High-dose intra-arterial cisplatin boost with hyperfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the tolerance and efficacy of intra-arterial (IA) cisplatin boost with hyperfractionated radiation therapy (HFX-RT) in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Forty-two patients with locally advanced primary SCCHN were treated on consecutive phase I/II studies of HFX-RT (receiving a total of 76.8 to 81.6 Gy, given at 1.2 Gy bid) and IA cisplatin (150 mg/m(2) received at the start of and during RT boost treatment). RESULTS: Acute grade 3 to 4 toxicities were as follows: grade 4 and grade 3 mucosal toxicity occurred in three (7%) and 31 patients (69%), respectively, and grade 3 hematologic, infectious, and skin events occurred in one patient each. Eight of 24 patients (33%) were unable to receive a second planned dose of IA cisplatin because of general anxiety (n = 5), nausea and/or emesis (n = 2), or asymptomatic occlusion of an external carotid artery (n = 1). Thirty-seven patients (88%) experienced complete response (CR) at primary site. Twenty-nine (85%) of 34 patients presenting with nodal disease experienced CR. The actuarial 2-year rates of locoregional control and disease-specific and overall survival are 73%, 63%, and 57%, respectively, with a median active follow-up of 30 months. CONCLUSION: In this highly unfavorable subset of patients, these results seem superior to previously reported chemoradiation regimens in more favorable patients. Use of a second dose of IA cisplatin boost was associated with increased toxicity without obvious therapeutic gain. This novel strategy allows for an incremental increase in the treatment intensity of the HFX-RT regimen recently established as superior to once-a-day RT.     

Postoperative reduced dose of cisplatin concomitant with radiation therapy in high‐ risk head and neck squamous cell carcinoma

BACKGROUND:

The role of low doses of cisplatin and concomitant postoperative radiotherapy in high risk head and neck squamous cell carcinoma has not yet been defined.

METHODS:

Patients treated with definitive surgery, who had histological evidence of involvement of more than 2 lymph nodes, extracapsular extension of disease, perineural and/or intravascular invasion, involved or close surgical margins, received postoperative radiotherapy plus 75 mg/m² of cisplatin every 3 weeks during the radiotherapy cycle. The primary endpoints were to evaluate treatment compliance and overall, cause‐specific, and disease‐free survival.

RESULTS:

A total of 142 patients were enrolled. With a median follow‐up of 40 months, 5‐year overall survival was 68%, cause‐specific survival 78% and disease‐free survival 82%. At multivariate analysis surgical margins status and extracapsular lymph node invasion were the only statistically significant prognostic factors. Fifty‐three percent of the patients developed severe mucositis and 14% hematologic toxicity of grade 3. The 3 planned concomitant chemotherapy cycles were delivered to 48% of the patients.

CONCLUSIONS:

Postoperative radiotherapy and concomitant low‐dose cisplatin was an effective treatment in high risk head and neck patients. The total toxicity observed was lower compared with that reported with higher doses of cisplatin, although the delivery of all the 3 planned chemotherapy cycles was challenging. The distant failure rate was high, which was an unsatisfactory result. Cancer 2009. © 2009 American Cancer Society.     

A phase II study of cisplatin and cytosine arabinoside for recurrent squamous cell carcinoma of the head and neck

Based on experimental data suggesting synergy between cisplatin and cytosine arabinoside, 17 patients with recurrent squamous cancer of the head and neck were treated with this combination. The response rate was 18% with no complete responses, and the partial responses were of brief duration. There were moderate hematologic and gastrointestinal toxicities and two therapy-related deaths. The study was stopped early because of low response. When compared to results reported for cisplatin alone, the combination of cisplatin and cytosine arabinoside offered no clear advantage.     

A phase II study of intra-arterial cisplatin with concurrent radiation and erlotinib for locally advanced head and neck cancer

Background

Based on the convenient oral dosing of erlotinib and the promising results of biologic therapy, we undertook a phase II study with 21 patients with locally advanced (T3–4) lesions combining radiation with intra-arterial (IA) cisplatin and oral daily erlotinib for a 7-week therapy.

