Microsoft word - cirro-ip020209-lunge.doc

- TARLAL -
- Tarceva And Radiotherapy in Locally Advanced Lung cancer -
Concomitant Tarceva® and irradiation in patients in local-regionally
advanced non-small cell lung cancer. A phase II study.

Version 1.24- 19.3.2009

Protocol committee
Olfred Hansen, Dept. Oncology, Odense University Hospital, Odense, Denmark
Tine Schytte, Dept. Oncology, Odense University Hospital, Odense, Denmark
Carsten Brink, Radiophysic Lab. Dept. Oncology, Odense University Hospital,
Odense, Denmark
Bente Thornfeldt Sørensen, Dept. Oncology, Vejle Sygehus, Vejle, Denmark
Marianne Knap, Dept. Oncology, Århus Kommunehospital, Århus, Denmark
Peter Melgaard, Dept. Oncology, Århus Kommunehospital, Århus, Denmark
Jens Benn Sørensen, Dept. Oncology, Rigshospitalet, Copenhagen, Denmark
Jan Nyman, Dept. Oncology, Rigshospitalet, Copenhagen, Denmark
Hanna Frank, Dept. Oncology, Aalborg Sygehus, Aalborg, Denmark
Anders Mellemgaard, Dept. Oncology, Herlev Hospital, Herlev, Denmark
Bente Holm, Dept. Oncology, Herlev Hospital, Herlev, Denmark
Kim Wedervang, Dept. Oncology and Hematology, Næstved Hospital, Denmark
Principal investigator:
Olfred Hansen, ph.d.
Dept. Oncology
Odense University Hospital
DK-5000 Odense C
+45 65412994
olfred.hansen@ouh.regionsyddanmark.dk
Table of Contents
1. Background . 3
1.1 Concurrent
EGFR blockage of the radiation response . 3 discontinuation of Tarceva in the individual patient. . 5 Criteria for efficiency and data-analysis . 8 Management of radiation complications during radiotherapy . 12 Management of radiation complications. 12 Management of rash inside and out side radiation field . 12 13. Appendixes. 16 Appendix 1: Performance status . 16 Appendix 2: Objective response criteria (RECIST). . 17 Appendix 3: Monitoring and data capture. . 17 Appendix 4: Dosage guidelines for management of study drug related toxicities . 18 Appendix 5: Dose calculation, treatment margins and reporting of the treatment plan . 19 TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer
1. Background
1.1 Concurrent chemo-radiotherapy
Lung cancer is the major cause of cancer-related death in Europe and North America. About 75% to
80% of lung cancer is non-small-cell cancer (NSCLC) with approximately 40% of patients
presenting with locally advanced disease. In patients with no malignant pleural effusions, the
treatment options have been irradiation up to 60-70 Gy against the primary lung tumor and lymph
nodes in mediastinum resulting in a median survival of 6 to 11 months and 5 years survival of 5%.
The treatment have until recently consisted of irradiation of the tumor bed and areas around with
high risk of relapse. The treatment has now being optimized by giving chemotherapy either before
irradiation or concomitant with radiation or both. The irradiation technique have been improved by
introduction of 3D-CT-scan based planning technique, and the prognosis have been somewhat
improved. Data from Odense shows a 5 year survival rate of 16% at 5 years (1). The treatment of
choice for locally advanced NSCLC is radiotherapy combined with chemotherapy since trials using
inductions chemotherapy and/or concomitant chemotherapy have demonstrated increased median
survivals to 13-15 months with a 5 years survival of 10-20%. The rationale for using of inductions
chemotherapy has been to reduce the treatment volume by reducing the tumor burden and to
eradicate micro-metastases.
A significant problem in the treatment of local advanced NSCLC is a high rate of local failure of up to 45% without distant metastases after irradiation. In 200 patients with NSCLC stage III treated in Odense the 1 year survival was 61%. 112 of these had received a platinum based induction chemotherapy regimen, and 3 had concomitant therapy with Taxotere. The local failure free survival was 70% 9 months after start of irradiation and 43 % after one year (unpublished data). The poor local control is partly due to the tumors content of radio-resistant cells in hypoxic areas of the tumor. The radio-resistance is in part due to an up-regulation of the epidermal growth factor receptor (EGFR). The radio-resistance of the tumor cells can be overruled at least from a theoretical point of view by using concomitant treatment with drugs, which either can bring the tumor cells in phases of the cell cyclus in which they are more sensitive to irradiation (G2- and M-phase) or Concurrent chemo-radiation is considered to be standard in radiation of local-regional advanced NSCLC (2). However, a number of patients are unfit or refuse chemotherapy. In these cases
radiotherapy at present has to be administered by itself.
1.2 EGFR blockage of the radiation response
Increased expression of EGFR has been observed in several solid tumors, including NSCLC and
squamous cell carcinoma of the head and neck. EGF binds to the EGFR stimulating
autophosphorylation of the intracellular tyrosine kinase domain of the receptor. Activation of the
EGFR signal transduction pathway enhances cellular processes involved in tumor growth and
progression, including the promotion of proliferation, angiogenesis, invasion, and metastasis.
