Silke Tribius

Prognostic Factors for Local Control and Survival After Radiotherapy of Metastatic Spinal Cord Compression

PURPOSE To evaluate potential prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression (MSCC). PATIENTS AND METHODS The following potential prognostic factors were investigated retrospectively in 1,852 patients irradiated for MSCC: age, sex, performance status, primary tumor, interval between tumor diagnosis and MSCC (< or = 15 v > 15 months), number of involved vertebrae (one to two v > or = three), other bone metastases, visceral metastases, pretreatment ambulatory status, time of developing motor deficits before radiotherapy (faster, 1 to 14 v slower, > 14 days), and radiation schedule (short-course v long-course radiotherapy). RESULTS On univariate analysis, improved local control of MSCC was associated significantly with favorable histology (breast cancer, prostate cancer, lymphoma/myeloma), no visceral metastases, and long-course radiotherapy. On multivariate analysis, absence of visceral metastases and radiation schedule maintained significance. On univariate analysis, improved survival was associated significantly with female sex, favorable histology, no visceral or other bone metastases, good performance status, being ambulatory before radiotherapy, longer interval between tumor diagnosis and MSCC, and slower development of motor deficits before radiotherapy. Long-course radiotherapy showed a trend. On multivariate analysis, histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MSCC, and time of developing motor deficits maintained significance. CONCLUSION Poorer local control after radiotherapy for MSCC is associated with visceral metastases and short-course radiotherapy. Long-course radiotherapy seems preferable for patients with more favorable prognoses, given that these patients may live long enough to develop MSCC recurrences. Long-term survival after radiotherapy for MSCC may be predicted if several prognostic factors are considered.

HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity

BACKGROUND AND PURPOSE When treated by radiotherapy, patients with squamous cell carcinomas of the head and neck (HNSCC) positive for HPV and p16(INK4a) possess a clearly favorable prognosis as compared to those with HPV-negative HNSCC. The aim of this work was to study whether the better outcomes might be caused by an enhanced cellular radiosensitivity. MATERIALS AND METHODS The radiation response of five HPV/p16(INK4a)-positive and five HPV-negative cell lines was characterized with regard to cellular radiosensitivity by colony formation assay. Furthermore G1- and G2-arrest, apoptosis and residual DNA double-strand breaks (DSB) were analyzed by the colcemid-based G1-efflux assay, propidium iodide staining, the detection of PARP cleavage, the fluorescence-based detection of caspase activity and the immunofluorescence staining of γH2AX and 53BP1 foci. RESULTS On average, the cellular radiosensitivity of the HNSCC cell lines positive for HPV and p16(INK4a) was higher as compared to the sensitivity of a panel of five HPV-negative HNSCC cell lines (SF3=0.2827 vs. 0.4455). The higher sensitivity does not result from increased apoptosis or the execution of a permanent G1-arrest, but is rather associated with both, elevated levels of residual DSBs and extensive G2-arrest. CONCLUSIONS Increased cellular radiosensitivity due to compromised DNA repair capacity is likely to contribute to the improved outcome of patients with HPV/p16(INK4a)-positive tumors when treated by radiotherapy.

Long-term radiation sequelae after breast-conserving therapy in women with early-stage breast cancer: an observational study using the LENT-SOMA scoring system

