Olivier Pradier

Efficacy of Selective Neck Dissection: A Review of 503 Cases of Elective and Therapeutic Treatment of the Neck in Squamous Cell Carcinoma of the Upper Aerodigestive Tract

OBJECTIVE: The purpose of this study was to evaluate the efficacy of selective neck dissection (SND) in elective and therapeutic treatment of the neck. METHODS: A retrospective review was undertaken of 503 previously untreated patients undergoing 711 SNDs as a part of initial therapy for squamous cell carcinoma of the larynx, oral cavity, oropharynx, and hypopharynx from August 1986 to June 1997 at a single institution. Lymph nodes were pathologically negative in 249 and positive in 254 patients. Postoperative radiotherapy was given to 14.5% of the node-negative and 62.2% of the node-positive patients. The median follow-up interval was 41 months. RESULTS: The 3-year regional recurrence rates estimated according to Kaplan-Meier were as follows: pN0, 4.7%; pN1, 4.9%; pN2, 12.1%. A comparison of recurrence rates with respect to the extent of neck disease and postoperative radiotherapy demonstrated a tendency to an improved regional control in irradiated patients with one metastasis and a distinctly improved regional control in patients with multiple metastases or metastases with extracapsular spread. CONCLUSION: The results achieved with SND compare favorably with the results reported for modified radical neck dissection. The application of SND might be extended to more advanced neck disease.

Conformal radiotherapy planning of cervix carcinoma: differences in the delineation of the clinical target volume. A comparison between gynaecologic and radiation oncologists.

PURPOSEnTo assess uncertainties in the definition of the clinical target volume (CTV) for patients scheduled for primary radiotherapy of cervix carcinoma.nnnMETHODS AND MATERIALSnSeven physicians (five radiation oncologists and two gynaecologists) independently contoured the CTVs for three patients. All observers were provided with the same clinical information. CTVs were entered directly in the treatment planning system. Differences were analysed qualitatively and quantitatively.nnnRESULTSnThe qualitative analysis revealed a good agreement by all observers on anatomical structures identified to be at risk for tumour spread. Quantitatively, however, a large interobserver variability was found. The ratio between largest and smallest volumes ranged between 3.6 and 4.9 for all observers (3.6-4.9 for the radiation oncologists, 1.3-2.8 for the gynaecologists). The median three-dimensional difference in gravity centres ranged between 10.9 and 26.3mm for the respective patients. The ratio of common volumes to encompassing volumes ranged between 0.11 and 0.13 for the radiation oncologists, and between 0.30 and 0.57 for the gynaecologists.nnnCONCLUSIONSnAlthough there was a good consistency in outlined anatomical structures, for the radiation therapy of carcinomas of the uterine cervix a large interobserver variability in CTV delineation concerning the magnitude and relative location of volumes was observed. Compared to other factors, e.g. set-up and organ motion, interobserver variability in CTV definition seems to have the highest impact on the geometrical accuracy in the radiotherapy of this tumour entity.

