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There are approximately 800 new cases of anal cancer every year in the United Kingdom, and most patients present with locally advanced disease. The current treatment protocol for locally advanced anal cancer is radical radiotherapy with concurrent chemotherapy. The 5 year overall survival rate for these patients is 60-73%. Recent evidence suggests that most cases of anal cancer over-express the epidermal growth factor receptor. Cetuximab is a chimeric monoclonal antibody which targets the epidermal growth factor receptor and has been shown to improve survival in head and neck cancer.
Whether cetuximab improves treatment outcome of non-metastatic anal cancer when given in addition to standard chemoradiation
Aims and objectives of study
To compare relapse-free survival in anal cancer with and without addition of cetuximab
To assess the toxicity of cetuximab when used in combination with chemoradiation in anal cancer.
To assess quality of life in patients with anal cancer given the two treatment regimens
Multi-centre randomized clinical trial. All patients above the age of 18 years with histologically confirmed anal cancer with no evidence of metastases, who are due to receive chemoradiation, will be eligible for the trial. After informed consent, patients will be randomly assigned to one of two arms A or B. Arm A will have patients on standard two-phase shrinking-field chemoradiation with 50.4 Gray in 28 fractions with the addition of 5-fluorouracil and mitomycin during weeks 1 and 4. Arm B patients will have the treatment given in arm A and also cetuximab infusions weekly for 5 weeks during treatment. Patients will be followed up for a period of 6 years following randomization. The primary outcome measure will be relapse-free survival while secondary outcome measures will be toxicity and quality of life. Toxicity will be assessed using the NCI CTCAE chemotherapy toxicity scale. Quality of life will be assessed using the EORTC QLQ-C30 v3.0 and EORCT QLQ-CR29 instruments.
Statistical analysis will be done using Stata 9. Interim analyses will be independently conducted to ensure that there is no excess mortality or severe toxicity in the new treatment arm. The primary outcome measure of relapse-free survival will be displayed using Kaplan-Meier curves and compared using Cox regression models. The results will be expressed as hazard ratios with 95% confidence intervals. The proportion of patients in each arm with Grade 3 or more toxicity will be compared using the Fisher's exact test. Quality of life scores in the two arms will be summarized following linear transformation of item scores. The trial will be reported in accordance with CONSORT guidelines.
There are approximately 800 new cases of anal cancer every year in the United Kingdom, and most patients present with locally advanced disease (Office for National Statistics England, 2009). It is relatively less common than other bowel cancers; for instance, there are approximately 30000 cases of colorectal cancer per year in the UK. However, the incidence is increasing in women and younger men (age < 45). This rise in incidence is thought to be due to changes in sexual behaviour and a strong aetiological association with human papilloma virus infection (Frisch, 2002 and Licitra et al, 2002).
The current treatment protocol for locally advanced anal cancer worldwide is radical radiotherapy with concurrent chemotherapy. The 5 year overall survival rate for patients treated in this manner is 60-73% (Johnson et al, 2004). The chemoradiation strategy is substantiated by two major clinical trials. The UKCCCR trial (1996) compared radiotherapy alone with a radiotherapy, 5-fluorouracil (5FU) and mitomycin. They had a large sample size of 577. Although there was no statistical difference in overall survival, there was better local control of disease and lower cancer-related deaths, in the chemoradiation group. There was a 46% reduction in the risk of local failure in the patients receiving combined modality treatment (relative risk 0.54, 95% CI 0.42 - 0.69, p < 0.0001).
Similar findings were obtained in a study conducted by the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups (Bartelink et al, 1997). They compared radiotherapy alone with chemoradiation in 110 patients. 5-fluorouracil and mitomycin was also used in this study. The locoregional control and colostomy-free survival were both higher in the group treated with chemoradiation.
The type of cytotoxic agent used with radiation has also been assessed in trials. 2 main regimens have been used - 5-FU/cisplatin and 5-FU/mitomycin. These have been compared head-to-head in an clinical trial (Ajani et al, 2008). The 5-year locoregional recurrence, distant metastasis, and cumulative colostomy rates were significantly better for the mitomycin-based therapy group compared with the cisplatin-based treatment group (10% versus 19%; P = 0.02). 5-FU/mitomycin is therefore the treatment regimen of choice in the United Kingdom, and will be used in the planned study.
Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase which has a key role in regulating proliferation and survival of tumour cells. Cetuximab is a chimeric monoclonal antibody which targets the epidermal growth factor receptor. Early laboratory studies using animal xenografts showed activity by C225 (the pre-marketing version of cetuximab) against tumour proliferation in a variety of cancer types. This included early work using prostate cancer xenografts (Prewett et al, 1996), where tumour growth in mice was shown to be inhibited by cetuximab alone and in combination with chemotherapy. Further studies were done by the same group using renal cancer xenografts showing a reduction in tumour volume and an increase in animal survival using cetuximab (Prewett et al, 1998). Activity against tumour growth and metastasis were also shown in bladder cancer xenografts (Perrotte et al, 1999).
