the two-drug group, median 4.5 vs. 2.3 months (P = .02). The overall survival for both groups was the same (median of 7.8 months). A detailed analysis of toxicity did not reveal any important differences between the two regimens. The addition of bleomycin and methotrexate to our cisplatin and 5-fluorouracil regimen resulted in an increase in effectiveness without adding toxicity.     

Chemotherapeutic drug resistance in the management of head and neck cancer

Summary Considerable progress has been made in the development of more effective chemotherapy regimens for squamous cell head and neck carcinomas. Unfortunately, increased response rates have not been translated into marked improvements in survival since durations of response have been brief, and the natural history of the disease has ultimately remained unaltered. Since the development of drug resistance is a major obstacle to successful antineoplastic chemotherapy, comprehensive efforts have been focused on understanding the underlying mechanisms. In this review, general and specific aspects of drug resistance related to head and neck cancer are addressed. In particular, mechanisms of resistance towards the most widely used antineoplastic drugs in head and neck malignancies — methothrexate, cisplatin, 5-fluorouracil, bleomycin, and vincristine — are discussed.     

Radiosensitization of advanced squamous cell carcinoma of the head and neck with cisplatin during concomitant radiation therapy

Treatment regimens for advanced squamous cell carcinoma of the head and neck require both attention to local tumor burden as well as contingencies for control of disseminated disease. Relatively new protocols utilizing cisplatin for radiosensitization of tumor cells during concomitant radiotherapy have shown progress in providing effective tumor control. Cisplatin as a chemotherapeutic agent induces DNA changes in malignant cells that may be mutagenic or lethal. Additionally, when used concurrently with radiation therapy, cisplatin acts as a radiosensitizer, increasing damage to malignant nuclear DNA to enhance the anti-neoplastic capability of radiotherapy. The mechanisms by which this radiosensitization occurs remain controversial, although one leading theory involves cisplatin’s ability to inhibit sublethal damage repair in radiated tumor cells. Recent investigations utilizing cisplatin with concurrent radiation for treatment of advanced squamous cell carcinomas of the head and neck are reviewed. The variations in protocols presented include route of administration, dosing, scheduling, timing with surgery, and combination therapy with 5-fluorouracil and radiation. Higher response rates, prolonged mean survival, increased survival rates, longer local recurrence-free survival rates, and considerable organ preservation with the use of concurrent cisplatin and radiation have been demonstrated by these studies. Further investigation of concurrent cisplatin and radiotherapy in patients with advanced disease is justified. Received: 5 March 1999 / Accepted: 15 March 1999     

Chemosensitivity of squamous cell carcinoma grown in implantable chambers

This study was motivated by the need to develop new methods to predict tumor response to chemotherapeutic agents. Using implantable cell-growth chambers, squamous carcinoma cells from head and neck tumors were xenografted into the peritoneal cavity of immunocompetent rats. Animals were divided into control and treatment groups. The treatment groups received intravenous cisplatin (CDDP) or 5-fluorouracil (5-FU) v normal saline solution for the control. Animals from each group were randomly selected and killed on days 3, 5, and 7 postimplantation. The chambers were retrieved, the media aspirated, and cells counted. Exponential growth curves were derived for the control and treatment groups. Statistically significant growth inhibition was observed for both treatment arms, compared with controls. This method of chemosensitivity testing proved to be inexpensive and reliable, and demonstrated tumor cell killing by 5-FU and CDDP.     

Radiolabeled antibody therapy for squamous cell carcinoma of the head and neck.

Immunohistochemical staining for ferritin was performed on 11 human head and neck squamous cell carcinomas transplanted in nude mouse xenografts. Seven tumors were found to be positive. Using ferritin as a tumor antigen target, escalating doses of yttrium-90-labeled antiferritin antibodies were injected intravascularly into nude mice that were transplanted with a ferritin-positive human squamous cell carcinoma. Forty-five days after injection, the mean treated tumor size was 25.6% of control in the 100-microCi group, and 20.6% of control in the 200-microCi group. Ninety days after injection the mean tumor size was 27.5% that of control in the 100-microCi group and 31.7% in the 200-microCi group. Higher doses of radiation (300 and 400 microCi per mouse) caused death of most of the animals due to radiation toxicity. Presensitization of the animal, before antibody injection, with a bolus intraperitoneal injection of 7.5 mg of cisplatin per kilogram of body weight, resulted in further reduction in tumor size when compared with antibody alone or cisplatin alone. This study demonstrates that radioimmunotherapy with selected doses of yttrium-90-labeled antiferritin antibodies is effective against human head and neck squamous cell carcinoma xenografts in nude mice.     

