Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02367443 |
| Other study ID # |
CentralHMIA |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
March 2014 |
| Est. completion date |
January 1, 2020 |
Study information
| Verified date |
November 2019 |
| Source |
Independent Public Care Health Facility of the Ministry of the Interior and Warmian & Mazurian Oncology Centre |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This is a phase I/II trial on concomitant RT-full dose CHT using accelerated
hypofractionation schedule as currently being in routine use in Poland for sequential
combination or RT alone. Objectives of the study are: to estimate rate of grade ≥ 3 CTCAE
adverse effects related to treatment and to estimate tumor control, progression
free-survival, and overall survival in patients treated with this regimen. Stage III NSCLC
patients are treated according to the following schedule: RT: 58.8 Gy in 21 fractions (2.8
Gy/fraction, 5 times a week, 6 times in the third week; CHT concomitant with RT (2 cycle of
Cisplatinum and Vinorelbine, every 21 days). Feasibility of the studied approach is evaluated
by scoring the toxicity during RT-CHT and therafter, as well as percentage of treatment
completion; efficacity is evaluated by estimation of local control and survival. If toxicity
and efficacity are similar or better than those observed in modern series of conventionally
fractionated RT-CHT, the studied regimen will become a routine treatment schedule in our
institution in order to spare RT resources. In the future, a randomized comparison of the
studied schedule with conventionally fractionated RT-CHT for locally advanced NSCLC is also
planned.
Description:
1. Background Lung cancer is the most common malignancy in Poland. In 2013, the annual lung
cancer incidence in Poland was 175/100 000 in men and 95/100 000 in women, substantially
higher than the EU value. Poland and UK are the first countries in Europe, where the
mortality from lung cancer has overtaken the mortality from breast cancer and became the
first cause of mortality from cancer in women. Thus besides the problem of prevention,
the efficient and rational from economical point of view treatment of lung cancer is one
of the crucial problems in Polish healthcare system. Prolongation of overall treatment
time is deleterious for patients with locally advanced (LA) - non-small cell lung cancer
(NSCLC) even if radio-chemotherapy (RT-CHT) is used. Current standard of treatment for
LA-NSCLC is concurrent radio-chemotherapy (RT-CHT), because survival benefit with the
increase of esophageal toxicity was demonstrated in a meta-analysis. Acceleration of
radiotherapy (RT) via hyperfractionation results in survival benefit as it was shown
also in a meta-analysis but at the expense of higher esophageal toxicity
Hyperfractionated RT schedules were used with low-doses of CHT, because of the fear of
accumulation of acute toxicity Hyperfractionation represents an additional burden for
equipment, staff and health care system and cannot be routinely realized, especially in
limited .resources setting. For patient, it is also associated with higher treatment
cost, i.e. by payment of cost of transport twice a day.
Alternative for acceleration of RT time is the use of hypofractionated RT schedule. Such
a radiation schedule is in the routine use in some countries. However, hypofractionation
has been often considered as palliative approach and even in limited resources countries
is still rarely proposed for curatively treated patients. In only three out of 36 (8%)
analysed Eastern and Central European centres that responded in the IAEA pattern of care
survey, the hypofractionation was used for curative treatment of LA-NSCLC. We have also
very few data from prospective studies that report on the concomitant hypofractionated
RTwith full dose CHT. The RTOG 0117 study arm that used slightly hypofractionated RT
schedule with dose escalation (75.25 Gy with 2.15 Gy fractional dose) and concomitant
full-dose CHT was interrupted because of the excessive toxicity. However, the total dose
escalation used in this study might be a reason for a failure of such an approach.
