Brief commnunication

Radiotherapy, combined with simulataneous chemotherapy with Mitomycin C and bleomycin for inoperable head and neck cancer—preliminary report

The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.

Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.

For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005).

The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.

The gold standard endpoint in randomised trials of locally advanced head and neck squamous-cell carcinoma (HNSCC) is overall survival. Our objective was to study whether duration of locoregional control or event-free survival (EFS) could be considered as surrogate endpoints to estimate the effect of radiotherapy and chemotherapy on overall survival. This would allow a reduction in the duration and cost of the development of new treatments.

Individual patient data from 104 trials (22 744 patients), with 116 treatment–control comparisons, from four meta-analyses on hyperfractionated or accelerated radiotherapy and concomitant, induction, or adjuvant chemotherapy were analysed. Duration of locoregional control was defined as the time from randomisation to the first locoregional event and EFS as the time to any first event (ie, locoregional relapse, distant recurrence, or death). At the individual level, a rank correlation coefficient between the surrogate endpoint and overall survival was used to assess surrogacy; at the trial level, a correlation coefficient R between treatment effects was used.

At the individual level, overall survival was more strongly correlated with EFS (range of correlations 0·82–0·90) than with locoregional control (0·65–0·76). For radiotherapy, treatment effects on both locoregional control and EFS were strongly correlated with those on overall survival (R=0·94 and 0·98, respectively). For chemotherapy, the correlations between treatment effects on EFS and overall survival were stronger than those between locoregional control and overall survival (range of R 0·79–0·93 vs 0·53–0·84, respectively).

EFS is a better correlate with overall survival than locoregional control and could be used as a surrogate for overall survival to assess the treatment effect of radiotherapy and chemotherapy in randomised trials of locally advanced HNSCC.

Programme Hospitalier de Recherche Clinique, the Association pour la Recherche sur le Cancer, the Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

To evaluate the toxicity and efficacy of concomitant chemoradiotherapy with mitomycin C and cisplatin in the treatment of advanced unresectable squamous cell carcinoma of the head and neck.

Treatment consisted of conventional radiotherapy (70 Gy in 35 fractions), mitomycin C 15 mg/m² IV, applied after the delivery of 10 Gy, and cisplatin at an initial dose of 10 mg/m²/d IV, applied during the last 10 fractions of irradiation (“chemoboost”). The cisplatin dose was escalated with respect to the toxic side effects by 2 mg/m²/d up to the maximum tolerated dose (MTD) or at the most 14 mg/m²/d (Phase I study), which was tested in the subsequent Phase II study.

All 36 patients had Stage T4 and/or N3 disease, and the majority had oropharyngeal (50%) or hypopharyngeal (39%) primary tumors. Six patients were treated at each of the three cisplatin dose levels tested (Phase I study). Dose-limiting toxicity was not reached even at 14 mg/m²/d of cisplatin, which was determined as the MTD and tested in an additional 18 patients (Phase II study). After a median follow-up time of 48 months, 4-year locoregional control, failure-free, and overall survival rates were 30%, 14%, and 20%, respectively. In 24 patients treated at the cisplatin dose level of 14 mg/m²/d, the corresponding rates were 40%, 20%, and 22%, respectively.

Concomitant chemoradiotherapy with mitomycin C and cisplatin “chemoboost” at 14 mg/m²/d is feasible, with encouraging survival results if the extremely poor disease profile of the treated patients is considered.

Concomitant chemoradiation is a widely used therapeutic concept in intensified locoregional treatment of high risk head and neck cancer patients. In this context, cisplatin monotherapy or in combination with other chemotherapeutics is recognized as the most effective drug to be added to radiotherapy.

The aim of this review is to present the rationale for combining radiotherapy with cisplatin in the treatment of head and neck cancer and to summarize the experience of the Institute of Oncology Ljubljana, Slovenia, gained through two prospective randomized trials on chemoradiation with mitomycin C and bleomycin in operable as well as inoperable head and neck cancer patients. Furthermore, recent developments in technology and biological drug modeling are discussed, which are considered to have a potential to add significantly to the locoregional effectiveness of radiotherapy.

