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.     

Adjuvant chemotherapy in stage III and IV squamous cell carcinoma of the head and neck

Initial combination drug regimen containing cisplatin in patients with stage III and IV head and neck cancer produced a high percentage of clinical response. This trial was initiated to assess the role of multimodality treatment (chemotherapy plus radiotherapy) versus chemotherapy alone. Ninety-six patients entered into this study; 80 patients were evaluable at time of analysis (Table I). Patients were randomized between chemotherapy and radiotherapy (group I) and chemotherapy alone (group II). The chemotherapy administered consisted of cisplatin, bleomycin and methotrexate and was given in 2 cycles over 35 days. Local radiotherapy followed. In group II 3 cycles of chemotherapy were given without radiotherapy. The overall tumour response after chemotherapy rose up to 75 per cent. After radiotherapy in group II the response rate sank to 59 per cent. In both regimes the remission duration was very short. Patients receiving only two cycles of chemotherapy do not have a statistically shorter survival than patients, who were treated by chemotherapy plus radiotherapy, or by a 3rd cycle of chemotherapy.     

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.     

Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. A preliminary report

A randomized, prospective trial utilizing cisplatin and fluorouracil as neoadjuvant chemotherapy in the treatment of advanced squamous cell carcinomas of the upper aerodigestive tract was initiated in January 1983. Sixty patients were stratified by site (oral cavity, 19; larynx, 14; hypopharynx, 14; oropharynx, 11; nasopharynx, one; and paranasal sinuses, one) and by stage (III, 19; IV, 41), and then randomized to receive either standard treatment (defined as preoperative irradiation followed by radical excision or irradiation alone) or adjuvant chemotherapy followed by standard treatment. An additional three patients were entered into the study, but withdrew. Chemotherapy consisted of three cycles for those patients in whom an objective tumor response was observed; nonresponders received standard treatment. Response to chemotherapy was complete in five and partial (greater than 50%) in 18 patients, for an overall response rate of 85%. The follow-up for surviving patients was a minimum of 24 months and a maximum of 44 months. Survival was compared for patients in both treatment groups according to the method of Lee and Desu. Despite excellent tumor response, actuarial survival was 70% in the standard treatment group as opposed to 56% in the experimental group. It was therefore evident that the high response rates reported in previous pilot studies do not necessarily result in improved survival in these cancers.     

Concurrent chemotherapy and "concomitant boost" radiotherapy for unresectable head and neck cancer

PURPOSE: For patients with advanced head and neck cancer, various combined chemoradiotherapy regimens have been used to improve local control. This study was carried out to assess the outcome of concomitant chemotherapy with a "concomitant boost" radiotherapy in the treatment of advanced unresectable head and neck cancer patients. MATERIALS AND METHODS: Forty-eight patients were treated with combined chemoradiotherapy between the years of 1990 and 1995. Cisplatinum (100 mg/m2) was given intravenously during week 1 and week 5. A "concomitant boost" external beam radiotherapy approach was used with twice-daily treatment delivered during the last 2 weeks. A total of 70 Gy was delivered over 6 weeks. Median follow-up was 23.5 months (2-79 months). RESULTS: Thirty-one (65%) and 17 (35%) patients achieved complete and partial response, respectively. Median survival in complete responders has not been reached. Overall survival at 2 years, 3 years, and 5 years were 58.7%, 52.8%, and 42.4%, respectively. Median overall survival was 38.8 months. Acute confluent mucositis (Radiation Therapy Oncology [RTOG] grade 3) developed in 50% of patients, but there was no severe long-term treatment-related toxicity. CONCLUSION: This combined chemoradiotherapy approach is safe and efficacious for advanced unresectable head and neck cancer. Treatment-related toxicity was acceptable with 50% of patients developing acute confluent mucositis. There was no severe long-term treatment-related toxicity.     

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.     

A comparison of radiotherapy or radiochemotherapy with symptomatic treatment alone in patients with advanced head and neck carcinomas

The choice of palliative treatment and the prognostic factors in unresectable head and neck cancer cases continue to be controversial. In the present study we compared the survival rates of untreated stage IV head and neck cancer patients with cases managed prospectively at A.C. Camargo Hospital for Cancer with neoadjuvant chemotherapy, concomitant chemotherapy or radiotherapy alone. Previous results had shown that while the type of treatment did not influence survival rates (P = 0.706), tumor response to treatment (whether complete, partial or none) significantly influenced survival (P = 0.00002). In the present study we compared the survival rates in the groups with untreated patients (who remained untreated until death) with the same demographic and clinical characteristics of patients receiving treatment. We found that there was a significant difference between the survival rates of the untreated group and those of the treated groups that was independent of the type of treatment performed (P < 0.00001) or the tumor response to treatment (P < 0.0001). Received: 19 October 1998 / Accepted: 15 April 1999     

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

Summary 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. Fiveyear 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.     

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.     

