Two-year results from a Swedish study on conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma - The ARTSCAN study

Background and purpose

Studies on accelerated fractionation (AF) in head and neck cancer have shown increased local control and survival compared with conventional fractionation (CF), while others have been non-conclusive. In 1998 a national Swedish group decided to perform a randomised controlled clinical study of AF.

Materials and methods

Patients with verified squamous cell carcinoma of the oral cavity, oropharynx, larynx (except glottic T1-T2, N0) and hypopharynx were included. Patients with prior chemotherapy or surgery were excluded. Patients were randomised to either CF (2 Gy/day, 5 days/week for 7 weeks, total dose 68 Gy) or to AF (1.1 Gy + 2.0 Gy/day, 5 days/week for 4.5 weeks, total dose 68 Gy). An extensive quality assurance protocol was followed throughout the study. The primary end point was loco-regional tumour control (LRC) at two years after treatment.

Results

The study was closed in 2006 when 750 patients had been randomised. Eighty-three percent of the patients had stages III-IV disease. Forty eight percent had oropharyngeal, 21% laryngeal, 17% hypopharyngeal and 14% oral cancers. There were no significant differences regarding overall survival (OS) or LRC between the two regimens. The OS at two years was 68% for AF and 67% for CF. The corresponding figures for LRC were 71% and 67%, respectively. There was a trend towards improved LRC for oral cancers treated (p = 0.07) and for large tumours (T3-T4) (p = 0.07) treated with AF. The AF group had significantly worse acute reactions, while there was no significant increase in late effects.

Conclusion

Overall the AF regimen did not prove to be more efficacious than CF. However, the trend towards improved results in AF for oral cancers needs to be further investigated.     

A dose escalation study of hyperfractionated accelerated radiation delivered with integrated neck surgery (HARDWINS) for the management of advanced head and neck cancer

BACKGROUND AND PURPOSE: To determine toxicity and outcome of radiation dose escalation with hyperfractionated accelerated radiation delivered with neck surgery (HARDWINS) for head and neck cancer. PATIENTS AND METHODS: Patients with stage III and IV squamous cell carcinoma of the oropharynx, hypopharynx or larynx were enrolled. Dose levels of 60, 62 and 64Gy were delivered with twice daily fractionation in 40 fractions over 4 weeks. Involved and at-risk nodal regions received microscopic dose (46.5-48Gy) with neck dissection for node positive patients 8 weeks after radiation. RESULTS: One hundred and sixty-nine patients were enrolled (60Gy n=22, 62Gy n=26, 64Gy n=121). No grade 4 acute toxicity was observed. Incidence of acute grade 3 toxicity was: skin (2%), larynx (6%), pharynx and esophagus (66%) and mucous membrane (75%). Feeding tube dependence was observed in 14% of patients receiving 64Gy. Overall survival, and relapse free rate at 5 years were 65% and 63%, respectively. Local, nodal and distant relapse free rates at 5 years were 77%, 94% and 81% (median follow-up 3.8 years). CONCLUSIONS: HARDWINS can be delivered without acute grade 4 toxicity but significant grade 3 acute toxicity. A significant proportion of the patients have prolonged swallowing dysfunction. Outcomes suggest this regimen represents an alternative to chemoradiation.     

Treatment of locally advanced squamous cell carcinoma of the head and neck with concurrent bleomycin and external beam radiation therapy.

Nineteen patients with advanced head and neck cancer were treated with bleomycin (15u BM and irradiation (180 rad, 5d/week, 5040 rad) and have analyzed the effects. Most patients went on to further radical treatment. Both epithelial toxicity and tumor regression seemed enhanced. Approaching 1 year minimum follow-up (2 years maximum) crude survival is 68% and disease-free survival is 57%. Late complications do not seem to be enhanced. Regression in advanced nodal disease was less impressive.     

A phase I trial combining oral cisplatin (CP Ethypharm) with radiotherapy in patients with locally advanced head and neck squamous cell carcinoma

Purpose

To determine the maximum tolerated dose (MTD) of oral cisplatin (CP Ethypharm®) in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC) and the recommended dose for phase II trials.

Patients and methods

Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. CP Ethypharm® was administered on five consecutive days every other week for 7 weeks (4 treatment cycles) in combination with radiotherapy. Eighteen patients with locally advanced HNSCC were allocated to four cisplatin dose levels: 10 mg/m²/day: 4 patients; 15 mg/m²/day: 4, 20 mg/m²/day: 5 and 25 mg/m²/day: 5. The inclusion of patients was dictated by occurrence of dose limiting toxicities (DLTs) at each dosing level.

