Karin Muller

Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study

This study was performed to assess the efficacy and safety of preoperative chemoradiation consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable (T2-3N0-1M0) oesophageal cancer. Treatment consisted of paclitaxel 50 mg m−2 and carboplatin AUC=2 on days 1, 8, 15, 22 and 29 and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by oesophagectomy. All 54 entered patients completed the chemoradiation without delay or dose-reduction. Grade 3–4 toxicities were: neutropaenia 15%, thrombocytopaenia 2%, and oesophagitis 7.5%. After completion of the chemoradiotherapy 63% had a major endoscopical response. Fifty-two patients (96%) underwent a resection. The postoperative mortality rate was 7.7%. All patients had an R0-resection. The pathological complete response rate was 25%, and an additional 36.5% had less than 10% vital residual tumour cells. At a median follow-up of 23.2 months, the median survival time has not yet been reached. The probability of disease-free survival after 30 months was 60%. In conclusion, weekly neoadjuvant paclitaxel and carboplatin with concurrent radiotherapy is a very tolerable regimen and can be given on an outpatient basis. It achieves considerable down staging and a subsequent 100% radical resection rate in this series. A phase III trial with this regimen is now ongoing.

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS)

BackgroundA surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial.Methods/designThe CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up.DiscussionThis study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen.Trial registrationISRCTN80832026

Rotterdam and Brussels CT-based neck nodal delineation compared with the surgical levels as defined by the American Academy of Otolaryngology–Head and Neck Surgery

PURPOSE/OBJECTIVE Rotterdam and Brussels have independently published guidelines for the definition and delineation of CT-based neck nodal Levels I-VI. This paper first reports on the adequacy of contouring of the Rotterdam delineation protocol. Rotterdam and Brussels differed slightly in translating the original surgical level definitions as proposed by the 2002 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) to CT guidelines. To adapt to the surgical level definitions to come to a unifying concept, adjustments of both CT-based classifications are proposed. METHODS AND MATERIALS The clinical neck nodal target volumes of patients irradiated in Rotterdam by three-dimensional conformal radiotherapy (3D-CRT) between December 1998 and March 2001 were reviewed. Thirty-four patients with N0 and 27 patients with N+ disease with primary tumors located in the oral cavity (n = 1) oropharynx (n = 24), hypopharynx (n = 7), and larynx (n = 29) were evaluated. Seven patients underwent unilateral (3 N0 patients, 4 N+ patients) and 54 underwent bilateral (31 N0 patients, 23 N+ patients) irradiation of the neck. In 11 N+ patients, 3D-CRT of the neck was followed by unilateral neck dissection. The dose to the primary and nonresected N+ necks was 70 Gy and to the N0 neck was 46 Gy. Neck levels were analyzed for adequacy of contouring, dose distribution, and patterns of relapse. The mean dose and the percentage of the volume receiving a minimum of 95% (V95) or >107% (V107) of the prescribed dose was computed. RESULTS In 4 patients treated with bilateral 3D-CRT, contouring was not in concordance with the guidelines of the protocol. The V95 and V107 in the 81 adequately contoured N0 necks (63 irradiated N0 necks from 33 N0 patients, 18 irradiated N0 necks from 24 N+ patients) was 95.6% and 6.3%, respectively. For the 26 N+ necks (15 N+ necks from 13 N+ RT-only patients, 11 N+ necks from 11 preoperatively irradiated patients), the V95 and V107 was 94.6% and 6.7%, respectively. With a median follow-up of 29 months, in 4 (8.6%) of 46 patients treated by 3D-CRT only, regional relapse was found. An actuarial regional and locoregional relapse-free survival and disease-free survival rate at 3 years of 90%, 78%, and 68%, respectively, was observed. All regional relapses were observed in the N0 necks of patients with supraglottic laryngeal carcinoma. Taking the surgical 2002 AAO-HNS classification as a reference, adjustments are proposed for the Rotterdam and Brussels delineation protocols to arrive at a unified CT-based neck nodal classification. CONCLUSION Adequate dose coverage for the Rotterdam CT-based contours of the neck nodal levels was found. In the RT-only patients, only four failures were observed: one regional and three locoregional relapses. As a next step in optimizing the current Rotterdam and Brussels CT-based delineation protocols, adaptations are proposed to resolve the discrepancies compared with the 2002 AAO-HNS surgical classification.

