Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03632603 |
| Other study ID # |
PARAT |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
November 22, 2018 |
| Est. completion date |
August 2025 |
Study information
| Verified date |
May 2024 |
| Source |
University of Aarhus |
| Contact |
Marianne Marquard Knap, PhD, MD |
| Phone |
0045 22985576 |
| Email |
mariknap[@]rm.dk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The aim of this study is to examine if a shorter palliative radiotherapy fractionation scheme
of 20 Gy / 4 F can reduce the early oesophageal toxicity compared to 30 Gy / 10 F in patients
with lung cancer in performance status (PS) 0-2. Secondary aims are to examine the effect on
lung cancer symptoms, quality of life (QoL) and survival. Furthermore, the investigators aim
at standardizing the quality of palliative thoracic radiotherapy in all Danish centres at the
highest technical level.
Description:
1. Background 1.1 Radiotherapy in lung cancer Non-small-cell lung cancer (NSCLC) is the
leading cause of cancer-related death in both men and women [1]. In stage IV disease
platinum-based chemotherapy yields a median overall survival (OS) of 8-10 months [2].
When diagnosed, more than 50% of the patients have distant metastases. Forty percent
have signs or symptoms originating from the thorax: dyspnoea, cough, haemoptysis,
recurrent pneumonia or chest pain [3]. Palliative thoracic radiotherapy can relieve
symptoms originating from intra-thoracic malignancy and improves quality of life (QoL)
in approximately one third of patients [4]. It is increasingly used in daily clinical
practice as an alternative to chemotherapy in patients without local symptoms with the
purpose of prolonging life and avoiding local thoracic symptoms. In addition, palliative
radiotherapy is used to relieve symptoms before initiating systemic treatment
(chemotherapy, targeted agents, immune therapy, etc). In this latter case, it is
important not to delay the systemic treatment unnecessary with long schedules of
radiotherapy. An optimal radiotherapy regimen will thus palliate symptoms with minimal
toxicity and consider the patient's time investment, as well as be compatible with any
additional treatments given. In a recent retrospective study of 159 consecutive Danish
NSCLC patients who received palliative thoracic radiotherapy (2010-11) median survival
was 4.2 months. One third of the patients died within two months and 22% within 30 days
[5]. This further underlines the importance of not subjecting patients to prolonged,
toxic treatments in their final year of life. A recent Cochrane review [6] found that
there was no consistent evidence to support that longer, more fractionated radiotherapy
regimens gave better or more durable palliation than shorter regimens. Furthermore,
there was no significant survival advantage associated with longer regimens with higher
biological radiation doses.
The most common acute toxicity is oesophagitis. It is often not technically possible to
avoid high dose exposure to the oesophagus because of the target localization in
proximity to the mediastinum. Radiation-induced oesophagitis is most often a reversible
condition. However, it compromises swallowing due to pain, causes weight loss and
deterioration of the performance state (PS) and QoL at a vulnerable time for the
patient, and it may impact the possibility of receiving further anti-neoplastic
treatment. The Cochrane review found that up to 50% of patients receiving palliative
thoracic radiotherapy reported severe oesophagitis. The studies differed widely in terms
of physician- or patient self-assessment, timing, and the method used, and no overall
judgement could be made. The review concluded that toxicity was comparable between
different radiotherapy regimens. However, recording and reporting of early toxicity was
lacking in the included studies. This absence of early toxicity data means that the
current evidence is insufficient for clinical decision making in this patient group.
2. Study design The patients will be invited to participate in the study prior to
initiation of palliative radiotherapy. After signing informed consent the patients will
be randomized 1:1 between two different radiotherapy dose fractionations: 30 Gy/10 F or
20 Gy/4 F. Physicians and patients will not be blinded to the randomization.
2.1 Systemic therapy Patients can receive chemotherapy, immunotherapy and targeted
therapy during radiotherapy.
