Introduction
Radiotherapy is an important therapeutic modality in the treatment of advanced (UICC stage III and IVA/IVB) head neck squamous cell carcinoma (HNSCC) in curative intent and is used either as adjuvant or primary treatment modality. It has been proven that concomitant chemotherapy improves overall survival as well as loco-regional control both in the primary and in the adjuvant situation (Bauchaud et al.
1996; Bernier et al.
2004; Browman et al.
2001; Cooper et al.
2004; El-Sayed and Nelson
1996; Pignon et al.
2000). However, concomitant chemotherapy also increases the risk of escalated acute toxicity. The optimal chemotherapy regimen has not been evaluated, yet. Common regimens besides several others are cisplatin 100 mg/m
2 on days 1, 22, and 43 of radiotherapy (Rades et al.
2008); 40 mg/m
2 weekly during radiotherapy (Geeta et al.
2006), or 20 mg/m
2 for 4 days in week 1 and 5 of radiotherapy (Lau et al.
2006), optionally combined with 5-FU (Adelstein et al.
2006). A relatively infrequent used regimen in radiochemotherapy for head and neck cancer is the use of daily low dose cisplatin, which includes the administration of cisplatin 6 mg/m
2 on each radiotherapy day. However, this application form is well established in the treatment of locally advanced non small cell lung cancers with primary radiochemotherapy (Pradier et al.
2005; Schaake-Koning et al.
1992; Semrau et al.
2007; Takiguchi et al.
2005). The experiences obtained from these studies regarding the treatment of NSCLC show that good treatment outcome with acceptable toxicity can be achieved with low dose cisplatin compared to radiotherapy alone. So far, there are only few reports on efficacy and toxicity of low dose cisplatin in radiochemotherapy for advanced HNSCC (Hoebers et al.
2007; Jeremic et al.
2004; Jeremic and Milicic
2008). Therefore, the purpose of this study was to evaluate the toxicity in patients treated with this regimen for locally advanced HNSCC either in the primary or adjuvant situation in our department.
Methods and patients
From October 2003 to October 2006, all stage III/IVA/B HNSCC patients treated in our department (primary or adjuvant) were designated to receive concomitant cisplatin 6 mg/m
2 on each radiotherapy day. No other cisplatin regimens were used in our department during the respective time period as patients, who were not able to receive cisplatin due to a reduced creatinine clearance (≤60 ml/min), which was determined in every case before starting treatment, were either selected to receive radiotherapy alone or radiotherapy plus cetuximab in the primary situation. In summary, 50 patients with locally advanced HNSCC received concomitant radiochemotherapy with cisplatin 6 mg/m
2 on each radiotherapy day in the respective time period and therewith qualified for inclusion in the presented study. All tumors were histologically determined as squamous cell carcinoma (41 histologic grade 2 and 9 grade 3). Forty-eight patients were males and two females, patients age ranged from 43 to 80 years (median 61 years). Tumors were localized as follows: oral cavity (6), oropharynx (29), hypopharynx (7), and larynx (8). Disease was staged according to the Union Internationale Contre le Cancer/American Joint Committee on Cancer (UICC/AJCC) criteria. Eight patients were in stage III, 35 patients were in stage IVA, and 7 patients were in stage IVB. Thereby, in 2 patients the primary tumor was staged as T1, in 7 patients as T2, in 15 patients as T3, and in 26 patients as T4. In summary, 43 patients presented with histologically proven positive cervical lymph nodes (6 patients N1, 30 patients N2, and 7 patients N3). One day before the start of radiochemotherapy, the hemoglobin level was determined in each patient, and its median was 8.9 mmol/l (13.9 g/dl) [range 6–11.5 mmol/l (9.3–17.9 g/dl)]. Four male patients presented with an anemia grade 1 according to the CTC score before radiochemotherapy. These patients received blood preservations to correct anemia before starting treatment. Pretreatment characteristics of patients entered in study are concluded in Table
1.
Table 1
Pretreatment characteristics of patients entered in study
Gender |
Male | 48 (96) |
Female | 2 (4) |
Tumor localization |
Oral cavity | 6 (12) |
Oropharynx | 29 (58) |
Hypopharynx | 7 (14) |
Larynx | 8 (16) |
Stage |
III | 8 (16) |
IVA | 35 (70) |
IVB | 7 (14) |
Histologic grade |
1 | 0 (0) |
2 | 41 (82) |
3 | 9 (18) |
Hemoglobin level before treatment |
>8.32 mmol/l (>13.9 g/dl) | 23 (54) |
<8.32 mmol/l (<13.9 g/dl) | 27 (46) |
Surgery |
Yes | 38 (76) |
No | 12 (24) |
Initial examinations before treatment included medical history, clinical ENT (ear-nose-throat) examination (magnifying laryngoscopy, upper bronchoscopy, esophagoscopy, ear-nose-throat endoscopy) with biopsies in potential mucosal primary sites, complete blood counts, biochemical analysis including creatinine clearance, electrocardiogram, chest X-rays, abdominal ultrasound, and CT scans of the thorax and the head and neck with contrast medium.
