The TNM tumor classification system has been

Transcription

1 ORIGINAL ARTICLE USEFULNESS OF MRI VOLUMETRIC EVALUATION IN PATIENTS WITH SQUAMOUS CELL CANCER OF THE HEAD AND NECK TREATED WITH NEOADJUVANT CHEMOTHERAPY Mehran Baghi, MD, 1 Martin G. Mack, MD, PhD, 2 Markus Hambek, MD, 1 Sotirios Bisdas, MD, 2 Ramona Muerthel, 2 Jens Wagenblast, MD, 1 Wolfgang Gstoettner, MD, PhD, 1 Thomas Vogl, MD, PhD, 2 Rainald Knecht, MD, PhD 1 1 Department for ENT-Surgery, University of Frankfurt/Main, Theodor-Stern-Kai, Frankfurt am Main, Germany. knecht@em.uni-frankfurt.de 2 Department of Diagnostic and Interventional Radiology, University of Frankfurt/Main, Theodor-Stern- Kai, Frankfurt am Main, Germany Accepted 5 May 2006 Published online 16 November 2006 in Wiley InterScience ( DOI: /hed Abstract: Background. The purpose was to evaluate the efficacy of tumor volumetry on MRI as predictive of response to treatment with induction chemotherapy, comparing the results with endoscopy. Methods. Fifty patients with advanced squamous cell carcinoma of the head and neck (SSCHN) who underwent MRI volumetry before and after neoadjuvant chemotherapy consisting of docetaxel, cisplatin, and 5-fluorouracil (TPF) were included in this study. The tumor volume was calculated by a slice-by-slice evaluation. With the standard software of a workstation, the area of the tumor was measured slice by slice using manual segmentation. To evaluate the efficacy of MRI volumetry, pretreatment volume was compared with pretreatment remission status as evaluated with endoscopy. Results. Forty-five (90%) patients demonstrated a tumor downstaging after chemotherapy. Fourteen (28%) patients showed a complete histologic remission (CR), 31 (62%) patients showed a partial remission (PR). Pretreatment tumor volume was significantly different between patients whose tumor completely responded (CR) and those whose tumor did not completely respond or whose disease was stable or was progressive (p ¼ Correspondence to: R. Knecht VC 2006 Wiley Periodicals, Inc ). We defined a threshold for the pretreatment tumor volume in patients with CR, which was equal to cc. Conclusion. We propose that MRI tumor volume analyses can be a useful parameter to predict the response to neoadjuvant chemotherapy in SCCHN. VC 2006 Wiley Periodicals, Inc. Head Neck 29: , 2007 Keywords: MR tumor volumetry; predicting factors in SCCHN The TNM tumor classification system has been established for malignant diseases, applied in nearly every clinical cancer trial. However, this system does not reflect the actual tumor mass presented at diagnosis. 1 Furthermore, it is standard practice to evaluate therapeutic response as partial remission based on 50% reduction or complete remission based on 100% reduction of primary tumor mass. Therefore, tumor volume as a 3- dimensional parameter seems to be more sensitive for assessment of treatment response. Traditionally, the assessment of response to treatment has been performed with 2-dimensional measurements of tumor size. Recent advances in MRI 104 MRI Volumetric Evaluation HEAD & NECK DOI /hed February 2007

2 technique and software technology contributed to considerable refinements in the accuracy of tumor size measurements. Furthermore, volume of primary tumor mass seems to be a predictor for response after treatment. In cervical cancer, MRI volumetry has been accepted as a sensitive predictor of treatment outcome after radiation therapy. 2 4 Tumor volume in advanced ovarian cancer was found to have predictive value for response to platinum-based chemotherapy; pretherapeutic tumor volume showed prognostic significance for the time to progression, whereas posttherapeutic volume showed significance for time to progression and survival. 5 Burghardt et al 6 associated the outcome of surgical treatment of 1028 cervical cancer patients to tumor volumetry data. The results of this study indicated that tumor volumetry permitted a more accurate assessment of therapeutic results in those patients than did the classification of International Federation of Gynecology Obstetrics (FIGO). Kikuchi et al 7 reported that the logarithmic tumor volume was the most important variable correlated with lymph node metastasis in early gastric cancer. Mayr et al 4 reported that MRI tumor volumetry seems to be useful for quantitative assessment of response in cervical cancers before, during, and after radiation therapy. In terms of head and neck cancers, there are also several trials indicating the usefulness of tumor volumetry. Mukhreji el al 8 showed that pretreatment CT volumetric measurement of the supraglottic cancers is a predictor of local control in patients with laryngeal cancer treated surgically. Local control rate for tumors with volumes <16 cc was 92%. Kurek et al 1 reported that in patients with a head and neck cancer treated by radiotherapy and concomitant chemotherapy, pretherapeutic tumor volume provides valuable information in terms of prognosis, and therefore, tumor volume should be included in all future clinical trials in head and neck cancer patients. Nevertheless, there are limited data on volumetry regarding head and neck cancers treated with neoadjuvant chemotherapy. There is no study attempting to determine whether an association exists between primary tumor volume and response to neoadjuvant chemotherapy in patients with advanced squamous cell cancer of head and neck (SCCHN). TPF as an induction chemotherapy consisting of docetaxel, cisplatin, and 5-fluorouracil has shown acceptable toxic effects with high rates of overall remission in primary treatment of head and neck cancer patients. 