Effectiveness of Adjuvant Radiotherapy in Small Oropharyngeal Squamous Cell Cancer and Single Lymph Node Metastasis.

Sponsor

Johannes Gutenberg University Mainz (Other)

Overall Status

Completed

CT.gov ID

NCT00964977

Collaborator

Deutsche Krebshilfe e.V., Bonn (Germany) (Other)

209

Enrollment

Locations

Arms

146

Duration (Months)

4.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Radiotherapy with or without adjuvant chemotherapy represents an important column of modern therapy in advanced squamous cell originated tumours of the head and neck. However to date no studies are available which study the effectiveness of radiotherapy in patients with resected small tumours (T1, T2) and concomitant ipsilateral metastasis of a single lymph node (pN1) for general treatment recommendation. The present study is designed as non-blinded, prospective, multicenter randomized controlled trial (RCT) for comparison of overall-survival as primary clinical target in patients receiving radiation therapy vs. patients without adjuvant radiation following curative intended surgery. Aim of the study is to enroll 560 adult males and females for 1:1 randomization to one of the two treatment arms (radiation/non-radiation. Secondary clinical endpoints are as follows: Incidence and time to tumor relapse (locoregional relapse, lymph node involvement and metastatic spread), Quality of life as reported by EORTC (QLQ-C30 with H&N 35 module) and time from operation to orofacial rehabilitation.

Condition or Disease	Intervention/Treatment	Phase
Oropharyngeal Cancer Oral Cancer Lymph Node Metastasis	Radiation: Radiation therapy	Phase 3

Detailed Description

Background

Prevailing curative intended therapeutic strategies combine radical resection of the tumor mass with a safety margin followed by radiation of the original tumor site and adjacent locoregional lymphatic drainage areas. To date selection of the individual therapeutic pattern is essentially guided by pre- and post-therapeutic TNM staging parameters. Exceptionally for advanced tumors postoperative radiotherapy and optional combination with (radiosensitizing) chemotherapeutic agents is favorable and recommended. Interdisciplinary guidelines stated the following detailed recommendations for application of adjuvant radiation therapy:

non in sano resection if reoperation is impossible (R1-, R2-status)
primary tumor status > pT2 and pN2, pN3
extranodular spread of the disease
lymphangiosis carcinomatosa
facultative: pN1 According to these recommendations postoperative radiotherapy of advanced tumors is feasible while for small tumors indication for adjuvant therapy depends on further parameters like the pN findings. Here verification of more than one singular lymph node metastasis (pN2) leads to additional radiotherapy. In tumors with a diameter less than 4 cm (T1, T2) and concomitant verification of a single lymph node metastasis no explicit therapeutic recommendation is offered to date displaying radiation an optional complement for these cases. Meta-Analysis revealed only a few studies taking this special group of patients into account stating adjuvant radiotherapy an additional risk factor for overall survival, however small patient numbers, inhomogeneous group distribution and ambiguous risk factors exhibited a significant bias.

The methodological key problems which had to be addressed in the protocol were the following:

extremely different treatment arms with strong preferences for one or the other therapy arm
low number of eligible patients per center
Inclusion criterion (pN1) including a pathological diagnosis and surgical treatment with possible differences
Radiation treatment as one arm with special need for quality control Thus the idea of presenting this paper is, to discuss how these specific issues were taken care of.

Methods/Design Study Design The study is designed as a non-blinded, prospective, randomized controlled clinical trial.

Study objectives Objective of the clinical study will be the investigation of two different patient collectives (irradiated/unirradiated) with pT1/2 primary and verification of a singular ipsilateral lymph node metastasis in parallel design in order to evaluate a possible significant benefit of radiation therapy. Investigation of further biological parameters will be concomitantly performed to assess a possible prediction of tumor progression and to evaluate surrogate markers of radioresistance. The following null hypothesis forms the basis of the present study: Radiation therapy will have no influence on the overall survival in patients with pT1/2, pN1 primary tumor. Secondary outcome variables include incidence and time to tumor relapse (locoregional relapse, lymph node involvement and metastatic spread), Quality of life as reported by EORTC (QLQ-C30 with H&N 35 module) and time from operation to orofacial rehabilitation.

