Clinical trial NCT01014130: Hypofractionated Radiotherapy (Stereotactic) Versus Conventional Radiotherapy for Inoperable Early Stage I Non-small Cell Lung Cancer (NSCLC)
Official title: A Randomised Phase III Trial of Highly Conformal Hypofractionated Image Guided ("Stereotactic") Radiotherapy (HypoRT) Versus Conventionally Fractionated Radiotherapy (ConRT) for Inoperable Early Stage I Non-small Cell Lung Cancer (CHISEL)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Non Small Cell Lung Cancer
Keywords: Non Small Cell Lung Cancer
Hypofractionated
Stereotactic Radiotherapy
Lead sponsor: Trans Tasman Radiation Oncology Group
Sponsor class: OTHER
First posted: 2009-11-16
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to investigate whether radiotherapy given as three large doses over a period of two weeks (hypofractionated radiotherapy) is more effective than standard radiotherapy for patients with non-small cell lung cancer that has not spread beyond the lung. Although surgery is the most effective treatment for early lung cancer, many patients are not fit enough for an operation. The alternative treatment to surgery is standard radiotherapy which is normally 'fractionated' that is, given as a number of small doses over a period of weeks. Experience has shown that many small treatments are safer than using a few large doses (hypofractionation) because there is less risk of damage to normal tissues.

Recent advances in technology have however resulted in greater accuracy and with it a reduction in the amount of normal tissue affected by the radiation, so the risks of hypo-fractionation damaging normal tissue are of less concern. Initial results obtained with hypo-fractionated radiotherapy for early stage non-small cell lung cancer indicate that it may be more effective in controlling the cancer. However, it has never been compared directly with standard fractionation in a randomised trial, so this study aims to determine if hypo-fractionation is more effective, results in longer life expectancy and if it is just as safe as standard fractionation.

Detailed description: This is a multicentre randomised phase III trial comparing hypo-fractionated ("stereotactic') radiotherapy with conventional radiotherapy with or without chemotherapy in patients with inoperable stage 1 peripherally located non-small cell lung cancer.

The accepted standard of care for stage 1 non-small cell lung cancer (NSCLC), that is, T1 or T2 tumors that have not metastasised to the regional lymph nodes, is surgical resection. However, many patients with lung cancer have significant cardiovascular and respiratory co morbidities which render them unfit for an operation. For these patients, the standard of care is radiotherapy - conventional fractionation (ConRT) which is administered as 20-30 fractions over a period of four to six weeks. This reduces the likelihood of long term damage to incidentally irradiated normal tissues compared with non-fractionated treatment. Local failure for this method, varies considerably between reports ranging from 6-70% with a median value of 40% using a current best practice for inoperable NSCLC dose of about 60 Gy. Concomitant chemotherapy in addition to CF improves local progression free survival by 16% at two years compared with radiotherapy alone.

Highly conformal hypo-fractionated image guided radiotherapy is an emerging technically complex method for precision irradiation of stage 1 NSCLC using doses with a higher biological effect than can be achieved with standard treatment techniques. Although rates of local control using hypo-fractionation appear greater, there are risks with serious late toxicity. However, there is recent evidence that 54-57Gy delivered in 3 fractions can be delivered safely with no excessive toxicity, provided the tumour has a peripheral location, the chest wall is not included in the high dose volume and the treatment plan is highly conformal. Although hypo-fractionation under the above conditions appears to be tolerable, and is associated with high levels of local control, the results of a small number of phase II trials cannot be regarded as sufficient evidence to recommend it as the standard of care for inoperable stage I NSCLC.

This randomised phase III trial tests whether highly conformal hypo-fractionated image guided radiotherapy for peripherally located inoperable T1 and T2a NSCLC using a dose of 54 Gy in three fractions results in superior control of disease at the primary site compared with standard care consisting of conventionally fractionated radiotherapy with or without concomitant chemotherapy.