In addition to direct effects in reducing proliferation and survival of tumour cells, cetuximab can function as a radiosensitizer. Huang and Harai (2000) investigated the capacity of cetuximab to modulate the in vitro and in vivo radiation response of human squamous cell carcinoma (SCC) tumour cells and xenografts. Their studies demonstrated complete regression of both newly established and well-established SCC tumours over a 55-100 day follow-up period in mouse xenografts treated with the combination of cetuximab and radiation. Cell cycle analysis confirmed that combined treatment with cetuximab and radiation induced an accumulation of cells in the more radiosensitive cell cycle phases (G1, G2-M) with concurrent reduction in the proportion of cells in the more radioresistant S phase. Results from analysis of cultured SCC cells demonstrated a strong inhibitory effect of cetuximab on post-radiation damage repair. Exposure of SCC cells to cetuximab also induced a redistribution of DNA-dependent protein kinase from the nucleus to the cytosol. This may be a potential mechanism whereby cetuximab may influence the cellular response to radiation. Immunohistochemical analysis of SCC tumour xenografts after administration of cetuximab demonstrated reduction of the in vivo expression of tumour angiogenesis markers.
Krause and Ostermann (2005) also examined effects of the anti-epidermal growth factor receptor monoclonal antibody cetuximab on proliferation, cell cycle phase distribution, apoptosis, and radiosensitivity in squamous cell carcinoma (SCC) from head and neck cancer patients. Exposure to cetuximab in cell culture inhibited SCC proliferation in a time-dependent manner, and the degree of growth inhibition ranged from 20 to 75% in comparison to controls. Flow cytometry analysis demonstrated that cetuximab treatment induced accumulation of cells in G1, which is accompanied by a 2-3-fold decrease in the percentage of cells in S phase. Examination of cetuximab effects on radiation response demonstrated enhancement in radiosensitivity, and amplification of radiation-induced apoptosis. These effects were observed in both single-dose and fractionated radiation experiments.
Use of cetuximab as adjuvant treatment with radiotherapy has been shown to improve survival in locally advanced head and neck cancer. The most compelling evidence for the use of cetuximab in this setting comes from a clinical trial done by Bonner et al. (2006). They conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients). The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. The results after 3 years of follow-up showed a significant improvement of relapse-free survival with a HR of 0.68 (0.52 - 0.89) (Bonner et al, 2006). The 5-year results have recently been published (Bonner et al., 2009). Median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity. With the exception of rash and infusion reactions, the incidence of grade 3 or greater toxic effects did not differ significantly between the two groups.
Cetuximab has also been tried as a radiosensitizer at other tumour sites. Arnoletti et al (2010) have published their findings of a phase 1 study on their use of cetuximab as a radiation sensitizer in the management of pancreatic cancer. They used it in combination with gemcitabine in patients receiving chemoradiation for locally advanced, non-metastatic pancreatic cancer. Their dosing schedule for cetuximab was a 400 mg/m2 loading dose followed by 250 mg/m2 weekly. They found that the combination was safe to use at these dose ranges, with only a 9% incidence of grade 3-4 toxicity.
Recent evidence suggests that most cases of anal canal cancer over-express the epidermal growth factor receptor (EGFR) (Walker et al, 2009). Alvarez el al (2006) analysed 38 primary squamous cell carcinomas of the anal canal. 55% of these samples over-expressed EGFR, with 62% showing high over-expression. Unusually, none of the over-expression was found to be due to gene amplification, indicating that other mechanisms may be responsible for the over-expression. Mutations of the downstream kRAS pathway are known to be a mechanism of resistance against cetuximab treatment, as have been shown in advanced colorectal cancer (Lievre et al, 2006). However, the frequency of kRAS mutations in anal cancer is low on available evidence. Van Damme et al (2010) in a review of 38 anal cancer specimens did not find any kRAS mutations in the series.
There have only been a few published case series and case reports of the use of cetuximab in any stage of anal cancer. Lukan et al (2009) reported their experience in the treatment of metastatic anal cancer. They used cetuximab monotherapy or a combination of cetuximab and irinotecan. In their series of 7 patients, 5 had stable disease or remission. Phan (2007) published their experience in a patient with refractory anal cancer following treatment with irinotecan alone. They achieved an excellent response using a combination of cetuximab and irinotecan. There has been one phase 1 trial in Brazil on the use of cetuximab in locally advanced anal cancer (Olivatto et al, 2008). They used cetuximab in combination with 5FU/cisplatin and radiotherapy. They had a strong complete response rate of 78% in their small series of 9 patients. There was also no major toxicity issues identified.
