Volume 24, Issue 1 , Pages 1-5, January 2003
Results of phase I-II trial of concomitant hyperfractionated radiation and oral etoposide (VP-16) in patients with unresectable squamous cell carcinoma of the head and neck
Article Outline
Abstract
Purpose: The purpose of the current study was to investigate the efficacy of concomitant oral etoposide and hyperfractionated radiation for patients with unresectable head and neck squamous cell carcinoma. Methods: A prospective nonrandomized phase I-II study was conducted using concomitant oral etoposide (50 mg/d for 13-27 days) and hyperfractionated radiotherapy (1.2 Gy twice daily to a total of 7,440 rads) for patients with unresectable squamous cell carcinoma of the head and neck. Toxicity was graded according to the NCI common toxicity criteria. Patients were followed for a minimal period of 2 years. Endpoints for follow-up were recurrence or death. Results: Seventeen patients were enrolled in the study. Grade III hematological toxicity occurred in 1 patient and moderate to severe mucositis occurred in all but 2 patients requiring a gastrostomy tube (n = 13) or intravenous fluids hydration (n = 2). One patient died of cardiac arrest unrelated to the treatment regimen. The overall response rates in patients that finished the protocol were 80% for the primary site and 100% for the neck. A complete response was observed in 47% at the primary site and 33% in the neck. Local control and disease-free survival (DFS) at an average follow-up of 3.7 years were 47% and 29%, respectively. Conclusions: Concomitant etoposide and hyperfractionated radiation is well tolerated and seems to be effective in the treatment of unresectable HNSCC with acceptable mucosal toxicity. (Am J Otolaryngol 2003;24:1-5. Copyright 2003, Elsevier Science (USA). All rights reserved.)
Radiotherapy with neoadjuvant chemotherapy has been commonly used in the treatment of patients with unresectable head and neck squamous cell carcinoma (HNSCC). However, survival benefit or improvement in the patient's quality of life have not been clearly shown, and the treatment-related toxicity has been significant. The overall response rate of patients with HNSCC to regimens combining chemotherapy and radiation varies between 20% to 80%, with the highest response rates reported with the use of methotrexate, Cisplatinum, 5-fluorouracil, and Bleomycin.1, 2, 3
Etoposide (VP-16, Vepesid) is commonly used for treating germ cell tumors,4 small cell carcinomas of the lung,5 and hematological malignancies.6, 7, 8 Etoposide has not been effective as a single agent in treating patients with head and neck cancer9; however, it has been found to act as a radiosensitizer when used in experimental models.10, 11 The purpose of this study was to determine the feasibility, toxicity, and efficacy of daily oral etoposide administered concomitantly with hyperfractionated radiotherapy in patients with locally advanced or recurrent, unresectable HNSCC.
Methods
Patient eligibility
Patients with advanced unresectable HNSCC were eligible to participate in this study. Informed consent was obtained before enrollment. Patients had normal laboratory tests and an Eastern Cooperative Oncology Group performance status greater than 2, as well as no history of previous radiation to the head and neck region. The study was approved by the Institutional Review Board.
Chemotherapy
Patients received etoposide in the radiation therapy department in the morning. During the weekends, the patients were asked to take the drug at the same time. This regimen was changed in cohorts of 4 patients as described in Table 1.
Table 1. Planned cohorts of patients for toxicity testing
| Cohort | Etoposide Given | No Etoposide | Etoposide Given | Total No. Days |
|---|---|---|---|---|
| 1 | Days 1-7 | Days 8-26 | Days 27-32 | 13 |
| 2 | 1-14 | 15-26 | 27-39 | 23 |
| 3 | 1-14 | 14-28 | 28-40 | 27 |
| 4 | 1-21 | 22-26 | 27-46 | 41 |
Radiation therapy
Patients were treated with 6 mV photons with laterally opposing fields delivered twice daily (1.2 Gy separated by 6 hours). After large field radiation to the entire neck reached 55.2 Gy (46 treatments), boost fields were designed to the site of the tumor with a total dose of 74.4 Gy.
Response evaluation
Complete response was defined as a complete disappearance of tumor for at least 1 month. Partial response was defined as a decrease of 50% or more in the sum of the products of diameters of all measurable lesions and stable disease as a decrease of less than 50% or increase of less than 25% in the sum of the products of diameters of measurable lesions for at least 1 month. Progressive disease was defined as an increase of 25% or more in the sum of the products of diameters of measurable lesions or appearance of new lesions during the study period.