Methods

Treatment for the primary tumor and upper neck was given to a total dose of 70 Gy. Chemotherapy with IA cisplatin (150 mg/m²) was given on days 1, 8, 15, and 22 concurrently with radiotherapy. During the 7-week treatment period, patients were given erlotinib 150 mg/day.

Results

Overall survival is 63 %, and the relapse/persistent disease rate stands at 36.8 %. A total of 15.2 % of serious adverse event was considered related to erlotinib.

Conclusion

Our study and several others now demonstrate the feasibility of combining anti-epidermal growth factor receptor (EGFR) therapy with chemoradiation, hint at improved survival outcomes with reduced distant metastatic rates, and suggest that maintenance therapy with anti-EGFR agent may be beneficial.     

Simultaneous therapy with high-dose cisplatin and radiation for unresectable squamous cell cancer of the head and neck: a phase I-II study

Studies using simultaneous radiation therapy and conventional doses of cisplatin have suggested improvement in local control and patient survival. This study was undertaken to determine toxicity and patient tolerance to concomitant high-dose cisplatin (40 mg/m2 per day X 5) and radiation (60 Gy in 6 wk +/- 10-Gy boost to residual tumor). Seventeen patients with advanced, inoperable squamous cell cancer primary tumor in the head and neck were treated (15 males and 2 females; median age, 57 yr). Cisplatin was started on day 1 of radiation therapy and repeated every 28 days for three cycles. Normal saline infusion (250 ml/hr) was started 12 hours prior to the first dose and continued 12 hours after the fifth dose. The daily dose of cisplatin was dissolved in 250 ml of 3% NaCl and given over 30 minutes. The cisplatin dose for subsequent cycles was reduced 10 mg/m2 per day only for a nadir granulocyte count less than 500/mm3 or fever greater than 101 degrees F during leukopenia. Of the 17 patients who started therapy, 15 have completed therapy; 1 patient died after one cycle, and 1 died after two cycles. Eleven patients received three cycles of cisplatin, and 10 patients required one dose reduction (6 at course 2 and 4 at course 3). Seven possible infections were successfully treated. Grade 2 neuropathy occurred in 3 patients, and renal toxicity greater than grade 1 occurred in 1 patient. Additional toxic effects were median WBC count nadir of 1.8 X 10(3)/mm3, platelet count nadir of 128 X 10(3)/mm3, hemoglobin nadir of 9.8 g/dl, and median weight loss of 5%.(ABSTRACT TRUNCATED AT 250 WORDS)     

A phase II study of concomitant boost radiation plus concurrent weekly cisplatin for locally advanced unresectable head and neck carcinomas.

BACKGROUND AND PURPOSE: This phase II study evaluated the efficacy and toxicity of weekly cisplatin along with concomitant boost accelerated radiation regimen in patients with locally advanced unresectable head and neck carcinoma. MATERIAL AND METHODS: A total of 94 patients (median age, 58 years) with UICC stage III (n = 19) and IV (n = 75) cancer of the oropharynx, larynx, hypopharynx and oral cavity were included. Patients received radiotherapy with a concomitant boost scheme (1.8 Gy on days 1-40 and 1.5 Gy boost on days 25-40 with a total dose of 72 Gy) and concurrent cisplatin, 40 mg/m(2) weekly, for the first 4 weeks. RESULTS: Most patients (95%) received both radiation and chemotherapy according to protocol. Toxicity was manageable with grade III mucositis and pharyngeal-oesophageal toxicity in 85 and 50% of patients, respectively. Haematological toxicity was mild. Four patients (4%) died due to complications. With a median follow of 41 months, median overall survival and time to progression were 27 and 25 months, respectively. The estimated overall survival at 4 years was 41%. CONCLUSIONS: Concomitant boost accelerated radiation plus concurrent weekly cisplatin is a feasible schedule in patients with locally advanced unresectable head and neck carcinoma, with acceptable toxicity and survival data.     

A phase 2 study of bevacizumab with cisplatin plus intensity-modulated radiation therapy for stage III/IVB head and neck squamous cell cancer

BACKGROUND:

For patients with stage III through IVB head and neck squamous cell carcinoma (HNSCC), concurrent high‐dose cisplatin plus radiation therapy is a widely accepted standard of care. HNSCC tumors that express high levels of vascular endothelial growth factor have been associated with a worse prognosis, and bevacizumab may sensitize tumors to cisplatin and radiation.