Based on basic biological evidence and the effect of cetuximab in other cancer sites, there is a strong case for assessing the benefit of cetuximab in non-metastatic anal cancer. However, there have not been any published randomized clinical trials on the use of cetuximab in this setting to date. I plan to conduct a clinical trial to determine whether cetuximab can safely improve treatment outcomes when given in conjunction with chemo-radiotherapy in anal canal carcinoma.
Does cetuximab improve treatment outcome of non-metastatic anal canal cancer when given in addition radiotherapy and concurrent 5-FU/mitomycin chemotherapy?
Can cetuximab be used safely in the above treatment setting of chemoradiation for non-metastatic anal canal cancer?
What are the effects of chemoradiation with cetuximab on quality of life of patients with non-metastatic anal canal cancer?
Objectives of study
To compare relapse-free survival in anal canal cancer with and without addition of cetuximab
To assess the toxicity of cetuximab when used in combination with chemoradiation in anal canal cancer.
To assess quality of life in patients with anal canal cancer given the two treatment regimens
A multi-centre parallel-group open-label trial design has been chosen for this project. This interventional study design would provide the best quality evidence to answer this oncological question. There have been a few observational case series in this tumour site which provide initial evidence to justify an interventional trial. There are also relatively large interventional studies on the use of cetuximab in other tumour sites which provide data on possible effect size to allow calculation of required sample size. There will be 2 arms in the trial and participants will be allocated to the arms using minimization with an element of randomization.
An open-label design has been chosen for this trial. The weekly formulation of cetuximab is given intravenously. Weekly intravenous injection of placebo would not be appropriate or ethical. In addition, the specific side effect profile of cetuximab includes a characteristic acneiform rash which is very common in a mild form. This would also make blinding impractical.
The main challenge in setting up this trial is the recruitment of adequate numbers of patients to maximize power of the trial. Anal canal carcinoma is a relatively uncommon cancer with an approximate incidence of 800 cases per year in the United Kingdom (Office of National Statistics, 2009). Therefore, a national multi-centre design is required to recruit the required number of cases. This study will be carried out at participating centres within the UK who will be required to complete a site assessment form to confirm that they have adequate resources and experience to conduct the trial. As a minimum, centres must have access to and experience with multi-slice CT scans for staging. They should have appropriate specialist lower GI or anal cancer multidisciplinary meetings which must include a specialist lower GI surgeon and clinical oncologist. Oncologists should have appropriate experience with concurrent chemoradiation in anal cancer. When using a multi-centre design, additional safeguards are required to ensure consistency in trial methodology between centres. However, this is not very difficult in clinical oncology due to the existing strong quality assurance and peer review framework in radiotherapy centres in the UK. There is also consensus on the dose and fractionation of standard radiotherapy in anal canal cancer. Following publication of evidence confirming 5-FU/mitomycin as the chemotherapy regimen of choice (Ajani et al, 2008), radiotherapy centres in the UK have now moved towards the use of this regimen in chemoradiation for anal canal carcinoma.
Histologically confirmed stage I-IIIB invasive anal canal squamous cell (epidermoid) carcinoma (AJCC, 2010).
No prior chemotherapy or radiotherapy for this malignancy
Prior treatment for other malignancies allowed provided patient has not had previous pelvic radiotherapy or systemic chemotherapy within the last 12 months.
Age over 18
ECOG/WHO performance status 0 - 2 (Oken et al, 1982)
No other prior invasive malignancy diagnosed within the past 24 months
No acute active, serious, uncontrolled opportunistic infection
No severe or poorly controlled diarrhoea
No medical or psychiatric illness that would preclude study requirements
Fertile female patients must use effective contraception
Absolute neutrophil count â‰¥ 1,500/mmÂ³
Platelet count â‰¥ 100,000/mmÂ³
Haemoglobin â‰¥ 11 g/dL (blood transfusions, granulocyte colony stimulating factor support allowed during treatment)
Creatinine â‰¤ 1.5 times upper limit of normal or creatinine clearance > 60 mL/min
AST and ALT â‰¤ 3 times upper limit of normal
Bilirubin â‰¤ 2 times upper limit of normal
Negative pregnancy test in all females
Mitomycin C 12 mg/m2 intravenous bolus (max 20mg) on day 1
5-Fluorouracil 1000 mg/m2 continuous intravenous infusion days 1-4 and days 29-32.
Mitomycin C 12 mg/m2 intravenous bolus (max 20mg) on day 1
5-Fluorouracil 1000 mg/m2 continuous infusion days 1-4 and days 29-32.