9,10 Thus the first aim of this study was to evaluate the relationship between primary tumor volume and the treatment response to induction chemotherapy with TPF to find out whether primary tumor volume could play a prognostic role, which makes it possible to stratify patients before treatment that may respond to neoadjuvant chemotherapy. PATIENTS AND METHODS During an organ preservation study, we analyzed 50 patients with SCCHN. All patients were to undergo 3 cycles of a triple chemotherapy regimen consisting of docetaxel 75 mg/m 2, cisplatin 100 mg/m 2, and 5-fluorouracil 1000 mg/m 2 (TPF) on days 1, 22, and 43 followed by chemoradiation according to our study protocol of organ preservation. All patients underwent diagnostic workup before and 3 weeks after the completion of chemotherapy, including clinical examination, MRI with volumetry, and endoscopy of the upper aerodigestive tract (EUA) with a minimum of 5 biopsies from the tumor region. Patient characteristics are listed in Table 1. Table 1. Clinical characteristics of patients. Characteristics Value Age, y Median 56 Range Sex Male 41 (82%) Female 9 (18%) Pretherapeutic volume Median 29.7 cc Range cc Initial tumor classification T2 6 T3 14 T4 28 Tx 2 Initial nodal classification N0 10 N1 4 N2a 6 N2b 9 N2c 14 N3 7 Tumor site Oropharynx 14 Larynx 17 Hypopharynx 15 Esophagus 1 Oral cavity 2 Nasopharynx 1 Values represent number of patients, except as otherwise stated. MRI Volumetric Evaluation HEAD & NECK DOI /hed February

3 The pretherapeutic and posttherapeutic volume of the primary tumor as well as of the lymph nodes was determined before chemotherapy started and 3 weeks after the third cycle of neoadjuvant chemotherapy was completed. MRI was performed using T2- and T1-weighted plain sequences and T1-weighted sequences after administration of 0.1 mmol/kg body weight gadolinium-diethylenetriaminepentaacetate (Gd-DTPA). The slice thickness of all sequences was 4 mm, and the distance factor between the slices was 0.4 mm. For manual tumor segmentation, the sequence was used, which allowed the best tumor delineation. The tumor volume (in cubic centimeter, cc) was calculated by a slice-by-slice evaluation by the same radiologist. With the standard software of a workstation, the area of the tumor was measured slice by slice, using manual segmentation. The measured area (cm 2 ) per slice was multiplied by the factor 0.44 cm. The factor of 0.44 cm is based on the slice thickness of 4 mm and a distance factor of 0.4 mm. Finally the volume of all measured slices containing tumor was summed up for total tumor volume. This manual segmentation was done for the primary tumor and the pathologic lymph nodes separately. We compared tumor volumes computed with MRI before neoadjuvant chemotherapy (prevolume) with remission status resulting from the endoscopic and histological examinations after the treatment. Patients with complete radiologic and histologic regression were considered to have complete remission (CR). In these patients, there was no posttherapeutic volume to determine. Patients whose tumor did not completely respond were considered to have partial remission (PR) or stable disease (SD) or progressive disease (PD) according to remission criteria of World Health Organization (WHO). We compared pretreatment tumor volumes of patients with CR versus patients with PR, pretreatment tumor volumes of patients with CR versus patients with SD, and pretreatment tumor volumes of patients with CR versus patients with PD. Furthermore, pretreatment tumor volumes of patients with PR and SD have also been compared with other groups. Additionally, we defined 2 groups: the first group included all patients with CR and the second group included all patients with a measurable residual tumor volume after the treatment including all patients with PR, SD, or PD (non-cr) comparing these 2 groups statistically whether there were significant differences between these 2 groups using the pretreatment tumor volume and the remission status. The Kruskal Wallis and Mann Whitney U-test were used to assess the statistical differences in pretherapeutic tumor volume between the different response groups (CR, PR, SD, and PD). A p value less than.05 was considered significant. The SPSS 10 software (SPSS, Chicago, IL, 1999) was used for statistical analysis. RESULTS Fiftypatientswereincludedinthisstudy.Patient characteristics are shown in Table 1. Forty-five (90%) patients demonstrated a tumor downstaging after chemotherapy. Fourteen (28%) patients showed an endoscopic and radiologic CR proved by histopathology, 