2.2 Study sample size and time frame According to the Danish Lung Cancer Registry, 50%
of the 4700 lung cancer patients diagnosed yearly are in advanced stage. Of these, one
third is supposed to benefit from palliative thoracic radiotherapy and of these, 400
patients (~50%) are expected to be enrolled on the trial each year. Since 1184
consecutive patients are required (see chapter 7) the study is expected to enrol
patients over a 3-year period. Given the declared support of all Danish radiotherapy
centres, this is considered a realistic time frame.
Following study closure, 3 weeks of follow-up after radiotherapy initiation will be
allowed for all patients, at which point data will be collected for primary analysis.
Further analysis will be performed 1 and 3 years after the last patient is enrolled.
Data will be kept in databases 15 years after the last patient is included.
3. Radiotherapy treatment planning 3.1 Target and organs at risk The gross tumour volume
(GTV) is defined by the referring oncologist based on a planning CT scan, and if
available, a diagnostic PET/CT scan. The oncologist will note in the CRF if the GTV
fully or only partially encompass all active malignant disease in the thorax. The
clinical target volume (CTV) is identical to the GTV, and thus not delineated.
Spinal cord or spinal canal, total lung, heart and the oesophagus are delineated for all
patients based on the guidelines in [5,6]. The heart is cranially limited defined by the
division of truncus pulmonalis. The oesophagus is delineated from cartilago criocoideum
to the gastro-oesophageal junction.
3.2 Dose planning Patients are treated with conformal treatment plans, conventional or
intensity-modulated.
4. Treatment verification and quality assurance 4.1 Verification of treatment position
Daily imaging must be performed and used for daily correction of treatment position.
5. Participants Patients with lung cancer stage III-IV not suitable for curative treatment,
being referred for palliative radiotherapy either alone or in addition to systemic
treatment.
5.1 Evaluations during treatment and follow up 5.1.1 Expected side effects Palliative RT
comes with a risk of side-effects including fatigue, pain and soreness in the throat and
chest, reddening of the skin in the irradiated area and dry cough and dyspnoea.
5.1.2 Scoring of symptoms and QoL Symptom scores on oesophagitis, cough, pain, dyspnoea,
bronchopulmonary haemorrhage, performance status and QoL will be registered at baseline,
end of treatment, 2 weeks, 3 weeks, 8-10 weeks and 6 months after radiotherapy
completion. If the patient has symptoms which need clinical assessment, the patient will
get an appointment with a physician. All complication (side effects) will be evaluated
according to the NCI-CTCAE v 5.0 during all follow-up visits or calls [7]. See appendix
C for an overview of the CTCAE v 5.0. Table 6.1 shows the evaluation plan for the trial.
Symptom scores on oesophagitis, cough, pain, dyspnoea, bronchopulmonary haemorrhage, and
assessment of performance status will be registered during the patient on-site visit at
baseline, end of treatment, 8-10 weeks after treatment and 6 months after treatment
completion. At 2 weeks and 3 weeks, symptom scores will be registered by a phone call.
Questionnaires for registration of QoL will be filled in on-site by the patient at
baseline, end of treatment, 8-10 weeks after completion of treatment and 6 months after
completion of treatment. In addition, two questionnaires for registration of QoL to be
filled in 2 weeks and 3 weeks after completion of treatment will be handed out at end of
treatment. During the phone calls at 2 weeks and 3 weeks, the patient will be reminded
to fill in the questionnaire. The questionnaires will be collected at the on-site visit
at 8-10 weeks after treatment. One or both phonecalls at 2 weeks and 3 weeks may be
substituted by on site visits.
After the end of the study-specified visit, patients will be seen every 3rd month
according to the guidelines by the Danish Health Authorities. Evaluation of toxicity
will be performed at every occasion. End of study is 3 years after commencement of
radiotherapy.
5.2 Quality of Life To examine the participants' quality of life (QoL) during follow up,
they will be asked to fill in a QoL questionnaire. The EuroQoL 5D (EQ-5D-5L)
questionnaire will be used.