Cetuximab 400 mg/m2 intravenous over 120 min week 1 (loading dose)
Followed by cetuximab 250 mg/m2 intravenous over 60 min from week 2 to week 6 inclusive
Radiotherapy treatment technique
All patients will be treated in the prone position. A two-phase shrinking field approach is used for the radiotherapy for both arms. This is based on the rationale that 30 Gray of chemoradiation is adequate for microscopic disease and 50 Gray is required to treat gross tumour (Melcher and Sebag-Montefiore, 2003). This is the standard radiotherapy technique for anal carcinoma chemoradiation in the United Kingdom. CT imaging will be used during planning.
â€¢ Phase I: 30.6 Gray in 17 daily fractions over 3 weeks and 2 days
â€¢ Phase II: 19.8 Gray in 11 daily fractions over 2 weeks and 1 day
Standard fractionation delivery rates of 5 fractions per week will be used.
Gross tumour volume (GTV) definition
Visible tumour as seen on the planning CT, taking into account the data from clinical examination, and MRI/PET CT if available. This includes positive inguinal lymph nodes - these may be defined as separate GTVs
Planned target volume (PTV)
Phase I: Includes GTV and all areas at risk of microscopic disease (inguino-femoral nodes and pelvic nodes). Always allow a minimum 3cm margin around any GTV in all directions.
Superior border: 2 cm above inferior aspect of the sacro-iliac joints
Lateral borders: approximately mid-point of femoral neck (to cover inguinal nodal area)
Inferior border: 3cm below anal verge or 3cm below inferior extent of tumour for anal margin tumours
Phase II: PTV = GTV + 3 cm
Phase I: Anterior and posterior opposed fields
Phase II: As per 3D conformal plan
Critical organs and tolerance doses
The multi-leaf collimator will be used as required to spare normal tissue. The aim is to minimize the amount of small bowel in the volume. The dose to femoral heads is to be kept below 45 - 50 Gray to reduce the risk of osteonecrosis of femoral heads. Verification imaging will be done for the first 3 fractions and weekly thereafter if initial imaging is acceptable.
In this protocol, chemotherapy is primarily employed as an adjunct to radiotherapy. The timing of chemotherapy is co-ordinated with the dose of radiotherapy. Chemotherapy should always be given synchronously with radiation and in full dose, provided it is well-tolerated. If there is significant toxicity, a short delay of up to a week should be used in preference to a dose reduction. If there is a delay due to toxicity which persists for more than a week, a dose reduction should be used and chemotherapy continued when feasible.
Cetuximab is not licensed for the indication of anal carcinoma. Therefore the drug will not be on the formulary of participating centres. The manufacturer will be supplying drugs for the study which will be labelled 'For CetAC trial use only' along with the required labelling information. Detailed information of the drug including the Summary of Product Characteristics (SPC) will also be made available to participating centres. Cetuximab is provided in ready to use vials at a concentration of 5mg/mL. Pharmacists will be required to document the receipt, dispensing, and return of cetuximab.
There are no known interactions between cetuximab and the other chemotherapy agents in the trial. The latter should therefore be administered according to the schedule and precautions in the product literature. The following advice applies just to the additional use of cetuximab.
Prior to the first infusion, patients on the cetuximab research arm of the study (Arm B) must receive pre-medication with an appropriate antihistamine. The antihistamine (to reduce the risk of an allergic reaction) should be administered prior to the starting dose and the subsequent weekly doses. Cetuximab 400mg/m2 (initial) dose shall be given as an IV infusion over 120 minutes. Subsequent weekly doses of 250mg/m2 shall be given as an infusion over 60 minutes. The maximum infusion rate must not exceed 10 mg/min cetuximab (corresponding to 2 mL/min ready-to-use solution). Close monitoring of the patient is required during the infusion and for at least 1 hour after the end of the infusion. Resuscitation equipment must be available. On days where patients are receiving radiotherapy, cetuximab should be given within 2 hours prior to radiotherapy. Cetuximab is contraindicated in patients with known grade 3 or grade 4 hypersensitivity reactions to cetuximab.
Dosage and Administration Procedure:
The total initial dose (first infusion) is 400 mg/mÂ² (80 mL/mÂ² ready-to-use solution) and is administered over a period of 120 minutes (maximum infusion rate of 10 mg/min, corresponding to 2 mL/min ready-to-use solution). Patients must be pre-treated with an antihistamine. Observe the patient during infusion and for one hour afterwards. Check the vital signs pre-, mid-, post- and one hour post-infusion. Use a sterile 0.9% NaCl solution to flush the line at the end of infusion.
The weekly dose (all further infusions) is 250 mg/mÂ² (= 50 mL/mÂ² ready-to-use solution) and is administered over a period of 60 minutes (maximum infusion rate of 10 mg/min, corresponding to 2 mL/min ready-to-use solution). It is recommended that the patient is pre-treated with an antihistamine prior to each infusion. Observe the patient during infusion and for one hour afterwards. Check the vital signs pre-, mid-, post- and one hour post-infusion. Use a sterile 0.9% NaCl solution to flush the line at the end of infusion.