Recently, the concept of dose escalation with concomitant CHT has been compromised for
LA-NSCLC. When using hypofractionation, the total radiation dose should probably be
adapted to correspond to biological doses of around 66 Gy, because we have reports that
confrm safety of such a schedule. In opposite to that the dose escalation using
hypofractionation for central tumors led to the excessive long-term toxicity due to the
bronchial tree stenosis and perforations. In a few centers in Poland, the
hypofractionated RT with total dose of 58.8 Gy in 21 fractions (in 4 weeks; in the third
week 6 fractions are given) following two cycles of CHT or as RT alone is routinely
used. Safety and efficacy of this approach was established in a phase II prospective
trial. A question arises if such a RT schedule may be used concurrently with CHT. Given
the proven benefit of concurrent RT-(full dose)CHT in stage III NSCLC, data on the value
of overall treatment time and in order to spare RT resources we have decided to conduct
a phase I/II trial on concomitant RT-(full dose)CHT using accelerated hypofractionation
schedule as currently being in routine use in Poland for sequential combination or RT
alone. Confirmation that toxicity and outcome in terms of local control and overall
survival are similar to those observed in contemporary series of conventionally
fractionated RT-CHT will lead to the incorporation of this schedule into routine
practice in Poland. Such a schedule with shortened overall treatment time via
hypofractionation will contribute to essential sparing of RT resources, still
insufficient in Poland. Positive outcome of this study may be also a basis for future
conduction of phase III study that compares conventionally fractionated RT-CHT with
accelearated hypofractionated RT-CHT for stage III NSCLC.
2. Objectives of the study:
To estimate toxicity and efficacy of accelerated hypofractionated RT combined with
concurrent full-dose CHT for locally advanced NSCLC.
STUDY HYPOTHESIS:
RTOG/EORTC grade III and higher esophageal or pulmonary acute toxicity will not be
higher than in conventionally fractionated concurrent RT-CHT i.e. 25%.
And Two-year overall survival rate will be at least 40% and median overall survival will
be higher than 20 months.
2.1. Main endpoints: A. To estimate rate of RTOG/EORTC grade III and higher esophageal
and pulmonary toxicity and grade IV and higher CTCAE version 3.0 hematological toxicity
within 6 months from start of treatment.
B. To estimate overall survival two years after start of RT-CHT.
2.2. Secondary endpoints: A. Rate of two-year local control. B. All types of toxicity
(esophagus, lung, skin, kidney, heart) within two years after start of RT-CHT.
C. Feasibility of the study (percentage of completion of both planned cycles of CHT and
full dose of planned CHT delivery; completion of planned RT, breaks in treatment and
prolongation of overall treatment time).
3. Inclusion criteria:
- Pathological or cytological confirmation of the diagnosis of NSCLC
- Confirmation of clinical stage III based on: clinical examination, CT of the chest
and abdomen (PET-CT highly recommended), bronchoscopy, CT or MRI of the brain if
suspicion of brain metastases
- No abnormalities in blood count precluding administration of full doses of
Cisplatin and Vinorelbine (Neutrophils ≥1.5x109/L; Platelets ≥100 x109/L;
Hemoglobin >11 g/dl)
- No abnormalities in renal and hepatic function precluding administration of full
doses of Cisplatin and Vinorelbine (creatinine clearance >50 ml/minute,
aminotransferases < 1.5 of upper limit of normal value)
- Age <75
- KPS: 80-100
- FEV1 > 1 liter (except cases with very low body surface, when FEV1 should be >40%)
- No chronic diseases causing contraindication to the use of CHT
- No previous RT on the thoracic region
- Informed consent of patient for the participation in the study
4. Exclusion criteria:
- Lack of meeting all inclusion criteria
- Presence of clinically examined supraclavicular lymph nodes
- Malignant pleural or pericardial effusion
5. Schema of the study:
Stage III NSCLC patients who met inclusion criteria and signed informed consent are
treated according to following schedule:
- RT: 58.8 Gy in 21 fractions (2.8 Gy/fraction, 5 times a week, 6 times in the third
week [treatment on Saturday])
- Two cycles of CHT concomitant with RT: D1 - Cisplatin i.v. 80 mg/m2, Vinorelbine 25
mg/m2 i.v.; D8 - Vinorelbine 25 mg/m2 i.v.; D22 - Cisplatin 80 mg/m2 i.v.;
Vinorelbine 25 mg/m2 i.v.; D29 - Vinorelbine 25 mg/m2 i.v.
Patients are followed once a week during RT-CHT for evaluation of toxicity, then one
month after treatment completion and every three months up two years after treatment,
every six months thereafter. CT of the chest is performed during f/up at every visit.
Blood tests for hematological toxicity will be performed at least once a week during
radiotherapy and at each follow-up visit thereafter. Other examinations will depend on
the clinical needs.
6. Chemotherapy (CHT) 6.1. General rules: Two cycles of CHT (Cisplatin & Vinorelbine) will
be administered during RT every 21 days.
