[Hypersalivation - Update of the S2k guideline (AWMF) in short form]. / Hypersalivation ­ Aktualisierung der S2k-Leitlinie (AWMF) in gekürzter Darstellung.

Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This update presents recent changes and innovation in the treatment of hypersalivation.Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, saliva aspiration, and oro-motor deficiencies. Clinical screening tools and diagnostics such as fiberoptic endoscopic evaluation of swallowing generate important data on therapy selection and control. Many cases profit from swallowing therapy programmes in order to activate compensation mechanisms as long compliances is given. In children with hypotonic oral muscles, oral stimulation plates can induce a relevant symptom release because of the improved lip closure. The pharmacologic treatment improved for pediatric cases as glycopyrrolate fluid solution (Sialanar®) is now indicated for hypersalivation within the E. U. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long lasting saliva reduction. Here, a phase III trial is completed for Incobotulinum toxin A and, in the U. S., is indicated for the treatment of adult patients with chronic hypersalivation. Surgical treatment should be reserved for isolated cases. External radiation is judged as a safe and effective therapy when using modern 3 D techniques to minimize tissue damage. Therapy effects and symptom severity has to be followed, especially in cases with underlying neurodegenerative disease.

Hypersalivation: update of the German S2k guideline (AWMF) in short form.

Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This update presents recent changes and innovation in the treatment of hypersalivation. Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, saliva aspiration, and oro-motor deficiencies. Clinical screening tools and diagnostics such as fiberoptic endoscopic evaluation of swallowing generate important data on therapy selection and control. Many cases profit from swallowing therapy programmes to activate compensation mechanisms as long compliances are given. In children with hypotonic oral muscles, oral stimulation plates can induce a relevant symptom release because of the improved lip closure. The pharmacologic treatment improved for pediatric cases as glycopyrrolate fluid solution (Sialanar®) is now indicated for hypersalivation within the EU. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long-lasting saliva reduction. Here, a phase III trial is completed for incobotulinum toxin A and, in the US, is indicated for the treatment of adult patients with chronic hypersalivation. Surgical treatment should be reserved for isolated cases. External radiation is judged as a safe and effective therapy when using modern 3D techniques to minimize tissue damage. Therapy effects and symptom severity have to be followed, especially in cases with underlying neurodegenerative disease.

The prognostic value of tumor necrosis in patients undergoing stereotactic radiosurgery of brain metastases.

BACKGROUND: This retrospective study investigated the outcome of patients with brain metastases after radiosurgery with special emphasis on prognostic impact of visible intratumoral necrosis on survival and local control. METHODS: From 1998 through 2008, 149 patients with brain metastases from solid tumors were treated with stereotactic radiotherapy at Luebeck University. Median age was 58.4 years with 11%, 78%, 10% in recursive partitioning analysis (RPA) classes I, II, III, respectively. 70% had 1 metastasis, 29% 2-3 metastases, 2 patients more than 3 metastases, 71% active extracranial disease. Median volume of metastatic lesions was 4.7 cm3, median radiosurgery dose 22 Gy (single fraction). 71% of patients received additional whole-brain irradiation (WBI). All patients were analyzed regarding survival, local, distant failure and prognostic factors, side effects and changes in neurologic symptoms after radiotherapy. The type of contrast-enhancement in MR imaging was also analyzed; metastatic lesions were classified as containing necrosis if they appeared as ring-enhancing with central areas of no or minimal contrast enhancement. RESULTS: Median survival was 7.0 months with 1-year and 5-year survival rates of 33% and 0.4%, respectively. Tumor necrosis (ring-enhancement) was visible on pretreatment MRI scans in 56% of all lesions and lesions with necrosis were larger than non-necrotic lesions (6.7 cm3 vs. 3.2 cm3, p = 0.01). Patients with tumor necrosis had a median survival of 5.4 months, patients without tumor necrosis 7.2 months. Local control rate in the irradiated volume was 70%, median survival without local failure 17.8 months. Control in the brain outside the irradiated volume was 60%, median survival without distant failure 14.0 months. Significant prognostic factors for overall survival were KPS (p = 0.001), presence of tumor necrosis on pretreatment MRI (p = 0.001) with RPA-class and WBI reaching marginal significance (each p = 0.05). Prognostic impact of tumor necrosis remained significant if only smaller tumors with a volume below 3.5 cm3 (p = 0.03). Side effects were rare, only one patient suffered from serious acute side effects. CONCLUSIONS: Results of this retrospective study support that stereotactic radiotherapy is an effective treatment option for patients with metastatic brain lesions. The prognostic impact of visible tumor necrosis (ring-enhancement) on pretreatment MRI scans should be further investigated.