Do not mix cetuximab solution with any intravenously administered medicinal product other than a sterile 0.9 % NaCl solution. Use a separate infusion line for cetuximab infusion. Wait at least one hour after completing the cetuximab infusion before patient receives chemotherapy.
Recommended materials, compatibility and stability
Infusion sets or syringes made of polyethylene, polyurethane, polyolefine thermoplastic, polyamide glass microfibre, polypropylene and polyvinyl chloride have been tested for compatibility with cetuximab, and are recommended for use. Cetuximab is stable, and is compatible with infusion systems made from any combination of the recommended infusion system components when administered at room temperature (up to 25Â°C). Preparations of cetuximab in the recommended infusion containers are chemically and physically stable for up to 48 hours at controlled room temperatures up to 25 Â°C. The product contains no antimicrobial agent and should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. In-use storage at 2-8 Â°C should not exceed 24 hours, unless preparation has taken place under controlled and validated aseptic conditions. Discard any unused portion of the vial.
5FU is commercially available in 10 ml. ampules containing 500 mg. 5FU shall always be administered as a continuous intravenous infusion in D5W or 1/2 NS. The rate of infusion shall remain constant over 96 hours. The first 5FU infusion shall consist of 1000 mg/m2/24 hrs, for 96 hours concurrent with radiation on days 1-4. The maximum 5FU dose per 24 hours shall be 2000 mg, and the total dose shall not exceed 8000 mg in 96 hours.
The second 5FU infusion will be given from days 29 - 32. Major hematopoietic suppression will require that radiation and chemotherapy be delayed 1 week to permit marrow recovery. If persistent hematopoietic suppression indicates 5FU dose reduction, this will be accomplished by administration of 5FU at 750 mg/ m2/24 hrs. for 96 hours, with a maximum of 1500 mg in 24 hours and a total dose of 6000 mg for the 96 hour infusion.
Mitomycin-C is commercially available in vials containing 5 or 20 mg. MMC will be given as an intravenous bolus concurrently with fraction 1 of the course of radiotherapy. The dose of MMC shall be 10 mg/m2, with the maximum dose per administration to be 20 mg. MMC should always be administered via the tubing of a free flowing infusion to minimize the potential hazard of extravasation.
Significant hematopoietic suppression will require that radiation and chemotherapy be delayed to permit marrow recovery. If after a 1 week delay blood counts remain suppressed, reduced dose MMC shall be administered at 7.5 mg/m2, with the maximum second dose to be 15 mg. Severe hematopoietic
suppression will require dose delay, reduction, or deletion. Major, life-threatening hematopoietic suppression (grade 4 toxicity) will mandate deleting the second dose of MMC. Anti-emetic medication in line with local guidelines is highly recommended before, during, and after MMC administration.
Patients must have epidermoid carcinoma of the anal canal confirmed by biopsy
Diagnostic imaging of the pelvis should be available from within 8 weeks prior to randomisation. This should be ideally a MRI scan, but if not available a spiral/multi-slice CT scan will be required. PET CT can be performed if available and may aid in planning of radiotherapy. The last staging assessment using a CT scan of the thorax and abdomen must have been carried out within 6 weeks prior to randomisation. PET scans and bone scans may be performed according to local practice and availability and/or if clinically indicated e.g. bone pain or biochemical profile.
The patient's written informed consent must be obtained on the specified form (appendix XXXX), before any procedures relating to the study are performed, The patient should be given a minimum of 24 hours after the initial invitation to participate before being asked to sign the consent form. The consent form and all other patient information will be included in the Case Report Form (CRF).
Within 2 weeks prior to randomisation:
History and physical examination (to include height, weight and ECOG/WHO performance status) should be performed by the clinical oncologist or authorized specialist registrar.
Quality of life questionnaire (QLQ-C30) and colorectal module (QLQ-CR29)
Blood tests including full blood count, serum electrolytes (including magnesium), serum creatinine, liver and bone profile.
Creatinine clearance calculated using Cockcroft & Gault Formula (Cockroft and Gault, 1976). An EDTA/24 hour urine collection will be required if predicted GFR <60mls/min
Negative pregnancy test in females of child bearing age.
Assessment and follow up
Before any study related procedures are undertaken the patient's written informed consent must be obtained. The patient should be given a minimum of 24 hours after the initial invitation to participate before being asked to sign the consent form.
Assessments during treatment
1. A planning CT scan to be carried out within 3 weeks of start of treatment
2. Physical exam to include weight (weekly).
3. Toxicity assessment (weekly).
4. Full blood count (FBC). As a minimum FBC should include haemoglobin, WBC including ANC and platelets (weekly, to be done within 3 days before the start of each chemotherapy cycle). Haemoglobin should be maintained above 12g/dL during radiotherapy.
