A Non Platinum Regimen for the Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Region. Results From an Extended Phase II Study With Paclitaxel and Capecitabine.

BACKGROUND: This study presents the results of an extended phase II study originally published in 2007, regarding the antitumor activity and toxicity of a non-platinum containing regimen with paclitaxel and capecitabine for the treatment of recurrent or disseminated squamous cell carcinoma of the head and neck region. Fifty patients were included in the original study. MATERIALS AND METHODS: A total of 183 patients with recurrent or disseminated squamous cell carcinoma were eventually included in the extended study. There were 37 women and 146 men. The mean age was 56 years. Performance status (WHO) was as follows: WHO 0:31, WHO 1:107, and WHO 2:45 patients. The treatment consisted of paclitaxel 175 mg/m2, once every third week and capecitabine 825 mg/m2 p.o. b.i.d for 2 weeks. RESULTS: The overall response rate (complete response and partial response) according to the WHO criteria was: 33% (CI 26-40). The median progression-free survival was 4.8 (CI 4.2-5.4) months. The median overall survival (OS) was 8.9 (CI 7.6-9.5) months. Compliance was good. Of the 1,131 cycles, only 13% had to be administered with a reduced dose and/or postponed to a later date. Toxicity was mild and grades 3 and 4 toxicities were uncommon. Two toxic deaths were registered though. CONCLUSION: The response rate and the OS for this low toxicity regimen makes it a feasible alternative for not cisplatin eligible patients.

DAHANCA 10 - Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group.

PURPOSE: To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS: Patients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl. RESULTS: Following a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events. The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16-2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event-free survival (HR: 1.36 [1.09-1.69]), disease-specific death (HR: 1.43 [1.08-1.90]), and overall survival (HR: 1.30 [1.02-1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting. CONCLUSION: Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival.

Saliva in relation to dental erosion before and after radiotherapy.

OBJECTIVE: Low saliva flow and abnormal saliva composition are common conditions after radiotherapy for oral cavity and pharyngeal cancer. Both conditions increase the susceptibility to dental caries and erosion, which may be further accelerated by changes in food preferences. The aim of this study was to determine changes in saliva flow and susceptibility to erosive challenges in pharyngeal cancer patients before and after radiotherapy to the head and neck. MATERIALS AND METHODS: The erosive potential of sucking acidic candies with and without calcium was determined in nine patients (50-68 years) before and after receiving a radiation dose of 66 Gy to the head and neck area. The erosive potential was evaluated from saliva degree of saturation with respect to hydroxyapatite (HAp) and by dissolution of HAp in candy-stimulated saliva. RESULTS: Sucking acidic candies increased saliva flow rates ≈ 17-fold before as well as after radiotherapy (p < 0.001). However, significantly lower unstimulated (p < 0.05) and stimulated (p < 0.01) saliva flow rates were obtained after radiotherapy. Also, saliva became more under-saturated with respect to HAp during (p < 0.01) and in a period after sucking the candies (p < 0.01). HAp dissolution was significantly lower with the candy containing calcium compared with the control candy, both before and after radiotherapy (p < 0.001 and p < 0.05). CONCLUSIONS: Radiotherapy to the head and neck area significantly reduced saliva flow and altered saliva composition in a way that may increase the susceptibility to dental disease. However, saliva could be stimulated by acidic candies, which could be made nearly non-erosive even in irradiated patients.

Does transfusion improve the outcome for HNSCC patients treated with radiotherapy? - results from the randomized DAHANCA 5 and 7 trials.

BACKGROUND: Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of hemoglobin often have a poor response to radiation that may be related to hypoxia-induced radioresistance. We have previously published the importance of hemoglobin level and the effect of transfusion by the results from the randomized DAHANCA 5 trial, including 414 patients in the analysis. Aim of the current analysis was to gain additional power by adding patients from the continued subrandomization in the DAHANCA 7 trial, now including a total of almost 1200 patients. MATERIAL AND METHODS: Patients were randomized to treatment in the DAHANCA 5 and 7 study (nimorazole vs. placebo and five fx/week vs. six fx/week), and in addition, patients with "low" pre-irradiation hemoglobin values (females <13 g/dl; males <14.5 g/dl) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a hemoglobin level in the "high" value range. RESULTS: A total of 1166 patients were included, 701 patients had high hemoglobin levels and 465 had low hemoglobin levels. Among the low hemoglobin patients, 235 were randomized to receive transfusion. Patient characteristics and treatment arms were well balanced. In the majority of patients, transfusion resulted in increased hemoglobin levels although this decreased slightly throughout treatment as in the non-transfused patients. Overall, the patients with low hemoglobin level had a significant reduced probability of locoregional control, disease-specific and overall survival. In the low hemoglobin group, transfusion did not improve the outcome in locoregional control, disease-specific or overall survival. In multivariate analyses, HPV/p16 status, T and N classification were significant factors for all outcome measures, whereas there was no significant influence of transfusion or hemoglobin level on endpoints. CONCLUSION: Transfusion prior to and during radiation treatment did not improve the outcome in patients with HNSCC and low hemoglobin values, but may have a negative impact on survival.

The importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy--results from the randomized DAHANCA 5 study.

BACKGROUND AND PURPOSE: Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of haemoglobin (Hb) often have a poor response to radiation which may be related to hypoxia induced radioresistance. The aim of the study was to evaluate the prognostic significance of low Hb level and its modification by transfusion in HNSCC patients treated with radiotherapy. The study was performed as a subrandomization in the DAHANCA 5 trial. MATERIAL AND METHODS: Patients were randomized to treatment with the hypoxic radiosensitizer nimorazole or placebo, and in addition, patients with "low" pre-irradiation Hb values (females<13 g/dL; males<14.5 g/dL) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a Hb level in the "high" value range. RESULTS: A total of 414 patients were included, 243 patients had high Hb levels and 171 patients had low Hb levels. Of the low Hb patients, 82 were randomized to receive transfusion and 89 not to receive transfusion. The treatment arms were well balanced. In the majority of patients, transfusion resulted in increased Hb levels although this tended to decline throughout treatment. Patients with high Hb levels had a significantly better probability of locoregional control, disease-specific survival and overall survival compared to 'low Hb no transfusion' patients. In the low Hb group, transfusion did not improve the outcome in locoregional control, disease-specific survival or overall survival. In multivariate analyses, T and N classifications were significant for all outcome measures, whereas there was no significant influence of transfusion or Hb level on endpoints. CONCLUSION: The univariate prognostic significance of high Hb level was demonstrated in patients with HNSCC treated with radiotherapy; however, transfusion prior to and during treatment did not improve the outcome in patients with low Hb values.

Erosive potential of calcium-modified acidic candies in irradiated dry mouth patients.

PURPOSE: Patients who have received irradiation therapy on the head and neck area are known to suffer from reduced saliva flow and may therefore use acidic candies to relieve symptoms of dry mouth. However, such acidic candies have erosive potential even among healthy individuals. Therefore, the aim of the present study was to determine if calcium-modified acidic candies have reduced erosive potential in irradiated cancer patients. MATERIALS AND METHODS: Nineteen cancer patients (26 to 70 years) ipsilaterally irradiated on the head and neck area sucked control and calcium-modified acidic candies, while their whole saliva was collected into a closed system. The erosive potential of both candies was evaluated from saliva degree of saturation with respect to hydroxyapatite and by dissolution of hydroxyapatite (HAp) directly in candy-stimulated saliva. The results were compared to normative data that were previously obtained on 20 healthy test persons (21 to 29 years). RESULTS: No significant difference was obtained in the saliva flow rates between control and calcium-modified candy. However, the saliva became significantly less undersaturated with respect to HAp when sucking calcium-modified compared to control candy (P < 0.001) and more undersaturated for both candies in ipsilaterally irradiated cancer patients compared to normative data (P < 0.001). HAp dissolution was found to be significantly lower in patients sucking the modified candy compared to the control candy (P < 0.01) and, surprisingly, slightly lower in patients compared to normative data. CONCLUSIONS: Modified acidic candy with calcium has reduced erosive potential in patients irradiated on the head and neck area and could therefore be used as a favourable stimulant for relief of dry mouth.

Squamous cell carcinoma of the nasal vestibule 1993-2002: a nationwide retrospective study from DAHANCA.

BACKGROUND: A retrospective nationwide study of cancer of the nasal vestibule was conducted to evaluate classification systems and prognostic factors for treatment outcome. METHODS: Patients treated between 1993 and 2002 at head and neck oncology centers in Denmark were included. RESULTS: The 5-year results were locoregional control 67%, overall survival 50%, cancer-specific survival 74%. Cancer-specific survival according to Wang classification was 83%, 63%, and 39% for T1, T2, T3, respectively (p < .000). Regarding T1 tumors, 5-year locoregional control for surgery, surgery + radiotherapy (RT), or RT was 94%, 87%, or 61%, respectively (p < .000). Fifty-four Gray in 18 fractions was found comparable with 66 Gy in 33 fractions regarding T1 tumors. CONCLUSION: This national survey is the largest series of nasal vestibule cancer ever published. Wang classification is more prognostic and easier to use than the Union Internationale Contre le Cancer 2002. Surgery or hypofractionated RT can be used for T1 lesions, whereas larger lesions should be treated with combined approach.

Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study.