Effect of Pentoxifylline and Tocopherol on Radiation Proctitis/Enteritis

Background and Purpose:Chronic radiation proctitis/enteritis is a relevant complication of pelvic irradiation, which is still mainly treated by supportive measures only. There is some evidence that the combined treatment with pentoxifylline and tocopherol might alter the pathogenesis of radiation-induced fibrosis. In a retrospective analysis the clinical benefit of the treatment with pentoxifylline/tocopherol on radiation-induced proctitis/enteritis was evaluated, compared to supportive care only.Patients and Methods:Of 30 patients with radiation-induced proctitis/enteritis grade I–II according to the RTOG/EORTC toxicity criteria, 21 were treated with pentoxifylline and tocopherol. Depending on physician’s decision nine patients received symptomatic treatment only.Results:With pentoxifylline/tocopherol treatment 15/21 patients (71%) experienced a relief of their symptoms. A reduction from grade I/II to grade 0 toxicity was observed in seven and from grade II to grade I toxicity in eight patients. No improvement was seen in six patients. The median time to improvement with pentoxifylline and tocopherol treatment was 28 weeks. In three of nine patients who were treated supportively only, deterioration of symptoms occurred. Three patients experienced no amelioration, and three patients with grade I toxicity experienced a spontaneous relief of their symptoms (33%).Conclusion:The combination treatment with pentoxifylline and tocopherol seems to have a benefit in patients with grade I–II radiation-induced proctitis/enteritis. The optimal schedule of treatment duration is not yet clear. From the observations made in this study it is assumed the treatment should be given for 6–12 months at least. A prospective phase II study should be undertaken to evaluate optimal treatment duration.Hintergrund und Ziel:Die strahleninduzierte chronische Proktitis/Enteritis ist eine relevante Komplikation nach Beckenbestrahlungen, die hauptsächlich symptomatisch therapiert wird. Die kombinierte Behandlung mit Pentoxifyllin und Tocopherol könnte die Pathogenese der strahleninduzierten Fibrose beeinflussen. In einer retrospektiven Analyse wurde der klinische Nutzen dieser Kombinationstherapie bei strahleninduzierter Proktitis/Enteritis ausgewertet und mit alleiniger symptomatischer Behandlung verglichen.Patienten und Methodik:Von 30 Patienten mit einer strahleninduzierten Proktitis/Enteritis Grad I–II nach den Kriterien der RTOG/EORTC wurden 21 mit Pentoxifyllin und Tocopherol behandelt. In Abhängigkeit von der ärztlichen Entscheidung wurden neun Patienten nur symptomatisch behandelt (Tabelle 1).Ergebnisse:15/21 Patienten (71%) unter Therapie mit Pentoxifyllin und Tocopherol erlebten eine Verbesserung ihrer Symptome (Tabelle 3, Abbildung 1). Eine Reduktion von Grad I/II zu Grad 0 trat bei sieben, von Grad II zu I bei acht Patienten auf. Keine Verbesserung konnte bei sechs Patienten erreicht werden. Die mittlere Zeit bis zur Verbesserung der Symptome unter Therapie mit Pentoxifyllin und Tocopherol betrug 28 Wochen (7 Monate) (Abbildung 3). Drei der neun symptomatisch therapierten Patienten erlitten eine Symptomverschlechterung. Drei Patienten erlebten keine Befundänderung, und drei Patienten mit Grad-I-Toxizität erfuhren eine spontane Verbesserung ihrer Symptome (33%) (Tabelle 4).Schlussfolgerung:Die Kombinationstherapie aus Pentoxifyllin und Tocopherol scheint einen Nutzen bei der strahleninduzierten Proktitis/Enteritis Grad I–II zu haben (Abbildung 2). Die optimale Behandlungsdauer ist nicht bekannt. Nach den Ergebnissen dieser Studie ist anzunehmen, dass die Medikamente mindestens 6–12 Monate gegeben werden sollten. Eine prospektive Phase- II-Studie sollte durchgeführt werden, um die optimale Behandlungsdauer zu evaluieren.

Effects of docetaxel in combination with radiation on human head and neck cancer cells (ZMK-1) and cervical squamous cell carcinoma cells (CaSki ).

The purpose of this study was to determine, as we did for paclitaxel, the cytotoxic and radiosensitizing potential of docetaxel in human head and neck cancer cells (ZMK‐1), and in cervical squamous cell carcinoma cells (CaSki). ZMK‐1 cells were incubated with docetaxel for 3, 9 or 24 hr before irradiation and 24 hr after irradiation. CaSki cells were incubated with docetaxel 24 hr before and after irradiation. For ZMK‐1 cells, the docetaxel concentrations (0.7, 0.7 and 0.35 nM) were determined to obtain approximately equivalent cell survival at the different incubation times (3, 9 and 24 hr, respectively). For CaSki cells, the necessary concentration of docetaxel was 0.07 nM. Radiation doses were given from 0 to 7 Gy. Cell survival was measured by a standard clonogenic assay after a 9‐day incubation. Flow cytometry was used to measure the capacity of docetaxel to accumulate cells in the G2/M phase of the cell cycle. We observed a weak accumulation of cells in the G2/M phase for the ZMK‐1 cells and a pronounced accumulation for CaSki cells. For docetaxel incubation before irradiation, the isoeffect enhancement ratios for ZMK‐1 cells determined at the 37% survival level were 1.18, 2.01, and 2.40 for pre‐incubation at 3, 9 and 24 hr, respectively; for CaSki cells the ratio was 1.44. For a docetaxel incubation of 24 hr after irradiation, the isoeffect enhancement ratios determined at the 37% survival level were 1.54 and 1.17 for the ZMK‐1, and CaSki cells, respectively. A radiosensitizing effect of docetaxel could be demonstrated unambiguously in the two cell lines used. In contrast to our previously published results with paclitaxel, docetaxel seems to be a better radiosensitizer than paclitaxel.

Effect of keratinocyte growth factor on the proliferation, clonogenic capacity and colony size of human epithelial tumour cells in vitro.