5. Serum renal, liver and bone profile (weekly) including urea, creatinine, sodium, potassium, magnesium, corrected calcium, albumin, bilirubin, AST/ALT, ALP and phosphate. An EDTA or 24 hour creatinine clearance should be performed if renal function has deteriorated by more than 25%.
6. Quality of life QLQ-C30 + colorectal module (QLQ-CR29) (week 1, 3, 6)
All blood tests and toxicity assessment using the CTCAE v4.0 toxicity scale should be performed within 3 days before starting each chemotherapy cycle and the results should be available before starting. This is standard practice during the administration of chemotherapy in the UK.
Post treatment (week 6, 12)
1. Physical examination.
2. Toxicity assessment.
3. Quality of life QLQ-C30 + colorectal module (QLQ-CR29)
Long-term follow up
Patients will be seen 3-monthly for the first year, 6 monthly in the 2nd to 6th years after treatment, after which follow up should be according to local guidelines. Repeat imaging using MRI scan or CT scan pelvis will be used to assess treatment response at 3 months, 6 months and 12 months. Further imaging and/or endoscopic assessment will be used to investigate symptoms suspicious of recurrence as clinically indicated. In the case of local recurrence it will be important to ascertain the relationship of the recurrent disease to the radiotherapy field by comparing endoscopic data at recurrence with the diagnostic/staging endoscopy and/or CT data with the staging/planning CT scans.
Case report forms will be checked by the trial management group (TMG) to ensure accuracy, consistency and compliance with protocol. Any discrepancies will be checked by secure written communication between the TMG and centre. Persistent deviations from protocol will lead to reassessment of the trial centre procedures.
Loss to follow-up
If a patient is lost to follow-up the trial management group will request the centre to contact the patient's general practitioner to obtain information on the patient's status.
Direct access to data
Investigators should agree to allow trial related monitoring, including audits and regulatory inspections by providing direct access to source data/documents as required. Patient consent for this will be obtained.
Quality assurance and quality control of data
A quality assurance program will be in place to ensure adherence to the protocol. Major and minor deviations will be collected. A monitoring Standard Operating Procedure (SOP) will be developed for the trial. We aim to review trial documentation and perform source data verification of at least 10% of
patients during the course of the trial.
End of trial
For the purpose of complying with UK Medicines for Human Use (Clinical Trial) Regulations (SI 2004/1021) introduced in May 2004, the end of the trial will be when the last patient has completed protocol treatment and the first 3 month assessment. For the purposes of the Research Ethics Committee approval, the study end date is deemed to be the date of last capture. For this trial this includes follow-up of all patients for a minimum of 6 years. This will be done via the hospital and via the general practitioner if required.
In consenting to the trial, patients are consenting to cetuximab (if allocated), trial follow up and data collection. If a patient wishes to withdraw from cetuximab, participating centres should nevertheless explain the importance of remaining on trial follow up. If the patient explicitly states their wish not to contribute further data to the trial, the research nurse should inform the TMG in writing.
Withdrawal from trial treatment
A patient may withdraw, or be withdrawn, from the treatment protocol for the following reasons:
a) Intolerable adverse effects as judged by the Investigator or the patient.
b) Patient decision to discontinue treatment.
c) Any patient whose treatment is delayed for longer than 3 weeks due to drug treatment related toxicity should discontinue therapy. Treatment delay for radiotherapy should be not be longer than 2 weeks.
d) Serious systemic allergic reaction to any of the study drugs e.g. angio-oedema, anaphylaxis.
The reason should be recorded on the treatment form and the withdrawal form.
In such cases patients will be clinically managed as deemed appropriate by their supervising clinician, but such treatment would not be expected to include cetuximab which is considered as an experimental treatment in this disease. The patient should however remain in the trial for the purposes of follow up and data analysis and follow up CRFs should be returned to the TMG.
Withdrawal from trial completely
If a patient explicitly withdraws consent to have any data recorded, their decision must be respected and recorded on the withdrawal form. Details of the withdrawal form should be noted in the patient records and no further CRFs should be completed for the patient.
The Medicines for Human Use (Clinical Trials) Regulations 2004 apply for this protocol:
Adverse Event (AE): any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product.
Adverse Reaction (AR): any untoward and unintended response in a subject to an investigational medicinal product which is related to any dose administered to that subject.
Serious Adverse Event (SAE): Any adverse event that results in death. Any adverse event which is life-threatening, or requires hospitalisation, or results in persistent or significant disability or incapacity would also be classed as SAEs.
Serious adverse reactions (SARs) are SAEs which are considered by the investigator to be possibly/probably/definitely related to the trial treatment. Most SARs are expected. Serious Adverse Reactions (SARs): SARs are SAEs which are considered by the investigator to be possibly/probably/definitely related to the trial treatment.