Blockage of the EGFR signaling pathway has been shown to enhance the radiation response in cell lines and in clinical studies. The blockage can be done by anti-EGFR monoclonal antibody, or by tyrosine kinase inhibitors like Tarceva (Erlotinib). Studies have demonstrated that blockage of the EGFR with the monoclonal antibody Cetuximab (IMC-C225) enhances radiation response in squamous cell lines of the head and neck (3) and in mice carcinomas (4). Blockage of the EGFR signaling pathway by tyrosine kinase inhibitors increased radiation response in human xenografts in mice (5), bladder carcinoma cell lines (6) and breast cancer cell lines (7). In clinical studies, tumors arisen from several different organs have been studied, and increased expression of EGFR has been correlated with disease progression and poor overall outcome after TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer radiotherapy. In a retrospective study of 155 patients with head and neck cancer treated with
standard radiotherapy the level of EGFR expression had highly significant correlation with the
survival rates and loco-regional control, but not with the incidence of distant metastasis (8). In a
randomized phase III study including 424 patients diagnosed with loco-regionally advanced
squamous cell carcinoma of the head & neck, and addition of cetuximab to radiation therapy, a
statistically significant prolongation in overall survival was obtained without augmenting the
radiation side-effects (9).
A small phase I study of daily Tarceva and concomitant chemo-radiotherapy has been carried out
in esophageal cancer (10). The chemotherapy consisted of Cisplatin and 5-FU. The radiation dose
was 50.4 Gy in fractions of 1.8 Gy. Doses of 50 mg, 100 mg, and 150 mg Tarceva daily were well
tolerated. The major toxicity was esophagitis (9% grade 4), diarrhea, skin rash, nausea, and
dehydration. No excess lung toxicity was experienced.
Preliminary data of a small randomized phase II study of ± Tarceva 150 mg/day administered
concomitant with 66 Gy /33 F in patients unfit for chemotherapy indicated that this schedule was
feasible (11). In 22 patients treated with concurrent Tarceva and radiation evaluable for toxicity, no
case of grade 3-4 pneumonitis or esophagitis was observed (information on poster).
1.3 Tarceva
Tarceva (Erlotinib hydrochloride is quinazolinamide that inhibit the intracellular tyrosin kinase
domain of the EGFR. It is formulated as immediate release tablets. Bioavailability of Erlotinib
following a 150 mg oral dose is about 60% (and almost 100% i taken together with food) and peak
plasma levels occur 4 hours after dosing. The median half-life is 36 hours, and the time to reach
steady-state plasma concentration is 7-8 days (12). Smokers have a 24% higher rate of Erlotinib
clearance. Erlotinib is metabolized by the liver cytochrome P450 system primarily by CYO3A4
which may be a cause of interaction with other drugs.
2. Objectives of the study
The trial is a phase II study of daily Tarceva combined with definitive radiotherapy in inoperable
locally advanced non small cell lung cancer (stage IIB-IIIB).
The objective of the phase II trial is to examine Tarceva concomitant with curatively intended irradiation 66 Gy (2 Gy x 33 F, 5 F per week): Primary endpoint - Local failure free survival at 9 months after start of radiotherapy evaluated at CT scan. Secondary endpoints - Toxicity - Local tumor control by CT-scan - Overall response rate (CR + PR). - Local tumor control at 9 months evaluated by PET-CT - Overall TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer 3. Study design and dosing regimen
3.1 Study design
The treatment plan is consisting of radiation; 3-D conformal radiotherapy given together with
Tarceva 150 mg/day. Induction chemotherapy may be used. No concurrent chemotherapy may be
used.

3.2 Dosing regimen
Tarceva will start at the day of the radiation in daily dose of 150 mg. The last dose will be given the
day the radiotherapy stops. Tarceva will be administered continuously for approximately 6.5 weeks.
Drug accountability will be registered according to Good Clinical Practice (GCP). The radiotherapy
is only administrated 5 days a week.
3.3 Interruption or discontinuation of Tarceva in the individual patient.
Toxicity grading will be according to the CTC version 3.0. Following dose adjustment for drug-
related toxicity is recommended: If any grade III or worse toxicity including skin toxicity or
diarrhea occurs, the Tarceva will be paused till toxicity has resolved to a grade II or better. The
Tarceva will be resumed in a dose of 100 mg if the dose before pausing was 150 mg, or 50 mg if the
dose was 100 mg. If the dose was already 50 mg, the Tarceva will not be resumed. The
radiotherapy should be continued. For management of radiation complication during therapy see
section 8.2. Management of Tarceva related toxicities see Appendix 4.
4. Planning of radiotherapy
The planning technique is based on ICRU62 recommendations, and the DOLG 2009 criteria. The
planning may, however, make use of 4-D scans, and that will influence the margins, se below. The
prescribed dose is 66 Gy /33 F / 5 F per week. If induction chemotherapy has been administered
radiation may start within 2-5 weeks after last dose of chemotherapy.