A total of 32 patients underwent curative surgery as a primary treatment followed by adjuvant radiochemotherapy up to a total dose of 64 Gy. Twenty-five of these patients had histologically proven involved lymph nodes; extracapsular extension of lymph nodes was detected in six of these patients. Eighteen inoperable patients were treated with primary radiochemotherapy to a total dose of 70 Gy. Thereby, all patients received conventional fractionated 3-D conformal external beam radiotherapy (2 Gy per fraction, five times a week, no alternative fractionation schemes like hyperfractionation were applied in our patient population). The first phase delivered a dose of 50 Gy to the primary tumor and associated nodal drainage sites. Subsequently, a boost was applied: In the primary setting, the boost included the primary tumor and macroscopic involved lymph node areas to a total dose of 70 Gy. In the adjuvant situation, the boost was applied to the primary tumor region and tributary lymph node regions including such lymph nodes with extranodal spread to a total dose of 64 Gy. Treatment was delivered with a Varian Clinac 600 C/D accelerator (Varian, Palo Alto, CA, USA). The prescribed dose was defined in accordance with the International Commission on Radiation Units and Measurement Report (International Commission on Radiation Units and Measurements Prescribing, recording and reporting photon beam therapy. ICRU report No. 50, Bethesda, MD: ICRU
1993). Simultaneous chemotherapy was given as follows to all patients in the study: Intravenous infusion of cisplatin 6 mg/m
2 was combined with 1l NaCl with facultative antiemetic medication on every radiotherapy day. Radiotherapy was applied after a minimum of 3 h following chemotherapy.
Toxicity was monitored weekly during radiochemotherapy and every second week following therapy until disappearance of acute toxicity. Subsequently, chronic toxicity was monitored at least quarterly. Toxicity was classified according to the CTC score for acute (Trotti et al.
2000) and according to the LENT scoring system for chronic toxicity (Rubin et al.
1995).
After radiochemotherapy, remission was evaluated by clinical ENT-examination (ear-nose-throat endoscopy, magnifying laryngoscopy, whenever necessary upper bronchoscopy, and esophagoscopy) and a computed tomography with contrast medium. Complete remission was defined as the complete regression of all tumor manifestations. Afterwards, patients underwent quarterly clinical ENT-examination, complete blood counts, biochemical analysis, chest X-rays, abdominal ultrasound or a computed tomography of the head and neck, if necessary. Biopsies were taken from suspect findings to receive histological confirmation of tumor growth.
Survival probabilities were calculated from the day of histological diagnosis. The Kaplan–Meier product-limit method was used to determine overall survival and loco-regional control. Loco-regional control was defined as the absence of local or regional recurrence or progression (Kaplan and Meier
1958). The impact of possible prognostic factors was estimated by univariate analysis (log-rank test) for gender, patient age, primary site, tumor stage, histological grading, surgery, and preradiotherapeutic hemoglobin levels. Statistical analyses were generated with the program StatSoft, Inc. (2002) STATISTICA for windows version 6.1.
Results
Toxicity
In summary, therapy was well tolerated. There were no treatment-related deaths. Acute grade 3 sole mucositis/dysphagia was seen in 11 patients (22%), sole hematologic toxicity ≥grade 3 occurred in 7 patients (14%) [5 leukopenia (3 of these patients with grade 4 toxicity), 1 patient thrombopenia grade 3 and one patient leukopenia and additionally anemia grade 3]. In another 4 patients (8%) mucositis/dysphagia and hematologic toxicity grade 3 (2 leukopenia and 2 leukopenia and thrombopenia) was observed. Thus, toxicity related changes of the therapy schedule were infrequently necessary. Overall, 94% of our patients received the intended dose of radiotherapy (in 2 patients receiving adjuvant treatment radiotherapy dose was reduced from 64 to 60 Gy and from 64 to 62 Gy, respectively and in one patient receiving primary radiochemotherapy from 70 to 62 Gy). More than 80% of the intended cumulative chemotherapy dose could be applied in 90% of our patients (chemotherapy break for more than one week was necessary in 8 patients, only). During follow-up, high grade chronic toxicity (grade 3) was also infrequent and occurred in nine patients (18%), only (3 patients xerostomia, 2 patients subcutaneous fibrosis, 2 patients lymphedema, and 2 patients subcutaneous fibrosis and lymphedema, respectively). No grade 4 chronic toxicity was observed in our patients during follow-up.
Follow-up, response and overall survival/loco-regional relapse, loco-regional control and development of distant metastases
All patients, who underwent surgery in curative intent, were at least macroscopically completely resected (28 patients R0-resection, 4 patients R1-resection). Complete remission after primary radiochemotherapy was seen in 12/18 patients (66%). In the other six patients, a partial remission was achieved. The median duration of follow-up was 24.2 months (range, 7.8–48.7 months). After this time, 38 patients (76%) remain alive. Death has occurred in 12 patients (24%); 9 of these died from tumor, and 3 died from intercurrent disease (secondary primary tumor, pulmonary embolism and one not known). Collectively, the 2- and 3-year overall survival rates were 72.7 and 67.1%, respectively. Loco-regional relapse (recurrence after complete or progress after partial remission) occurred in ten patients (in 7 patients after adjuvant and 3 patients after primary radiochemotherapy); the median time to relapse was 9 months (range 0.8–13.9). In nine patients, the initial site of relapse was local and in one patient regional. Distant metastases occurred in two patients (one hepatic and one pulmonal), in both cases not associated with a loco-regional recurrence. Collectively, the 2- and 3-year loco-regional control rates were 78%.
Prognostic factors
To evaluate the prognostic value of individual factors, univariate subgroup analyses concerning gender, patient age, primary site, tumor stage, histological grading, surgery, and preradiotherapeutic hemoglobin levels have been done. Subgroup analysis of tumor stage (stage III versus stage IVA/B) showed that disease stage III at the time of diagnosis is associated with a statistical significant (P = 0.02) higher 2- and 3-year year overall survival compared to the patients staged IVA/B (100 vs. 65.3%, and 100 vs. 57%, respectively). In contrast, subgroup analyses concerning gender, patient age, primary site, histological grading, surgery, and preradiotherapeutic hemoglobin levels showed no statistically significant influence on overall survival or loco-regional control. Still, this may be due to the small sample size.