6.2. Antiemetics: All patients will receive antiemesis prophylaxis before and during
administration of CHT. This prophylaxis is mandatory sixty minutes before Cisplatin
infusion.
Recommended drugs are: Dexamethasone (12 mg p.o. or i.v. D1 and 22; 8 mg p.o. or i.v.
D2, D3, D4; D23, D24, D25); 5-HT3 receptor antagonists, f.ex. Ondansetron 8 mg. i.v. D1,
D22; NK-1 receptor antagonists, f.ex. Aprepitant 125 mg p.o. D1, D22 and 80 mg D2, D3,
D23, and D24.
The use of all other and additional antiemetics and combinations are possible, depending
on the clinical indications and individual tolerance of drugs. Routine premedication
before administration of Vinorelbine is not required.
6.3. Doses of CHT and their modifications 6.3.1. Dose of Cisplatin is calculated based
on the body-surface area - 80 mg/m2; diluted in 1000 ml of sodium chloride 0.9% and
given over two-hours in i.v. infusion D1 and D22; Cisplatin will be administered after
i.v. injection of Vinorelbine.
6.3.2. Dose of Vinorelbine is calculated based on the body-surface area - 25 mg/m2;
diluted in 125 ml of sodium chloride 0.9% and given over 20 minutes in i.v. infusion D1,
D8, D22 and D29.
6.3.3. Doses of CHT will be modified in consecutive cycles depending of hematological
toxicity. Neutrophils level before each cycle of CHT should be ≥1.5x109/L and platelets
level should be ≥100 x109/L. In case of incidence of hematological toxicity, the drug
doses will be modified according to the schema presented in Table 1.
Table 1. CHT dose modifications for 2nd cycle of CHT depending on hematological toxicity
observed at the first CHT cycle.
Nadir of Platelets (x109/L) Nadir of Neutrophils (x109/L) Dose modification; Action
taken >100 and > 1.5 100% 75-100 or 1.0-1.5 One week deferral <75 or <1.0 One week
deferral and reduction of dose to 75% of initial dosing
Persistent Grade III or higher CTC toxicity up to end of RT Persistent Grade III or
higher CTC toxicity up to end of RT Discontinuation of Chemotherapy
6.3.4. Hematopoietic growth factors won't be used for primary prophylaxis of febrile
neutropenia.
7. Radiotherapy (RT)
7.1. Target volume definition: Whole treatment will be planned in the three-dimensional
(3D) planning system, according to the requirement of ICRU recommendations of planning,
delivering and reporting doses of 3D-conformal radiotherapy (3D-CRT) [13]. IMRT
technique won't be used for planning in this study.
GTV will be considered as radiologically and bronchoscopically visualized tumor, as well
as pathological regional lymph nodes (LN). Mediastinal and hilar LN will be considered
as pathological if FDG-avid in PET-CT scan. In case of absence of abnormal FDG-uptake
all LN with short axis diameter ≥1.5 cm will be considered as pathological and included
in the GTV, unless clinical and radiological judgment will indicate with high
probability other than malignant etiology of lymph node enlargement. Pathological
confirmation of abnormal FDG up-take in regional lymph nodes won't be mandatory. In rare
cases of lack of PET-CT for staging, LN with short axis diameter >1 cm will be
considered as pathological, unless the formal exclusion of their metastatic origin is
provided by radiologist, i.e. benign appearance.
CTV: will be created by adding 0.5 cm to the GTV of primary tumor. Nodal CTV will
consist of the whole LN station (LNS), in which pathological LN are found. Borders of
LNS will be designed according to the guidelines of Michigan Atlas [14] with
modification of Kepka et al. [15] for hilar motion uncertainty.
PTV: will be created by adding 1 cm margin to the CTV. Sometimes PTV margin will be
modified individually depending of respiratory motion and spirometry test's results of
the patient.
7.1. Radiotherapy planning: CT for planning will be done in therapeutic patient's
position and immobilization as for all other thoracic localizations in the department.
Scan thickness is 3 mm. The i.v. contrast use for planning is not mandatory.
Dose will be prescribed in ICRU point; energy of 6 (or exceptionally 15) MV photons will
be used.
Dose per fraction: 2.8 Gy, RT once a day, 5 times a week in 1st, 2nd and 4th week of RT;
6 times a week in the 3rd week of RT (treatment on Saturday).