4.1 Target volumes
GTV comprise the tumor as seen on the planning CT scan (the size after chemotherapy) plus any
pathological lymph node during time before start of radiotherapy even if they have disappeared
after induction chemotherapy.
TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer CTV encompass the GTV plus the following margins: 1.0 cm in the mediastinum and 0.5 cm in lung tissue. The margins are modified if the CTV is close to the large vessels, bones, trachea or the thoracic wall, then the anatomic structures constitute the demarcation of the CTV as long as no invasion is seen in the surrounding tissue. For a primary in the lung, not involving the hilar region or the mediastinum, the CTV should not be expanded into the mediastinum. For lymph nodes not invading lung tissue, the CRV should not be expanded into healthy lung tissue. No elective radiation will be used to unaffected lymph nodes. ITV: If the treatment is based on a standard 3D CT scan without 4D planning, the following margins are used: CTV + 0.5 cm. ITV should be set to zero towards columna, apex and contralateral lung. If a 4D CT scan is used for the treatment planning, it is allowed to create patient specific margins. In that case the treatment plan should be carried out on the mid-ventilation phase as described by Wolthaus et al. (13). The size of the margin related to the respiration shall be calculated as described by Van Herk et al. (14). PTV margins should be based on experience related to type of fixation used in the clinic. If patient
specific margins are to be used, a study of the size of PTV margin has to be performed at the
institution. For the patient specific margins, the size of the PTV margin has to be calculated based
on the same formalism as for the ITV (14). For patient specific margins it is important that ITV and
PTV margins are not added linearly but as the square-root of the sum of the squares. Thus it might
be beneficial to expand directly from CTV to PTV, so that the ITV is contained in the PTV, since
most planning systems only supports linear addition of margins. If patient specific margins are
applied, it is important to report the size of the margin (appendix 5).

4.2 Doses to organs at risk
The dose to the lungs, spinal cord, heart, and esophagus must be reported. In the treatment of lung
cancer with combination treatments the dose the constraints to the organs at risk are given as:
1. Both lungs must be outlined: V20 ≤40% i.e. a maximum of 40% of the lungs (outside the GTV)
may receive a dose exceeding 20 Gy or more. 2. The spinal cord must be outlined as the spinal canal: The dose must not exceed 45 Gy. 3. The whole of the heart must be outlined: V50 ≤20%. 4. Esophagus through out the thorax: 66 Gy as a maximum dose.
5. Study population
The study population is patients with NSCLC stage IIB - IIIB without pleural effusion suitable for
curatively intended irradiation and concomitant Tarceva.

5.1 Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for participation in this
program.
- Age
- Patients with histologically or cytologically documented diagnosis locally advanced NSCLC stage IIB to IIIB without pleural effusion - Serum bilirubin must be ≤1.5 upper limit of normal (ULN) - ALAT ≤2 x ULN - Able to comply with study and follow-up procedures TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer - Patients with reproductive potential must use effective contraception
- Written (signed) informed consent to participate in the study
5.2 Exclusion criteria
Patients who meet any of the following exclusion criteria are not to be enrolled in this study: - Any unstable systemic disease (including active infection, unstable angina, congestive heart failure, severe hepatic, renal, or metabolic disease) - Any other malignancies within 5 years (except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer) - Inability to take oral medication, or requirement of intravenous alimentation - Nursing
5.3 Monitoring during therapy
The patient may receive induction chemotherapy before inclusion in the study, and is as such not
part of the study. The patients cannot be included in the study before a plan has been worked out
showing that curatively intended radiation is possible, and informed consent has been obtained (Fig.
1).
Screening/
Treatment Period Day 30-45 after stop of
Baseline
treatment
(1 Hematology: Hemoglobin, WBC, granulocytes and platelet count, INR (Only for patients receiving warfarin or coumarin-derivative). Biochemistry: Alkaline phosphatase, Serum bilirubin, Serum creatinine, ALAT (SGPT), LDH. Only laboratory abnormalities linked to unexpected clinical symptoms will be documented in the CRF. (2 FEV1/FVC test. If neoadjuvant chemotherapy, the test must be performed after cessation of chemotherapy. (3 CT scans, PET CT scans per institutional standards, EBUS or mediastinoscopy may be accepted as mediastinal evaluation if PET-CT is not available (4 If no PET-CT available (5 Side effects to be recorded according to CTC version 3.0 (6 Pharmacy log TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer 5.4 Follow-up
The patients will be followed until 5 years after the start of radiotherapy or to recurrent disease
according to the follow-up schedule. After discontinuation in the study the patient will be followed
according to local standard.