头颈部中晚期鳞癌大剂量滴注化疗的应用

对３６例初治头颈部中晚期鳞癌患者进行前瞻性随机对照研究。第一组（２０例）为大剂量顺铂（ｐＤＤ）加５－氟脲嘧啶（５－Ｆｕ）１２０小时连续滴注组（连续组）。另一组（１６例）为ＰＤＤ加５－Ｆｕ常规点滴组（常规组）。连续组和常规组有效率分别为９０．０％（完全缓解２０％，部分缓解７０％）和４３．８％（完全缓解６，３％，部分缓解３７．５％），差异有非常显著性意义（Ｐ＝０．００３９）。二组副作用相似且临床可接受（各项Ｐ值均大于０．０５）。认为２～３段大剂量ＰＤＤ＋５－Ｆｕ１２０小时连续滴注化疗是高度有效和安全的。     

The effects of delay in standard treatment due to induction chemotherapy in two randomized prospective studies

It is often suggested that tumors will respond to induction chemotherapy and result in improved survival for patients with squamous cell carcinoma of the head and neck. Two regimens of induction chemotherapy were studied in separate randomized, prospective trials over the last 6 years. Eighty-three patients with advanced disease were entered into the first study (43/chemotherapy; 40/control), and 60 into the second (27/chemotherapy; 33/control). Patient randomization was stratified by stage (III/IV) and site (oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, paranasal sinuses). The first study utilized bleomycin, Cytoxan, methotrexate and 5-fluorouracil in two cycles (one cycle if no tumor response), followed by standard treatment which consisted of combined irradiation and surgery or, in some instances, primary irradiation alone. The second study utilized cisplatin and 5-fluorouracil in three cycles prior to standard treatment. An objective tumor response to chemotherapy was observed in 68% in the first study and 85% in the second. The patient survival in both studies (at 24 months in the first; at 19 in the second) was better in the control than that in the experimental groups (43% to 31%; 69% to 46%). In the second study, the average length of delay of standard treatment was longer than in the first study (95 days vs. 66 days; P less than .02). Results combining the P-values of both studies indicate that the relative risk of having persistent disease was 2.9 times greater for patients who received chemotherapy. While toxicity to chemotherapy was not a factor in survival, the number of patients who withdrew from the studies and those who did not comply with treatment were greater in the chemotherapy groups. Except for new drug regimens of exceptional promise, it is recommended that future studies be designed so that chemotherapy is given concurrent with, or following the completion of standard treatment.     

Chemosensitivity of head and neck cancer with the rapid thymidine incorporation assay and its clinical application

Summary The chemosensitivity of various head and neck cancers was investigated with the 5-day rapid thymidine incorporation assay in soft agar culture. The evaluability rate was 56%. Head and neck cancers were sensitive in vitro, in decreasing order, to peplomycin, cisplatin, bleomycin, 5-fluorouracil, mitomycin C, and doxorubicin. Primary tumors and neck metastases exhibited the same sensitivity, with 21% of all specimens tested responding. In vitro chemosensitivities were similar among patients younger than 69 years of age and those older than 70. The predictive accuracy for sensitivity tested prospectively in five cases was 80% and that for resistance in four was 75%. Correspondence to: H. Saito     

Erfahrungen mit dem Zytostatikum Cisplatin bei Plattenepithelkarzinomen im HNO-Bereich

Summary Twenty-one patients with unresectable, previously untreated or treated squamous cell carcinoma of the head and neck were given cisdiamminedichloroplatinum (II) (cisplatin). On day 1, they received a low dose of bleomycin (15 mg/m²) and methotrexate (20 mg/m²), on day 2 a high dose of cisplatin (120 mg/m²). Even very old patients in poor general condition tolerated up to 5 therapy courses with intervals of at least 3 weeks. With a present survival rate of up to 16 months the toxicity was more acceptable and the tumor response considerably better than with the combined bleomycin-methotrexate chemotherapy. The effect of cisplatin in our patients confirms experiences in the USA for several years with malignant tumors in various areas.