Total dose: 58.8 Gy Dose homogeneity criteria: 95-107% of the prescribed dose; minimum
dose of 90% will be also allowed in the PTV (as point dose).
Doses for critical structures:
Spinal cord: maximum dose - 45 Gy; 40 Gy for a length < 5 cm. Lung: mean dose ≤20 Gy (or
less depending on individual physician decision if respiratory reserve of patient is
limited); 35% of total lung volume receives ≤20 Gy Heart: 50% of heart volume receives
less than 40 Gy; avoidance of hot-spot within this organ Esophagus: recommended mean
dose <34 Gy; avoidance of hot-spots within this organ.
7.2. Radiotherapy delivery: Physician will be present at the first RT session. The
set-up verification with KV portals will be done and portal imaging for all therapeutic
portals will be done and fused with respective DRR at the first RT session. MV cone beam
verification will be possible at the request of the physician, but not mandatory. Next
KV set-up verification will be realized at least once a weak. On-line and off-line QA
procedures won't differ from those for other curative treatments in the RT Department.
8. Toxicity evaluation Early lung and esophageal toxicity will be scored according to the
RTOG/EORTC scale once a week during radiotherapy, next one month after completion of RT,
and in the third and sixth month after treatment. During the same follow-up visit all
types of toxicity from other organs, like skin, heart will be scored according to the
same scale [15].
Late radiation toxicity will be evaluated after 6 months of follow-up every three months
within two years and every six months thereafter according to the RTOG/EORTC scale.
Hematological toxicity will be evaluated according to the CTCAE vs 3.0 [17] in the same
intervals than esophageal and pulmonary toxicity during radiotherapy and thereafter, or
more often if clinically indicated. Other types of CHT toxicity will be also reported
according to the CTCAE scale, if they occur.
9. Evaluation of the outcome of RT-CHT CT of the chest will be done one month after
treatment completion. Then CT of the chest as well as the physical examination and blood
tests will be done at each follow-up visit. Other radiological examinations will be
prescribed if clinically indicated.
Overall survival will be estimated according to the Kaplan-Meier method and calculated
from the first day of RT-CHT. Actual risk of loco-regional failure will also be
estimated using the Kaplan-Meier method. Distant metastases occurrence and their sites
will be scored and reported.
10. Number of patients and study duration Study will be conducted in one institution. Ethic
Committee agreement for study conduction is required. It is planned to include 100
patients during first three years; minimum follow-up required after inclusion of last
patient is one year. Thus planned time of study conduction is four years, meant as the
time to the submission of publication that reports the outcome. Before that, the
publication of interim analyses is allowed if judged as clinically and scientifically
relevant by the investigators.
11. Predefined rules of study earlier halting or termination
Study will be earlier terminated or appropriately modified after Investigators Meeting
and consultation of Ethical Committee if:
- After completion of 6 months of follow-up for first 10 included patients, the CTCAE
hematological toxicity of grade IV or higher will occur in 3 or more patients
and/or the grade III or higher RTOG/EORTC pulmonary or esophageal toxicity will
occur in 3 or more patients, and also if two or more toxic deaths* will be
reported.
- After completion of 6 months of follow-up for first 30 included patients, the CTCAE
hematological toxicity of grade IV or higher will occur in ≥30% of patients and/or
the grade III or higher RTOG/EORTC pulmonary or esophageal toxicity will occur in
≥30% of patients, and also if three or more toxic deaths* will be reported.
- Every toxic death will lead to the extra meeting of the study investigators in
order to ascertain if immediate study modification is not necessary. Every
death scored as for unknown reason will require an undertaking of all
necessary steps to find all its circumstances to qualify with the highest
possible probability its cause.
12. Expected outcomes of the study We expect to confirm prospectively the safety and
efficacy of studied approach, meant as esophageal and pulmonary toxicity not higher and
overall survival not lower than that observed in contemporary series with conventionally
fractionated concurrent RT-CHT. After confirmation of the study hypothesis, a phase III
study that compares the studied schedule with conventionally fractionated RT-CHT will be
justified. The studied accelerated hypofractionated RT-CHT schedule may become routine
treatment protocol for stage III NSCLC patients what will reduce treatment cost and
enable better sparing of accessible RT technological resources.