Purpose : The effect of recombinant human keratinocyte growth factor (rHuKGF) on the proliferation, clonogenic capacity and colony size of low-passage human epithelial tumour cells was tested in vitro. Materials and methods : Five tumour cell cultures derived from head and neck squamous cell carcinomas, three cultures derived from pleural effusions of carcinomas of different origin and normal human nasal epithelial cells were analysed in passages 2-4. Expression of FGF7 and its receptor (FGFR2) were determined by the RNase protection assay. Cells were incubated with rHuKGF (10-200 ng ml −1) 3 days before or immediately after plating for clonal growth in serum-depleted media. To determine cellular radiosensitivity, single doses of 1-8 Gy X-rays were applied. Colony formation as well as colony size, reflecting the number of cell divisions, was determined after 10-15 days of growth in rHuKGF-treated and control cells. Results : Normal nasal epithelial cells showed a two- to threefold increase in the number of cell divisions due to rHuKGF-treatment. In tumour cell cultures, significant stimulation of proliferation occurred in only one of eight samples. Tumour cells expressed FGF7 mRNA and protein, and low levels of FGFR2 mRNA. The addition of rHuKGF to the medium of the tumour cell cultures influenced neither radiation-induced impairment of proliferation nor clonogenic cell survival. Conclusion : rHuKGF has been shown to ameliorate the radiation tolerance of normal epithelia. The minimum in vitro tumour cell response to rHuKGF compared with normal epithelial cells suggests a potential for selective protection of normal epithelia during radiotherapy. The low FGFR2 expression as well as the FGF7 expression in the tumour cells may contribute to their resistance to rHuKGF treatment.

In vitro response of human dermal fibroblasts to X-irradiation: relationship between radiation-induced clonogenic cell death, chromosome aberrations and markers of proliferative senescence or differentiation.

Purpose : To analyse the relationship between radiation-induced clonogenic cell death, chromosome aberrations and markers of proliferative senescence or differentiation. Materials and methods : Plateau-phase human dermal fibroblasts from 18 donors were irradiated with graded doses of 1-6 Gy 200kV X-rays. Cell survival was determined by a colony-forming assay. Markers of differentiation or senescence were: spontaneous and radiation-induced clonal differentiation, which was determined morphologically and by the cellular potential to proliferate in clonal culture, also single-cell g -galactosidase (g -gal) staining at pH 6.0; and the secretion of transforming growth factor- g (TGF- g 1) into the culture medium. Chromosome aberrations were determined as genomic yields of dicentric chromosomes and the excess acentric fragments, scored in Giemsa-stained metaphases, and as partial yields of reciprocal translocations for chromosomes 4, 7 and 9 using the FISH method. Results : A broad spread was found in the shapes of the survival curves, with SF2 ranging from 0.041 - 0.015 to 0.63 - 0.05. Radiation-induced clonal differentiation as well as the secretion of TGF- g 1 was elevated in radiosensitive samples. With respect to chromosome aberrations, a significant correlation was found between clonogenic survival and radiation-induced excess acentric fragments. Conclusions : In the fibroblast cell system, in vitro radiosensitivity is determined not only by processes directly involved in DNA-damage recognition and repair, but also by intracellular signalling cascades, which will lead to differentiation processes.