Single brain metastasis: resection followed by whole-brain irradiation and a boost to the metastatic site compared to whole-brain irradiation plus radiosurgery.

OBJECTIVE: The most appropriate treatment for a single brain metastasis is still controversial. This matched-pair analysis compared whole-brain irradiation plus radiosurgery (WBI+RS) to neurosurgical resection followed by whole-brain irradiation and a boost to the metastatic site (NR+WBI+B). METHODS: The data of 46 patients treated with WBI+RS were matched 1:1 to 46 patients treated with NR+WBI+B with respect to age, gender, Karnofsky performance score (KPS), tumor type, extracerebral metastases, and interval from first diagnosis of cancer to treatment of the metastasis, RPA class, and GPA score. Both groups were compared for local control of the treated metastasis, intracerebral control, and survival. RESULTS: The 1-year local control rates were 85% after WBI+RS and 78% after NR+WBI+B (p=0.35). The 1-year intracerebral control rates were 74% and 68% (p=0.33), respectively. The 1-year survival rates were 64% and 58% (p=0.70), respectively. A multivariate analysis was not performed for local and intracerebral control, because no factor achieved significance on univariate analyses for these endpoints. Improved survival was associated with KPS>70 (p=0.032), absence of extracerebral metastases (p=0.003), RPA-class 1 (p=0.014), and GPA score of 3.0-4.0 (p=0.010). CONCLUSION: Treatment outcomes were not significantly different after WBI+RS or NR+WBI+B. Because WBI+RS is less invasive, it may be preferable for many patients with a single brain metastasis.

Comparison of radiochemotherapy alone to surgery plus radio(chemo)therapy for non-metastatic stage III/IV squamous cell carcinoma of the head and neck: A matched-pair analysis.

BACKGROUND AND PURPOSE: The standard treatment for non-metastatic stage III/IV squamous cell carcinoma of the head and neck varies worldwide. This study compared the outcomes of radiochemotherapy alone to surgery followed by radio(chemo)therapy (radiotherapy plus/minus concurrent chemotherapy). PATIENTS AND METHODS: Data from 148 patients treated with radiochemotherapy alone were matched to 148 patients treated with surgery plus radio(chemo)therapy. Groups were matched 1:1 for nine potential prognostic factors including age, gender, performance status, tumor site, histologic grade, T category, N category, AJCC stage, and hemoglobin level before radiotherapy, and compared for locoregional control, metastases-free survival, and overall survival. RESULTS: Locoregional control rates at 1, 2, and 3 years were 81%, 73%, and 67% after surgery plus radio(chemo)therapy and 81%, 74%, and 65% after radiochemotherapy alone (p = 0.89). Metastases-free survival rates were 86%, 80%, and 75% after surgery plus radio(chemotherapy) versus 87%, 80%, and 72% after radiochemotherapy alone (p = 0.57). Overall survival rates were 80%, 64%, and 63% after surgery plus radio(chemo)therapy versus 83%, 68%, and 60% after radiochemotherapy alone (p = 0.96). On multivariate analyses, T category (p < 0.001), N category (p = 0.004), and hemoglobin level prior to radiotherapy (p < 0.001) were associated with locoregional control. Histologic grade (p = 0.045), T category (p < 0.001), N category (p = 0.003), and hemoglobin level prior to radiotherapy (p < 0.001) were associated with metastases-free survival. Histologic grade (p = 0.030), ECOG performance status (p = 0.033), T category (p = 0.007), N category (p = 0.024) and hemoglobin level before radiotherapy (p < 0.001) were associated with overall survival. CONCLUSION: Outcomes of radiochemotherapy alone appeared similar to those of surgery plus radio(chemo)therapy. Randomized trials comparing both treatments for different tumor sites are warranted.

