Abstract
Background/Aim: Many patients developing a loco-regional recurrence of squamous cell carcinoma of head and neck (SCCHN) have a poor prognosis. Often, recurrences are unresectable, and patients require a second course of radiotherapy or chemoradiation. We present an approach of chemoradiation including mainly 30 Gy of radiotherapy (1.5 Gy twice daily) plus concurrent paclitaxel. To further improve the prognoses of these patients, we increased the radiation dose from 30 to 36 Gy. Patients and Methods: In four patients with recurrent and previously irradiated SCCHN (60-70 Gy) chemoradiation was carried out using 36 Gy (1.5 Gy twice daily) and concurrent paclitaxel (4-5 times 20-25 mg/m2). Results: One-year loco-regional control rates were 75% inside and 67% outside re-irradiated regions. One-year survival was 50%, and median survival time 11 months. Toxicities were mild (grade 0-2). Conclusion: Re-irradiation with 36 Gy (1.5 Gy twice daily) plus paclitaxel appears feasible and may lead to promising outcomes. This study is preceding a phase I trial.
About half the patients who were treated for advanced non-metastatic squamous cell carcinoma of the head and neck (SCCHN) develop a loco-regional recurrence either at the primary tumor site and/or in regional lymph nodes (1-3). In case of such a recurrence, a complete resection is often not safely possible, and the patients are referred to radiotherapy, ideally combined with concurrent chemotherapy (4). However, many of these patients had already received 60-70 Gy of radiotherapy (usually with 5 daily fractions of 2 Gy per week) as part of their primary treatment, either as a definitive or an adjuvant approach. For the treatment of a loco-regional recurrence, the second course of radiotherapy cannot be safely administered with 60-70 Gy again when taking into account the tolerance doses of the organs at risk in the head and neck region (5). This problem may be partly overcome with the addition of concurrent chemotherapy, which can be assumed to represent more than additional 10% of the radiotherapy dose regarding the effect of tumor cell kill (6). Cisplatin and carboplatin are the most commonly used agents for SCCHN. However, many patients, particularly in recurrent disease after chemoradiation, may not be able to receive platin-based chemotherapy again due to expected toxicity such as nausea, vomiting and renal failure (7). For these patients, taxanes may be an alternative option, since these agents have been proved effective as a monotherapy in patients with SCCHN (8-10). In addition to concurrent chemotherapy, twice-daily administration of radiotherapy with lower doses per fraction (e.g. of 1.5 Gy) is a relatively novel approach to improve treatment outcome in such coditions. The risk of late radiation morbidity can be decreased with the use of lower doses per fraction (11). Normal tissues can recover from radiotherapy after 6 to 8 hours, whereas tumor cells generally do not recover. We followed this approach in a previous report of patients receiving mainly 30 Gy of radiotherapy with two daily fractions of 1.5 Gy supplemented by 20-25 mg/m2 of paclitaxel administered twice weekly (12). However, the question arose whether a better outcome could be achieved with a higher radiation dose than 30 Gy. Therefore, we increased the total radiation dose to 36 Gy in the present series and investigated the feasibility and efficacy of this regimen.
Patients and Methods
Four patients with head-and-neck cancer, two women and two men, underwent this therapy regimen. These patients had developed an advanced loco-regional recurrence of SCCHN following surgery plus postoperative platin-based chemoradiation. Two patients had oropharynx cancer, one patient cancer of the oral cavity and one patient larynx cancer. Initial tumor stages ranged from T1N2b to T4 N2b. Initial treatment included surgery followed by radiotherapy (60-70 Gy with 5 daily fractions of 2.0 Gy per week) supplemented by concurrent platin-based chemotherapy.
Outcomes of the patients, referenced from the first day of re-irradiation.
The median interval between the end of initial radiotherapy and the start of re-irradiation for the loco-regional recurrence was 103 months (range=14-225 months). Loco-regional recurrence consisted of an isolated recurrence of the primary tumor in two patients, an isolated recurrence of cervical lymph nodes in one patient and a recurrence of both primary tumor and lymph nodes in one patient. Re-treatment consisted of chemoradiation with 36 Gy of radiotherapy (two daily fractions of 1.5 Gy with an interval between the fractions of at least 6 hours given on five consecutive days per week). Radiotherapy was performed as volumetric modulated arc therapy encompassing the recurrence plus margins of 2-3 cm. It was supplemented by concurrent administration of paclitaxel (infusion over 1 hour) at doses of 20-25 mg/m2 twice per week. In total, the patients received 4×20 mg/m2, 5×20 mg/m2, 4×25 mg/m2 and 5×25 mg/m2 of paclitaxel, respectively (Table I). Premedication included 2 mg of clemastine, 1mg of granisetron and 8mg of dexamethasone, all given intravenously.
Investigated treatment outcomes included loco-regional control defined as freedom from another loco-regional recurrence in the head-and-neck region (inside or outside re-irradiated ares), metastases-free survival and survival, calculated from the first day of re-irradiation. These analyses were performed with the Kaplan-Meier method. In addition, acute toxicity was assessed using the Common Terminology Criteria of Adverse Events (CTCAE) version 4.0 (13).