6. Statistical considerations and planned data analyses 6.1 Sample size calculation for
primary endpoint - acute oesophagitis The primary study endpoint is reduction in early
oesophageal toxicity, as assessed two weeks after completion of radiotherapy. The
investigators assume that 50% of patients who receive the standard treatment (30 Gy in
10 fractions) will experience grade 2 or worse oesophagitis, compared to their baseline
prior to treatment. A reduction in acute toxicity of 10%-point with the experimental
treatment (odds ratio between arms of 0.67) will be clinically meaningful and will
justify a change of practice for this patient group. This corresponds to an expected 40%
rate of acute oesophagitis in the experimental arm. With 90% power and a 2-sided type 1
error rate of 5%, 1184 patients will be required (assuming 1:1 allocations between
treatment arms, and incorporating a 10% loss to follow-up). There are some clinical
indications that oesophageal-related toxicity will mainly be seen in patients with
centrally located tumours (where palliative radiotherapy results in irradiation of
mediastinal structures). These patients make up approximately two thirds of the
palliative radiotherapy patient population. An incidence of oesophagitis of 70% in these
patients (and ~10% in patients with peripheral tumours) is consistent with the observed
overall toxicity rate. Enrolling 790 patients with central tumours in the study will
result in >95% power to detect a 15%-point reduction of toxicity in this subgroup, from
70% to 55% (consistent with an overall reduction of 10%, assuming very limited effect in
patients with peripheral tumours). Alternatively, there will be nearly 80% power to
detect a 10%-point toxicity reduction in the central tumour subgroup. Any such subgroup
analyses will be completely exploratory. All sample size and power calculations for the
primary endpoint are based on two-group chi-squared tests (continuity corrected) of
equal proportions.
6.2 Non-inferiority of overall survival Current best evidence indicates that overall
survival should not be different with shorter compared to longer palliative treatment
regimens, although the literature is not conclusive. The proposed study will have the
power to test for non-inferiority of the short (experimental) treatment arm compared to
the standard treatment: Assuming a median OS of 4.2 months, inclusion of 1184 patients
over 3 years (with one year of additional follow-up) will give approximately 90% power
to test that median OS in the experimental arm is at most 3 weeks shorter than in the
standard arm (one-sided significance level of 95%). Power calculations for overall
survival are based on Cox's proportional hazards model.
6.3 Planned data analyses All analyses will be conducted on an intention to treat (ITT)
basis. The primary endpoint analysis will take place once all enrolled patients have
reached the primary endpoint assessment (2 weeks after completion of radiotherapy). A
multivariate logistic regression model will be used to compare rates of grade 2+ acute
oesophagitis in the two treatment arms, adjusted for stratification factors. Robustness
of the primary endpoint to the timing of oesophagitis assessment will be examined in
secondary analyses, comparing the two arms with respect to oesophagitis rates at 3 weeks
after end of therapy as well as oesophagitis rates at 4 weeks after the start of therapy
(two weeks after end of therapy in the standard arm and three weeks after end of therapy
in the experimental arm). Significance testing will be two-sided, with a 95%
significance level.
Analysis of secondary endpoints will depend on the follow-up required for each endpoint;
with most endpoints (QoL, response assessment) available at the time of primary
analysis, and initial analysis of overall survival conducted one year after
randomisation of the final patient.
6.4 Randomization
- Patients are stratified prior to randomization by treatment institution,
performance status 0/1 versus 2, and histology (small cell carcinoma vs squamos
cell carcinoma vs non-squamos cell carcinoma).
- Patients will be randomized 1:1 between the two different radiotherapy dose
fractionations
7. Complications All complication (side effects) will be evaluated according to the
NCI-CTCAE v 5.0 during all followup visits.
8. References [1] Jemal A, CA Cancer J Clin 2011 Mar;61(2):69-90 [2] Wao H, Syst Rev 2013
Feb 4;2:10 [3] Beckles MA1Chest. 2003 Jan;123(1 Suppl):97S-104S. [4] L angendijk JA, Int
J Radiat Oncol Biol Phys 2000 Apr 1;47(1):149-55 [5] Støchkel Frank M, BMC Palliat Care.
2018 Jan 5;17:15. [6] S tevens R, Cochrane Database Syst Rev 2015 Jan 14;1:CD002143. [7]
Kong FM, Int J Radiat Oncol Biol Phys 2011 Dec 1;81(5):1442-57.