Dose escalation for metastatic spinal cord compression in patients with relatively radioresistant tumors.

PURPOSE: Radiotherapy alone is the most common treatment for metastatic spinal cord compression (MSCC) from relatively radioresistant tumors such as renal cell carcinoma, colorectal cancer, and malignant melanoma. However, the results of the "standard" regimen 30 Gy/10 fractions need to be improved with respect to functional outcome. This study investigated whether a dose escalation beyond 30 Gy can improve treatment outcomes. METHODS AND MATERIALS: A total of 91 patients receiving 30 Gy/10 fractions were retrospectively compared to 115 patients receiving higher doses (37.5 Gy/15 fractions, 40 Gy/20 fractions) for motor function and local control of MSCC. Ten further potential prognostic factors were evaluated: age, gender, tumor type, performance status, number of involved vertebrae, visceral or other bone metastases, interval from tumor diagnosis to radiotherapy, pretreatment ambulatory status, and time developing motor deficits before radiotherapy. RESULTS: Motor function improved in 18% of patients after 30 Gy and in 22% after higher doses (p = 0.81). On multivariate analysis, functional outcome was associated with visceral metastases (p = 0.030), interval from tumor diagnosis to radiotherapy (p = 0.010), and time developing motor deficits (p < 0.001). The 1-year local control rates were 76% after 30 Gy and 80% after higher doses, respectively (p = 0.64). On multivariate analysis, local control was significantly associated with visceral metastases (p = 0.029) and number of involved vertebrae (p = 0.043). CONCLUSIONS: Given the limitations of a retrospective study, escalation of the radiation dose beyond 30 Gy/10 fractions did not significantly improve motor function and local control of MSCC in patients with relatively radioresistant tumors.

Comparison of four cisplatin-based radiochemotherapy regimens for nonmetastatic stage III/IV squamous cell carcinoma of the head and neck.

PURPOSE: To compare the outcomes of four cisplatin-based radiochemotherapy regimens in 311 patients with Stage III/IV squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Concurrent chemotherapy consisted of three courses of cisplatin 100 mg/m(2) on Day 1 (Group A, n = 74), two courses of cisplatin 20 mg/m(2) on Days 1-5 plus 5-fluorouracil 1,000 mg/m(2) on Days 1-5 (Group B, n = 49), two courses of cisplatin 20 mg/m(2) on Days 1-5 plus 5-fluorouracil 600 mg/m(2) on Days 1-5 (Group C, n = 102), or two courses of cisplatin 20 mg/m(2) on Days 1-5 (Group D, n = 86). The groups were retrospectively compared for toxicity and outcomes, and 11 additional factors were evaluated for outcomes. RESULTS: No significant difference was observed among the groups regarding radiation-related acute oral mucositis and radiation-related late toxicities. Acute Grade 3 skin toxicity was significantly more frequent in Group B than in the patients of the other three groups (p = .013). The chemotherapy-related Grade 3 nausea/vomiting rate was 24% for Group A, 8% for Group B, 9% for Group C, and 6% for Group D (p = .003). The corresponding Grade 3 nephrotoxicity rates were 8%, 1%, 2%, and 1% (p = .019). The corresponding Grade 3-4 hematologic toxicity rates were 35%, 41%, 19%, and 21% (p = .027). Chemotherapy could be completed in 50%, 59%, 74%, and 83% of the Group A, B, C, and D patients, respectively (p = .002). Toxicity-related radiotherapy breaks occurred in 39%, 43%, 21%, and 15% of Groups A, B, C, and D, respectively (p = .005). The 3-year locoregional control rate was 67%, 72%, 60%, and 59% for Groups A, B, C, and D, respectively (p = .48). The corresponding 3-year metastasis-free survival rates were 67%, 74%, 63%, and 79% (p = .31), and the corresponding 3-year survival rates were 60%, 63%, 50%, and 71% (p = .056). On multivariate analysis, Karnofsky performance status, histologic grade, T/N category, preradiotherapy hemoglobin level, completion of chemotherapy, and radiotherapy breaks were associated with the outcome. CONCLUSION: The four compared radiochemotherapy regimens were not significantly different regarding treatment outcomes. Two courses of cisplatin 20 mg/m(2) on Days 1-5 were better tolerated than the other three regimens.