METHODS:

Planned treatment consisted of definitive intensity‐modulated radiation therapy (IMRT) (total, 70 grays) with concurrent cisplatin (50 mg/m² on days 1, 2, 22, 23, 43, and 44) and bevacizumab (15 mg/kg on days 1, 22, and 43). The primary endpoint was 2‐year progression‐free survival (PFS), and overall survival (OS) was a secondary endpoint.

RESULTS:

Forty‐two previously untreated patients (34 men and 8 women; median age, 55 years; range, 27‐75 years) with stage III through IV HNSCC without distant metastasis (oropharyngeal carcinoma, 39 patients; laryngeal carcinoma, 3 patients) were treated. Human papillomavirus (HPV) status by was determined by in situ hybridization (HPV positive, 16 patients; HPV negative, 14 patients, unknown HPV status, 12 patients). The toxicities (determined according to version 3.0 of Common Terminology Criteria for Adverse Events Common) that were experienced by all patients (any grade) were mucositis, lymphopenia, leukopenia, throat pain, fatigue, and anemia. There were 2 treatment‐related deaths, including 1 sudden death and 1 death from aspiration pneumonia. The median follow‐up was approximately 31.8 months (range, <3 to 51 months). The 2‐year PFS rate was 75.9% (95% confidence interval, 63.9%‐90.1%), and the 2‐year OS rate was 88% (95% confidence interval, 78.6%‐98.4%). Among 32 patients for whom post‐treatment Head and Neck Performance Status Scores were obtained (median, 5.6 months after completing radiation therapy), scores of 100 for eating, speech, and diet, respectively, were recorded among 75%, 84%, and 50% of patients.

BACKGROUND:

The addition of bevacizumab to high‐dose cisplatin plus IMRT did not appear to increase toxicity to unacceptable levels among patients with HNSCC, and the efficacy results were encouraging. Cancer 2012. © 2012 American Cancer Society.     

A phase II study of primary reirradiation in squamous cell carcinoma of head and neck.

BACKGROUND AND PURPOSE: In this prospective study, the effect of a second course of primary radiotherapy on locoregional control, survival and toxicity was investigated, in patients who underwent a second course of high dose irradiation for second primary or locoregional recurrent squamous cell head and neck carcinoma (HNSCC) in a previously irradiated area. PATIENTS AND METHODS: A total of 34 patients with second primary (n=26) or locoregional recurrent (n=8) tumours were treated with a second course of high dose radiotherapy. Patients were selected for re-irradiation in case of inoperable and/or unresectable tumours. In most cases, the target volume for re-irradiation was confined to the gross tumour volume (GTV). No elective radiotherapy was applied in the former high-dose area. A total dose of 46 Gy was applied to elective areas with a boost up to 60 Gy with conventional fractionation. The median follow-up period was 32 months. RESULTS: The locoregional control rate after 2 years was 27%. The 3-year overall survival was 22%. The most frequently reported acute side-effect was acute mucositis resulting in swallowing complaints. Pharyngeal and oesophageal late morbidity was also the most important late side-effect. In general, acute and late radiation-induced morbidity remained within acceptable limits. CONCLUSIONS: In conclusion, primary re-irradiation appears to be feasible in terms of acute and late radiation-induced toxicity. To improve outcome in terms locoregional control and survival, future studies should be focussed on optimising radiation schedules and the addition of concomitant chemotherapy.     

A phase I study of prolonged infusion 5-fluorouracil and concomitant radiation therapy in patients with squamous cell cancer of the head and neck

The radiosensitization properties of 5-FU are well documented, and clinical trials have suggested improved local control and survival in head and neck cancer. Clinical trials to date have used bolus injection or short term (less than or equal to 5 days) 5-FU infusions. To determine the maximum tolerated dose (MTD) of 5-FU given as continuous intravenous infusion for 12 weeks concomitant with conventional radiation therapy, 18 patients with advanced inoperable head and neck cancers were treated with conventional irradiation and 100, 200, 250, or 300 mg/m2/day of 5-FU. A dose of 250 mg/m2/day was determined to be the maximum tolerated dose and is recommended for Phase II studies.     