Follow up (±1 month after
30, 36, 42,
start of RT)
48, 54, 60
(1 Hematology: Hemoglobin, WBC, granulocytes and platelet count, INR (Only for patients receiving warfarin or coumarin-derivative). Biochemistry: Alkaline phosphatase, Serum bilirubin, Serum creatinine, ALAT (SGPT), LDH. Only laboratory abnormalities linked to unexpected clinical symptoms will be documented in the CRF (2 FEV1/FVC test. (3 RECIST criteria (appendix 2)
(4 PET CT scans if available at the institution
(5 Radiation sequelae
5.5 Tumor response criteria.
Although PET-CT is allowed, the tumor response will be evaluated according to RECIST-criteria
(version 1.1) by CT-scans of thorax and upper abdomen (15). Suspected recurrent tumor locally or
regionally should verified by biopsy if appropriate.

6. Criteria for efficiency and data-analysis
6.1 Statistical considerations
All calculations will be performed on the basis of intention to treat. 2 sided tests will be performed.
Level of type 1 error is 5%.
6.2 Sample size calculation:
Observed local failure free survival rate after 9 months after initiation of radiation was 70% among
300 patients treated in Odense for NSCLC stage IIB-IIIB. The study will be designed to find local
recurrence free survival of 80% at 9 months after initiation of radiation equivalent to about 6-7
months after finishing radiotherapy. A rate of 80% would be clinical interesting, and should be
included in the confidence interval of the phase II trial at a power of 90%. This requires 57 patients
to be included in the phase II trial.
6.3 Interim analysis
An interim analysis to evaluate toxicity will be performed after patient number 20 has completed
radiotherapy and has one month of follow-up. An independent interim analysis committee will be
TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer appointed to the task. The study will stopped if the rate of grade 4 pneumonitis or esophagitis
exceeds 15% in the study, or unexpected severe toxicity appears at any time.
6.4 Expected time frame of study
The study is expected to recruit patients during a 2-year period starting q2 2009 and ending q2
2011. Analyses of results will be performed 9 months after last patient has been included, and
results will be reported. Further analyses may be performed 5 years after the last patient has been
included. Each site is expected to include between 3-15 patients.
6.5 Data management
Data from all included patients will be reported. Every year during the time of inclusion of patients
to the study and the next 3 year period safety data will be reported to the authorities. After final
analyses of the study the data will stored for 15 years from inclusion of last patient in study. The
data will be available for the authorities at all times.
7. Administration of drugs
7.1 Tarceva® (erlotinib)
Tarceva is an orally active, potent, selective inhibitor of the EGFR tyrosine kinase. Tarceva will be
administered on an outpatient basis at a fixed dose according to schedule as a single daily oral dose.
Dosage is not based upon body weight or body surface area. The Tarceva used in the study after the
induction period in combination with radiotherapy will be labelled to each patient, and records of
batch numbers for each patient will be kept at the pharmacy for 15 years
Prescribed daily dose is to be taken preferably in the morning, with up to 200 mL of water. Tarceva should be taken at least 1 hour before or 2 hours after the ingestion of any food or other medications, including grapefruit juice, vitamins and iron supplements. Missed daily doses should be skipped. Doses should be taken at the same time each day. If the patient vomits after taking the tablets, the dose is replaced only if the tablet can actually be seen and
counted. If a patient misses a dose normally taken in the morning, the dose should not be taken later
on.
7.2 Concomitant medication
Patients with a history of dry eyes should be advised to use an ocular lubricant.
- Concomitant treatment with warfarin or coumarin-derivative is permitted provided increased
vigilance occurs with respect to monitoring INR (International Normalized Ratio). However, it is recommended to use low-molecular heparin. - Patients who receive protocol treatment should not receive any other (non-anticancer) investigational drugs until after the post-treatment assessment (at least 30 days after the final dose of protocol treatment). - Patients who continue to wear contact lenses may have an increased risk of ocular adverse
7.3 Potential drug interactions
Substances that are potent inhibitors of CYP3A4 activity (eg, ketoconazole) decrease Tarceva
metabolism and increase Tarceva plasma concentrations. This increase may be clinically relevant
as adverse experiences are related to dose and exposure; therefore, caution should be used when
administering CYP3A4 inhibitors with Tarceva.
Substances that are potent inducers of CYP3A4 activity (eg, rifampin, phenytoin) increase Tarceva metabolism and significantly decrease Tarceva plasma concentrations. TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer INR elevations and/or bleeding events have been reported in some cancer patients taking warfarin while on Tarceva. Patients taking warfarin or other coumarin-derivative anticoagulants
should be monitored regularly for changes in prothrombin time or INR.
Tobacco smoking may diminish the plasma levels of Tarceva, and may diminish the effect of
radiation and should be avoided during the study period.
8. Adverse events
An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient
administered a pharmaceutical product regardless of its causal relationship to the study treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory
finding), symptom, or disease temporally associated with the use of medicinal (investigational)
product.
The occurrence of an AE may come to the attention of study personnel during study visits and
interviews of a study recipient presenting for medical care, or upon review by a study monitor.