Suspected Unexpected Serious Adverse Reactions (SUSARs): These are SARs which are classified as "unexpected" i.e. an adverse reaction the nature and severity of which is not consistent with the information about the medicinal product in question set out in the summary of product characteristics (SPC) and Investigators Brochure (IB) for that product. A copy of the SPCs and IB (cetuximab) for the investigational medicinal products has been sent to sites as part of the investigator site file. If an adverse reaction is more severe than expected or it is thought that it is exacerbated by the study treatments, this must be considered in the assessment of the event.
Expected side effects of cetuximab from protocol treatment (listed in alphabetical order) are shown in Appendix 1.
The sample size was calculated using the ART add-on package with Stata 9 (Barthel et al, 2005). It was based on the best available measures for estimated effect size using the primary outcome variable of relapse-free survival (RFS). A 13-year follow-up study of the UKCCCR ACT 1 trial was published recently (Northwood et al, 2010). The median RFS for patients was localized anal cancer on standard chemoradiation from this study was 4.6 years. This is the best estimate for outcomes in anal cancer with chemoradiation in the UK setting. The hazard ratio for risk of locoregional recurrence in this study was 0.46. A more realistic estimate of the additional effect of cetuximab is from the Bonner trial data in head and neck cancer. The hazard ratio for improvement in RFS with cetuximab chemoradiation in head and neck cancer reported by them is 0.68. 4.6 years was used as the median time to failure for the primary outcome, 0.68 was used as the estimated hazard ratio for improvement in RFS. A significance level of 0.05 and a power of 80% were used. A recruitment period of 3 years with uniform accrual and a follow-up time of 6 years were used. A trial dropout rate of 10% over the total trial period was included. With these statistics, the estimated total sample size is 517.
Treatment allocation will be performed centrally by the trial management group using the method of minimisation. Minimisation will ensure balanced treatment allocation by centre and a number of potential prognostic factors (Treasure and MacRae, 1998). Factors included in the minimization will include tumour stage and performance status. A 1:1 allocation ratio will be used.
Treatment allocation will only be performed after the trial management group has confirmed that the patient is eligible, the patient has signed the consent form and completed a baseline Quality of Life (QoL) questionnaire. After baseline evaluation the research clinician (authorized doctor or specialist trial nurse) should complete the randomisation form and telephone the randomization line. At randomisation, the patient will be allocated to a treatment arm (chemo-radiation or chemo-radiation and cetuximab) and given a unique patient trial number. It may be possible for patients to be enrolled in other clinical trials, provided it will not have any treatment or toxicity interactions. However, this will need to be explicitly discussed with the principal investigator prior to randomization. A dedicated randomisation telephone line will be open working hours.
The primary endpoint in this trial is relapse-free survival. In the context of anal carcinoma, this is a clinically relevant outcome. A 13-year follow-up study of the UKCCCR ACT 1 trial was published recently (Northwood et al, 2010). Only 7% of patients developed metastatic disease without earlier locoregional relapse and there were few locoregional relapses after 5 years. Based on this information, RFS is a good primary endpoint for trials in epidermoid anal cancer. With a relatively long overall survival of 7.6 years reported in the UKCCCR trial, RFS is also the more practical approach for clinical trials in this tumour site. RFS would allow for earlier evaluation of new treatment modalities and earlier incorporation into clinical practice.
The incidence of serious adverse events (SAE) is a secondary endpoint in this trial. This will be measured using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) toxicity score v. 4.0 (appendix XXXX). The NCI CTC were developed in 1982 for use in adverse drug experience reporting, particularly in relation to investigational drugs for the US Food and Drug Administration (FDA). The CTC have been used widely for collecting treatment-related adverse event data to facilitate the evaluation of new cancer therapies. It has been updated in version 4.0 to bring it in line with Medical Dictionary for Regulatory Activities (MedDRA) definitions. The scoring scale is from 1 - Mild, 2 - Moderate, 3 - Severe, 4 - Life-threatening, to 5 - Death. For the purpose of this trial all scores of 3 and above will be recorded as trial-related adverse events. Radiation-related toxicity will be assessed and scored according the RTOG late effects scale (appendix 2).
The other secondary endpoint is quality of life, which will be assessed using two standardized European Organization for Research and Treatment of Cancer (EORTC) questionnaires. Overall quality of life will be measured using the QLQ-C30 quality of life tool (appendix 3), which is a validated questionnaire with 30 questions assessing cancer-specific QoL. The second tool, QLQ-CR29 (appendix 4), assesses site specific (ano-rectal) quality of life. This module is a self-rating questionnaire that comprises 29 questions. It has sections which are specific for patients with stomas and also explores gender-specific problems. The principal items of this questionnaire include urinary symptoms, pain, faecal incontinence, gastro-intestinal function, stoma function and body image. For each question, a scale from 1 to 4 is used (1: not at all, 2: a little, 3: quite a bit, 4: very much). Although the QLQ-CR29 has been validated primarily for colorectal cancer, it has recently been evaluated successfully in patients receiving radiotherapy for anal cancer (Provencher et al, 2010).
