Background
Importance of CTRT in head and neck cancers
Locally
advanced head and neck cancers have poor survivals. The 2 year , 5 year and 10
year overall survival post standard fractionation radiation are 45.6%, 29.3%
and 18.3% respectively ( Beitler et al, RTOG 9003).1 The addition
of concurrent chemotherapy to radiation leads to an improvement in survival.
The 2 year and 5 year overall survival post concurrent chemoradiation are 55 %
and 33.7 % in accordance with the MACH-NC analysis .2 The benefit of the
addition of chemotherapy is consistent
in all tumour locations, with hazard ratios between 0.87 and 0.88 . The 5-year
absolute benefits associated with the concomitant chemotherapy are 8.9%, 8.1%,
5.4% and 4% for oral cavity, oropharynx, larynx and hypopharynx tumours,
respectively. The benefit of chemotherapy on survival does not differ
significantly postoperative radiotherapy (HR 0.79 [0.68–0.91]), or curative
radiotherapy with conventional (HR 0.83 [0.78–0.88]) or altered fractionation
(HR 0.73 [0.65–0.82]).
In
accordance with MACH-NC analysis there is no significant difference (p = 0.19)
between mono-chemotherapy (HR 0.84) and poly-chemotherapy (HR 0.78). Among
mono-chemotherapy group the impact of platinum was significantly higher than
non platinum(p = 0.006). The hazard ratio for mono platinum was 0.74
[0.67;0.82] while it was 0.89 [0.82;0.96] for mono-non platinum therapy 2. Among
platinum cisplatin HR of 5-year OS was 0.67 (95% CI, 0.49 to 0.92; P=0.01) ,
which showed a significant difference in favor of the cisplatin group.3 So cisplatin
based chemoradiation is routinely used.
In a
study reported from TMH by Sarbani et al cisplatin based CTRT was associated
with similar benefit. The locoregional control was better in the CTRT arm
compared with the other 2 arms of Rt and accelerated RT (5 year locoregional
control: RT group 32%, CTRT group 49%, and accelerated RT group 27%; p = .049;
log-rank test). On comparison among the groups, the CTRT arm was significantly
better than accelerated RT in terms of locoregional control (p = .01). The CRT
arm showed a significantly better DFS compared with the other 2 arms (5-year
DFS: RT group 25%, CRT group 39%, and accelerated RT group 20%; p = .03).
Similarly, OS was better in the CRT arm as compared with the other 2 arms
(5-year OS: RT group 36%, CRT group 56%, and accelerated RT group 41%).4
So
to sum up cisplatin based CTRT is associated with an absolute survival
advantage of 20% over conventional RT and 15% over accelerated RT in TMH. This
huge benefit is lost when patients who are eligible for CTRT but are unfit for
cisplatin.
Criteria for unsuitability to cisplatin
Cisplatin
based CTRT is associated with considerable morbidity. In MACH-NC analysis
patients with age >70 years and those with poor performance status had
higher non cancer related mortality nullifying the beneficial impact on
concurrent chemotherapy.2 Hence it’s
important to select patients for cisplatin and identify patients who are
unsuitable for it. However until recently
there
was a lack of clinical consensus criteria for defining these patient
populations. A group of experts in the field of head and neck cancer from the
Asia Pacific Region convened in August 2014 in Korea and developed a set of
clinical criteria in order to fill the knowledge gap and provide a reference
tool for head and neck oncologists. The following criteria’s were given for
selection of patients who are unsuitable for cisplatin based therapy.5
Criteria for Contraindication (CI)
1.
Performance status ECOG (Eastern Cooperative Oncology Group) score
of grade 3 or higher
2.
Organ dysfunction of grade 2 or higher based on the NCI CTC
(National Cancer Institute Common Toxicity Criteria) version 4.0 , such as
hearing loss and tinnitus and neurologic disorders
3.
Hypersensitivity to Cisplatin,
4.
Pregnancy and lactation
5.
CD4 count less than 200/microlitre in HIV/AIDS patients.
6.
Calculated creatinine clearance (CCR) value of <50 ml/min
Criteria for high risk
1.
Performance status score of grade 2
2.
Borderline organ function
3.
Weight loss ( > 10-20% baseline body weight)
4.
Nutritional status : Malnourished
5.
Concomitant use of nephrotoxic drugs.
Patients
with any of the criteria mention in contraindications have a contraindication
for administration of cisplatin. While presence of any criteria mention in high
risk criteria have a high risk of
toxicity and morbidity when administered cisplatin
Proportion of patients with these criterias
In
routine practice around 10-12% patients with locally advanced head and neck
cancers have CCR below 60 ml/min.6 The CCR
decreased with aging, and the percentages of patients with CCR lower
than 65 ml/min per 1.73 m(2) were 27.1% of patients in their fifties, 36.8% in
their sixties, 62.3% in their seventies, and 87.5% in their eighties.7 In investigator’s experience 15-20% of
patients will fall in either CI or high risk criterias.
Treatment options
Treatment
options in these patients are limited. The options commonly provided are no
radiosensitization, carboplatin based radiosensitization, cetuximab based radio
sensitization or taxane ( docetaxel)
based radiosensitization.