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Erscheint ausführlich in HNO     

High-dose intra-arterial cisplatin therapy followed by radiation therapy for advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: To assess the effectiveness of a protocol consisting of 4 cycles of high-dose intra-arterial cisplatin infusions followed by radiation therapy for improving chemotherapy response rates, organ preservation, and survival in patients with advanced-stage untreated and previously treated squamous cell carcinoma of the head and neck. DESIGN AND SETTING: A prospective study of sequentially enrolled patients treated in an academic medical center. The Kaplan-Meier method was used for survival analysis. PATIENTS: Fifty-eight nonpregnant adults, 18 years of age or older, with measurable untreated or recurrent advanced biopsy-proven squamous cell carcinoma of the head and neck. MAIN OUTCOME MEASURES: Response rate to targeted intra-arterial cisplatin infusions, organ preservation, and survival. RESULTS: Fifty-eight patients (44 men and 14 women) were followed up for at least 2 years (median duration of follow-up, 27 months). Twenty-nine (67%) of the 43 previously untreated patients had a complete response to intra-arterial cisplatin therapy. Of the untreated patients, 28 are alive and disease free after a median follow-up time of 30 months. Five of the patients with recurrent disease had a complete response to intra-arterial cisplatin therapy. There were 4 survivors after a median follow-up time of 17.5 months. Of note, there were no deaths or serious complications related to the treatment in either group. CONCLUSIONS: High-dose intra-arterial cisplatin therapy provides a high complete and partial response rate (91%). The combination of high-dose intra-arterial cisplatin and radiation therapy is effective in improving survival and organ preservation rates in patients with previously untreated, advanced squamous cell carcinoma of the head and neck. This treatment protocol is much less effective for recurrent disease.     

Treatment results and prognostic factors for advanced squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy

Objective

To review our experience in the treatment of concurrent chemoradiotherapy (CCR) for patients with advanced squamous cell carcinoma of the head and neck (SCCHN) and to evaluate the different factors affecting survival and primary organ preservation.

Methods

We reviewed the records of 101 patients with SCCHN treated with CCR between February 1998 and April 2004. Of 101 patients, 76 were treated with a cisplatin, 5-fluorouracil, methotrexate, and leucovorin (PFML) regimen and 25 were treated with a carboplatin and uracil-tegafur (CBDCA-UFT) regimen. Overall survival (OS), disease-specific survival (DSS) and DSS with primary organ preservation were estimated using Kaplan-Meier methods. The log-rank test and Cox proportional hazards regression were employed to identify significant prognostic factors for OS, DSS, and DSS with primary organ preservation.

Results

The 5-year OS and DSS for all patients were 51.6 and 67.4%, respectively. On multivariate analysis, resectability of the tumor and degree of histological differentiation were significant predictors of survival for patients undergoing CCR; T stage and differentiation were significant prognostic factors for primary organ preservation.

Conclusion

In the treatment of CCR for advanced SCCHN, the survival rate of the patients with resectable tumors was excellent and significantly greater compared with the patients with unresectable tumors. T1 to T3 disease in patients with advanced resectable SCCHN is a good predictor of organ preservation. CCR may improve not only primary organ preservation (local control) but also survival in patients with poorly differentiated tumors.     

The status of sequential chemo-/radiotherapy in inoperable head and neck cancers. Personal results and review of the literature

Between March 1986 and October 1987 75 patients with advanced cancer of the head and neck were treated with initial chemotherapy before surgery and/or radiotherapy. Chemotherapy consisted of three courses of cisplatin or carboplatin combined with 5-fluorouracil (5-FU). Three weeks after the last course of chemotherapy 34 patients with unresectable tumours received conventional fractionated radiotherapy (60-64 Gy). Of these 34 patients, 32 were evaluated for response and survival with a minimal follow-up of 3 years (22% stage III, 78% stage IV). As the response to cisplatin/5-FU and carboplatin/5-FU was similar (72% versus 64%), survival rates of both chemotherapeutic regimens are presented together. At the end of sequential chemo-radiotherapy 11 patients (34%) were clinically free of disease with an overall response rate of 69%. The survival after 3 years was 12.5% (4 patients) with a median of 15 months. Disease-free survival was 27% (3/11). These poor results confirm the results of other investigators. They indicate that induction chemotherapy does not improve the results of conventional radiotherapy in unresectable carcinomas of the head and neck, even when using highly effective platinum-containing regimens.     