Prognostic factors for outcomes after whole-brain irradiation of brain metastases from relatively radioresistant tumors: a retrospective analysis.

BACKGROUND: This study investigated potential prognostic factors in patients treated with whole-brain irradiation (WBI) alone for brain metastases from relatively radioresistant tumors such as malignant melanoma, renal cell carcinoma, and colorectal cancer. Additionally, a potential benefit from escalating the radiation dose was investigated. METHODS: Data from 220 patients were retrospectively analyzed for overall survival and local control. Nine potential prognostic factors were evaluated: tumor type, WBI schedule, age, gender, Karnofsky performance score, number of brain metastases, extracerebral metastases, interval from diagnosis of cancer to WBI, and recursive partitioning analysis (RPA) class. RESULTS: Survival rates at 6 and 12 months were 32% and 19%, respectively. In the multivariate analysis, WBI doses >30 Gy (p = 0.038), KPS ≥70 (p < 0.001), only 1-3 brain metastases (p = 0.007), no extracerebral metastases (p < 0.001), and RPA class 1 (p < 0.001) were associated with improved survival. Local control rates at 6 and 12 months were 37% and 15%, respectively. In the multivariate analyses, KPS ≥70 (p < 0.001), only 1-3 brain metastases (p < 0.001), and RPA class 1 (p < 0.001) were associated with improved local control. In RPA class 3 patients, survival rates at 6 months were 10% (35 of 39 patients) after 10 × 3 Gy and 9% (2 of 23 patients) after greater doses, respectively (p = 0.98). CONCLUSIONS: Improved outcomes were associated with WBI doses >30 Gy, better performance status, fewer brain metastases, lack of extracerebral metastases, and lower RPA class. Patients receiving WBI alone appear to benefit from WBI doses >30 Gy. However, such a benefit is limited to RPA class 1 or 2 patients.

Acute toxicity of three versus two courses of cisplatin for radiochemotherapy of locally advanced squamous cell carcinoma of the head and neck (SCCHN): a matched pair analysis.

This matched pair analysis compared the toxicity of two cisplatin-based radiochemotherapy regimens in patients with locally advanced (stages III or IV) squamous cell carcinoma of the head and neck (SCCHN). Two courses of fractionated cisplatin (20mg/m(2)/d1-5) given concurrently with radiotherapy are better tolerated than other common cisplatin-based regimens. However, in several countries, three courses of unfractionated cisplatin (100mg/m(2)/d1) is standard therapy. Three courses of fractionated cisplatin (20mg/m(2)/d1-5) is another option. In this prospective study, 10 consecutive patients with stage III/IV SCCHN received three courses of fractionated cisplatin (group A). These patients were matched (1:3) to 30 patients who received two courses of fractionated cisplatin (group B). The patients were matched for age, gender, performance status, tumor site, T-category, N-category, tumor stage, and surgery. At least seven factors should match between the matched patients. Because of severe acute toxicity, the planned chemotherapy could not be completed in 90% of group A and 13% of group B patients, respectively (p=0.001). At least one grade >or= 3 toxicity occurred in 90% of group A and 20% of group B patients, respectively (p=0.005). Two courses of fractionated cisplatin appeared much better tolerated than three courses of fractionated cisplatin.