Information to be collected includes event description, time of onset, clinician’s assessment of
grade, relationship to study product (assessed only by those with the training and authority to make
a diagnosis), seriousness, action taken with study drug, outcome, and time of
resolution/stabilization of the event. All AEs occurring while on study must be documented
appropriately regardless of relationship. All AEs will be followed to adequate resolution. All AEs
must be reported on CRF to sponsor in order to record them for a final report to the Danish
Medicines Agency.
Any medical condition that is present at the time that the patient is screened should be considered
as baseline and not reported as an AE. However, if it deteriorates at any time during the study, it
should be recorded as an AE.
Changes in the severity of an AE should be documented to allow an assessment of the duration
of the event at each level of intensity to be performed. Adverse events characterized as intermittent
require documentation of onset and duration of each episode.

8.1 Serious adverse events (SAEs)
An SAE is defined as an AE that meets one of the following conditions:
- Death during the period of protocol defined surveillance
- Life-threatening event (defined as a patient at immediate risk of death at the time of the event)
- An event requiring inpatient hospitalisation or prolongation of existing hospitalisation during the
period of protocol defined surveillance with the exception of treatment-related enteritis or fatigue, leucopenia, thrombocytopenia or hospitalization due to treatment administration or other elective measures - Results in congenital anomaly or birth defect - Results in a persistent or significant disability/incapacity - Any other important medical event that may not result in death, be life threatening, or require hospitalisation, may be considered a serious adverse experience when, based upon appropriate medical judgment, the event may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalisation, or the development of drug dependency or drug abuse. In this study unexpected and related SAEs are defined as adverse reactions with at least a possible relationship to study therapy that are not consistent with the approved summary of product TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer characteristics (SPC) and which to their nature are serious. The SPC is available at: www.emea.europa.eu All SAEs will be recorded on the appropriate SAE CRF, followed through resolution by the investigator, and reviewed and evaluated by the Medical Monitor Abnormal laboratory values and clinical adverse events will be reported as SAEs if they are graded higher than 3 on the CTC v3.0.
Any adverse event that is considered SERIOUS must be reported within one working day
(IMMEDIATELY) by the investigator to the Sponsor. Sponsor must make sure that
information on all suspected unexpected serious adverse reactions (SUSARs) which are fatal
or life-threatening are reported as soon as possible and within 7 days to the Danish Medicines
Agency after sponsor has received knowledge himself (if applicable also to local health
authorities as per national regulations). All other SURSARs must be reported to Danish
Medicines Agency within 15 days. All related and unexpected SAEs are also immediately
reportable to Roche A/S as expedited reports:
Drug Safety Roche A/S
Fax: +45 3639 9930
Tel.: +45 3639 9828/+45 3639 9821
Not immediately reportable SAE:
Progression or deterioration of the malignancy under study (including new metastatic lesions and
death due to disease progression) will be part of the efficacy assessment and should NOT be
reported as AE/SAE. Signs and symptoms clearly associated with the malignancy under study
should NOT be reported as AE/SAE unless:
- Newly emergent (i.e. not present at baseline) and association with the underlying malignancy
and old/new metastatic lesions is unclear - If the investigator attributed deterioration of malignancy-associated signs and symptoms directly - Should there be any uncertainty regarding the attribution of the malignancy under study to an AE, it should be reported as an AE or a SAE accordingly. TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer 8.2 Expected adverse effect
Tarceva: The most common, expected adverse events for Tarceva include: Rash, pruritus, dry skin,
diarrhea, nausea, vomiting, stomatitis, abdominal pain, fatigue, dyspnoe, cough, anorexia, infection,
conjunctivitis, and keratoconjunctivitis sicca.
Irradiation: The toxicity of irradiation of NSCLC is determined of the dose and treatment volume
of organs at risk. These are as followed:
Radiation myelitis4 (neurological deficits) (1: The risk of acute pneumonitis may increase in irradiation when Tarceva is combined with -radiation. The risk of pneumonitis increases with the V20 of the lung. The symptoms may develop before stop of irradiation. The treatment in the case of pneumonitis is steroid ± antibiotics.
(2 Occurrence of esophagitis is connected to treatment volume and concomitant therapy.
(3 Lhermitte sign is a transient self-limiting symptom of radiation impact on the cervical spinal cord.
(4Pericarditis and radiation myelitis: no cases of these side effects are expected in this study.
8.3 Management of radiation complications during radiotherapy
In case of grade 3 or worse esophagitis or pneumonitis, the administration of Tarceva will be
terminated for that patient.

8.4 Management of radiation complications
In case of increasing dyspnoe during radiation or within 3 months after cessation of radiation
pneumonitis must be suspected. Treatment with steroids is recommended e.g. prednisolone 25-50
mg or higher doses if necessary administered as 1-2 daily doses. Since infection is difficult to rule
out, it is recommended to start treatment with antibiotics. Since tumor progression, myocardial
infarction, and tromboembolic conditions may occur in these patients, ECG and appropriate
biochemistry should be obtained. CT-scan or ECCO of the heart may be necessary.