Toxicity and dose modifications
Toxicity was graded according to the National Cancer Institute common toxicity criteria, version 2.0. Any death that occurred within 30 days after cessation of the protocol or that seemed to be a result of the treatment, even when it occurred after more than 30 days, was considered treatment related. Blood counts were checked weekly, and etoposide was discontinued when platelet count dropped below 50,000/mm3 or granulocytes count below 1,000/mm3. Etoposide was not resumed if platelet count were found to be lower than 75,000/mm3 and granulocytes lower than 1,500/mm3 after 14 days. Criteria for removal from the study are summarized in Table 2.
Table 2. Criteria for removal from study
| Criteria for Removal |
| Disease progression during therapy |
| Failure to achieve WBC >1,500/mm3 after holding etoposide for 2 weeks |
| Grade IV mucositis |
| Unexpected grade III-IV toxicity |
| Non compliant patient |
| Patient/physician feel that discontinuing the protocol is of patient's interest |
Results
Between 1995 and 1997, seventeen patients were enrolled in the study. The patient's age ranged from 33 to 71, and the average age was 54.8 years. All patients, except one with a nasopharyngeal primary, had a history of smoking (average of 50 pack years) and consumed alcohol on a regular basis. The most common primary tumor site was the oropharynx (Table 3).
Table 3. Site of the primary tumor
| Site of the Primary Tumor | No. of Patients |
|---|---|
| Pharyngeal wall | 7 |
| Base of tongue | 3 |
| Supraglotic larynx | 2 |
| Oral tongue | 2 |
| Tonsil | 1 |
| Soft palate | 1 |
| Nasopharynx | 1 |
Fifteen patients finished treatment as prescribed by the protocol; 1 patient dropped out because of personal reasons, and 1 patient developed a stroke, so radiation was stopped at 5,920 rads.
Etoposide was given in 3 cohorts; 6 patients were treated in cohort 1 (total of 13 days), 4 in cohort 2 (23 days), and 7 in cohort 3 (27 days). More patients than planned were included in cohorts 1 and 3 because previous patients did not finish their treatments; thus, new patients could not be put in a more advanced cohort. Only 5 patients finished cohort 3. Treatment-related mortality occurred in 1 patient, who died at home on the last day of radiation therapy from a cardiac arrest. This patient had only mild toxicity related to the treatment regimen (grade 2 mucositis) but is regarded as treatment-related mortality because of the timing of the lethal event. Ten of the patients (66%) developed grade III mucositis, and in 6 patients a gastrostomy tube was placed for feeding because of decreased oral intake. In 7 subsequent patients, a gastrostomy tube was placed before initiation of treatments to prevent dehydration. Two other patients were treated with intravenous fluids for dehydration, and only 2 patients managed to finish the protocol without a feeding tube while maintaining sufficient oral intake. Other side effects were uncommon. The toxicity in relation to the different cohorts of treatment is shown in Table 4.
Table 4. Toxicity after etoposide and fractionated radiation
| Cohort No. | Grade | Mucositis* | Hematological* | GI* | Weight* Loss | Other* |
|---|---|---|---|---|---|---|
| 1 | I-II | 1 | 0 | 0 | 1 | Bleeding 1 |
| III | 3 | 0 | 0 | |||
| 2 | I-II | 3 | 0 | 0 | 1 | Bleeding 1 |
| III | 1 | 0 | 0 | Cerebrovascular accident 1 | ||
| 3 | I-II | 1 | 1 | 2 | 3 | Pain 4 |
| III | 6 | 1 | 0 | 0 | Ototoxicity 1 | |
| *No grade IV toxicity was observed. | ||||||
Of the 15 patients who finished the course of radiation and chemotherapy, complete response at the primary site was observed in 7 patients (47%), and complete resolution of the nodal metastases was observed in 5 patients (33%, Table 5).
Table 5. Response to etoposide and fractionated radiation
| Response at Primary Site | Response of the Regional Disease | No. of Patients |
|---|---|---|
| CR | CR | 3 |
| CR | PR | 4 |
| PR | CR | 2 |
| PR | PR | 3 |
| PR | NA | 1 |
| NR | PR | 2 |
| NR | CR | 1 |
| NR | NR | 1 |
Five patients (29%) are alive with no evidence of disease at a minimal follow-up of 30 months; the average follow-up was 44.6 months (Table 6).