BACKGROUND: The benefit of a complementary fluorodeoxyglucose-positron emission tomography (FDG-PET) scan to standard workup for carcinoma of unknown primary (CUP) and metastatic neck lesions was prospectively studied. METHODS: Sixty-seven patients underwent standardized diagnostic workup according to national guidelines including panendoscopies, multiple mucosal biopsies, and diagnostic CT/MRI scans. Median follow-up was 40 months (range, 2-65 months). RESULTS: In 60 eligible patients, FDG-PET indicated a primary tumor or metastatic disease in 30 patients (50%). Additional investigations confirmed a primary tumor in 18 patients: hypopharynx in 5, oropharynx in 5, nasopharynx in 2, lung in 1, axilla in 1, bone in 1, rectum in 1, as well as multiple metastatic lesions from CUP in 2 patients. In retrospect, MRI was able to detect 1 of the PET-detected primaries, leading to an overall detection rate of PET of 29% in CUP. A therapeutic change of treatment was made in 25% as a consequence of FDG-PET. PET before panendoscopy demonstrated fewer false-positive pathological foci. CONCLUSION: FDG-PET is a valuable tool in addition to conventional extensive workup in CUP and neck metastases. Consequently, FDG-PET is now recommended as an early diagnostic modality in the workup of these patients.

Phase II analysis of paclitaxel and capecitabine in the treatment of recurrent or disseminated squamous cell carcinoma of the head and neck region.

BACKGROUND: The aim of this phase II study was to evaluate the antitumor activity and toxicity of a non-platin-containing regimen with paclitaxel and capecitabine. METHODS: Fifty patients with recurrent or disseminated squamous cell carcinoma were included in the study. The treatment consisted of paclitaxel 175 mg/m(2) once every third week and capecitabine 825 mg/m(2) per oral (p.o.) twice daily (bid) for 2 weeks. RESULTS: The overall response rate according to the World Health Organization (WHO) criteria was 42%. Two patients had a complete response (CR), 19 patients had a partial response (PR), 14 patients had no change (NC), 12 patients had progressive disease (PD), and 3 patients were not evaluable (NE). The median survival time was 8 months. Toxicity was very moderate. Only 10% of 315 delivered treatments had to be given in reduced dose or postponed for a week or more. CONCLUSIONS: The toxicity was low and manageable. The overall response rate was comparable to the commonly used cisplatin/5-fluorouracil regimen.

The Danish national guidelines for treatment of oral squamous cell carcinoma.

The treatment strategy for oral squamous cell carcinoma in Denmark has traditionally varied between the different head and neck oncology centres. A study group within the Danish Society for Head and Neck Oncology (DSHHO) was formed with the aim of optimising and standardising the treatment strategy. The approach was to use single modality treatment for stage I, stage II and some stage III and combined modality treatment for stage III and IV. Surgery was the preferred treatment when it was considered possible to perform a radical excision of the tumour and possible lymph node metastases with acceptable aesthetic and functional outcome. The implementation of a recognised national guideline facilitates prospective studies on a large well-characterised cohort. This increases the possibility of obtaining valid data on parameters such as morbidity, loco-regional control and survival. In addition the establishment of a reference program facilitates national monitoring of the treatment using defined indicators and standards.

Changes from 1992 to 2002 in the pretreatment delay for patients with squamous cell carcinoma of larynx or pharynx: a Danish nationwide survey from DAHANCA.

In Denmark, a general impression of prolonged pretreatment delay for patients with head and neck cancer led to a nationwide study of time spans from symptom debut over first health care contact to start of treatment. Charts of consecutive new patients with squamous cell carcinoma of the pharynx and larynx, seen at the five Danish oncology centers in January-April 1992 and 2002, respectively, were reviewed. Of the 288 patients identified, definitive treatment was radiotherapy in 264 cases, surgery in one case. Twenty-three patients had neither surgery nor radiotherapy. Total time from first health care contact to start of definitive treatment was significantly longer in 2002 than in 1992 (median 70 versus 50 days, p<0.001). There was no significantly difference in time used for diagnosis. Time for treatment preparation and planning was 46 days in 2002 versus 31 days in 1992 (p<0.001). Significantly more diagnostic procedures (CT, MR, US, PET) were done in 2002. In conclusion, this nationwide study showed that waiting time before start of radiotherapy was significantly longer in 2002 compared to 1992. An increasing number of imaging procedures including CT-based dose planning was observed. The prolongation was mainly related to shortage of radiotherapy capacity. The three weeks extra pretreatment delay could theoretically lead to a 10% lower tumor control probability in 2002 compared to 1992.

Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial.