PURPOSE To evaluate the long-term toxicity after breast-conserving therapy in women with early-stage breast cancer. METHODS AND MATERIALS Late toxicity according to the late effects of normal tissue-subjective, objective, management, and analytic (LENT-SOMA) criteria and cosmetic outcome (graded by physicians) were evaluated in 590 of 2943 women with early-stage breast cancer who were irradiated between 1983 and 1995 using the following fractionation schedules: group A, 1983-1987, 2.5 Gy 4x/wk to 60 Gy; group B, 1988-1993, 2.5 Gy 4x/wk to 55 Gy, group C, 1994-1995, 2.0 Gy 5x/wk to 55 Gy. RESULTS LENT-SOMA Grade 3-4 toxicity was observed as follows: group A (median follow-up 171 months; range 154-222 months), fibrosis 16% (7 of 45), telangiectasia 18% (8 of 45), and atrophy 4% (2 of 45); group B (median follow-up 113 months; range 78-164 months), pain 2% (8 of 345), fibrosis 10% (34 of 345), telangiectasia 10% (33 of 345), arm edema 1% (2 of 345), and atrophy 8% (27 of 345); and group C (median follow-up 75 months, range 51-96 months, n = 200), occurrence of Grade 3-4 late morbidity <or=2%. The cosmetic outcome was very good to acceptable in 78% (35 of 45) of patients in group A, 83% (286 of 345) in group B, and 94% (187 of 200) in group C. CONCLUSION In our population, the long-term side effects after breast-conserving therapy were not rare, but were mainly asymptomatic. The LENT-SOMA breast module is a practical tool to assess radiation-induced long-term toxicity.

Increasing the rate of late toxicity by changing the score? A comparison of RTOG/EORTC and LENT/SOMA scores

PURPOSE The Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue Task Force subjective, objective, management, and analytic (LENT/SOMA) scores were compared in a group of breast cancer patients. The impact of the classification system on grading late effects was evaluated. MATERIALS AND METHODS Telangiectasia, skin pigmentation, and fibrosis were scored according to both LENT/SOMA and RTOG criteria. The results were compared with respect to up- or downgrading and correlated (Spearmans rho). Other side effects were recorded using LENT/SOMA criteria. Interobserver variability was calculated with Cohens kappa. Two hundred fifty-nine subsequent relapse-free patients who underwent breast-conserving therapy between 1981 and 1995 were examined. The median dose of radiotherapy to the breast was 55 Gy. Adjuvant chemotherapy was given to 31 patients and tamoxifen to 52 patients. The median follow-up was 8 years. RTOG skin and s.c. tissue scales and LENT/SOMA breast and pigmentation scales were used. Two doctors examined 45 patients jointly. RESULTS Of all patients, 20% had telangiectasia, 22% pigmentation, 43% fibrosis, 4% breast edema, 77% retraction/atrophy, and 54% pain. In comparison, when LENT/SOMA criteria were used, telangiectasia and pigmentation were upgraded in 34% and 36%, respectively, and telangiectasia was downgraded in 45%. Fibrosis correlated well (Spearmans rho 0.78, p = 0.01). An additional 356 side effects, mainly retraction/atrophy were observed in 226 patients using LENT/SOMA criteria. Interobserver variability was similar for both classification systems and ranged from Cohens kappa 0.3 (retraction) to 0.91 (telangiectasia). CONCLUSIONS LENT/SOMA criteria seem to be the better tool in grading and recording late radiation toxicity compared with the RTOG scale. There was some upgrading with the RTOG score when skin toxicity is evaluated. In contrast, fibrosis scores correlated very well. Adjustments of the LENT/SOMA scoring system should be considered to standardize reporting of late radiation morbidity.

HPV DNA, E6*I-mRNA expression and p16INK4A immunohistochemistry in head and neck cancer – How valid is p16INK4A as surrogate marker?

It has been proposed that p16(INK4A) qualifies as a surrogate marker for viral oncogene activity in head and neck cancer (HNSCC). By analyzing 78 HNSCC we sought to validate the accuracy of p16(INK4A) as a reliable marker of active HPV infections in HNSCC. To this end we determined HPV DNA (HPVD) and E6*I mRNA (HPVR) expression status and correlated these results with p16(INK4A) staining. In tonsillar SCC 12/20 were HPVD+ and 12/12 of these showed active HPV infections whereas in non-tonsillar SCC 10/58 were HPVD+ and 5/10 showed active HPV infections. Thus, we prove about 8% of non-tonsillar SCC to be also correlated with HPV-associated carcinogenesis. Strikingly, 3/14 (21.4%) of tonsillar and non-tonsillar HPVD+/HPVR+ cases did not show p16(INK4A) overexpression and these cases would have been missed when applying initial p16(INK4A) staining only. However, in 13 cases negative for HPV, DNA p16(INK4A) was overexpressed. In conclusion, our data confirm tonsillar SCC to be predominantly but not only associated with active HPV infections. Furthermore, our data show that p16(INK4A) overexpression is not evident in a subgroup of HNSCC with active HPV infection. Definitive HPV data should therefore be utilized in diagnostics and treatment modalities of HPV positive and HPV negative HNSCC patients, resulting in a paradigm shift regarding these obviously different tumor entities.