Neck Lymph Node Metastases from an Unknown Primary Tumor

Background and Purpose:Up to 10% of all neck lymph node metastases present without a known primary site. The optimal treatment strategy for these patients is still undefined. The purpose of this retrospective analysis is to assess the outcome in patients with neck metastases from an unknown primary tumor (CUP). Furthermore, prognostic factors and treatment modalities are discussed.Patients and Methods:From 1984 to 2003, 28 patients with squamous cell neck metastases from a CUP were treated at the authors’ institution. In 17 patients, neck dissection (twelve radical, five modified radical) was performed. In that case, adjuvant radiotherapy was carried out with a mean of 56.7 Gy. In eleven patients, only biopsies were done. These patients received definitive radiotherapy with a mean of 66.8 Gy. In summary, 25 patients received extended radiotherapy including both sides of the neck and potential mucosal primary sites. Additional chemotherapy was administered to five patients.Results:The duration of follow-up was 4.1–189.5 months (median 45.1 months). After this period of time, ten patients (36%) remained alive. 5-year overall survival was 40.1%, neck control rate 72.7%. No subsequent primary could be detected. Extracapsular extension and surgery had significant influence on prognosis. Grade 3 toxicity (mucositis or skin reactions) was seen in three patients; no hematologic toxicity > grade 2 was observed. 19 patients suffered from grade 2 xerostomia.Conclusion:With radical surgery followed by radiotherapy good survival rates in patients with neck metastases from a CUP can be obtained. Whether limited radiotherapy might be equal to extended irradiation and can reduce side effects, must be shown in ongoing clinical trials.Hintergrund und Ziel:Bei bis zu 10% aller Patienten mit zervikalen Lymphknotenmetastasen wird der Primärtumor nicht gefunden. Die Behandlungskonzepte für diese Patienten sind bisher noch uneinheitlich. Die vorliegende retrospektive Analyse zeigt die Therapiemodalitäten und Behandlungsergebnisse in der Universitätsklinik Göttingen. Außerdem werden Therapieoptionen und prognostische Faktoren diskutiert.Patienten und Methodik:Von 1984 bis 2003 wurden 28 Patienten mit zervikalen Lymphknotenmetastasen eines Plattenepithelkarzinoms mit unbekanntem Primärtumor in der Universitätsklinik Göttingen behandelt. 17 der Patienten wurden zervikal lymphdisseziert (zwölf radikal, fünf modifiziert radikal). Sie erhielten anschließend eine adjuvante Strahlentherapie mit durchschnittlich 56,7 Gy. Elf Patienten wurden biopsiert und mit primärer Radiotherapie behandelt (durchschnittliche Dosis: 66,8 Gy). Die Bestrahlung umfasste bei insgesamt 25 Patienten die zervikalen Lymphabflussgebiete beidseits sowie den gesamten Rachenraum, vier Patienten wurden lediglich ipsilateral zervikal bestrahlt.Ergebnisse:Die Nachbeobachtungszeit betrug median 45,1 Monate (4,1–189,5 Monate). Nach 5 Jahren betrugen das Gesamtüberleben 40,1% und die lokoregionäre Kontrollrate am Hals 72,7%. Ein Primärtumor konnte im Verlauf bei keinem Patienten identifiziert werden. Patienten, die radikal lymphdisseziert wurden, zeigten signifikant bessere Überlebens- sowie lokoregionäre Kontrollraten als Patienten, bei denen eine Biopsie durchgeführt wurde. Die lokoregionäre Kontrolle war bei Lymphknoten mit Kapseldurchbruch signifikant schlechter als ohne Kapseldurchbruch.Schlussfolgerung:Mit radikaler Operation und anschließender adjuvanter Radiotherapie können bei Patienten mit zervikalen Lymphknotenmetastasen eines unbekannten Primärtumors gute Überlebens- und lokoregionäre Kontrollraten erzielt werden. Ob durch eine—weniger toxische—auf das ipsilaterale zervikale Lymphabflussgebiet limitierte Bestrahlung dieselben Ergebnisse wie durch eine ausgedehnte Bestrahlung der gesamten Rachenregion erreicht werden können, muss durch laufende klinische Studien gezeigt werden.

Concurrent low-dose cisplatin and thoracic radiotherapy in patients with inoperable stage III non-small cell lung cancer: a phase II trial with special reference to the hemoglobin level as prognostic parameter

PurposeTo evaluate the efficacy of concurrent radiochemotherapy in patients with stage III non-small cell lung cancer (NSCLC), and to examine the effect of hemoglobin levels on survival of those patients. The negative impact of anemia on survival has been noticed for other cancer sites including the head and neck, and the uterine cervix, but it has been rarely described in NSCLC cancer patients treated with radiotherapy.MethodsFrom April 1995 through March 2002, 56 patients with inoperable stage III non-small lung cancer were treated with radiotherapy consisting of 60xa0Gy (50xa0Gy+10xa0Gy boost) given in 30 fractions of 2xa0Gy daily, 5 days a week, over a period of 6 weeks, and concurrent low-dose daily chemotherapy (CHT) consisting of 6xa0mg/m2 of cisplatin given Mondays–Fridays during weeks 1–2 and 5–6. All patients had stage III disease and ages ranged from 39 to 81 years old (median 63.9 years).ResultsThe 2-year and 3-year survival rates were 34% and 16%, respectively. Patients with a pretreatment hemoglobin level superior or equal to 11.6xa0g/dl had a 2-year survival rate of 52% as compared to 15.5% for patients with a pretreatment hemoglobin level inferior to 11.6xa0g/dl (p=0.0075). Patients with higher KI (>70%) showed better survival rates than those with lower KI. Surprisingly, patients in stage IIIA did not survive significantly longer than those in stage IIIB. Hematological toxicity (grade ≥2) prevailed (25%), followed by esophageal (5.4%) and bronchopulmonary (2%) toxicity. Only three patients experienced acute grade 3 hematological toxicity. Because of acute toxic effects, irradiation was interrupted in 8 patients (14.3%) for 7–13 days (median 7.5 days). Late high-grade (≥3) toxicity was not found. No grade 4 toxicity or treatment-related deaths were observed during this study.ConclusionOur data show that concurrent radiotherapy with daily low dose cisplatin is well tolerated, and shows survival rates comparable to more aggressive treatment regimens. A combination of this chemotherapy with accelerated hyperfractionated radiotherapy might improve the results in the future. Furthermore, we could show that the hemoglobin levels prior to therapy have an influence on the prognosis, where lower levels were associated with worse outcome. Further trials should consider supplementation with erythropoietin.