A phase II study of Adriamycin in previously untreated squamous cell carcinoma of the head and neck

Twenty patients with squamous cell carcinoma of the head and neck (SCC H/N) were treated with Adriamycin (doxorubicin) at a dosage of 60 mg/m2 at 3-week intervals. No patient had received surgery, radiation, or chemotherapy before treatment with Adriamycin. Responses were observed in 44% of 18 evaluable tumors. We conclude that Adriamycin is a highly active drug in SCC H/N when no prior treatment has been administered.     

Final results of a phase II single-institutional trial with hyperfractionated radiation therapy (HFX) and four-weekly continuous cisplatin in locally advanced head and neck carcinoma

Background

To evaluate the efficacy and toxicity of hyperfractionated radiation therapy and continuous infusion of cisplatin on weeks 1 and 5 in locally advanced head and neck carcinoma.

Methods

There were 53 patients: 3 (5.7 %) T2 patients, 31 T3 patients (58.4 %), and 19 T4 patients (35.8 %). Forty-one patients (77.4 %) were N-positive. According to the AJCC, 40 (75.4 %) patients had stage IV and the rest stage III. Treatment consisted of hyperfractionated radiation therapy, 120 cGy bid to a dose of 76.8–81.6 Gy, and cisplatin 20 mg/m²/day administered by continuous infusion over 120 h during days 1–5 and 21–25 of radiation therapy.

Results

Tumor response and toxicity There were 40 (75.5 %) complete responses, 6 partial responses (11.3 %), and 5 (9.4 %) non-responses or progression. Two patients were non-evaluable for response due to toxic death. All patients had some acute toxicity grade, the most frequent being mucositis (grade 3–4 in 33 patients) and epithelitis (grade 3–4 in 30 patients). Regarding late toxicity, only 2/24 long-term survivors had tracheostomy, and none of them needed enteral nutrition. Survival and local control With a median follow-up of 66 months, the 5-year overall survival rate for all the series was 49.1 % (95 % CI 58.9–39.3 %) with a median survival duration of 32.83 months. Five-year local control was 68.4 % (95 % CI 81.3–55.5 %).

Conclusions

Hyperfractionated radiation therapy and continuous infusion of cisplatin during weeks 1 and 5 are an active treatment in patients with LAHNC. Nevertheless, new strategies are necessary to increase the local control rates and reduce the incidence of distant metastasis and second tumors.     

A phase II study of cisplatin and continuous infusion of vindesine in metastatic head and neck squamous cell cancer

The chemotherapeutic treatment of recurrent and/or metastatic squamous cell carcinoma (SCC) of the head and neck (H & N) has a very dismal prognosis, with survival usually not exceeding 1 year. Reported objective response rates vary between 3% and 70%. This difference appears largely attributable to the heterogeneity of the patient populations included in most published Phase II studies in H & N cancer. They usually include together initially metastatic, recurrent, and post primary treatment metastatic disease patients. These patients respond differently to chemotherapy. Because of this situation, we decided to study a more homogeneous patient population consisting of metastatic patients only. Cisplatin (CDDP) and vindesine (VDS) are active agents in H & N SCC. As VDS has a cycle-specific activity, the therapeutic index may be increased if it is administered in a continuous infusion (CI) schedule. Thirty-three patients with metastatic H & N (69% biopsy proven) were treated with a combination regimen including CDDP (100 mg/m2) day 1 and VDS 0.6 to 1 mg/m2 for 96 hours of CI. Thirty-one patients were evaluable for response: five had a complete response (CR; 16%) and 11 had a partial response (PR; 36%) with an overall rate response of 52% (95% confidence limit: 33% to 70%). Median duration of CR was 6.4 months (3 to 19 months) and 4.4 months for PR (3 to 6 months). A decrease in the leukocytes was the main toxicity encountered with this regimen. This combination regimen containing CDDP and CI VDS was well tolerated and active in H & N SCC. The incorporation of an active vinca-alkaloid in neoadjuvant regimens should be considered.     

The superselective intra-arterial infusion of cisplatin and concomitant radiotherapy (RADPLAT) is effective for metastatic lymph nodes in head and neck squamous cell carcinoma

International Journal of Clinical Oncology - Superselective intra-arterial infusion of cisplatin and concomitant radiotherapy (RADPLAT) is a very promising treatment modality for locally advanced...     