Results
Following the chemoradiation with 36 Gy plus paclitaxel for recurrent SCCHN, the 1-year rates of overall loco-regional control, loco-regional control outside re-irradiated areas and loco-regional control inside re-irradiated areas were 38% (Figure 1), 67% (Figure 2) and 75% (Figure 3), respectively. Distant metastases were not observed during the follow-up period (median=11 months in all patients).
The 1-year rate of survival was 50% (Figure 4), and the median survival time was 11 months. The individual outcomes of the four patients are given in Table I. The treatment was well tolerated by all patients. Acute toxicities were grade 2 or less according to CTCAE version 4.0 (Table II).
Discussion
In patients developing a loco-regional recurrence of SCCHN, a complete resection is often not safely possible and the patients receive chemoradiation or radiotherapy alone, either as definitive treatment or following debulking surgery (4, 14). The recommended curative radiotherapy dose amounts to 60 Gy or higher. However, if the patients had already received chemoradiation or radiotherapy as part of their primary treatment, a second course of radiotherapy with at least 60 Gy is not possible considering the tolerance doses of the surrounding normal tissues. The risk of late radiation damage to these structures can be significantly decreased using a dose per fraction of less than 1.8-2.0 Gy such as 1.5 Gy (8). If doses per fraction of 1.5 Gy are administered twice daily with an interval of 6-8 hours, irradiated normal tissues are able to recover between the two fractions in contrast to the tumor cells. To further augment the efficacy of re-irradiation, radiotherapy may be supplemented by concurrent chemotherapy (6). Cisplatin, the most common agent, may lead to significant side effects and cannot be used in many patients with recurrent SCCHN (7). Beside other systemic treatments, paclitaxel may be an alternative option for these patients, which has been reported to be effective and associated with favorable toxicity profiles (8-10). For example, in a prospective study of 35 patients with locally advanced SCCHN, 70.2-72 Gy of radiotherapy plus three courses of paclitaxel resulted in a median survival of 56.5 months, and most toxicities were grade 2 or less (9). Furthermore, a randomized phase II trial compared 65 Gy of radiotherapy plus concurrent gemcitabine (100 mg/m2 weekly) or paclitaxel (20 mg/m2 weekly) in a total of 216 patients with locally advanced SCCHN (10). At 2 years, survival and freedom from progression rates were better in the paclitaxel group than in the gemcitabine group (67% versus 56%, respectively, and 64% versus 54%, respectively). Moreover, paclitaxel was associated with significantly less grade 3 mucositis (24% versus 36%, p=0.04) and grade 3 radiation dermatitis (13% versus 24%, p=0.049). These promising results led to our previous report investigating chemoradiation with paclitaxel in patients with a loco-regional recurrence of SCCHN (12). The patients mainly received 30 Gy of radiotherapy with two daily fractions of 1.5 Gy plus concurrent paclitaxel (20-25 mg/m2 twice per week). This regimen was very well tolerated. Toxicity was mostly limited to grade 1, grade 3 toxicity was not observed. Moreover, the 1-year survival rate of 75% was more favorable than in most other recent studies using chemoradiation or external beam radiotherapy alone including modern high-precision techniques such as tomotherapy, CyberKnife®, protons and charged particles for an advanced loco-regional recurrence of SCCHN. The 1-year survival rates in most of the other studies ranged from 33% to 62.5% (15-19). In one study using conformal radiotherapy, intensity-modulated radiotherapy or tomotherapy, the survival at 1 year was 77% (20).
Kaplan–Meier curve for overall loco-regional control (control inside and outside re-irradiated areas in the head-and neck region).
Kaplan–Meier curve for loco-regional control outside re-irradiated areas.
Kaplan–Meier curve for loco-regional control inside re-irradiated areas.
Kaplan–Meier curve for survival.
The results of our previous study (12) and the question whether the results can be further improved by increasing the radiation dose led to the present study. The radiation dose was increased to 36 Gy supplemented by 4-5 administrations of 20-25 mg/m2 of paclitaxel. Again, the outcomes were quite promising taking into account that the recurrent tumors were more advanced than in our previous study. The 1-year loco-regional control rate inside the re-irradiated areas of 75% was at the top of the range of 44-80% found in other studies (15-20). And the 1-year survival rate of 50% was well in the range of 33% to 77% reported in the other studies. The chemoradiation regimen used in the present study was well tolerated; grade 3 toxicities were not observed. In other studies, grade 3 or greater toxicities were reported in up to 36% of patients and treatment-related deaths in up to 12% of patients (15-20).
Toxicity according to CTCAE version 4.0.
In conclusion, re-irradiation with 36 Gy (1.5 Gy twice daily) plus 20-25 mg/m2 of paclitaxel administered twice weekly appears feasible and may lead to promising loco-regional control and survival rates. This study will drive forth to a phase I trial aiming to identify the appropriate radiation dose when combined with paclitaxel in patients with recurrent and previously irradiated SCCHN.
Footnotes
This article is freely accessible online.
Conflicts of Interest
On behalf of all Authors, the corresponding Author states that there is no conflict of interest related to this study.
- Received October 20, 2017.
- Revision received November 1, 2017.
- Accepted November 2, 2017.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