BACKGROUND: Although head and neck cancer can be cured by radiotherapy, the optimum treatment time for locoregional control is unclear. We aimed to find out whether shortening of treatment time by use of six instead of five radiotherapy fractions per week improves the tumour response in squamous-cell carcinoma. METHODS: We did a multicentre, controlled, randomised trial. Between January, 1992, and December, 1999, of 1485 patients treated with primary radiotherapy alone, 1476 eligible patients were randomly assigned five (n=726) or six (n=750) fractions per week at the same total dose and fraction number (66-68 Gy in 33-34 fractions to all tumour sites except well-differentiated T1 glottic tumours, which were treated with 62 Gy). All patients, except those with glottic cancers, also received the hypoxic radiosensitiser nimorazole. Analysis was by intention to treat. FINDINGS: More than 97% of the patients received the planned total dose. Median overall treatment times were 39 days (six-fraction group) and 46 days (five-fraction group). Overall 5-year locoregional control rates were 70% and 60% for the six-fraction and five-fraction groups, respectively (p=0.0005). The whole benefit of shortening of treatment time was seen for primary tumour control (76 vs 64% for six and five fractions, p=0.0001), but was non-significant for neck-node control. Six compared with five fractions per week improved preservation of the voice among patients with laryngeal cancer (80 vs 68%, p=0.007). Disease-specific survival improved (73 vs 66% for six and five fractions, p=0.01) but not overall survival. Acute morbidity was significantly more frequent with six than with five fractions, but was transient. INTERPRETATION: The shortening of overall treatment time by increase of the weekly number of fractions is beneficial in patients with head and neck cancer. The six-fractions-weekly regimen has become the standard treatment in Denmark.

Salvage laryngectomy and pharyngocutaneous fistulae after primary radiotherapy for head and neck cancer: a national survey from DAHANCA.

OBJECTIVE: In 1998, the Danish Society for Head and Neck Oncology decided to conduct a nationwide survey at the five head and neck oncology centers with the aim of evaluating the surgical outcome of salvage laryngectomy after radiotherapy with special emphasis on identifying factors that could contribute to the development of pharyngocutaneous fistulae. PATIENTS: A total of 472 consecutive patients undergoing postirradiation salvage laryngectomy in the period July 1, 1987-June 30, 1997 were recorded at the five head and neck oncology centers in Denmark. Age ranged from 36 to 84 years, median 63 years, 405 men and 67 women. Primary tumor site was glottic larynx (n = 242), supraglottic larynx (n = 149), other larynx (n = 45), pharynx (n = 27), and other (n = 9). All patients had received prior radiotherapy. RESULTS: Median time between radiotherapy and laryngectomy was 10 months (range, 1-348 months). A total of 89 fistulae lasting at least 2 weeks were observed, corresponding to an overall average fistulae risk of 19%. The number of performed laryngectomies per year decreased linearly (from 58 to 37), whereas the annual number of fistulae increased slightly (from 7 to 11), which meant that the corresponding estimated fistulae risk increased significantly from 12% in 1987 to 30% in 1997. Other significant risk factors for fistulae in univariate analysis included younger patient age, primary advanced T and N stage, nonglottic primary site, resection of hyoid bone, high total radiation dose, and large radiation fields. Multiple logistic regression analysis of these parameters suggested that nonglottic tumor site, late laryngectomy period (1987-1992 vs 1993-1997), and advanced initial T stage were independent prognostic factors for fistulae risk. Surgical parameters like resection of thyroid/tongue base/trachea or radiotherapy parameters like overall treatment time or fractions per week did not influence fistulae risk. CONCLUSIONS: The risk of fistulae is especially high in patients initially treated with radiotherapy for nonglottic advanced stage tumors. A significant decrease in the number of performed salvage laryngectomies over the 10 years was seen. Over the same time period, the annual number of fistulae remained almost constant. The resulting more than doubling of fistulae rate could thus in part be explained by less surgical routine.

Esthesioneuroblastoma: a Danish clinicopathological study of 40 consecutive cases.

Aims. To review all cases of esthesioneuroblastoma in Denmark from 1978 to 2000 with respect to staging, grading, histopathological and immunohistochemical evaluation, and prognostication. Methods and results. Possible cases of esthesioneuroblastoma were retrieved from Danish oncology departments. Patients were included on the basis of review of their files or pathology reports, and/or on the basis of histopathological and immunohistochemical examination. Forty-nine possible cases were retrieved. Nine cases were excluded. Esthesioneuroblastoma is a malignant neuroendocrine tumour originating in the olfactory mucosa. It is a small blue cell neoplasm with a characteristic lobular architecture. It has a neuroendocrine immunophenotype and a sustentacular S-100 staining pattern. The tumours were staged according to Kadish and graded according to Hyams. Kaplan-Meier survival analysis was used to identify prognostic factors. Conclusion. The Kadish staging system was able to group the patients into prognostically relevant groups. Intracranial involvement and metastases at the time of diagnosis were found to be poor prognostic factors. Hyams grading system is difficult to work with and it was not possible to divide patients into prognostically relevant groups. Presence of necrosis, a diffuse growth pattern and a high proliferation index proved to be equally poor prognostic factors.