Table 6. Data on surviving patients
| Primary | T | N | Etoposide Cohort No. | Radiation (rads) | Response at Primary site | Nodal Response | Surgery | Follow-up (mo) |
|---|---|---|---|---|---|---|---|---|
| Tonsil | 4 | 2b | 3 | 7440 | PR | CR | P + ND* | 30 |
| Pharynx | 4 | 1 | 3 | 7440 | PR | PR | P + ND | 39 |
| Oral tongue | 3 | 3 | 3 | 7440 | CR | PR | ND | 42 |
| Supraglottis | 4 | 2a | 3* | 5920* | CR | PR | ND | 47 |
| Oropharynx | 3 | 2b | 1 | 7440 | CR | CR | ND | 65 |
| *Patient dropped off because of mental disorientation/CVA. | ||||||||
Discussion
This study showed the feasibility of combined oral etoposide (50 mg/d for a total of 27 days) and hyperfractionated radiation with tolerable side effects. Etoposide administered orally has been shown previously to be as effective as intravenous etoposide with similar serum half-life, clearance, volume of distribution, and toxicity.12 Oral etoposide for 21 consecutive days has been used in the treatment of patients with various types of cancer with tolerable side effects.13 The current study shows similar findings with minimal, although somewhat different, side effects; hematological toxicity, which was previously reported as the most common and the dose limiting side effect,14 was minimal in the patients included in this study, whereas mucositis was the most common side effect. The high rate of mucositis observed in this study is comparable with that observed by others using hyper-fractionated radiotherapy alone,15, 16 which suggests that the addition of etoposide to the hyperfractionated radiation may not add significant morbidity. A total of 15 patients (88%) finished the protocol, and the 2 patients that stopped it did so for reasons unrelated to treatment toxicity, which is indicative of the high tolerance of this regimen. Treatment-related mortality occurred in only 1 patient who had almost no other side effects. Even though the proximity of the death to the treatment suggests that this could have been a toxic event, its relation to therapy is not clear.
Concomitant or sequential chemotherapy and radiation are currently considered more effective than radiation alone for the treatment of unresectable HNSCC.11, 17, 18 This was supported recently by Wendt et al19 who reported the results of a prospective randomized trial comparing radiotherapy alone to radiotherapy and concomitant cis-platinum and 5-fluorouracil in 270 patients with HNSCC. The 3-year survival was significantly better for the radiochemotherapy arm.19 However, the efficacy of concomitant chemotherapy and radiation for the treatment of unresectable HNSCC had been questioned in a well-designed prospective randomized study of 461 patients, in which no survival benefit was observed from neoadjuvant cisplatinum and 5-fluorouracil compared with radiation alone in patients with advanced HNSCC.20 Other regimens of radiation therapy are thus being evaluated; Harrison et al16 have reported their results with delayed accelerated fractionated radiation and concomitant chemotherapy (of various types) in patients with unresectable HNSCC. They used conventional once a day radiation for the first 4 weeks and then treated with radiation twice a day for 2 more weeks. The 3-year local control rate was 58%, and the overall survival was 36%. Two patients died as a result of the treatment. Severe and late complications occurred in 34% and 7% of the patients, respectively. In a recent study of 116 patients with locally advanced (resectable and unresectable) HNSCC, Brizel et al21 reported observing a significantly improved 3-year survival (55% v 34%) and locoregional control (70% v 41%), when comparing concomitant chemotherapy and hyperfractionated radiation with radiation alone. The rate of mucositis reported by these authors was 77%, a rate similar to that observed in our series. Our results are also in agreement with the results of Dragovic et al22 who had a 38% 3-year survival rate in patients with unresectable HNSCC treated with hyperfractionated radiation and concomitant cis-platinum and 5-fluorouracil.
Conclusions
Concomitant oral etoposide (50 mg/kg/d for 21 days) and hyperfractionated radiation is a reasonably well-tolerated and effective regimen for the treatment of patients with unresectable HNSCC.
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PII: S0196-0709(02)32409-8
doi:10.1053/ajot.2003.7
© 2003 Published by Elsevier Inc.
Volume 24, Issue 1 , Pages 1-5, January 2003