A comparison of combined modalities and single modality in the management of advanced head and neck tumors

Advanced head and neck cancer patients can be managed by single modality or combined modalities, Between 1976 and 1979, three treatment groups were retrospectively identified. One group received induction chemotherapy, surgery, and postoperative radiation therapy. The second group received chemotherapy followed by radiotherapy. The third group was treated during the same time period with radiation alone. These groups were matched with respect to age, site of primary tumor, nodal status, absence of metastatic disease, and no prior cancer treatment. The combined modality groups were initially treated with two doses of cis-platinum and a bleomycin infusion. Evaluation of tumor response was done 2 weeks following chemotherapy; 24 patients had surgery and postoperative radiation, 23 had radiotherapy without surgery and 24 patients were treated with radiotherapy alone. Median survival was 22 and 13 months respectively for the 2 combined modality groups and 4.7 months for the radiotherapy group. Disease-free survival was a projected value of 40 and 35 months for the combined modality groups and an actual 3 months for the radiotherapy group. Combined modality treatment with chemotherapy and surgery and/or radiotherapy offers a higher response rate and prolonged survival than radiotherapy alone.     

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.     

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.     

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.     

Results of an organ preservation protocol with induction chemotherapy and radiotherapy in patients with locally advanced pyriform sinus carcinoma

An alternative to the classical treatment for locally advanced (T3-T4 stage) pyriform sinus carcinoma with surgery and postoperative radiotherapy is to begin treatment with induction chemotherapy in an organ preservation approach. In patients with complete clinical response, this treatment is followed by radiotherapy; in non-complete responders, it is followed by surgery and postoperative radiotherapy. We conducted a retrospective study to evaluate such treatment in a cohort of 78 patients with locally advanced pyriform sinus carcinoma treated at a single institution between 1985 and 1997. In all patients, induction chemotherapy with cisplatin and 5-fluoruracil was carried out. Two patients died as a consequence of complications associated with chemotherapy treatment. Of the 76 patients who completed treatment, 23 (30%) achieved a complete response at the primary site, 38 (50%) attained a partial response, and 15 patients (20%) had a stabilization-progression. The 5-year adjusted survival of patients treated with radiotherapy alone was 57% and, in patients treated with surgery, 51%. There were no significant differences in survival related to the subsequent treatment used (P > 0.05). The larynx was preserved in 14 of the 23 patients (61%) who completed treatment with induction chemotherapy and radiotherapy. The frequency of organ preservation for the group of 78 patients who began treatment with induction chemotherapy was 18%. Received: 20 October 2000 / Accepted: 28 June 2001     

Laryngeal preservation by treatment with induction chemotherapy and radiotherapy protocol for stage III & IV carcinoma larynx--results of a pilot study.

Total laryngectomy for advanced carcinoma of the larynx is effective but functionally disabling. In an effort at laryngeal preservation, 33 patients of stage III/IV carcinoma larynx were treated between 1987 and 1991 with induction chemotherapy followed by definitive radiation. Two chemotherapy protocols were administered. Group I patients received one to three cycles of cisplatin 100 mg/m2 (day 1), bleomycin 15 U/m2 (day 1), and 5-fluorouracil 1000 mg/m2/day (day 2 to 5) at three weekly intervals. This was then followed by radiotherapy. Group II received one to six weekly injections of single agent methotrexate 50 mg/m2 with or without leucocovorin rescue followed by radiotherapy. Any recurrence was salvaged by surgery. Midway through the study, Group II protocol was discontinued as the initial results were not comparable with Group I or standard treatment. The Group I protocol, however, yielded an initial locoregional control rate of 83.3 per cent With the addition of surgical salvage the locoregional control rate was 94.4 per cent and the control rate with laryngeal preservation was 88.8 per cent. The Kaplan-Meier probability of two years and five years disease-free survival was 81.9 per cent and 61.4 per cent respectively. For disease-free survival with laryngeal preservation the corresponding figures for two years and five years were 58.3 per cent and 41.7 per cent. The control group of 51 patients treated with radical surgery followed by radiotherapy yielded survival figures at two years and five years of 64.3 per cent and 57.2 per cent. The difference in the survival of Group I and the control group was not statistically significant (p value = 0.280). These initial results indicate that for stage III and for surgically resectable stage IV laryngeal carcinomas, a protocol of induction combination chemotherapy consisting of cisplatin, bleomycin and 5-fluorouracil followed by radiotherapy and combined with surgical salvage whenever required, can lead to comparable cure rates. In addition, a large proportion of patients are spared the morbidity of a total laryngectomy.     

Preoperative chemotherapy in advanced resectable head and neck cancer: final report of the Southwest Oncology Group

In 1980, the Southwest Oncology Group instituted a multi-institutional, prospective, randomized phase III trial to evaluate whether inductive chemotherapy improved survival in patients with advanced stage resectable squamous cell carcinoma of the head and neck. From a group of 158 eligible patients, 76 were randomized to conventional treatment (surgery and postoperative radiotherapy), and 82 were assigned to experimental treatment (induction chemotherapy, surgery, postoperative radiotherapy). Median follow-up for living patients was approximately 5 years. These analyses include chemotherapy responses and toxicities, surgical complications, radiotherapy toxicities, patient compliance, survival time, and patterns of treatment failure. Overall chemotherapy response was 0.70 (0.19 CR, 0.51 PR). The median survival time for conventional treatment was longer than the time for patients receiving preoperative chemotherapy, although the survival time differences were not statistically significant. This final analysis demonstrates no benefit in survival using preoperative chemotherapy for advanced stage, resectable head and neck squamous cell carcinoma.     