Results

The most frequently experienced AEs were gastrointestinal (GI) disorders. Five DLTs were observed, including three at 25 mg/m² level (two grade 2 renal toxicities, one grade 3 GI and renal toxicities), one at 20 mg/m² level (grade 3 GI disorders), one at 10 mg/m² level (grade 4 mucositis). PK analysis showed no significant difference of C_max values between day 1 and day 5 of treatment at each dose level (total & ultrafilterable platinum).

Conclusion

Due to 3 DLTs experienced at 25 mg/m²/day, MTD was reached and the recommended dose for phase II studies was determined as 20 mg/m²/day.     

Concomitant boost radiotherapy for advanced squamous cell carcinoma of the head and neck

The concomitant boost technique is a variant of accelerated fractionation whereby the boost is delivered as a second daily fraction during the basic treatment course to reduce the total duration of treatment. From April 1972 through June 1983, 53 patients with advanced squamous cell carcinoma of various sites in the head and neck region were treated for cure at U.T. M. D. Anderson Hospital with this technique. In 12 patients, the concomitant boost was used because of rapid recurrence following surgical resection either before or after initiation of planned postoperative radiotherapy; the remaining patients had rapidly growing untreated or recurrent disease in the primary site, neck, or both. In most cases, the concomitant boost was delivered in fractions of 120-150 cGy, separated by 3-6 h from the basic daily treatment of 180-200 cGy. The boost treatments were given 2-3 times a week for 3-5 weeks, delivering an average of about 17 Gy in 12 fractions. Two different treatment techniques were used. Patients with predominantly neck disease (30) were treated with glancing AP and PA fields or with appositional electron beam portals to spare the mucous membranes, while those with advanced or rapidly progressive primary lesions, with or without nodal disease (23), received their concomitant boost through lateral photon or high energy electron beams to include the primary tumor site. As expected, the acute mucosal reactions were most severe in the latter group, but only three patients required interruption of treatment because of severe mucositis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fast neutron radiation therapy for unresectable squamous cell carcinomas of the head and neck: the results of a randomized RTOG study

Forty patients with advanced, unresectable squamous cell carcinomas of the head and neck were entered on a prospective, randomized study comparing fast neutron radiation therapy with conventional photon radiation therapy. Twenty-six patients were randomized to neutrons, and 14 patients were randomized to photons. The randomization was purposefully unbalanced in favor of the experimental treatment. The complete response rate for the neutron-treated group of patients was 52%. The complete response rate for the photon-treated group of patients was 17%. The difference is statistically significant at the p = .04 level. The two-year survival rates for the neutron-treated group and the photon-treated group were 25 and 0%, respectively. The major complication rates were not statistically significantly different for the two groups (18% for neutrons, and 33% for photons).     

局部晚期头颈部鳞癌术后辅助治疗的进展

局部晚期头颈部鳞癌的术后辅助治疗在整个治疗中占有重要地位,方案的选择日益注重个体化.调强技术使放疗更精确和适形.术后应尽早开始放疗,超过6周降低局部控制率.综合治疗在11周内完成较好.PET指导勾画靶区的作用仍有待进一步研究和形成共识.术后同步放化疗可以提高高危患者的疗效,但未能明显减少远处转移的发生.分子靶向治疗(西妥昔单抗)的疗效已经在非术后临床试验中被证实.人乳头瘤病毒、表皮生长因子受体和抑癌基因p53是目前分子生物学研究的热点,有望成为寻找个体化治疗新途径的突破口.     

Postoperative radiotherapy for head and neck squamous cell carcinomas: Feasibility of a biphasic accelerated treatment schedule

: It has been suggested that postoperative tumor cell proliferation may influence the outcome of advanced head and neck squamous cell carcinomas treated by surgery and postoperative radiotherapy. This Phase I pilot study was undertaken to determine the feasibility of a biphasic accelerated radiotherapy regimen with early and late concomitant boost delivery for postoperative treatment of patients with advanced head and neck cancers.

: From April 1993 to April 1994, 29 patients with advanced head and neck cancers were enrolled in this study after they underwent complete surgical resection. The basic radiation course delivered a median dose of 49 Gy in 25 fractions over 5 weeks at 1.8–2 Gy/fraction. The concomitant boost was delivered to the high-risk areas as a second daily fraction during the first (1.4 Gy/fraction) and fifth weeks (1.6 Gy/fraction). The total dose to the high-risk areas was 64 Gy in 35 fractions over 5 weeks.

: Twenty-seven patients (93%) completed the treatment without interruptions. Only two patients experienced severe acute toxicity requiring treatment breaks of 6 and 8 days, respectively. All patients developed confluent mucositis; in 69% of the cases it covered >50% of the treated surface. No patient developed Grade 5 (ulceration/bleeding) mucosal reaction. Mucositis required a median time of 7 weeks for complete healing (range 3–43. Two patients developed transient bone exposure. The median weight loss was 5.5% of pretreatment body weight (range 1.2–17.1%), and four patients required nutritional with nasogastric feeding tube.

