]
showed that adding CHT to locoregional treatment
improves the treatment outcome. While induction and
adjuvant CHT did not offer a significant advantage, it
was observed only with concurrent administration of
RT and CHT.
Among many drugs used in this setting, cisplatin
(CDDP) has most consistently been used as a single-agent
with radical RT (mostly 70 Gy in 35 daily fractions
over seven weeks). It was administered as three cycles
of 100mg/m2 on days 1, 22 and 43 of the RT course.
This specific administration, however, leads to a significant
toxicity and frequent dose omissions or reduction
and frequent treatment interruptions. Therefore,
researchers attempted to offer an alternative via altered
administration of CDDP, using mostly 40 mg/m2 given
weekly for seven weeks. This was based on the assumption
that it would lead to lesser toxicity while, at the
same time, offer better (more prolonged) radiosensitization
due to a more frequent CDDP administration.
While a direct comparison of the two modes of
CDDP administration in the definitive treatment of
locally advanced SQC HNC is basically lacking, a recent
summary of existing meta-analyses that attempted
to solve this issue disclosed somewhat conflicting results.[] One of the questions that also remains largely
unexplored is the total CDDP dose that may seem as
necessary to reach when administered concurrently
with radical RT irrespective of the mode of CDDP administration
(weekly or three weekly or daily) or RT
fractionation (conventional-CF, hypofractionated-Hfx
or accelerated-Acc).
Total dose of CDDP administered with concurrent
RT
In addition to data from trials that showed that only
60-80% of the patients were able to receive all three
cycles of 100 mg/m2 of CDDP, some studies indicated
that CDDP could be administered more frequently
with reduced toxicity and good both local control and
survival. Studies of SAKK [] (total, 200 mg/sqm) and
Jeremic et al.[,] (total, 210 mg/m2) showed that one
might perhaps not need 300 mg/sqm total CDDP dose
for good results. As discussed by Ang [], perhaps
again, a cumulative dose of CDDP of approximately
200 mg/m2, might need not be significantly surpassed,
if at all, if one expected a beneficial antitumor effect.
The results of two meta-analyses seem to add to this
suggestion. Analysis carried out regarding the CHT in
MAC-HNC [,] showed that single-agent cisplatin
(CDDP) given with radical RT might be preferred
treatment option, with an interesting observation that
the single negative concurrent RT/CDDP study was the
one where total cumulative CDDP dose was 140 mg/
m2.[] Italian literature-based meta-analysis of concurrent
RT/CDDP in SQC HNC, although published only
in an abstract form [], did not observe reduced risk of
death between total cumulative doses of CDDP of 300
mg/m2 and <300 mg/m2, both given with 5- fluorouracil (5-FU), when RT/CDDP/5-FU was compared to RT
alone. Importantly, however, when CDDP was administered
without 5-FU, there was a significant difference
in death risks between total cumulative CDDP dose of
200-225 mg/m2 (HR, 0.68) and total cumulative dose
of <150 mg/mV; (HR, 1.04). Intrigued by these discussions
and subset analyses, HNC researchers readily
responded by embarking on further studies aiming to
additionally enlighten this issue.
An international collaborative group [] undertook
a systematic review to evaluate evidence on the
CDDP dose-response when given concurrently with
RT in locally advanced, nonmetastatic SQC HNC.
They have used an indirect approach that compared
the survival of RT alone versus RT and different CDDP
dose intensities. There were 11 randomized trials (of
which eight were definitive treatments) and seven nonrandomized
studies. While no significant relationship
was observed between the cumulative CDDP dose and
the survival advantage on a linear regression done with
all randomized trials when the analysis was limited to
trials with definitive RT (n=6), superior OS was noted
for higher total cumulative CDDP doses, the relationship
is linear. There was a 2.2% (95% CI, 0.4%-4%) absolute
benefit in OS favoring RT/CDDP over RT-only
arm observed for every 10 mg increase in the cumulative
CDDP dose. In the range of doses of CDDP that
existed in those studies (140 mg/m2 to 270 mg/m2),
the model was statistically significant (p=0.027). Unfortunately,
due to a small available data points, other
endpoints could not be meaningfully evaluated, leaving,
therefore, an unanswered question of whether improvement
in any of these endpoints (e.g., locoregional
tumor control) may have contributed an improvement
in OS for higher total cumulative CDDP doses.
Similarly, Carlsson et al.[] reviewed the literature
with the aim of comparing high-dose (3 weekly 100
mg/m2) to low dose CDDP given concurrently with
radical RT, the latter including both weekly and daily
CDDP administration. There were six prospective and
seven retrospective studies. The median 3-year OS was
68% for high-dose CDDP and 61% in low dose CDDP.
The 3-year locoregional failures were 21% versus 28%,
while distant metastases were 13% versus 14.5% for
the two CDDP administrations, respectively. The cumulative
dose of CDDP was reported in five out of
eight studies using high-dose CDDP and in three out
of six of those using low-dose CDDP. Of these eight
trials, the median cumulative CDDP dose was available
in three trials only, while five trials lacked such
data. Overall, a median of 86% versus 79% of patients
received a cumulative CDDP dose of ≥200 mg/m2 in
high dose versus low dose regimens, respectively. Due to the inability of authors to perform formal statistical
comparisons, their findings remained, unfortunately,
mainly descriptive.