The prognostic influence of induction chemotherapy on advanced head and neck carcinoma

We examined the influence of induction chemotherapy integrated with surgery and postoperative radiotherapy on 5-year treatment results of 107 patients suffering from advanced head and neck carcinomas. The chemotherapy regimen consisted of one to three cycles of a combination of cisplatin, methotrexate and bleomycin. The overall response rate to induction chemotherapy was 58% with a 26% complete response rate. Using actuarial life tables, survival was 44% for all patients. The initial tumor stages were found to be predictive for patients' responses to chemotherapy as well as for their survivals. The overall response rate was 65% for T-3 tumors vs 29% for T-4 tumors. Five-year survival was 54% for T-3 vs 24% for T-4 tumors. The other predictive factor for survival was response to chemotherapy. Five-year survival was 73% for those patients achieving a complete response vs 17%-37% for patients with any residual disease after drug treatment. Since a favorable response to chemotherapy was strongly associated with a lesser T-stage as well as with significantly better survival of patients in our study, we conclude that induction chemotherapy may best benefit those patients with smaller tumors. Our findings show that a complete response to chemotherapy can also serve as a good prognostic sign, although an a priori better prognosis is still associated with patients who have smaller tumors.     

Head and neck cancer. Relationship of the prechemotherapy serum alkaline phosphatase levels to response rate of induction chemotherapy

Fifty-one patients with stage III or IV squamous cell carcinoma of the head and neck who received induction chemotherapy with cisplatin and bleomycin sulfate with and without high-dose methotrexate were studied. The relationship of the prechemotherapy levels of serum alkaline phosphatase, lactic dehydrogenase, SGOT, SGPT, BUN, creatinine, calcium, total protein, albumin, hemoglobin, uric acid, and bilirubin and the WBC and platelet counts was correlated with the response rate. The overall response rate was 65%. No notable relationship between any of the laboratory values and the response rate was found. In contrast to an earlier report, patients with a low alkaline phosphatase level responded as well as patients with an elevated serum alkaline phosphatase level.     

Simultaneous chemoradiation in the treatment of advanced head and neck cancer.

Fifty-eight patients with either advanced or unresectable squamous cell carcinoma of the head and neck were randomly selected to receive either twice daily radiation alone or twice daily radiation plus concomitant chemotherapy with cisplatin and fluorouracil (5-fluorouracil). There was no advantage in survival or time to progression with the addition of chemotherapy to twice daily radiation for patients with advanced resectable cancers. In the group of patients with unresectable cancers, however, there was a statistically significant advantage to the addition of chemotherapy, both in terms of disease-free survival and date to progression.     

DNA ploidy of primary and metastatic squamous cell head and neck cancers.

Regional metastases are a major determinant in the treatment outcome of patients with squamous cell carcinoma of the head and neck. Metastases do not respond as well to cytotoxic therapy as do primary tumors. DNA diploid tumors or tumor components also respond poorly to intermittent cytotoxic therapy. In our series of 497 patients with squamous cell carcinoma of the head and neck, the percentage of pure DNA diploid tumors and the mean DNA indexes in 497 primary tumors and 82 regional metastases were 34% and 1.54 and 50% and 1.34, respectively. Paired comparisons were performed in 61 patients and revealed a statistically significant increase in the frequency of DNA diploid tumors (27.4% to 41.2%) in associated lymph node metastases. The clinical observation that patients with squamous cell carcinoma of the head and neck and regional lymph node metastases have a poorer prognosis and a poorer response to cytotoxic therapy may in part be explained by the increased incidence of DNA diploid tumors in their regional lymph nodes, and the poorer response of such tumors to cytotoxic therapy.     