8.5 Management of rash inside and out side radiation field
Management of rash should be treated according to institution guidelines.
9. Ethical consideration
Patients with locally advanced non-small cell lung cancer have a very poor long-time survival as
only about 15% of the patients are alive 5 years after curatively intended radiotherapy (1). A major
cause of these poor results is lack of local control of the tumor after radiotherapy. Standard
treatment prescribes concurrent chemo-radiation but in many cases use of concurrent chemo-
radiation is not feasible. Another problem in the treatment of locally advanced NSCLC is
occurrence of toxicity. There is therefore an urgent need to develop treatment that increases local
control without increasing toxicity to an unacceptable level. The current study is designed to do
that. The protocol fulfils the Helsinki II declaration and the national requirement to studies of
TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer patients with a cancer disease. The patients will be fully informed about the aspects of the treatment
and risk included in participating. Informed consent will be obtained after sufficient time of
reflection has been given.
10. Study conduct and economy
The study is investigator initiated and will be conducted according to the ICH-CGP guidelines and
according to regulatory requirements. Olfred Hansen is the principal investigator (sponsor). The
study is part of the Danish Center for Interventional Research in Radiation Oncology (CIRRO),
protocol CIRRO IP020209. The patients will be recruited among patients referred for treatment at
each participating center. Economical support of 15,000 DKK per patient included to carry out the
study will be applied from the company Roche a/s, DK, which manufacture Tarceva. This support is
to compensate the additional time used by the staff, primarily by research nurses, who help with
registration of effects and side effects of the treatment, and the amount will be paid to the research
unit at the oncology centers. There is no economical befit for neither the department, the
investigators in the study, nor the staff.
11. Publication
The study will be published in an international journal despite the result. The first draft of the
manuscript will be prepared by Olfred Hansen. Other members of the protocol committee will be
authors if the institutions they represent include patients. Any other center including 3 patients or
more will be offered authorship according to the Vancouver rules of authorship.
TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer 12. Reference list
1. Hansen O, Paarup H, Sørensen P, et al.: Kurativt anlagt strålebehandling af lokal avanceret ikke-småcellet lungekræft. Otte års erfaring fra Odense. Ugeskr Læger 167:3497-3502, 2005 2. Jett JR, Schild SE, Keith RL, et al.: Treatment of Non-small Cell Lung Cancer, Stage IIIB: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition). Chest 132:266S-276, 2007 3. Huang SM, Bock JM, Harari PM: Epidermal Growth Factor Receptor Blockade with C225 Modulates Proliferation, Apoptosis, and Radiosensitivity in Squamous Cell Carcinomas of the Head and Neck. Cancer Res 59:1935-1940, 1999 4. Milas L, Fan Z, Andratschke NH, et al.: Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys 58:966-971, 2004 5. Huang SM, Li J, Armstrong EA, et al.: Modulation of Radiation Response and Tumor- induced Angiogenesis after Epidermal Growth Factor Receptor Inhibition by ZD1839 (Iressa). Cancer Res 62:4300-4306, 2002 6. Maddineni SB, Sangar VK, Hendry JH, et al.: Differential radiosensitisation by ZD1839 (Iressa), a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines. Br J Cancer 92:125-130, 2005 7. Rao GS, Murray S, Ethier SP: Radiosensitization of human breast cancer cells by a novel ErbB family receptor tyrosine kinase inhibitor. Int J Radiat Oncol Biol Phys 48:1519-1528, 2000 8. Ang KK, Berkey BA, Tu X, et al.: Impact of Epidermal Growth Factor Receptor Expression on Survival and Pattern of Relapse in Patients with Advanced Head and Neck Carcinoma. Cancer Res 62:7350-7356, 2002 9. Bonner JA, Giralt J, Harari PM, et al.: Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. Proc Annu Meet Am Soc Clin Oncol 22 (Suppl. ):A5507, 2004 10. Dobelbower MC, Russo SM, Raisch KP, et al.: Epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, and concurrent 5-fluorouracil, cisplatin and radiotherapy for patients with esophageal cancer: a phase I study. Anticancer Drugs 17:95-102, 2006 11. Martinez E, Martinez M, Viñolas N, et al.: Feasibility and tolerability of the addition of erlotinib to 3D thoracic radiotherapy (RT) in patients (p) with unresectable NSCLC: A prospective randomized phase II study. J Clin Oncol 26 (May 20 suppl; abstr 7519), 2008 12. Johnson JR, Cohen M, Sridhara R, et al.: Approval Summary for Erlotinib for Treatment of Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer after Failure of at Least One Prior Chemotherapy Regimen. Clin Cancer Res 11:6414-6421, 2005 TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer 13. Wolthaus JWH, Sonke JJ, van Herk M, et al.: Comparison of Different Strategies to Use Four-Dimensional Computed Tomography in Treatment Planning for Lung Cancer Patients. Int J Radiat Oncol Biol Phys 70:1229-1238, 2008 14. Van Herk M, Remeijer P, Rasch C, et al.: The probability of correct target dosage: dose- population histograms for deriving treatment margins in radiotherapy. Int J Radiat Oncol Biol Phys 47(4):1121-1135, 2000 15. Eisenhauer EA, Therasse P, Bogaerts