Intensity-modulated radiotherapy versus conventional and 3D conformal radiotherapy in patients with head and neck cancer: Is there a worthwhile quality of life gain?

BACKGROUND Intensity-modulated radiotherapy (IMRT) is a technique that allows delivery of lower doses of radiation to normal tissue, while maintaining or increasing the tumour dose, compared with two-dimensional radiotherapy (2DRT) or three-dimensional conformal radiotherapy (3DCRT). This review of published data was undertaken to assess whether IMRT is associated with quality of life (QoL) benefits versus 2DRT and 3DCRT. DESIGN English-language literature published between January 2005 and August 2010 was searched for studies comparing IMRT versus 2DRT or 3DCRT in head and neck cancers that included QoL evaluation. Fourteen studies (five prospective and nine retrospective) were identified, two in abstract form only. Only one study was randomised. Studies included patients with nasopharyngeal cancer only, oropharyngeal cancer only and mixed populations. RESULTS The EORTC QLQ-C30 was the most widely used instrument, generally supplemented with the head and neck cancer module H&N35. IMRT was associated with statistically significant improvements in certain QoL domains versus 2DRT and 3DCRT, particularly those relating to xerostomia, including dry mouth, sticky saliva and eating-related domains. Improvements in global QoL were also observed in the IMRT groups in some studies. CONCLUSION Based on the studies reviewed, patients treated with IMRT experience statistically significant improvements in several important QoL domains versus 2DRT and 3DCRT. However, studies included heterogeneous populations, different timepoints for measurements and a variety of instruments for QoL assessment. Accepting the difficulties in execution, IMRT should be compared with 3DCRT in prospective randomised studies in homogeneous patient populations, using appropriate QoL assessments and clinical end points, to establish if IMRT provides enough value for the additional resources involved.

Radiochemotherapy including cisplatin alone versus cisplatin + 5-fluorouracil for locally advanced unresectable stage IV squamous cell carcinoma of the head and neck.