Simultaneous radio‐ and chemotherapy for squamous cell carcinoma of the head and neck in daily clinical practice: 5 years experience in a University Hospital

Several randomized studies and meta‐analyses have shown that simultaneous radio‐ and chemotherapy prolongs survival in patients with unresectable squamous cell carcinoma of the head and neck as compared with conventional radiotherapy. We assessed the feasibility and effectiveness of simultaneous radiotherapy (35 × 2 Gy) and chemotherapy [cisplatinum 100 mg/m² or carboplatin (AUC 6) on days 1, 22 and 43] in daily clinical practice in a cohort of 87 patients treated at our institute between 1998 and 2002. Eighty patients completed radiotherapy according to schedule. Eighty patients received two courses of chemotherapy and 50 patients three courses. Nephrotoxity, bone marrow suppression and ototoxicity were the most frequent side‐effects. Median weight loss was 8.5%. Median survival was 15 months and 44% of the patients were alive at 2 years. Patients receiving three courses of chemotherapy had a better survival than patients receiving two or less courses. Treatment with simultaneous radio‐ and chemotherapy for advanced head and neck cancer is a demanding, but feasible treatment in daily clinical practice. Survival seems to be comparable with the results achieved in patients selected for clinical trials.     

Simultaneous radio- and chemotherapy for squamous cell carcinoma of the head and neck in daily clinical practice: 5 years experience in a University Hospital

Several randomized studies and meta-analyses have shown that simultaneous radio- and chemotherapy prolongs survival in patients with unresectable squamous cell carcinoma of the head and neck as compared with conventional radiotherapy. We assessed the feasibility and effectiveness of simultaneous radiotherapy (35 x 2 Gy) and chemotherapy [cisplatinum 100 mg/m(2) or carboplatin (AUC 6) on days 1, 22 and 43] in daily clinical practice in a cohort of 87 patients treated at our institute between 1998 and 2002. Eighty patients completed radiotherapy according to schedule. Eighty patients received two courses of chemotherapy and 50 patients three courses. Nephrotoxity, bone marrow suppression and ototoxicity were the most frequent side-effects. Median weight loss was 8.5%. Median survival was 15 months and 44% of the patients were alive at 2 years. Patients receiving three courses of chemotherapy had a better survival than patients receiving two or less courses. Treatment with simultaneous radio- and chemotherapy for advanced head and neck cancer is a demanding, but feasible treatment in daily clinical practice. Survival seems to be comparable with the results achieved in patients selected for clinical trials.     

Final Results of a Randomized Trial Comparing Chemotherapy Plus Radiotherapy With Chemotherapy Plus Surgery Plus Radiotherapy in Locally Advanced Resectable Hypopharyngeal Carcinomas

After neoadjuvant chemotherapy, a routine conservative approach followed by salvage surgery was evaluated in terms of local control and survival in cases of advanced potentially resectable hypopharyngeal carcinoma. Between 1985 and 1989, 92 patients with T3 or T4-N0,N3 operable squamous cell hypopharyngeal carcinomas received three courses of neoadjuvant chemotherapy every 2 weeks involving a combination of cisplatin, 100 mg/m², on day 1 and fluoruracil, 1 g/m², on days 2 to 5, followed by total laryngopharyngectomy plus postoperative radiotherapy in 47 patients (arm A) or radiotherapy alone in 45 patients (arm B). Randomization was always performed prior to chemotherapy. The response rates of tumor and node to chemotherapy were, respectively, 67% in arm A versus 79% in arm B (P > 0.05) and 54% in arm A versus 73% in arm B (P > 0.05). Grade III or IV toxicity was similar, affecting 15% of patients and 7% of cycles in arm A versus 16% of patients and 6% of cycles in arm B. After a mean follow-up of 92 months, survival was statistically better (P = 0.04) in arm A (5-year overall survival, 37%; median survival, 40 months) than in arm B (19% and 20 months) because of a better local control rate (63% versus 39%; P < 0.01). Better results were obtained for mutilant surgery in terms of local control and overall survival, regardless of response to neoadjuvant chemotherapy.     

Pretreatment with chemotherapy in patients with advanced head and neck cancer

Average survival for advanced head and neck cancer (AHNC) is 18 months. In an attempt to improve this we treated 29 AHNC patients between 1978-82 with two courses of chemotherapy. Chemotherapy consisted of cyclophosphamide, methotrexate, 5 fluorouracil and bleomycin; or bleomycin, cisplatinum and methotrexate. Chemotherapy was given prior to definitive therapy of radiotherapy or radiotherapy and surgery. All patients were stage 3 or 4. All patients were Eastern Co-operative Oncology Group status performance 0 or 1. Response to chemotherapy did not improve survival. Pretreatment with chemotherapy should be investigational until increased survival has been documented.