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

Methods 

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

If 2 patients at the same cohort developed grade IV hematological toxicity or grade III nonhematological toxicity, the dose was considered the maximum tolerated dose, and all subsequent patients were treated with 1 level below that one for the phase II portion of the study.

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

Abbreviation: WBC, white blood cell.

Patients were followed for a minimum of 2 years or until death. Follow-up evaluations were performed every 2 months for the first year, every 3 months during the second year, and every 4 months during the third year. From then on, patients were followed routinely every 6 months.

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

Abbreviations: CR, complete response; PR, partial response; NR, no response (either stable or progressive disease); NA, not applicable (no nodal metastases at presentation).

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.

Abbreviations: P, primary site; ND, neck dissection; CR, complete response; PR, partial response.

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.