Treatment summary: Investigational arm - radical radiotherapy to a total dose of 54 Gy in 3 fractions of 18 Gy each, delivered weekly on days 0, 7 and 14 with a maximum deviation of +/- 2 days from the specified time allowed. Conventional arm - radical radiotherapy to a total dose of 60-66 Gy in 30-33 daily 2 Gy fractions over 6 weeks, with or without chemotherapy consisting of weekly carboplatin at an AUC of 2 and paclitaxel 45 mg/m2.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed non-small cell lung cancer diagnosed within 6 weeks prior to randomisation. The following primary cancer types are eligible: squamous cell carcinoma, adenocarcinoma, large cell carcinoma, bronchioloalveolar cell carcinoma, large cell neuroendocrine, and non-small cell carcinoma not otherwise specified.
* Aged 18 years or older.
* Disease stage T1N0 or T2aN0 (UICC TNM stage, 7th Ed, 2009), based on FDG PET/CT performed within 4-6 weeks prior to randomisation. T stage should be based on tumour size alone (i.e. no atelectasis).
* An ECOG performance status score of 0 or 1.
* The tumour has a peripheral location, defined as at least 1 cm beyond the mediastinum and 2 cm beyond the bifurcation of the lobar bronchi.
* Tumour is assessed as inoperable either i) because of unfitness for surgery as determined by the lung multidisciplinary team including thoracic surgeons and respiratory physicians or ii) because the patient refuses surgery.
* Female patients of childbearing potential and male patients must agree to use adequate contraception throughout the treatment phase of the study.
* If female and of childbearing potential, a negative pregnancy test was performed within 7 days prior to randomisation.
* Patient is expected to survive and be available for follow up for two years.
* Patient has provided written informed consent for participation in this trial prior to any protocol-specified procedures.
* Patient undergoing chemoradiation has satisfactory haematological and biochemical parameters as described below:

  * ANC ≥ 1.5 x 109,
  * Platelets ≥ 100 x 109/L, Hb ≥ 100g/L,
  * Creatinine clearance ≥ 40mls/min (patients with calculated creatinine clearance ≥ 40mls/min and \< 60mls/min must have this confirmed by nuclear medicine GFR scan),
  * Bilirubin \< 1.5 x ULN, and
  * ALT or AST \< 2x ULN.

Exclusion Criteria:

* Centrally located tumours (\< 1.0 cm from mediastinum or \< 2.0 cm from bifurcation of lobar bronchus).
* Tumours within 1.0 cm of the chest wall.
* Prior chemotherapy.
* Previous radiotherapy to the area to be treated.
* Women who are pregnant or lactating.
* Patient with multiple synchronous primary tumours requiring radiotherapy.

Primary outcomes:
measure: Time to Local Failure
timeFrame: Completion of the two year follow up period for all patients.
Secondary outcomes:
measure: Overall Survival
timeFrame: Completion of the two year follow up period for all patients.
measure: Cancer Specific survival
timeFrame: Completion of the two year follow up period for all patients.
measure: Treatment Related Toxicity
timeFrame: Completion of the two year follow up period for all patients.
measure: Quality of Life
timeFrame: Completion of the two year follow up period for all patients.
Other outcomes:
Locations:
city: Canberra
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: Calvary Mater Hosipital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Bendigo
country: Australia
facility: Peter Maccallum Cancer Centre
state: Victoria
city: Heidelburg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre - Box Hill
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre - Morrabbin
state: Victoria
city: Prahran
country: Australia
facility: Alfred Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Epsom
country: New Zealand
facility: Auckland Hospital
state: Auckland
city: Roslyn
country: New Zealand
facility: Midcentral District Health Board
state: Palmerston North
city: Christchurch
country: New Zealand
facility: Canterbury District Health Board
Study officials:
affiliation: Peter MacCallum Cancer Centre, Australia
name: David Ball, MBBSMDRANZCR
role: STUDY_CHAIR
References:
citation: Ball D, Mai GT, Vinod S, Babington S, Ruben J, Kron T, Chesson B, Herschtal A, Vanevski M, Rezo A, Elder C, Skala M, Wirth A, Wheeler G, Lim A, Shaw M, Schofield P, Irving L, Solomon B; TROG 09.02 CHISEL investigators. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol. 2019 Apr;20(4):494-503. doi: 10.1016/S1470-2045(18)30896-9. Epub 2019 Feb 12.