An intention-to-treat analysis will be used for this trial. This will allow the trial to maintain the randomization of the groups while also allowing for a pragmatic measure of clinical effectiveness of this treatment strategy for anal carcinoma. A likelihood-based mixed-effects model repeated measures (MMRM) approach will be used to adjust for missing data in the statistical analysis. This has been shown to be superior to simpler methods of adjusting for missing data such as last-observation-carried-forward (Mallinckrodt et al, 2003, Lane, 2008). All deviations from randomization, missing responses and imputation methods used in analysis of missing variables will be reported at the end of the trial.
The main analysis will compare relapse-free survival between the two groups using a log rank test. The secondary outcomes of proportions of patients with SAEs will be compared using a chi-squared test. If the incidence of serious adverse events is very low, the Fisher's exact test will be used to ensure statistical validity. Subgroup analysis will only be carried out to assess for difference in treatment effect in different participant groups using tests for interaction if appropriate.
The trial will be reported in a peer-reviewed journal in full accordance with CONSORT guidelines (Schulz et al, 2010).
The efficacy of cetuximab in combination chemotherapy and chemoradiation regimes in other tumour sites has been clearly demonstrated. Initial US Food and Drug Administration (FDA) approval was granted on 12 February 2004 for cetuximab in combination chemotherapy for colorectal cancer (Food and Drug Administration, 2004). European Union approval was also granted for this indication in the same year. Further approval was granted by the FDA for use in chemoradiation for head and neck cancer in March 2006. The safety profile of cetuximab has therefore been established in post-marketing surveillance since 2004. Ethical and regulatory approval for the trial will be obtained from the Medicines and Healthcare Products Regulatory Agency (MHRA) via the Integrated Research Application System (IRAS) pathway.
All participants will be given an information leaflet with information on the trial and chemoradiation regimen (appendix XXXX). The trial will be introduced to the patient by the oncologist involved in his/her care. Patients will be assured that they will receive the same general standard of care irrespective of their decision relating to participation in the trial. Potential participants will be also informed of safeguards relating to confidentiality of medical records. Data will be handled and stored in accordance with the Data Protection Act (1998). A period of at least 48 hours will be given for the patient to consider the trial prior to consent. The consent form (appendix XXXX) will also be filled by the clinical oncologist or an authorized specialist registrar. All trial investigators and consenting clinicians would require to have undergone Good Clinical Practice (GCP) training, and be on a trial register of authorized personnel.
Funding for the trial will be sought from Cancer Research UK to cover all trial costs and support costs. Excess treatment costs will be met by the manufacturer who will supply the cetuximab medication for all trial patients for the duration of the trial. The total cost of the trial is estimated to be £50000, assuming 10 centres in the UK. A detailed costing analysis will be submitted to each trial sponsor.
5-FU - 5-fluorouracil
AJCC - American Joint Committee on Cancer
AST - Aspartate aminotransferase
ALP - Alkaline phosphatase
ALT - Alanine aminotransferase
CONSORT - Consolidation of the Standards of Reporting Trials
CRF - Case Report Form
CT - Computed tomography
CTC - Common Toxicity Criteria
CTV - Clinical Target Volume
ECOG - Eastern Cooperative Oncology Group
EDTA - Ethylene di-amine tetracetic acid
EGFR - Epidermal growth factor receptor
EORTC - European Organization for Research and Treatment of Cancer
FBC - Full blood count
FDA - US Food and Drug Administration
G1 - cell cycle growth phase 1
G2 - cell cycle growth phase 2
GCP - Good Clinical Practice
GFR - Glomerular filtration rate
GTV - Gross tumour volume
Gy - Gray
HR - Hazard ratio
IRAS - Integrated Research Application System
kRAS - Kirsten rat sarcoma oncogene
MedDRA - Medical Dictionary for Regulatory Activities
MHRA - Medicines and Health Regulatory Authority
MMC - Mitomycin C
MMRM - mixed-effects model repeated measures
MRI - Magnetic Resonance Imaging
NCI - National Cancer Institute
ONS - Office for National Statistics England
PET - Positron emission tomography
PTV - Planning target volume
QoL - Quality of life
RFS - Relapse-free survival
S phase - synthesis phase of cell cycle
SAE - Serious adverse event
SCC - squamous cell carcinoma
SPC - Summary of Product Characteristics
TMG - Trial Management Group
UKCCCR - United Kingdom Coordinating Committee on Cancer Research
WBC - White blood count
WHO - World Health Organization