Radiotherapy for oligometastatic disease in patients with spinal cord compression (MSCC) from relatively radioresistant tumors.

BACKGROUND: Radiotherapy alone is the most common treatment for metastatic spinal cord compression (MSCC). Patients with relatively radioresistant tumors and oligometastatic disease may benefit from more intensive therapies (surgery, high-precision radiotherapy). If such therapies are not available, one can speculate whether patients benefit from dose escalation beyond the standard regimen 30 Gy in ten fractions. PATIENTS AND METHODS: Of 206 patients with MSCC from relatively radioresistant tumors (renal cell carcinoma, colorectal cancer, malignant melanoma), 51 had oligometastatic disease (no visceral or other bone metastases, involvement of only one to three vertebrae). In this subset, 21 patients receiving 30 Gy in ten fractions were retrospectively compared to 30 patients receiving higher doses. Seven further potential prognostic factors were investigated: age, gender, tumor type, performance status, interval from tumor diagnosis to radiotherapy of MSCC, pretreatment ambulatory status, and time developing motor deficits before radiotherapy. RESULTS: Motor function improved in 52% of patients after 30 Gy and 40% after higher doses (p = 0.44). On multivariate analysis, functional outcome was associated with interval from tumor diagnosis to radiotherapy (p = 0.020). 1-year local control rates were 84% after 30 Gy and 82% after higher doses (p = 0.75). No factor was associated with local control. 1-year survival rates were 76% after 30 Gy and 63% after higher doses (p = 0.52). On multivariate analysis, survival was associated with performance status (p = 0.022) and interval from tumor diagnosis to radiotherapy (p = 0.039), and almost with pretreatment ambulatory status (p = 0.069). CONCLUSION: Dose escalation beyond 30 Gy in ten fractions did not improve motor function, local control, and survival in MSCC patients with oligometastatic disease from relatively radioresistant tumors.

Hypofractionated whole-brain radiotherapy for multiple brain metastases from transitional cell carcinoma of the bladder.

PURPOSE: Brain metastases in bladder cancer patients are extremely rare. Most patients with multiple lesions receive longer-course whole-brain radiotherapy (WBRT) with 10 × 3 Gy/2 weeks or 20 × 2 Gy/4 weeks. Because its radiosensitivity is relatively low, metastases from bladder cancer may be treated better with hypofractionated radiotherapy. This study compared short-course hypofractionated WBRT (5 × 4 Gy/1 week) to longer-course WBRT. METHODS AND MATERIALS: Data for 33 patients receiving WBRT alone for multiple brain metastases from transitional cell bladder carcinoma were retrospectively analyzed. Short-course WBRT with 5 × 4 Gy (n = 12 patients) was compared to longer-course WBRT with 10 × 3 Gy/20 × 2 Gy (n = 21 patients) for overall survival (OS) and local (intracerebral) control (LC). Five additional potential prognostic factors were investigated: age, gender, Karnofsky performance score (KPS), number of brain metastases, and extracranial metastases. The Bonferroni correction for multiple tests was used to adjust the p values derived from the multivariate analysis. p values of <0.025 were considered significant. RESULTS: At 6 months, OS was 42% after 5 × 4 Gy and 24% after 10 × 3/20 × 2 Gy (p = 0.31). On univariate analysis, improved OS was associated with less than four brain metastases (p = 0.021) and almost associated with a lack of extracranial metastases (p = 0.057). On multivariate analysis, both factors were not significant. At 6 months, LC was 83% after 5 × 4 Gy and 27% after 10 × 3/20 × 2 Gy (p = 0.035). Improved LC was almost associated with a KPS of ≥70 (p = 0.051). On multivariate analysis, WBRT regimen was almost significant (p = 0.036). KPS showed a trend (p = 0.07). CONCLUSIONS: Short-course WBRT with 5 × 4 Gy should be seriously considered for most patients with multiple brain metastases from bladder cancer, as it resulted in improved LC.