Patients

Males and females with histological verified diagnosis of a primary squamous cell carcinoma of the oral cavity or the oropharynx are eligible. Inclusion criteria are as follows:

maximum tumor diameter less than 4 cm in the pathohistological specimen irrespective of histological grading (pT1 or pT2)
concomitant histological verification of a singular ipsilateral lymph node metastasis less than 3cm in diameter (pN1) without penetration of the lymph node´s capsule and without presence of lymphangiosis carcinomatosa
radical resection of the tumor within adequate resection margins (R0)
written informed consent from the patient
adequate performance status ECOG Index ≤ 2 Patients with an age less than 18 and pregnant women are to be excluded. Further criteria of exclusion are reported drug addiction or intake of remedies with potential influence on compliance or impaired judgment. In addition patients with mental disorders or conceivable physical, familial or job related embarrassments which may preclude the patient to realize the study schedule. Moreover patients with physical impairment by inadequate treatment of derailed diseases e.g. untreated diabetes mellitus or acute heart insufficiency (ECOG-Index >2).

Study interventions Radiotherapy should begin within 6 weeks after the last surgical intervention, whereas a minimal postoperative healing period of at least 8 days should be respected. Causes for delay of intervention are to be documented. Application of radiotherapy defines group 1 versus the non irradiated group (group 2).

Surgical treatment The primary is considered radically resected if macroscopic and histologic evaluation approved resection margins without tumor residuals (R0 status). For surgical proceeding a safety margin of at least 1cm is established. For surgical considerations of lymph node resection the tumor localization is divided in level I (below occlusional plane) and level II (above occlusional plane) respecting pre-, postcanine or retromolar finding in addition. Classification of cervical regions follows the recommendations of Robbins from 2002. Hence, the neck is divided into 6 different sections.

Ipsilateral N0 state of cervical lymph nodes Pre- and postcanine localized tumors of level I require a selective neck dissection of the cervical level 1-3. In level I tumours of the retromolar triangle selective neck dissection of ipsilateral level 1-5 is proceeded. In level II tumors no selective neck dissection is considered.

Contralateral N0 state No neck dissection is performed Ipsilateral N1- N2 state For retromolar localized level I tumors a modified radical neck dissection is performed. If the tumor is localized pre- or postcanine intraoperative frozen sections of level 1 lymph nodes are evaluated. Positive intraoperative results lead to modified radical resection of level 1-5 lymph nodes. In case of negative results resection of the lymph nodes within level 1-3 is affiliated. Negative instantaneous sections in level II tumors require no lymph node dissection. All metastatic affection of level II-III lymph nodes necessitates modified radical neck dissection.

Contralateral N1-N2 state Instantaneous section is performed for level 1 lymph nodes. Modified radical neck dissection is performed in positive, resection of level 1-3 lymph nodes is conducted in negative results. Metastases spread in level 2-3 lymph nodes acquire modified radical neck dissection.

Lymph node therapy of midline tumors Midline tumors may require bilateral resection of lymph node echelons at risk. Bilateral modified neck dissection is performed for staging purposes if indicated. Contralateral lymph node dissection of the level 1-3 in precanine localized tumors is mandatory.

Technical conditions and practical execution of radiation therapy Radiotherapy is performed by photons of 4 to10 MeV or/and electrons of 6 to 15 MeV maximum energy. Individual 3 dimensional dose distribution calculation is mandatory and has to be made on the basis of a postoperative native computer tomogram. All patients are to be treated while immobilized by a custom made face mask made of thermoplast or equivalent. Clinical target volume definition compasses the original tumor site with a safety margin of 2 cm in each direction.

Floor of mouth, anterior tongue Irradiation of the anterior two third of the tongue as well as the anterior floor of mouth is irradiated by lateral opposing beams, while the maxilla is separated by insertion of a bite block.