31 (62%) patients showed a partial remission (PR), which was confirmed by endoscopic and radiologic evaluation. The median MRI volume of tumors before treatment and after neoadjuvant chemotherapy was 29.7 cc (range, cc) and 3.85 cc (range, ). The median pretherapeutic tumor volume depending on remission status was cc (range, cc) for patients with CR and cc (range, cc) for patients with PR. The pretherapeutic tumor volume was related to the remission after the treatment in all patients (p <.001). Furthermore, the pretreatment tumor volume was significantly different between patients (n ¼ 14) whose tumor completely responded and those (n ¼ 36) whose tumor did not completely respond or whose disease was stable or progressive (Figure 1, p ¼.00023). FIGURE 1. Boxplot of pretreatment tumor volume versus tumor remission after induction chemotherapy. CR, complete remission group; non-cr, group with partial remission, stable disease, or progressive disease. Difference between groups was statistically significant (Mann-Whitney U-test, p ¼.00023). 106 MRI Volumetric Evaluation HEAD & NECK DOI /hed February 2007

4 There was also a significant difference between patients with CR and PR (p ¼.001). There was no significant difference in pretreatment tumor volume between patients with CR and SD (p ¼.15), patients with PR and SD (p ¼.82) and patients with PR and PD (p ¼.12) after the treatment. Furthermore there was a statistical significance between pretreatment tumor volume of patients with CR and PD (p ¼.012). Thirteen of 14 (93%) patients with CR showed a pretherapeutic tumor volume cc. The value of cc could be defined as prognostic threshold for tumor volume in patients with CR. DISCUSSION Neoadjuvant chemotherapy is getting more popular and considered an effective treatment option for locally advanced SCCHN. Previous studies of larynx preservation indicate that the synergistic effect of a multiple chemotherapy regimen like the triple regimen with TPF allows a significant tumor response and improves resectability, local control, and survival Tumor downstaging after neoadjuvant chemotherapy has also resulted in an increased rate of organ preservation in patients with SCCHN. TPF regimen demonstrates a trend toward improved survival and decreased recurrence However, the question whether tumor volume is a predictor of response for neoadjuvant chemotherapy in SCCHN remains unsolved. The complexity of tumor biology causes a multitude of unanswered questions, which make it difficult to find a biological parameter for prediction of response. In other words, it is essential to dispose of a clinical parameter predicting the treatment outcome before starting the treatment. Traditionally, the assessment of response to therapy has been performed with 2-dimensional measurements of tumor size. 2,19,20 Advances in MRI technique and developments in software technology have led to considerable refinements in the accuracy of tumor size measurements. Today it is possible to measure the accurate tumor volume in cubic centimeter. There are several investigations, indicating tumor volumetry as a sensitive predictor of treatment outcome after therapy for different cancer entities. In cervical cancer, MRI tumor volumetry has been accepted as a sensitive parameter to assess the treatment outcome after radiation. 2 4 Tumor volumetry in advanced ovarian cancer was found to have predictive value for response to platinum-based chemotherapy. 2 The efficacy of tumor volume in head and neck cancer after radiation, combined radiochemotherapy, or surgery has also been reported by different authors. 2 5,8 Volumetric analyses were also performed by Doweck et al 20 in a group of patients with cancers of hypopharynx, larynx, oral cavity, and oropharynx treated by radiochemotherapy. The authors defined a prognostic threshold for primary tumor volume, equal to 19.6 cc. A Greek German collaborative study demonstrated the impact of tumor volume on the survival of patients with locally advanced head and neck cancers treated by platinum-based radiochemotherapy. The authors analyzed 107 patients and concluded that the addition of chemotherapy to radiation (p ¼.017) and the pretherapeutic tumor volume (p ¼.014) were the only factors significantly associated with survival among all initial patient characteristics assessed for prognostic value. 