Short-course whole-brain radiotherapy (WBRT) for brain metastases due to small-cell lung cancer (SCLC).

OBJECTIVE: Many patients with brain metastases due to SCLC have a poor survival prognosis. The most common treatment is whole-brain radiotherapy (WBRT). This retrospective study compares short-course WBRT with 5x4Gy in 1 week to standard WBRT with 10x3Gy in 2 weeks. METHODS: Forty-four SCLC patients receiving WBRT with 5x4Gy were compared to 102 patients receiving 10x3Gy for survival (OS) and local (intracerebral) control (LC). Seven further potential prognostic factors were investigated: age, gender, Karnofsky Performance Score (KPS), number of brain metastases, extracerebral metastases, interval from tumor diagnosis to WBRT, RPA (Recursive Partitioning Analysis) class. RESULTS: After 5x4Gy, 12-month OS was 15%, versus 22% after 10x3Gy (p=0.69). On multivariate analysis, improved OS was associated with age or=70 (p<0.001), <4 brain metastases (p=0.011), and RPA class 1 (p<0.001). 12-month LC was 34% after 5x4Gy versus 25% after 10x3Gy (p=0.32). On multivariate analysis, improved LC was associated with KPS >or=70 (p<0.001), <4 brain metastases (p=0.027), and RPA class 1 (p<0.001). CONCLUSION: In patients with brain metastases due to SCLC, short-course WBRT with 5x4Gy provided similar outcomes as 10x3Gy and appears preferable, particularly for patients with poor estimated survival.

Evaluation of prognostic factors and two radiation techniques in patients treated with surgery followed by radio(chemo)therapy or definitive radio(chemo)therapy for locally advanced head-and-neck cancer.

BACKGROUND AND PURPOSE: Conventional radiotherapy (RT) still is the standard technique for head-and-neck cancer in many centers worldwide, whereas other centers replaced this technique by 3-D conformal RT, which is associated with more appropriate dose distributions. Comparative studies regarding outcome and toxicity are lacking. This study compared both techniques for overall survival (OS), metastases-free survival (MFS), loco-regional control (LC), and toxicity in stage III/IV head-and-neck cancer. PATIENTS AND METHODS: Data of 345 patients irradiated for stage III/IV squamous cell head-and-neck cancer were retrospectively analyzed. Patients received conventional RT (group A, n = 166) or 3-D conformal RT (group B, n = 179). Both techniques were compared for outcomes and toxicity. Eleven further potential prognostic factors were investigated: age, gender, performance status, tumor site, grading, T-stage, N-stage, AJCC-stage, chemotherapy, surgery, pre-RT hemoglobin. RESULTS: 3-year-OS was 62% in group A and 57% in group B (p = 0.15). 3-year-MFS was 67% and 76% (p = 0.46), 3-year-LC was 65% and 68%, respectively (p = 0.71). On multivariate analysis, gender (p = 0.005), performance status (p < 0.001), T-stage (p = 0.002), and N-stage (p < 0.001) were associated with OS. MFS was influenced by performance status (p < 0.001) and N-stage (p < 0.001), LC by gender (p = 0.021), T-stage (p < 0.001), and pre-RT hemoglobin level (>or= 12 better than < 12 g/dl, p = 0.004). Grade 2-3 xerostomia was less frequent with 3-D conformal RT (43% vs. 58%, p = 0.06). Otherwise, toxicities were similar. CONCLUSION: Both RT techniques resulted in similar treatment outcomes. Because xerostomia was less with 3-D conformal RT, this technique appeared beneficial for patients, in whom one parotid gland can be spared. Outcome was associated with gender, performance status, tumor stage, and pre-RT hemoglobin.