Quality of Life During Neoadjuvant Treatment and After Surgery for Resectable Esophageal Carcinoma

PURPOSE Because of the trade-off between the potentially negative quality-of-life (QoL) effects and uncertain favorable survival effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable esophageal cancer, we assessed heath-related QoL (HRQoL) for up to 1 year postoperatively in these patients treated with preoperative CRT with a non-platinum-based outpatient regimen followed by esophagectomy. METHODS AND MATERIALS Patients undergoing neoadjuvant paclitaxel and carboplatin therapy concurrent with radiotherapy followed by surgery completed standardized HRQoL questionnaires before and after CRT and at regular times up to 1 year postoperatively. We analyzed differences in generic Qol core questionnaire [QLQ-C30] and condition-specific (esophageal site-specific [OES-18]) HRQoL scores over time by using a linear mixed-effects model. RESULTS Mean scores of most HRQoL scales deteriorated significantly during neoadjuvant CRT. The largest deterioration was observed for physical and role-functioning scales. All except two symptom scores worsened significantly. Postoperatively, most mean HRQoL scores improved until recovery to baseline level. Speed of improvement varied. Average taste score returned to baseline 3 months postoperatively, whereas it took 1 year for the average role-functioning score to restore. The emotional-functioning score showed a different pattern; it was worst at baseline and increased over time during CRT and postoperatively. Dysphagia and pain scores worsened considerably during CRT, restored to baseline 3 months postoperatively, and were even significantly better 1 year postoperatively. CONCLUSIONS Preoperative CRT with paclitaxel and carboplatin for patients with resectable esophageal cancer had a considerable temporary negative effect on most aspects of HRQoL. Nonetheless, all HRQoL scores were restored or even improved 1 year postoperatively.

Report of a study on IMRT planning strategies for ethmoid sinus cancer

Aim: This communication reviews the planning strategies and dose statistics of nine IMRT plans generated for a complex head and neck case. Patient and Method: An ethmoid sinus cancer case was sent as an IMRT planning task to all participants of the ESTRO course on “IMRT and Other Conformal Techniques in Practice”, held in Amsterdam in June 2001. Results: Nine IMRT plans were generated for the case, the majority of the plans generated with commercial planning systems. The number of beam incidences ranged between four and eleven, while five of the nine beam setups were coplanar. The planning target volume dose homogeneity was inversely correlated with the degree of sparing of the surrounding organs at risk. Conclusion: IMRT strategies for complex head and neck cases, such as ethmoid sinus cancer, can be strikingly different in various aspects, such as beam setup, total number of segments, PTV dose coverage and dose statistics for organs at risks.Ziel: Diese Kurzmitteilung beschreibt und vergleicht die Planungsstrategien und Dosisstatistiken von neun IMRT-Plänen für einen Nasennebenhöhlentumor. Patient und Methode: Die Planung einer intensitätsmodulierten Strahlenbehandlung (IMRT) für einen Nasennebenhöhlentumor im Siebbein wurde den Teilnehmern des ESTRO-Kurses “IMRT and Other Conformal Techniques in Practice” in Amsterdam im Juni 2001 als Aufgabe gestellt. Ergebnisse: Für den vorgegebenen Fall wurden neun intensitätsmodulierte Bestrahlungspläne erstellt, die Mehrzahl unter Verwendung kommerzieller Bestrahlungsplanungssysteme. Die Zahl der Einstrahlrichtungen variierte zwischen vier und elf, fünf der neun Strategien verwendeten ausschließlich koplanare Einstrahlrichtungen. Die Homogenität der Dosisverteilung im Planungszielvolumen korrelierte invers mit dem Schonungsgrad der umliegenden Risikostrukturen. Schlussfolgerung: IMRT-Planungsstrategien für komplexe HNO-Fälle, wie beispielsweise Nasennebenhöhlentumoren, weisen für eine Vielzahl von Aspekten, wie Zusammenstellung der Felder, Gesamtzahl der Segmente, Homogenität der Dosisdeposition im Planungszielvolumen oder Dosisstatistik der Risikostrukturen, auffallende Unterschiede auf.