J, et al.: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009 16. Knoos T, Wieslander E, Cozzi L, et al.: Comparison of dose calculation algorithms for treatment planning in external photon beam therapy for clinical situations. Phys Med Biol 51(22):5785-5807, 2006 17. Sonke JJ, Lebesque J, van Herk M: Variability of Four-Dimensional Computed Tomography Patient Models. Int J Radiat Oncol Biol Phys 70:590-598, 2008 18. Wolthaus JWH, Schneider C, Sonke JJ, et al.: Mid-ventilation CT scan construction from four-dimensional respiration-correlated CT scans for radiotherapy planning of lung cancer patients. Int J Radiat Oncol Biol Phys 65:1560-1571, 2006 19. Bertelsen A, Nielsen M, Westberg J, et al.: The representitativeness of patient position during the first treatment fractions. Acta Oncol in press, 2008 TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer 13. Appendixes
Appendix 1: Performance status
Eastern Cooperative Oncology Group
(Zubrod-ECOG)1,2
Description Grade Fully active, able to carry on all pre-disease activities without restriction. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature e.g. light house work, office work. Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours. Capable of only limited self care, confirmed to bed or chair more than 50% of waking hours. Completely disabled. Cannot carry on any self care. Totally confined to bed or chair. 1 Zubrod, C.G., et al. Appraisal of Methods for the Study of Chemotherapy of Cancer in Man. Journal of Chronic Diseases, 11:7-33, 1960. 2 Oken, M.M., et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol (CCT) 5: 649- TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer

Appendix 2: Objective response criteria (RECIST).

Complete Response: Disappearance of all clinical and radiological evidence of tumor (both target
and nontarget) including normalization of elevated tumor markers at baseline, if documented. The
patient must be free of all tumor-related symptoms. Complete Response must be confirmed at a
second tumor assessment not less than 28 days apart from the assessment at which CR was
observed.
Partial Response: At least a 30% decrease in the sum of LD of target lesions taking as reference
the baseline sum LD. Partial Response must be confirmed at a second tumor assessment not less
than 28 days apart from the assessment at which PR was observed.
Stable Disease: Steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD. Stable disease must be documented to be present at least 28 days from
the start of the therapy. There may be no appearance of new lesions for this category.
Progressive Disease: At least a 20% increase in the sum of LD of measured lesions taking as
references the smallest sum LD recorded since the treatment started. Appearance of new lesions
will also constitute PD. In exceptional circumstances, unequivocal progression of nontarget lesions
may be accepted as evidence of disease progression.


Appendix 3: Monitoring and data capture.

Study conduct and monitoring will be done according to GCP. The monitoring will be performed
by the GCP unit at Odense University Hospital together with the GCP units at participating centers.
TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer Appendix 4: Dosage guidelines for management of study drug related toxicities
Toxicity,
Study Drug Dosage
CTC Grade
Modification
Guideline for Management
Diarrhea
Consider Loperamide (4 mg at first onset, followed by 2 mg every 2 – 4 hours until diarrhea free for 12 hours) Appropriate rehydration Loperamide (4mg at first onset, followed by 2 mg every 2 – 4 hours until diarrhea free for 12 hours) Appropriate rehydration Loperamide (4 mg at first onset, followed by 2mg
every 2 – 4 hours until diarrhea free for 12 hours)
and Interrupt TarcevaTM until resolution to Grade ≤
1, and restart at reduced dose
Appropriate rehydration
Loperamide (4 mg at first onset, followed by 2mg every 2 – 4 hours until diarrhea free for 12 hours) Appropriate rehydration Rash
Any of the following: minocycline a, topical tetracycline, topical clindamycin, topical silver sulfadiazine, diphenhydramine, oral prednisone (short course) at discretion of the investigator. (or intolerable re-escalated when rash is ≤ Recommended dose: 200 mg orally bid (loading dose) followed by 100 mg orally bid × 7–10 days. TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer Appendix 5: Dose calculation, treatment margins and reporting of the treatment plan
1. Planning
Energy for treatment is 6-10 MV. If available the treatment plans should be calculated using models
that in an approximate way consider changes in lateral electron transport (e.g. Pinnacle/CC,
Eclipse/AAA, OMP/CC and XiO/Super ) (16).
2. Margins
The planning margins needed to ensure dose coverage of a tumour depends strongly on the imaging
equipment used for planning of the treatment and as well as the imaging equipment used during the
treatment. New emerging technique (e.g. 4D CT and Cone Beam CT) will soon make it possible
individualise the margins for each patient. However, these techniques are not standard clinical
practice yet thus each institution can choose between two different sets of margins 1) standard
margins 2) individual margins. Each institution shall report which of the two sets of margins they
are using. For the individual margins all patient specific value of Σ and σ shall be reported for each
patient (all institution specific values of Σ and σ is only to be reported for the first patient)
2.1 Standard margins
Refer to protocol §4.1.
