Determination of the predictive value of FDG-PET-CT scans, blood proteins and blood cells for the prognosis for patients with lung cancer receiving concurrent chemo-radiation

Until the 1980*s, the "standard of care" for the dose, volume and beam
arrangements for the treatment of non-small cell lung cancer (NSCLC) were
established by the Radiation Therapy Oncology Group (RTOG) dose-escalation
trial 7301 (1). In this study, 375 patients were randomly assigned to receive
either 40 Gy in 4 weeks with a 2-week break (split-course), 40 Gy in 4 weeks,
50 Gy in 5 weeks, or 60 Gy in 6 weeks. The complete and partial response rates
(as assessed clinically and radiographically) were 48% in patients treated with
40 Gy, 53% in those treated with 50 Gy, and 56% in those receiving 60 Gy. The
incidence of local failure (also evaluated clinically) was lower in patients
treated with 60 Gy (33%) than in those receiving 50 Gy (39%) or 40 Gy
(44%-49%). Despite a modest improvement at three years, by five years the
overall survival was approximately 5%.

In the early 1990*s, the results of several large randomised trials reported
increased survival with the addition of cisplatin-based chemotherapy (2-5).
Each of these trials utilized conventional radiation therapy and delivered
40-50 Gy to the elective nodal regions and 60-65 Gy to the gross disease.
Despite the modest improvement demonstrated in these trials, there remains much
room for improvement. Long-term survival was still only 8-14%. LeChevalier and
co-workers (3,4) reported a decreased incidence of distant metastases, but both
arms had a local control rate of only 15-17% when evaluated by bronchoscopy and
biopsy at 3 months and 10% at 2 years after completion of therapy. These
results are considerably lower than the local control rates of 40-60% reported
by soft clinical evaluation (1).

In addition, lung cancers are usually quite large at presentation. It is the
norm to have bulky tumours measuring greater than 2-5 cm. It is thought that
doses up to 100 Gy may be necessary to sterilize the size of tumours frequently
treated in bronchogenic carcinoma (6).

Further attempts at dose escalation were carried out in the RTOG prospective
hyperfractionation trial 8301 (5). A total dose of 60 Gy, delivered in 2 Gy per
day fractions in 6 weeks, was compared with 69.6 Gy BID and with chemotherapy
followed by 60 Gy in 458 patients, the overwhelming majority of them suffering
from stage III NSCLC. The 5-year survival was respectively 5 %, 6 % and 8 %.

The overall treatment time, in which radiotherapy is delivered, is of utmost
importance for survival. In general, both anti-tumour effects and the acute
side- effects increase when shortening the overall treatment time, but late
side effects are less sensitive to a change in overall treatment time.
Prolongation of the radiation treatment by a few days or a treatment
interruption by several weeks such as the rest period introduced in a split
course schedule led to a decrease in tumour control or in survival. In the RTOG
trial evaluating different hyperfractionated schedules, the 2-year survival
rate dropped from 33% to 14% if the treatment had been delayed for more than 5
days (7). However, the proof of principle came from the CHART (continuous
hyperfractionated accelerated radiation therapy) trial in which 563 patients of
whom the majority had stage III NSCLC were randomised between the classical 60
Gy in 30 fractions in 6 weeks and 54 Gy in 12 days (three fractions per day) in
order to overcome the accelerated tumour proliferation in standard daily
radiotherapy (8). The absolute 2-year survival was 20 % in the 60 Gy in 6 weeks
group, compared to 29 % in the CHART arm (p=0.008). Moreover, the relative risk
of local progression was reduced by 21 % (p=0.033). However, ultimately, only
13 % of the patients in the CHART group and 9 % in the standard arm were free
of local cancer.

Two phase III trials demonstrated superior survival, but at the cost of higher
toxicity, by delivering chemotherapy and radiotherapy concomitantly, compared
to the delivery of chemotherapy followed by radiation (9,10). In a 220 patient
trial, Furuse et al could demonstrate a 5-year survival of 15.8 % when
chemotherapy was given together with radiation, which compares favourably with
a survival rate of
8.9 % by sequential chemotherapy and radiotherapy (9). Similarly, Curran and
co-workers found a median survival of 17.0 months in the concurrent QD arm and
14.6 months in the sequential arm with corresponding 4-year survival rates of
respectively 21 % and 12 % (p=0.046) in a trial with 597 evaluable patients
(10). The better survival was due to a better local control by delivering
radiation and chemotherapy at the same time (9). The drawback was, however, a
higher incidence of toxicity.
In patients suffering from stage III B NSCLC, even sequential treatment with
vindesin, ifosfamide and cisplatin, followed by cisplatin sensitised
radiotherapy to a dose of 52 Gy in 20 fractions resulted in a local failure
rate of 70 % (11).

It is thus clear that even with the best classical radiation and chemotherapy
schedule, results remain disappointing.

However, the fact that increasing the local control rate by delivering
radiotherapy either in a short period of time like in the CHART trial, or
concomitantly with chemotherapy improves survival supports the idea that
radiation dose escalation could lead to further improvements of prognosis.

Radiation dose escalation is however limited by radiation-induced lung and
oesophageal damage (8, 9, 12-26). The dose-volume parameters for lung injuries
are known to some extend (for review, see 27). In general, with a mean lung
dose (MLD) of 10 Gy, < 5 % of the patients will develop a reversible grade 2
(i.e. corticosteroid dependent) radiation pneumonitis. When the MLD increases
to 15 Gy, about 10 % of the patients will develop grade 2 radiopneumonitis, and
with a MLD of 20 Gy, 15 % will have a grade 2 or more pneumonitis, with about
1% of toxic deaths. The MLD also gives a hint for the post-treatment lung
function, with a decrease of approximately 1 % per Gy, but the variability is
large. It has also been suggested that pneumonitis is more frequent in patients
with lower versus upper lobe tumours. This may be due to the inclusion of the
proximal conducting airways within the CT-defined superior part of the lung,
thus over-estimating the volume of *functional* lung.
For radiation-induced oesophageal damage, the relation between dose-volume
parameters and the incidence of injury is less clear, and no firm conclusions
could be drawn (28).

The objective of this study is to investigate the evolution of the
18F-deoxyglucose (FDG) uptake and the tumour characteristics determined in the
plasma of patients with lung cancer during and after concurrent radiotherapy
and chemotherapy.

Prospective study.

One extra FDG-PET-CT scan and five extra blood collections.