Oropharynx, buccal plane, soft palate confined to one side For tumors of the buccal plane, the tonsilla, the soft palate and the retromolar triangle two types of planning target volume may be applied.

In case of negative contralateral cervical nodes an ipsilateral target volume for the primary is defined including the lymph nodes of group IB, IIA and IIB. Irradiation technique recommended is a two wedge fields typically angulated by 90 to 120 degrees. The ipsilateral node levels III-V are treated by an anterior portal down to clavicle. The contralateral neck is spared.

Tumors of the lateral and dorsal pharyngeal wall and their lymphatic drainage (levels II, III, IV and V) are irradiated bilaterally with opposing beams. Irrespective of technique used 3 D conformal dose shaping is highly recommended.

Dosage and fractionation Target volume definition and dosage has to be performed according to the rules of ICRU report 50. At the primary tumor site and at involved lymph node levels a total dose of 59.4 Gy in 33 fractions within 45 days is scheduled. At electively irradiated volumes a total dose of 50.4 Gy in 28 fractions is scheduled. All fractions of 1.8 Gy each are given five times per week. In case of machine break down an additional fraction per week is recommended with an at least 6 h interval between two fractions on the same day or on Saturday. Total treatment duration (including planned/unplanned interruptions) is to be documented in days. Any patient must be available for intent to treat analysis.

Instead of the classical portal arrangements and dose distributions intensity modulated radiotherapy using an inverse calculation algorithm may be used in experienced centers. Dose constraints for normal tissues are at the discretion of the participating centers. Dose specification according to the RTOG protocol H 0022 is recommended. Details are given in a standard operation procedure.

Follow-Up Recruitment phase will be 4 years with physical examination, ECOG index, and quality of life questionnaire will be performed 3, 6 and 12 months after end of radiation. Further follow up will be performed annually up to 5 years to obtain sufficient clinical data.

Randomization and Sample Size The present study setup consists of a two armed randomized controlled trial (RCT) as primary study aim. Patients rejecting their participation to a randomized approach and preference to a certain procedure (radiation/no radiation) will be included into a prospective observational study after given informed consent. This parallel constructed observational trial will be performed with a maximum of consistency to treatment and observation compared to the RCT. In case of positive attendance the patients will be randomized, stratified by the criteria of adequate lymph node therapy (yes/no) as formulated by the DOESAK. Randomization to both groups (radiation group/control group) will be 1 to1. Patients will be recruited over a period of 4 years and follow-up will be annually until the trial ends, i.e. at least for 5 years for each patient. Sample size calculation will be performed for the two-sided log rank test at a significance level of 5%. Assuming an exponential distributed survival with survival probabilities after 5 years of 45% within the control group and of 55% within the radiation group (results observed from the DOESAK collective) and a drop-out rate of 5% per year, 280 patients per group are required to detect a significant difference in overall survival with a power of 70%. In case of impaired patient recruitment within the randomized trial, it is intended to recruit at least 280 patients per group in the observational study.

Analysis of RCT and observational trial

Initiation of this trial is only arguable with a realistic chance of statistical evaluation of an adequate count of randomized patients. Hence an intermediate assessment of attendance to randomization will be performed after the first and the second year of recruitment. If less than 5% of patients agreed to randomization within the first and 10% within the second year RCT will be stopped and the study is continued solely as observational trial (see table 1). Intermediate assessment is performed with presumption of accelerating involvement to achieve a minimum of 20% randomized patients after the recruitment phase. As consequence to the study design two different collectives (randomized collective/ collective with preferred form of therapy) will exist. The following scenarios of analysis are possible:

If a sufficient number of patients was randomized, treatment comparison will be performed within the randomized collective. The non-randomized collective will be used to evaluate the external validity of observed treatment effects.
If no sufficient number of patients could be randomized, all recruited patients will be analyzed. Descriptive comparison of treatment groups will be performed for all baseline variables. All analyses will be performed with adjustment to baseline variables affecting survival. Results have to be interpreted with respect to any group differences in baseline variables.