Advanced squamous carcinoma of the head and neck. A preliminary report of neoadjuvant chemotherapy with cisplatin, bleomycin, and methotrexate

Between Oct 1, 1979 and Aug 1, 1982, 93 patients with advanced squamous carcinoma of the head and neck were given neoadjuvant treatment with cisplatin, bleomycin sulfate, and methotrexate before standard local treatment. Ninety-three patients were evaluable for response. The response rates were as follows: complete response, 24%; partial response, 64%; and no response, 12%. Differences in primary tumor site, performance status at presentation, histologic grade, and tumor size did not correlate with response to this chemotherapy. For patients achieving notable tumor reduction to 2 cm or less, standard local treatment with either surgery plus radiotherapy or high-dose radiotherapy alone was effective in controlling local disease. For patients with larger tumor masses following neoadjuvant chemotherapy, surgical resectability appeared to improve local control rates. In our series, patients not receiving maximal standard local treatment often had relapse of local disease despite favorable responses to chemotherapy.     

Predefinitive and postdefinitive chemotherapy for locally advanced squamous carcinoma of the head and neck.

Advanced squamous carcinoma of the head and neck remains refractory to the best combinations of surgery and radiotherapy. Weekly methotrexate in high doses with leucovorin "rescue" is able to produce significant remissions in a majority of patients treated palliatively for recurrent disease yet is associated with little or no toxicity. We have attempted to improve the cure of patients with advanced disease by the use of high dose methotrexate (3-7.5 g/M2) and leucovorin prior to and following definitive surgery and/or radiotherapy. In a series of 24 patients we have achieved a response rate of 52%, with minimal toxicity during chemotherapy, and no apparent potentiation of toxicity with radiotherapy. Survival free of disease appears to be prolonged in patients with response to this chemotherapy. Multimodality approaches to locally advanced squamous carcinoma of the head and neck may soon yield improved cure rates.     

Neoadjuvant docetaxel and cisplatin chemotherapy followed by local irradiation is highly active on locoregionally advanced squamous cell carcinoma of the head and neck

The purpose of this study was to determine the treatment outcome of neoadjuvant docetaxel and cisplatin chemotherapy followed by local radiotherapy for chemotherapy-na?ve patients with locoregionally advanced squamous cell carcinoma of the head and neck. Thirty-seven patients with stage III or IV squamous cell carcinoma of the head and neck who received docetaxel and cisplatin regimen for a maximum of three cycles followed by radiation therapy were enrolled in this study. The overall response rate to the regimen was 91.9 per cent (34 of 37) (the complete remission rate was 48.6 per cent). The median time to treatment failure was 38 months (95 per cent confidence interval, 15-61 months). The four year estimated overall survival rates were 85.1 per cent. The most frequent moderate-to-severe toxicity was grade 3-4 neutropenia. The most common acute non-haematologic toxicities included anorexia, nausea and asthenia. Neoadjuvant docetaxel and cisplatin chemotherapy followed by radiotherapy is a feasible treatment strategy for patients with locoregionally advanced squamous cell carcinoma of the head and neck.     

Concomitant chemoradiotherapy with cisplatin, 5-fluorouracil and hydroxyurea in poor-prognosis head and neck cancer.

Based on encouraging results with 5-fluorouracil (5-FU), hydroxyurea, and concomitant radiotherapy in patients with advanced or recurrent head and neck cancer, an attempt was made to modulate the regimen by the addition of cisplatin as a third active agent. A cohort of 26 patients with head and neck cancer of all histologies were entered into a broad phase I study investigating simultaneous radiation therapy, 5-FU (with or without leucovorin), HU, and infusional cisplatin administered on an alternate-week schedule. Eleven patients (group 1) had failed prior curative local therapy and 15 patients (group 2) were considered to have a poor prognosis with standard therapy. The median follow-up was 30 months. The response rate for all evaluable patients was 82% (14/17), and the complete response rate was 65% (11/17). Patients in group 1 demonstrated a high failure rate (9/11), while few group 2 patients failed after treatment (2/15). The median time to progression was 4.4 months in group 1 and has not been reached in group 2. Patients in group 1 failed locally (7/11), while no local failures were observed in group 2. Acute and cumulative hematologic toxicity was encountered at all dose levels and schedules tested and prevented escalation of the cisplatin dose beyond the desired level of 100 mg/m2 per months. Mucositis was a second significant toxicity in patients with head and neck cancer and was more pronounced during cycles containing leucovorin. A detailed analysis of survival, time to progression, and site of failure is presented.