References were retrieved using the online data base of the National Library of Medicine (PubMed: http://www.ncbi.nlm.nih.gov/PubMed). Terms used included: head and neck carcinoma, squamous cell carcinoma, concomitant chemoradiotherapy, cisplatin, mitomycin C, bleomycin. The results of studies using cisplatin-based chemoradiation regimens in the treatment of patients with inoperable tumors and on postoperative stetting were compared with the results of the studies, conducted at the Institute of Oncology and ENT Department at the Clinical Center Ljubljana, Slovenia.

When comparing mitomycin C-bleomycin chemotherapy with other comparable series on exclusively inoperable oropharyngeal cancer, but with cisplatin (or carboplatin) and 5-fluorouracil chemotherapy, and to standard dose cisplatin regimen used in postoperative setting, the effectiveness of our unconventional drug combination appeared to be at least equivalent to the well established platinum-based chemotherapy standard.

At the moment, concomitant chemoradiation with cisplatin-based chemotherapy is the most widely used way for potentiation of locoregional effect of radiotherapy in high risk head and neck cancer patients. Our clinical experiences with mitomycin C and bleomycin chemoradiation showed that there was still a window of opportunity to achieve equivalent clinical results with other drug combinations.

To evaluate the treatment results of squamous cell carcinoma of the oral cavity treated with radical or postoperative radiotherapy at the Institute of Oncology Ljubljana, in the period 1990–1995.

The medical records of patients were used to collect the data according to the predefined Data Acquisition Protocol. The impact of individual clinical and histopathological factors on the treatment outcome was evaluated by uni- and multivariate analysis.

Combined therapy was performed in 142 patients, and 93 patients had radiotherapy only. In each of the two subgroups, the performance status of patients was assessed as “poor” in 7% and 30%; the proportion of T1–2 tumours was 53.6% and 16.1%, and the proportion of cN0-stage tumours was 38% and 29%. The 5-year survival without local failure in surgically treated and irradiated only patients was 89% and 30%, without neck failure 85.7% and 50.3%, without any failure 79.1% and 27.5%, and overall survival 43.9% and 11.5%, respectively (all P<0.0001). In multivariate analysis, the performance status and cT-stage emerged as independent prognostic factors for all four types of survival analyzed. The type of therapy retained its independent prognostic value only in the case of survival without local failure.

The only independent predictors of survival were performance status and cT stage, whereas the type of therapy impacted only local cure rate. The difference in survival results between the two treatments reflects primarily selection bias which occurred when patients were directed to one of the two treatment options.

Previous randomized trials have shown a benefit with concurrent use of the hypoxic cell cytotoxin mitomycin C (MC) and radiation (RT) in the management of squamous cell cancer of the head and neck (SCCHN). We conducted a randomized trial comparing MC with porfiromycin (POR) in combination with RT in the management of SCCHN.

Between 1992 and 1999, 128 patients with SCCHN were enrolled in this prospective randomized trial. Patients were stratified by management intent, and balanced with respect to stage and site of disease. They were randomized to receive MC (15 mg/M²) or POR (40 mg/M²) on Days 5 and 47 (or last day) of RT. Of 121 evaluable patients, 61 were randomized to MC and 60 to POR. Patients were treated with standard daily RT to a total median dose of 64 Gy over 47 days. Patients were well balanced with respect to management intent, stage, site, age, sex, hemoglobin levels, tumor grade, radiation dose, and days on treatment.

There were no significant differences between the two arms with respect to acute hematologic or nonhematologic toxicities. As of January 2003 with a median follow-up of 6.3 years, there have been 19 local relapses (4 MC vs. 15 POR), 21 regional relapses (7 MC vs. 14 POR), 24 distant metastases (11 MC vs. 13 POR), and 66 deaths (33 MC vs. 33 POR). MC was superior to POR with respect to 5-year local relapse-free survival (91.6% vs. 72.7%, p = 0.01), local-regional relapse-free survival (82% vs. 65.3%, p = 0.05), and disease-free survival (72.8% vs. 52.9%, p = 0.026). There were no significant differences between the two arms with respect to overall survival (49.2% vs. 54.4%) or distant metastasis–free rate (79.9% vs. 75.9%).

Despite promising preclinical data, and an acceptable toxicity profile, POR was inferior to MC as an adjunct to RT in the management of SCCHN. This randomized trial emphasizes the need for randomized studies to evaluate new agents in the management of SCCHN.