Background and Purpose:The optimal radiochemotherapy regimen for advanced head-and-neck cancer is still debated. This nonrandomized study compares two cisplatin-based radiochemotherapy regimens in 128 patients with locally advanced unresectable stage IV squamous cell carcinoma of the head and neck (SCCHN).Patients and Methods:Concurrent chemotherapy consisted of either two courses cisplatin (20 mg/m2/d1–5 + 29–33; n = 54) or two courses cisplatin (20 mg/m2/d1–5 + 29–33) + 5-fluorouracil (5-FU; 600 mg/m2/d1–5 + 29–33; n = 74).Results:At least one grade 3 toxicity occurred in 25 of 54 patients (46%) receiving cisplatin alone and in 52 of 74 patients (70%) receiving cisplatin + 5-FU. The latter regimen was particularly associated with increased rates of mucositis (p = 0.027) and acute skin toxicity (p = 0.001). Seven of 54 (13%) and 20 of 74 patients (27%) received only one chemotherapy course due to treatment-related acute toxicity. Late toxicity in terms of xerostomia, neck fibrosis, skin toxicity, and lymphedema was not significantly different.The 2-year locoregional control rates were 67% after cisplatin alone and 52% after cisplatin + 5-FU (p = 0.35). The metastases-free survival rates were 79% and 69%, respectively (p = 0.65), and the overall survival rates 70% and 51%, respectively (p = 0.10). On multivariate analysis, outcome was significantly associated with performance status, T-category, N-category, hemoglobin level prior to radiotherapy, and radiotherapy break > 1 week.Conclusion:Two courses of fractionated cisplatin (20 mg/m2/day) alone appear preferable, as this regimen resulted in similar outcome and late toxicity as two courses of cisplatin + 5-FU, but in significantly less acute toxicity.Hintergrund und Ziel:Das optimale Radiochemotherapieregime bei der Behandlung fortgeschrittener Kopf-Hals-Tumoren ist nicht hinreichend geklärt. Diese nichtrandomisierte Studie vergleicht zwei cisplatinbasierte Regimes in einer Serie von 128 Patienten (Tabelle 1) mit lokal fortgeschrittenem (Stadium IV) nichtresektablem Plattenepithelkarzinom der Kopf-Hals-Region (SCCHN).Patienten und Methodik:Die simultan zur Strahlentherapie applizierte Chemotherapie bestand aus zwei Kursen Cisplatin (20 mg/m2/d1–5 + 29–33; n = 54) oder zwei Kursen Cisplatin (20 mg/m2/d1–5 + 29–33) + 5-Fluorouracil (5-FU; 600 mg/m2/ d1–5 + 29–33; n = 74).Ergebnisse:Mindestens eine Grad-3-Toxizitat trat bei 25 von 54 Patienten (46%) unter alleiniger Cisplatingabe und bei 52 von 74 Patienten (70%) unter Cisplatin + 5-FU auf. Das letztgenannte Regime war insbesondere mit hoheren Raten an Mukositis (p = 0,027) und akuter Hauttoxizitat (p = 0,001) assoziiert (Abbildung 1). Sieben von 54 (13%) und 20 von 74 Patienten (27%) erhielten toxizitatsbedingt nur einen Kurs Chemotherapie. Die Spattoxizitat (Xerostomie, Halsfibrose, Hauttoxizitat, Lymphodem) war in beiden Gruppen vergleichbar (Abbildung 2).Die Raten fur die lokoregionale Kontrolle nach 2 Jahren betrugen 67% nach alleiniger Cisplatingabe sowie 52% nach Cisplatin + 5-FU (p = 0,35; Abbildung 3). Die Raten fur das metastasenfreie Uberleben lagen bei 79% und 69% (p = 0,65; Abbildung 4), die Raten für das Gesamtüberleben bei 70% und 51% (p = 0,10; Abbildung 5). In der Multivarianzanalyse waren die Therapieergebnisse signifikant mit dem Allgemeinzustand, der T-Kategorie, der N-Kategorie, dem Hamoglobinwert vor Strahlentherapie und einer Radiotherapiepause > 1 Woche assoziiert (Abbildung 3, Tabelle 2).Schlussfolgerung:Das aus alleiniger fraktionierter Cisplatingabe (20 mg/m2/d) bestehende Regime scheint besser geeignet zu sein als die Kombination Cisplatin + 5-FU. Das erstgenannte Regime führte zu vergleichbaren Therapieergebnissen, war allerdings mit signifikant geringerer Akuttoxizitat assoziiert als die Kombination Cisplatin + 5-FU.

HPV status in patients with head and neck of carcinoma of unknown primary site: HPV, tobacco smoking, and outcome.

OBJECTIVES Infection with human papillomavirus (HPV) is linked to oropharyngeal cancer. This analysis investigated possible associations between HPV status, smoking history and survival outcome in patients with neck metastasis and carcinoma of unknown primary (CUP). MATERIALS AND METHODS Registries at the Universities of Hamburg and Kiel were searched for patients with CUP diagnosed from 2002 to 2011 who had formalin-fixed and paraffin-embedded metastatic lymph node samples available. All patients underwent routine diagnostic procedures to establish the primary site and received radiotherapy (60Gy using conventional fractionation) with or without concurrent cisplatin-based chemotherapy depending on disease extent. Genotyping was performed using polymerase chain reaction; p16([INK4a]) expression was assessed using immunohistochemistry. RESULTS Sixty-three patients were included; 23 (37%) had HPV DNA/p16+ samples and 40 (63%) were negative for either/both markers. A high proportion of patients had a history of tobacco smoking; significantly fewer patients with HPV+/p16+ samples were smokers than those who were negative for either/both markers (61% vs. 90%, respectively; p = 0.0067). There were no statistically significant differences between overall or recurrence-free survival in HPV+/p16+ patients vs. those negative for either/both markers. Overall survival appeared to be superior in patients with <10 pack-years smoking history and HPV+/p16+ disease. CONCLUSIONS This study, the largest to date investigating HPV status in head and neck CUP, identified HPV and p16 overexpression in over one-third of patients. Tobacco smoking history appeared to affect survival in HPV+/p16+ patients. Smoking status should be considered as a prognostic factor in patients with CUP, along with HPV DNA status.