It is also important to put these data and observations
into the context of existing and increasingly used
altered fractionated RT regimens, as well as to emphasize
the importance of increasing scientific focus after
the emergence of HPV+ HNC, in particular, oropharyngeal
cancer (OPC) as a separate entity. Altered fractionated
RT regimens have been practiced for decades
and have shown both in prospective randomized trials
[] and meta-analysis [] to have an advantage
over conventionally fractionated RT. Although it was
shown that this intensification of the RT approach is
usually accompanied by an increase in toxicity, HNC
researchers, nevertheless, attempted to combine it with
CHT, CDDP being given either alone or in combination
with 5FU. In one such study, RTOG0129, three cycles of
CDDP were given conventionally with fractionated RT
and were compared to an accelerated RT regimen with
concurrent two cycles of CDDP. Both initial report []
(OS; hazard ratio, HR, 0.90; 95% CI, 0.72 to 1.13) and
its long term update [] (OS, HR, 0.96; 95% CI, 0.79 to
1.18; p=0.37; 8-year survival, 48% vs. 48%), PFS (HR,
1.02; 95% CI, 0.84 to 1.24; p=0.52; 8-year estimate, 42%
vs. 41%), LRF (HR, 1.08; 95% CI, 0.84 to 1.38; p=0.78;
8-year estimate, 37% vs. 39%), or DM (HR, 0.83; 95%
CI, 0.56 to 1.24; p=0.16; 8-year estimate, 15% vs 13%)
showed any difference favoring higher dose CDDP and
intensified RT. The authors hypothesized that the lack
of benefit of accelerated RT could be a result of the total
of three cycles of CDDP which, still managed to compensate
for presumably higher tumor clonogen repopulation
presumably happening during the prolonged
fractionated RT course (seven weeks). In other words,
one week, which was "saved" in accelerated RT, seemed
to have had an equal effect as approximately one (the
third) cycle of CDDP. Indirectly supporting these data
are the data from GORTEC 99-02 (The Groupe d"Oncologie
Radiothérapie Tête et Cou), a three-arm randomized
phase III trial of RT with or without CHT in
locally advanced SQC HNC.[] Two arms consisted
of RT (CF or Acc), and concurrent CDDP, the former
being given with three cycles, the latter with two cycles.
Similarly to RTOG0129 [,], no difference was
found in outcomes between the two RT-CHT arms.
However, interesting data from a recent meta-analysis
compared altered fractionated regimens with two cycles
of concurrent CDDP (100 mg/sqm) given with a
3-4 week split with weekly low dose CDDP regimens
(<50 mg/sqm for >4 doses).[] Despite similar overall
and complete response rates, altered fractionated
regimens, and two cycles of high dose CDDP achieved superior overall survival (p=0.0185). Interestingly,
planned high dose CDDP had been delivered with
better compliance than low-dose weekly CDDP (95%
vs. 71%, p=0.0353). Furthermore, it led to significantly
less severe acute and late toxicity, including 30-day
mortality. Authors concluded that even with altered
fractionated regimens, almost all patients have been
able to receive planned 200 mg/m2.
While HPV+ HNC had become one of the major
focuses of clinical research in HNC/OPC, identification
of risk groups led to an attempt towards treatment
de-intensification. Initial results showed the superiority
of RT/CDDP over RT/cetuximab in two recent
prospective randomized trials.[,] In both studies,
CDDP 100 mg/sqm was used, and no subset analysis
regarding planned versus delivered dose and relationship
with outcome was provided. However, Spreafico et
al.[] retrospectively analyzed all patients with OPC,
carcinoma of the unknown primary and laryngo-hypopharyngeal
region from two institutions irrespective
of their HPV status treated with RT and single-agent
CDDP and directly compared two distinct HPV status
groups of patients. In patients with HPV- cancers,
3-year OS for the patients who received total CDDP
dose <200, =200, and >200 mg/m2 were 52%, 60%,
and 72%, respectively (p=0.001) while corresponding
figures for HPV+ cancer patients were 91%, 90%, and
91%, respectively (p=0.30). In HPV-cancer patients,
the total dose of CDDP >200 mg/m2 was independent
prognostic factor for improved survival (HR, 0.5, 95%
CI: 0.3-0.7, p<0.001). Contrary to this, no such observation
was made in HPV+ patients (HR 0.6, 95% CI:
0.4-1.1, p=0.104). However, a subset analysis of patients
with HPV+ status showed that there was a strong trend
favoring OS in the T4 or N3 high-risk group when a total
doe of CDDP >200 mg/m2 was given (HR 0.5, 95%
CI: 0.2-1.1, p=0.07). These results indicated that for
the present times, a total CDDP dose of >200mg/sqm
might not be important in all HPV+ patients, rather in
patients who are deemed the high risk for locoregional
and/or distant failure. On the other side, HPV- patients
seem to remain dependent on the total CDDP dose due
to significantly superior outcomes with doses of >200
mg/m2 in both univariate and multivariate analysis.