Outcome measurements Primary clinical endpoint Overall survival Secondary clinical endpoints Incidence of tumor relapse

Time to occurrence of lymphatic metastases
Time to occurrence of local relapse
Time to occurrence of distant metastases
Tumor related death due to local tumor progression or metastatic spread Life quality
Time to provisional orofacial rehabilitation
Time from operation to first intermediate prosthesis intake
Time from operation to definitive prosthesis application
Life Quality report (EORTC QLQ-C30 with H&N 35 module)

Overall survival will be evaluated in a Cox proportional hazard model with treatment and adequate lymph node therapy (yes/no) as covariates. Further covariates may be considered if they affect survival.

Study Design

Study Type:

Interventional

Actual Enrollment :

209 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Effectiveness of Adjuvant Radiotherapy in Patients With Oropharyngeal and Floor of Mouth Squamous Cell Carcinoma and Concomitant Histological Verification of Singular Ipsilateral Cervical Lymph Node Metastasis (pN1-state)

Study Start Date :

Oct 1, 2009

Actual Primary Completion Date :

Oct 1, 2021

Actual Study Completion Date :

Dec 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: no irradiation Patients within this arm only receive curative intended radical surgery
Active Comparator: Radiation Patients receive radiation within 6 weeks after curative intended radical surgery.	Radiation: Radiation therapy Patients receive radiation within 6 weeks after surgery. At primary tumour site and involved lymph node level a total dose of 59.4 Gy in 33 fractions within 45 days is scheduled according to the rules of ICRU report 50.

Arm

Intervention/Treatment

No Intervention: no irradiation

Patients within this arm only receive curative intended radical surgery

Active Comparator: Radiation

Patients receive radiation within 6 weeks after curative intended radical surgery.

Radiation: Radiation therapy

Patients receive radiation within 6 weeks after surgery. At primary tumour site and involved lymph node level a total dose of 59.4 Gy in 33 fractions within 45 days is scheduled according to the rules of ICRU report 50.

Outcome Measures

Primary Outcome Measures

Primary study object: overall survival [9 years]
The objective of the clinical study will be to investigate two different patient groups (irradiated/unirradiated) with pT1/2 primary and verification of a singular ipsilateral lymph node metastasis in parallel design in order to evaluate the possible benefit of radiation therapy. The following null hypothesis forms the basis of the present study: Radiation therapy will have no influence on the overall survival in patients with pT1/2, pN1 primary tumor. First patients will be observed for 9 years, last patient in will be followed-up for 5 years.

Secondary Outcome Measures

Time to occurrence of local relapse [2, 3 and 6 months; 1 year to 9 years]
Recruitment phase will be 4 years and follow up 5 years. First patients will be observed following the schedule above for 9 nine years, last patients will be observed for a minimum of 5 years.
Time to lymphatic metastasis [2, 3 and 6 months, 1 year to 9 years]
Recruitment phase will be 4 years and follow up 5 years. First patients will be observed following the schedule above for 9 nine years, last patients will be observed for a minimum of 5 years.
Time to occurence of distant metastasis [2,3,6 months and 1 year to 9 years annually]
Recruitment phase will be 4 years and follow up 5 years. First patients will be observed following the schedule above for 9 nine years, last patients will be observed for a minimum of 5 years.
Quality of Life [after 6 months, 1 year and annually till end of study]
QLQ 30 and HN35 Questionnaire will be assessed after 6 months and annually Course of provisional and definite orofacial rehabilitation will be assessed in each meeting

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

histological diagnosis of a primary squamous cell carcinoma of the oral cavity or the oropharynx
maximum tumor diameter less than 4 cm in the pathohistological specimen irrespective of histological grading (pT1 or pT2)
concomitant histological verification of a singular ipsilateral lymph node metastasis less than 3cm in diameter (pN1) without penetration of the lymph node´s capsule and without presence of invasion of lymphatic vessels (lymphangiosis carcinomatosa)
radical resection of the tumor within adequate resection margins (R0)
written informed consent from the patient
adequate performance status ECOG Index ≤ 2