Lacrimal Gland Radiosensitivity in Uveal Melanoma Patients

PURPOSE To find a dose-volume effect for inhomogeneous irradiated lacrimal glands. METHODS AND MATERIALS Between 1999 and 2006, 72 patients (42 men and 30 women) were treated with fractionated stereotactic radiotherapy in a prospective, nonrandomized clinical trial (median follow-up, 32 months). A total dose of 50 Gy was given on 5 consecutive days. The mean of all Schirmer test results obtained > or =6 months after treatment was correlated with the radiation dose delivered to the lacrimal gland. Also, the appearance of dry eye syndrome (DES) was related to the lacrimal gland dose distribution. RESULTS Of the 72 patients, 17 developed a late Schirmer value <10 mm; 9 patients developed DES. A statistically significant relationship was found between the received median dose in the lacrimal gland vs. reduced tear production (p = 0.000) and vs. the appearance of DES (p = 0.003), respectively. A median dose of 7 Gy/fraction to the lacrimal gland caused a 50% risk of low Schirmer results. A median dose of 10 Gy resulted in a 50% probability of DES. CONCLUSION We found a clear dose-volume relationship for irradiated lacrimal glands with regard to reduced tear production and the appearance of DES.

Pathological analysis after neoadjuvant chemoradiotherapy for esophageal carcinoma: The rotterdam experience

Multimodality treatment is increasingly used in the treatment for esophageal cancer. We determined the tumor regression grade after preoperative chemoradiation and correlated the effect of specific pathologic and clinical findings to overall survival. For this purpose esophageal biopsies and surgical specimens of 67 patients treated with neoadjuvant paclitaxel and carboplatin concurrent with radiotherapy were reviewed. Neoadjuvant chemoradiotherapy led to a significant downstaging. Complete tumor regression was found in 24% of the patients resulting in a trend towards better survival. It was found more frequently in poorly differentiated tumors. Patients with pre‐treatment nodal involvement, assessed by endoscopic ultrasound, had a significantly worse survival compared to patients without. Contrastingly, this was not found for post‐treatment nodal involvement, as determined by pathological examination, speculating that survival is more determined by (submicroscopic) distant disease, than by locoregional tumor cells. J. Surg. Oncol. 2009;100:32–37.

Fractionated stereotactic radiotherapy for uveal melanoma, late clinical results

PURPOSE To determine local control, late toxicity and metastatic free survival (MFS) of patients treated with fractionated stereotactic radiation therapy (fSRT) for uveal melanoma (UM). METHODS AND MATERIALS Between 1999 and 2007, 102 UM patients were included in a prospective study of a single institution (median follow-up (FU) 32 months; median tumor thickness 6 mm); five fractions of 10 Gy were given. Primary endpoints were local tumor control and late toxicity (including visual outcome and eye preservation). Secondary endpoint was MFS. RESULTS Local tumor control was achieved in 96% of the patients. Fifteen enucleations were performed, 2-85 months after radiation. Four eyes were enucleated because of local tumor progression. Nine patients developed grade 3 or 4 neovascular glaucoma (NVG), 19 developed severe retinopathy, 13 developed opticoneuropathy grade 3 or 4, 10 developed cataract grade 3, and 10 patients suffered from keratitis sicca. Best corrected visual acuity (BCVA) decreased from a mean of 0.26 at diagnosis to 0.16, 3 months after radiation and it gradually declined to 0.03, 4 years after therapy. The 5-year actuarial MFS was 75% (95% CIs: 62-84%). CONCLUSIONS fSRT is an effective treatment modality for uveal melanoma with a good local control. With that, fSRT is a serious eye sparing treatment modality. However, our FU is relatively short. Also, the number of secondary enucleations is substantial, mainly caused by NVG.

Risk factors associated with secondary enucleation after fractionated stereotactic radiotherapy in uveal melanoma

To evaluate risk factors for secondary enucleation after fractionated stereotactic radiotherapy (fSRT) in uveal melanoma.

Quality of life: fractionated stereotactic radiotherapy versus enucleation treatment in uveal melanoma patients

To report the quality of life and visual functioning in uveal melanoma patients treated with enucleation or fractionated stereotactic radiation therapy (fSRT).