A phase II study of pirarubicin in patients with advanced recurrent head and neck squamous cell carcinoma

Background: Head and neck squamous carcinoma (HNSCC) is a chemotherapy-sensitive tumour, but this sensitivity is not reflected in an impact on survival. The study of new drugs is therefore indicated. Pirarubicin (4-O-tetrahydropyranyl-doxorubicin) has a higher preclinical index than doxorubicin, with low cardiotoxicity in animal models. Patients and methods: Twenty-six patients with squamous cell carcinoma of the head and neck and documented progression after or during previous chemotherapy were entered into the study. Two patients were ineligible for evaluation. Pirarubicin was given at a dose of 70 mg/m² every 3 weeks. Results: Partial remission was seen in 1 of the 24 evaluable patients. The predominant toxicity was bone marrow depression, with leucopenia in 62% of the patients. One patient died due to a gastrointestinal haemorrhage during a period with WHO grade IV thrombocytopenia. Conclusion: On the basis of these results, pirarubicin cannot be recommended as second-line treatment in patients with recurrent and metastatic HNSCC. Its possible relevance for first-line treatment cannot be judged from these data.Authors are members of the EORT Head and Neck Cancer Cooperative Group     

A Phase I study of docetaxel and cisplatin for advanced squamous cell carcinoma of the head and neck

A Phase I study of docetaxel (DOC) and cisplatin (CDDP) combination therapy was conducted as second-line treatment for advanced squamous cell carcinoma of the head and neck in order to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) of DOC, and the recommended dose (RD) for this combination therapy. Twenty patients with recurrence for whom failed first-line chemotherapy with CDDP and 5-FU proved in-effective (17 male, 3 female; age range 38-74 years; performance status 0=7, 1 =8, 2=5) were included in this study. DOC at dose level I (40 mg/m2), level II (50 mg/m2), level III (60 mg/m2) and level IV (70 mg/m2) was used, followed by CDDP administration at a fixed dose of 80 mg/m2. Originally, chemotherapy was repeated every 3 weeks. In level I, grade 4 hypokalemia occurred in one patient. No DLT occurred at level II. At level III, one patient experienced grade 4 vomiting. At level IV, grade 2 creatinine clearance decrease occurred in a total of two patients. The maximum tolerated dose in this combination therapy was DOC 70 mg/m2, and CDDP 80 mg/m2. The recommended dose for this combination therapy is DOC 60 mg/m2, and CDDP 80 mg/ m2. A multicenter cooperative phase II study in this RD is recommended.     

Targeted therapy for squamous cell carcinoma of the head and neck

Targeted agents have emerged as novel drugs in the oncology field based on our understanding of the biology of individual malignancies, and have had a promising impact in several tumors. Squamous cell carcinoma of the head and neck (SCCHN) is a common disease with little progress made in survival over the past few decades. SCCHN is characterized by overexpression of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), both of which appear to have a prognostic value. Hence these receptors and their downstream pathways make attractive therapeutic targets. This review discusses targeted therapies currently being evaluated for their role in squamous cell carcinoma of the head and neck.     

A phase II trial of cisplatin and methylglyoxal bis-guanylhydrazone (MGBG) in recurrent squamous cell carcinoma of the head and neck

Thirty-one patients with unresectable squamous cell carcinoma of the head and neck, 28 with local or distant recurrences following primary surgery and/or radiation and three with distant metastases at diagnosis, were treated with cisplatin and methylglyoxal bis-guanylhydrazone (MGBG). Cisplatin was given at 60 mg/m2 i.v. every 21 days X 3, followed by 80 mg/m2 every 28 days in responding patients. MGBG 500 mg/m2 i.v. was given weekly X 5, then every 14 days. Each dose of MGBG was to be escalated in the absence of toxicity, but in the majority of patients doses greater than 500 mg/m2 resulted in unacceptable toxicity. Gastrointestinal symptoms were the major side effects of this combined treatment. In 28 evaluable patients there were two complete remissions and nine partial remissions. This 39% response rate is not different from that reported with either drug alone. Combined cisplatin and MGBG as administered in this study had no apparent advantage compared to either agent alone in this group of patients.