: The results of this study show that this biphasic acceleration regimen is feasible with acceptable acute toxicity.     

Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation

BackgroundDespite clear differences in clinical presentation and outcome, squamous cell carcinomas of the head and neck (SCCHN) arising from human papilloma virus (HPV) infection or heavy tobacco/alcohol consumption are treated equally. Next-generation sequencing is expected to reveal novel targets for more individualised treatment.Patients and methodsTumour specimens from 208 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity, all uniformly treated with adjuvant cisplatin-based chemoradiation, were included. A customised panel covering 211 exons from 45 genes frequently altered in SCCHN was used for detection of non-synonymous point and frameshift mutations. Mutations were correlated with HPV status and treatment outcome.ResultsMutational profiles and HPV status were successfully established for 179 cases. HPV– tumours showed an increased frequency of alterations in tumour suppressor genes compared to HPV+ cases (TP53 67% versus 4%, CDKN2A 18% versus 0%). Conversely, HPV+ carcinomas were enriched for activating mutations in driver genes compared to HPV– cases (PIK3CA 30% versus 12%, KRAS 6% versus 1%, and NRAS 4% versus 0%). Hotspot TP53 missense mutations in HPV– carcinomas correlated with an increased risk of locoregional recurrence (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.5–12.1, P = 0.006) and death (HR 2.2, 95% CI 1.1–4.4, P = 0.021). In HPV+ SCCHN, driver gene mutations were associated per trend with a higher risk of death (HR 3.9, 95% CI 0.7–21.1, P = 0.11).ConclusionsDistinct mutation profiles in HPV– and HPV+ SCCHN identify subgroups with poor outcome after adjuvant chemoradiation. Mutant p53 and the phosphoinositide 3-kinase pathway were identified as potential druggable targets for subgroup-specific treatment optimisation.     

Phase II trial of gemcitabine concurrent with radiation for locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Concurrent chemoradiation is the current standard of treatment for patients with advanced unresectable head and neck squamous cell carcinoma (HNSCC). Due to the potent radiosensitizing properties of gemcitabine, we decided to assess its efficacy and toxicity with concurrent radiation in patients with advanced HNSCC. PATIENTS AND METHODS: From January 1997 to December 2001, 27 patients with locally advanced HNSCC (stage III, 37%; stage IV, 63%) were enrolled. All received a course of radiotherapy (70 Gy over 7 weeks) concurrent with weekly infusions of gemcitabine at 100 mg/m2 or 50 mg/m2. RESULTS: All patients were assessable for toxicity and 26 for response. Severe mucositis (grade 3-4) was observed in 74% of patients (grade 4, 41%). Severe hematological toxicity was uncommon. Mild and moderate xerostomy was the most common late toxicity in 23 patients (85%). The median radiation dose delivered was 70 Gy (40-80 Gy), 25 patients (93%) received > or = 80% of the intended dose. Gemcitabine dose intensity was > or = 80% in only 13 (48%) patients. The rate of complete and partial responses were 61% and 27%, respectively, for an overall response rate of 88%. At a median follow-up of 13 months (range 6-62), the actuarial 3-year progression-free survival (PFS) and overall survival (OS) were 37% and 33%, respectively. The only variable associated with prolonged survival (P = 0.0001) was the degree of response. No difference was observed in response or toxicity with either gemcitabine 50 or 100 mg/m2. CONCLUSIONS: The concurrent use of radiotherapy and gemcitabine is effective but produces manageable severe mucositis in a high percentage of patients.     

USC-HN2, a new model cell line for recurrent oral cavity squamous cell carcinoma with immunosuppressive characteristics

Head and neck squamous cell carcinomas (HNSCC) are common and aggressive tumors that have not seen an improvement in survival rates in decades. These tumors are believed to evade the immune system through a variety of mechanisms and are therefore highly immune modulatory. In order to elucidate their interaction with the immune system and develop new therapies targeting immune escape, new pre-clinical models are needed.A novel human cell line, USC-HN2, was established from a patient biopsy specimen of invasive, recurrent buccal HNSCC and characterized by morphology, heterotransplantation, cytogenetics, phenotype, gene expression, and immune modulation studies and compared to a similar HNSCC cell line; SCCL-MT1.Characterization studies confirmed the HNSCC origin of USC-HN2 and demonstrated a phenotype similar to the original tumor and typical of aggressive oral cavity HNSCC (EGFR⁺CD44v6⁺FABP5⁺Keratin⁺ and HPV⁻). Gene and protein expression studies revealed USC-HN2 to have highly immune-modulatory cytokine production (IL-1β, IL-6, IL-8, GM-CSF, and VEGF) and strong regulatory T and myeloid derived suppressor cell (MDSC) induction capacity in vitro. Of note, both USC-HN2 and SCCL-MT1 were found to have a more robust cytokine profile and MDSC induction capacity when compared to seven previously established HNSCC cell lines. Additionally, microarray gene expression profiling of both cell lines demonstrate up-regulation of antigen presenting genes. Because USC-HN2 is therefore highly immunogenic, it also induces strong immune suppression to evade immunologic destruction. Based upon these results, both cell lines provide an excellent model for the development of new suppressor cell-targeted immunotherapies.     