Exclusion Criteria:

an age less than 18 years old
pregnant women
reported drug addiction
intake of remedies with potential influence on compliance or impaired judgment
patients with mental disorders or conceivable physical, familial or job related embarrassments which may preclude the patient to realize the study schedule
inadequate performance status ECOG Index > 2

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universiätsklinikum Tübingen	Tübingen	Baden Württemberg	Germany
2	Universitätsklinikum Erlangen	Erlangen	Bayern	Germany
3	Universitätsklinik München	München	Bayern	Germany
4	Universität Regensburg	Regensburg	Bayern	Germany	93053
5	Johann-Wolfgang Goethe-Universität	Frankfurt am Main	Hessen	Germany	60590
6	Universitätsklinik Greifswald	Greifswald	Mecklenburg Vorpommern	Germany	17475
7	Universitätsklinikum Dortmund	Dortmund	Nordrhein Westfalen	Germany
8	Universitätsklinikum Köln	Köln	Nordrhein Westfalen	Germany
9	Department of Oral and Maxillofacial Surgery,	Mainz	Rheinland Pfalz	Germany	55131
10	Otto von Guericke Universität Magdeburg	Magdeburg	Sachsen-Anhalt	Germany	39120
11	Universitätsklinik Rostock	Rostock	Schleswig Holstein	Germany	18057
12	Friedrich Schiller Universität Jena	Jena	Thüringen	Germany	07740
13	Universtiätsklinikum Aachen	Aachen		Germany
14	Klinikum Augsburg	Augsburg		Germany
15	Helios Kliniken Bad Saarow	Bad Saarow		Germany
16	Charité Berlin	Berlin		Germany
17	Universitätsklinikum Bonn	Bonn		Germany
18	Klinikum Bremen-Mitte	Bremen		Germany	28177
19	Klinikum Bremerhaven	Bremerhaven		Germany
20	Universitätsklinikum Dresden	Dresden		Germany
21	Universitätsklinikum Düsseldorf	Düsseldorf		Germany
22	Universitätsklinikum Essen	Essen		Germany
23	Klinikum Frankfurt Oder	Frankfurt/Oder		Germany
24	Universitätsklinikum Freiburg	Freiburg		Germany
25	Klinikum Fulda	Fulda		Germany
26	Marienhospital Gelsenkirchen	Gelsenkirchen		Germany
27	Justus Liebig Universtität	Gießen		Germany
28	Kreiskrankenhaus Gummersbach	Gummersbach		Germany
29	Georg August Universitätsklinikum Göttingen	Göttingen		Germany
30	Universitätsklinik Hamburg Eppendorf	Hamburg		Germany	20246
31	Medizinische Hochschule Hannover	Hannover		Germany
32	Ruprecht-Karls-Universität Heidelberg	Heidelberg		Germany
33	Universitätsklinikum Homburg/Saar	Homburg/Saar		Germany
34	Universitätsklinikum Kiel	Kiel		Germany
35	Bundeswehrkrankenhaus Koblenz	Koblenz		Germany
36	Universitätsklinikum Leipzig	Leipzig		Germany
37	Universitätsklinikum Schleswig-Holstein / Campus Lübeck	Lübeck		Germany
38	Universitätsklinikum Mannheim	Mannheim		Germany
39	Universitätsklinikum Marburg	Marburg		Germany
40	Kliniken Maria Hilf Mönchengladbach	Mönchengladbach		Germany
41	Universitätsklinikum Münster	Münster		Germany
42	Brüderkrankenhaus St. Josef Paderborn	Paderborn		Germany
43	Helios Kliniken Schwerin	Schwerin		Germany
44	Klinikum Traunstein	Traunstein		Germany
45	Universitätsklinikum Ulm	Ulm		Germany
46	Helios Klinik Wuppertal	Wuppertal		Germany
47	Universitätsklinikum Würzburg	Würzburg		Germany
48	Universitätsklinikum Utrecht	Utrecht		Netherlands
49	Universitätsspital Basel	Basel		Switzerland