2.2 Individual margins
GTV and CTV as for standard margins (refer to protocol §4.1).
ITV and PTV is combined to one volume based on the margin formula by (14) Herk et al.
PTV: The PTV is the CTV plus a margin of M as defined below:
where Σ and σ is the standard deviation of the systematic and random uncertainty, respectively. σp is a measure for the shape of the penumbra of the total dose distribution. The β-value is a constant related to the isodose level which should cover the target. For coverage of the target by 95% of the prescribed dose the value of β is 1.64 (for details see (14)). Since M depends on σp, M depends on the field arrangement as this can influence the shape of the penumbra of the overall treatment plan. However, the exact value of σp is not very critical since the margin recipe do only depend weakly on this value. Typical value of σp is 6-7 mm in the lung region (17). Both Σ and σ is a combination of all the uncertainties involved in the treatment process which can be divided in tumour delineation (no random component), intra-fractional tumour uncertainty and inter-fractional tumour uncertainty. The idea of using patient specific margins is to minimize the margins as much as possible for the individual patient. To achieve this goal a number of the above mentioned uncertainties needed to be assessed in the specific institution. Below is a brief description of each uncertainty. For some of the components typical values are given, however these needs to be validated at each institution. It should also be stressed that residual errors will always persist, thus for some of the uncertainties a lower bound of the value is given. Σdelineation: Difficult to measure, a value of 2 mm shall be used for a 4D planning CT (17). The uncertainty is larger for a 3D CT due to distortion of the tumour. TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer Σintrafractional: For standard 3D planning CT equal to σintrafractional. Using 4D CT planning can be based on the mid-ventilation phase (18). For planning using the mid-ventilation phase Σintrafractional is very close to zero. However, a residual error will always exist, thus a value of 1 mm is to be used. σintrafractional: Is to be measured in a 4D CT as the standard deviation of the tumour position in each respiration. A lower bound of 1 mm is to be applied for σintrafractional. The values of Σinterfractional and σinterfractional need to be assessed in each individual institution. The inter-fractional uncertainty depends strongly on the imaging technique used during the treatment. Especially it is important whether the imaging is based on the bony anatomy or on the soft tumour tissue. If the imaging technique is based on bony landmarks the inter-fractional uncertainty needs to include the movement of the tumour relative to the bony structure ( 2 baseline and σbaseline is 2-4 mm and 2 mm, If the imaging is based on the soft tumour tissue the inter-fractional component do not contain two component, but is just the setup uncertainty relative to the soft tissue. Typical values of Σinterfractional and σinterfractional are about 1 mm (17, 19). In Sonke et al (17) there is a graph (fig. 5) showing an example of the overall CTV to PTV margin in their institution. It is seen that the margin do not dependent strongly on the respiration amplitude. This does not indicate that it is possible to just apply a large value of the respiration movement and then disregard 4D CT for treatment planning. The data in Sonke et al. is based on the assumption that the treatment planning is performed in the mid-ventilation phase which is only possible if a 4D CT is used for treatment planning. It is important to stress that all the above mentioned typical values is only a guideline for the approximate size of the individual parameters. All the values need to be validated at the local
institution before use.
3. Reporting of the treatment plan
Reporting of the physical properties of the treatment plan is based on DICOM RT. All plans will be
collected in a database such that whey will be available to all institutions.
The database will be hosted at Odense University Hospitals and will be available as a service on on a closed net dedicated for transfer of patient data on secure lines. All data is reported in DICOM RT such that each institution by a simple operation can export al available instead of using time to extract a few key values of the DVH’s After upload of the treatment plan (CT images, point, regions of interest, dose and plan) the DVH data will be extracted and added to a common database. Names of Regions of interest (ROI): In order to obtain usable information from the DICOM RT plans it is important that regions which might be of scientific interest are named in the same way for all patients within each institution. Thus each institution should report a list of their naming convention such that their DVH structures can be recognised automatically. The list of ROI names should consist of the following regions: Left Lung (suggestion LeftLung) Right Lung (suggestion RightLung) Heart (suggestion Heart) TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer The spinal canal (suggestion Medulla) Esophagus (suggestion Esophagus) Gross tumour volume (suggestion GTV or if more than one GTV1, GTV2, …) Clinical target volume (suggestion CTV or if more than one CTV1, CTV2,…) Internal target volume (suggestion ITV or if more than one ITV1, ITV2,…) Planning target volume (suggestion PTV or if more than one PTV1, PTV2,…) It is important to be consistent in the names of ROI. However, misunderstanding will occur thus each institution should also forward an e-mail on the person to contact if interpretation of the ROI name is not feasible. TARLAL - Tarceva And Radiotherapy in Locally Advanced Lung cancer

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