18 Nevertheless, there are no reports in terms of tumor volumetry in SCCHN after neoadjuvant chemotherapy. Thus it is justified to investigate whether there is an association between pretreatment tumor volume and the response to neoadjuvant treatment with chemotherapy. For the first time, we performed MRI volumetry in 50 patients with advanced SCCHN. All our data were evaluated using MRI with tumor volumetry and EUA with biopsy before and after the treatment. The remission status has been assessed according to the criteria of WHO. Independent of the tumor site, we found a correlation between pretherapeutic tumor volume and response to TPF (p <.001). Pretreatment tumor volume was significantly different between the patients (n ¼ 14) whose tumor completely responded (CR, Figure 1) and those (n ¼ 36) whose tumor did not completely respond or who had stable or progressive disease (non-cr, Figure 1, p ¼.00023). Furthermore, we calculated statistically a threshold for pretreatment tumor volume, which was equal to cc for patients with CR. This could be a prognostic value to stratify patients that may respond completely to neoadjuvant chemotherapy. One limitation of our study was that we had a small and heterogeneous patient population with different disease stages and tumor sites. Furthermore, there were only a limited number of patients with stable and progressive disease. We think this should be 1 possible reason we did not find a significant correlation comparing the tumor volume of patients with CR versus patients with SD as well as tumor volume of patients with PR versus patients with SD and PD. Nevertheless, the high MRI Volumetric Evaluation HEAD & NECK DOI /hed February

5 significant correlation between patients with CR and those without CR (non-cr) underlines the efficacy of pretreatment tumor volume as a sensitive prognostic parameter for patients with complete remission, and therefore, this clinical parameter should be included in all future clinical trials performing with induction chemotherapy for further investigations. REFERENCES 1. Kurek R, Kalogera-Fountzila A, Muskalla K, et al. Usefulness of tumor volumetry as a prognostic factor of survival in head and neck cancer. Strahlenther Onkol 2003;179: Mayr NA, Magnotta VA, Ehrhardt JC, et al. Usefulness of tumor volumetry by magnetic resonance imaging in assessing response to radiation therapy in carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1996;35: Mayr NA, Taoka T, Yuh WT, et al. Method and timing of tumor volume measurement for outcome prediction in cervical cancer using magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2002;52: Mayr NA, Yuh WT, Zheng J, et al. Tumor size evaluated by pelvic examination compared with 3-D quantitative analysis in the prediction of outcome for cervical cancer. Int J Radiat Oncol Biol Phys 1997;39: Andreopoulou E, Andreopoulos D, Adamidis K, et al. Tumor volumetry as predictive and prognostic factor in the management of ovarian cancer. Anticancer Res 2002; 22: Burghardt E, Baltzer J, Tulusan AH, Haas J. Results of surgical treatment of 1028 cervical cancers studied with volumetry. Cancer 1992;70: Kikuchi S, Sakuramoto S, Kobayashi N, Shimao H, Sakakibara Y, Sato K, Kakita A. Tumor volumetry: proposal of a new concept to predict lymph node metastasis in early gastric cancer. Anticancer Res 2000;20: Mukherji SK, O Brien SM, Gerstle RJ, et al. The ability of tumor volume to predict local control in surgically treated squamous cell carcinoma of the supraglottic larynx. Head Neck 2000;22: Knecht R, Baghi M, Hambek M, Tesch H, Gstoettner W. Response rate and outcome of a novel induction chemotherapy regimen (TPF) in the first-line therapy of advanced head and neck carcinomas (SCCHN). Proc Am Soc Clin Oncol 2003;22: Knecht R, Tesch H, Baghi M, Hambek M, Zamboglou N, Gstoettner W. Response rate and outcome of a novel first-line therapy for advanced head and neck carcinoma. J Clin Oncol 2004;22(Suppl): Janinis J, Papadakou M, Panagos G, et al. Sequential chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil in patients with locally advanced head and neck cancer. Am J Clin Oncol 2001;24: Janinis J, Papadakou M, Xidakis E, et al. Combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in previously treated patients with advanced/recurrent head and neck cancer: a phase II feasibility study. Am J Clin Oncol 2000;23: Licitra L, Grandi C, Guzzo M, et al. Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J Clin Oncol 2003;21: Schrijvers D, Van Herpen C, Kerger J, et al. Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: a phase I- II feasibility study. Ann Oncol 2004;15: Tsukuda M, Mikami Y, Tanigaki Y, et al. Phase I trial of combined chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for patients with locally advanced squamous cell carcinoma of the head and neck. Int J Clin Oncol 2004; 9: Bernier J, Cooper JS. Chemoradiation after surgery for high-risk head and neck cancer patients: how strong is the evidence? Oncologist 2005;10: Colevas AD, Busse PM, Norris CM, et al. Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase I/II trial. J Clin Oncol 1998;16: Plataniotis GA, Theofanopoulou ME, Kalogera-Fountzila A, et al. Prognostic impact of tumor volumetry in patients with locally advanced head-and-neck carcinoma (non-nasopharyngeal) treated by radiotherapy alone or combined radiochemotherapy in a randomized trial. Int J Radiat Oncol Biol Phys 2004;59: Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Mancuso AA. Parameters that predict local control after definitive radiotherapy for squamous cell carcinoma of the head and neck. Head Neck 2003;25: Doweck I, Denys D, Robbins KT. Tumor volume predicts outcome for advanced head and neck cancer treated with targeted chemoradiotherapy. Laryngoscope 2002;112: MRI Volumetric Evaluation HEAD & NECK DOI /hed February 2007