Does the standardized helmet technique lead to adequate coverage of the cribriform plate? An analysis of current practice with respect to the ICRU 50 report

PURPOSEnTo investigate whether the standardized helmet technique adequately covers the cribriform plate.nnnMETHODS AND MATERIALSnFor 11 patients with acute leukemia or primary intracerebral neoplasms undergoing irradiation with the standardized helmet technique, three-dimensional isodose distributions were evaluated with special respect to the dose to the cribriform plate and the ocular lenses.nnnRESULTSnThe average dose received by 95% of the cribriform plate with the standardized helmet technique was 85% of the prescribed dose. To enclose the cribriform plate by the 95% isodose (according to the ICRU 50 report) with a 10-mm safety margin allowing for deviations during treatment planning and delivery, the eye block had to be moved in the ventrocaudal direction with an average vector length of 13.6 mm. Consequently, the mean dose received by 5% of the lenses rose from 18% to 91% of the prescribed total dose.nnnCONCLUSIONnSufficient lens shielding is usually not compatible with safe irradiation of the frontobasis by the standardized helmet technique.

Sodium butyrate enemas in the treatment of acute radiation-induced proctitis in patients with prostate cancer and the impact on late proctitis. A prospective evaluation.

PurposeTo evaluate prospectively the effect of sodium butyrate enemas on the treatment of acute and the potential influence on late radiation-induced proctitis.Patients and Methods31 patients had been treated with sodium butyrate enemas for radiation-induced acute grade II proctitis which had developed after 40 Gy in median. During irradiation the toxicity was evaluated weekly by the Common Toxicity Criteria (CTC) and subsequently yearly by the RTOG (Radiation Therapy Oncology Group) and LENT-SOMA scale.Results23 of 31 patients (74%) experienced a decrease of CTC grade within 8 days on median. A statistical significant difference between the incidence and the severity of proctitis before start of treatment with sodium butyrate enemas compared to 14 days later and compared to the end of irradiation treatment course, respectively, was found. The median follow-up was 50 months. Twenty patients were recorded as suffering from no late proctitis symptom. Eleven patients suffered from grade I and 2 of these patients from grade II toxicity, too. No correlation was seen between the efficacy of butyrate enemas on acute proctitis and prevention or development of late toxicity, respectively.ConclusionSodium butyrate enemas are effective in the treatment of acute radiation-induced proctitis in patients with prostate cancer but have no impact on the incidence and severity of late proctitis.ZusammenfassungZielDiese prospektive Untersuchung wurde durchgeführt, um den Effekt von Natriumbutyrat-Einläufen in der Therapie der akuten Proktitis sowie den potentiellen Einfluss auf radiogene rektale Spätreaktionen zu evaluieren.Patienten und Methodik31 Patienten wurden mit Natriumbutyrat-Einläufen bei radiogen induzierter akuter Grad-II-Proktitis behandelt, die im Mittel nach 40 Gy aufgetreten war. Während der Radiotherapie wurde die Toxizität wöchentlich anhand der Common Toxicity Criteria (CTC) und anschließend jährlich anhand der RTOG- und LENT-SOMA-Skalen erhoben.Ergebnisse23 von 31 Patienten (74%) erfuhren eine Abnahme des CTC-Grades innerhalb von 8 Tagen im Median. Dadurch war der Unterschied in der Häufigkeit und Schwere der Proktitis vor Therapiebeginn und 14 Tage später bzw. am Ende der Radiotherapie statistisch signifikant. Der mediane Follow-up lag bei 50 Monaten. 20 Patienten entwickelten keine späte Proktitis. 11 Patienten entwickelten eine Grad-I- und 2 von diesen Patienten ebenfalls eine Grad-II-Toxizität. Es konnte keine signifikante Korrelation zwischen der Effektivität der Natriumbutyrat-Einläufe und Prävention bzw. Entwicklung einer späten Toxizität entdeckt werden.SchlussfolgerungNatriumbutyrat-Einläufe sind effektiv in der Behandlung der akuten radiotherapieinduzierten Proktitis bei Patienten mit Prostatakarzinom, haben aber keinen Einfluss auf die Häufigkeit und Schwere der späten Proktitis.