Impact of HPV status on treatment of squamous cell cancer of the oropharynx: What we know and what we need to know

Studies report an increasing incidence of oropharyngeal cancers linked to infection by human papillomavirus (HPV). We reviewed trials assessing outcomes by HPV DNA status in patients with locally advanced oropharyngeal cancer. Seven of the eight studies identified showed significantly better survival in patients with HPV DNA-positive tumors vs. HPV DNA-negative tumors. The review also describes what needs to be defined regarding optimal treatments. Future trials should incorporate HPV DNA status as a risk determinant and explore treatments for high-risk patients needing therapy intensification, and low- and intermediate-risk patients needing treatment de-intensification to improve tolerability, without compromising 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 (≥ 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.Hintergrund und Ziel:Die konventionelle Strahlentherapie ist in vielen Institutionen weltweit noch die Standardtechnik bei Kopf-Hals-Tumoren. Andere Institutionen haben diese Technik durch die 3D-konformale Strahlentherapie ersetzt. Vergleichende Studien fehlen. Diese Studie vergleicht beide Techniken hinsichtlich Gesamtüberleben (OS), metastasenfreien Überlebens (MFS), lokoregionaler Kontrolle (LC) und Toxizität bei Patienten mit einem Plattenepithelkarzinom der Kopf-Hals-Region im Stadium III/IV.Patienten und Methodik:Daten von 345 Patienten wurden retrospektiv analysiert (Tabelle 1). Die Patienten erhielten eine konventionelle (Gruppe A, n = 166) oder 3D-konformale (Gruppe B, n = 179) Strahlentherapie (Abbildungen 1 und 2). Elf weitere potentielle Prognosefaktoren wurden untersucht: Alter, Geschlecht, Allgemeinzustand, Tumorsitz, Grading, T-Stadium, N-Stadium, AJCC-Stadium, Chemotherapie, Operation, Hämoglobin vor Strahlentherapie (Tabellen 2 bis 4).Ergebnisse:Die 3-Jahres-Überlebensraten waren 62% in Gruppe A und 57% in Gruppe B (p = 0,15, Abbildung 3). Die MFS-Raten waren 67% und 76% (p = 0,46, Abbildung 4), die LC-Raten 65% und 68% (p = 0,71, Abbildung 5). In der Multivarianzanalyse waren Geschlecht (p = 0,005), Allgemeinzustand (p < 0,001), T-Kategorie (p = 0,002) und N-Kategorie (p < 0,001) mit dem OS assoziiert. Allgemeinzustand (p < 0,001) und N-Stadium (p < 0,001) waren mit dem MFS assoziiert, Geschlecht (p = 0,021), T-Stadium (p < 0,001) und Hämoglobin vor Strahlentherapie (≥ 12 g/dl besser als < 12 g/dl, p = 0,004) mit der LC. Xerostomie Grad 2–3 war seltener nach 3D-konformaler Strahlentherapie (43% vs. 58%, p = 0,06). Ansonsten waren Akut- und Spättoxizität in beiden Gruppen ähnlich (Abbildungen 6 und 7).Schlussfolgerung:Beide Bestrahlungstechniken führten zu ähnlichen Behandlungsergebnissen. Da die Xerostomie nach 3Dkonformaler Strahlentherapie geringer ausgeprägt war, scheinen Patienten, bei denen eine Parotis geschont werden kann, von dieser Technik zu profitieren. Die Behandlungsergebnisse wurden durch das Geschlecht, den Allgemeinzustand, das Tumorstadium und den prä-strahlentherapeutischen Hämoglobinwert beeinflusst.