Outpatient chemotherapy for recurrent and/or advanced squamous cell carcinoma of the head and neck

Background. The efficacy of the treatment of cancer has been traditionally judged by outcome measures such as disease-free survival, overall survival, and tumor response rate. Our goal of salvage and/or adjuvant chemotherapy is to improve not only the survival period but also the quality of life (QOL). The conventional regimens containing cisplatin (CDDP) require hospitalization of patients, which has been responsible for disappointingly low QOL. Thus, we developed a new outpatient regimen that has same magnitude of activity and less toxicity compared with conventional CDDP-containing regimens. Methods. Sixteen patients with recurrent or advanced head and neck cancer were treated by the outpatient setting Long-CF regimen. The Long-CF regimen consisted of cisplatin (CDDP) (CDDP, 5 mg/m²/2 h infusion on days 1–5, 8–12, 15–19, 22–26) and 5-fluorouracil (5-FU) [oral administration of tegaful-uracil (UFT-E), 400 mg/body on days 1–28]. Results. Among 16 patients entered in this trial, 1 patient was disqualified from analysis for reasons of protocol violation. Of 15 patients evaluable for response, 2 complete responses (13%) and 4 partial responses (27%) were achieved, with an overall response rate of 40%. Myelosuppression was the major side effect. Leukopenia and anemia (13% greater than WHO grade III) were dose-limiting toxicities. Other adverse reactions including mucositis were all mild and transient. Conclusion. As this regimen is given in an outpatient setting, we concluded that this regimen produced a beneficial effect in patients with recurrent and/or advanced head and neck cancer. Moreover, the toxicity of this regimen was limited; thus, attempts to increase the complete response rate by dose escalation or intensive scheduling appear warranted. Received: May 18, 1998 / Accepted: May 27, 1999     

Randomized controlled study comparing simultaneous modulated accelerated radiotherapy versus simultaneous integrated boost intensity modulated radiotherapy in the treatment of locally advanced head and neck cancer

Objectives

Comparison of two fractionation schedules of intensity modulated radiotherapy (IMRT) for locally advanced head and neck cancer – simultaneous integrated boost (SIB-IMRT) and simultaneous modulated accelerated radiotherapy (SMART) boost in terms of toxicity and survival end-point measures.

Salvage therapy with oral etoposide in recurrent and/or metastatic squamous cell carcinoma of the head and neck

Background: The purpose of this retrospective evaluation was to assess the palliative effect of oral etoposide in heavily pretreated patients with squamous cell carcinoma of the head and neck. Patients and Methods: Between October 1995 and February 2003, a total of 26 patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck (SCCHN) were treated with oral etoposide. Therapy consisted of etoposide at a total dose of 100 mg daily for 7 days and was repeated every 4 weeks until progression of disease or for a maximum of 8 courses. Eighteen patients underwent primary surgery of the tumour followed by adjuvant irradiation or surgery after neoadjuvant radiochemotherapy. Eight patients had primary irradiation with or without concomitant chemotherapy. All patients previously received at least one palliative chemotherapy with cisplatin/5-floururacil (5-FU) or cisplatin/taxotere. Patients did not routinely receive anti-emetic medication. Results: All patients were eligible for toxicity and survival assessment, and 24 of 26 patients for response evaluation according to an intention-to-treat principle. Two patients had a partial response (8 percent); disease was stable in 9 patients (35 percent) and progressed in 13 patients (50 percent). The median time to progression for all patients was 3 months (range, 2-54), and median overall survival was 10 months (range, 2-52). Toxicity was in general mild and moderate (Grade 1 and 2), except three patients, who experienced Grade 3 anaemia, and one patient who had Grade 3 thrombocytopenia without bleeding complications. Severe nonhematologic adverse reactions were not seen, except for alopecia. Conclusion: Our data suggest that oral etoposid is markedly effective, in regard to stabilization of disease and survival, and an excellent tolerated therapy for pretreated patients with recurrent and/or metastatic head and neck carcinomas. Its advantage over other commonly used and more intensive regimens such as 5-fluorouracil (5-FU) + cisplatin or taxane-containing combinations is its superior tolerance, in particular the incidence of nausea and vomiting, complete alopecia, and/or hematologic complications.