Carboplatin
Large
randomized trials comparing carboplatin and cisplatin in the CCRT setting are
lacking, Carboplatin is frequently used in routine clinical practice when
cisplatin is not tolerated or contraindicated or patient has high risk
features. There has been multiple studies which has explored the activity of
carboplatin when combined with RT. Aguiar P N et al in a meta-analysis compared
carboplatin to cisplatin in the setting of chemoradiation. This meta-analysis
concluded that 5-year survival rate: 30 and 27%, respectively for cisplatin and
carboplatin (p = 0.33) which was not statistically significant.16
Rades D et al did a matched pair analysis for cisplatin to carboplatin in
patients receiving chemoradiation. The author compared 131 patients
receiving two cycles of cisplatin (20
mg/m2/d1--5 or 25 mg/m2/d1-4) and were matched to 45
patients receiving carboplatin (AUC 1.0/d1-5 or AUC 1.5/d1-4). Overall Survival
at 2 and 3 years were 83% and 79% vs. 83% and 75% (p = 0.64), respectively in cisplatin and carboplatin arm.
Subgroups receiving definitive or adjuvant chemoradiation had similar outcome.
No significant differences were found regarding toxicities. More patients in
the carboplatin group completed
chemotherapy (78% vs. 66%, p =
0.15). Inspite of patients in carboplatin arm having worse renal function and
being older patients, carboplatin arm had similar outcomes and toxicities as
cisplatin. Authors concluded that carboplatin in a good option for
patients who are not fit for cisplatin.17
Xiang
M et al did SEER data base analysis to compare outcome of patients receiving
cisplatin or carboplatin with radiotherapy in head and neck cancer. There were
807 patients who received cisplatin and 342 patients who received carboplatin
in this study. This study showed that carboplatin-based chemoRT group had
similar number of death attributable to HNSCC compared with those treated with
cisplatin-based chemoRT (3-year CSM 29% vs 26%, respectively; P=.19).18
There
have been no large randomised studies to compare cisplatin to carboplatin in
head and neck cancer patients receiving chemoradiation. There have been two
prospective studies. Jeremic B et al randomised 159 patients in three arms, RT
vs RT with daily cisplatin (6mg/m2) vs daily carboplatin (25mg/m2). This study
showed that chemoradiation arms had significantly longer median survival and
higher 5-year survival than in RT arms. Median survival of 32 months vs 30
months vs 16 months in CTRT arm with cisplatin vs CTRT arm with carboplatin vs
RT arm. 5 yaer survival of 32% vs 29% vs 15%, respectively; P = 0.011 and P =
0.019, respectively. Chitapanarux et al did another study in nasopharyngeal
cancer. 206 patients were randomised to receive either cisplatin or carboplatin
in this study. The 3 year overall survival rates was 77.7% and 79.2% for
cisplatin and carboplatin groups, respectively (p=0.9884) with better safety
profile for carboplatin arm. 19, 20
Carboplatin
is routinely used by clinicians in the clinic in the patients not suitable for
cisplatin based therapy in chemoradiation setting of head and neck cancer. But
carboplatin has not been compared with cisplatin or docetaxel in well powered
randomised study.
Cetuximab
Though
cetuximab use has been reported from our centre in patients unsuitable for
cisplatin based CTRT. Its use was well tolerated and was associated with the
2-year locoregional control, disease-free survival, and overall survival was
35.5%, 29.5%, and 44.4% respectively. However cetuximab has not been tested in
oral cavity in radical setting.8 Further
cetuximab alone has not been tested in adjuvant setting in a large randomized
study. The issue with cetuximab is its cost. In low -middle income countries
below 1% of patients can afford it.9 Hence though
cetuximab can be considered an option in pharyngeal and laryngeal cancers who
are unsuitable for cisplatin and undergoing radical CTRT, it cannot be
considered a logistically feasible option for majority of patients.
Docetaxel
Docetaxel
has been reported in head and neck cancers as radiosensitizing agent.
In
2004 Fujii et al reported a phase 1 study for use of Docetaxel as
radiosensitizing agent in head and neck cancers. Docetaxel 15 mg/m(2) was
considered the maximum tolerated dose (MTD). The recommended dose was decided
as 10 mg/m(2).10 Matsumoto et
al in 2006 reported a study evaluating
the concomitant use of weekly docetaxel using 10 mg/m2 weekly dose and altered fractionation radiotherapy for
the treatment of head and neck cancer (HNC).The initial overall response rate
was 88.0%, while the complete response rate was 68.0%. The 2-year actuarial
overall survival was 47.3%, and the cause-specific survival was 81.8%.11 The authors
suggested that initial response rate and overall survival were promising. The
updated results showed the 5-year local control rate and overall survival rate
were 62.6% and 61.6%, respectively.12
In
another study reported by Calais et al a total of 63 patients were recruited in
a multicentric phase 2 study by GORTEC groupe. Radiotherapy delivered was
conventional fractionation, 70 Gy in 35 fractions. Patients received during the
period of radiotherapy seven cycles of Docetaxel (20 mg/m2 each
week).Three-year overall actuarial survival and disease-free survival rates
were, respectively, 47% (95% CI = 39-68%) and 39% (95% CI = 30-57%). The local
and regional control rate was 64%. The adjunction of weekly Docetaxel to
conventional radiotherapy is feasible. Mucositis and skin toxicity were the
major acute toxic effects. Therapeutic results were similar to those observed
with concomitant chemotherapy using platinum and/or 5-FU.13
In a
recently reported meta analysis in 2014 taxane based radiosensitization was
associated with a survival benefit. The weighted mean of the overall median
survival time was 36.7 months
in
taxane based studies (N = 197) versus 25
months in non taxane based studies (N = 503).14 The median OS
was found to be significantly longer in the taxane arm; P < 0.001.Similarly
in RTOG 0234 postoperative high risk patients were randomly assigned to cetuximab once per week plus either cisplatin
30 mg/m2 or docetaxel 15 mg/m2 once per week. There was a 24% reduction (HR,
0.76; 95% CI, 0.54 to 1.06) in the DFS failure rate for the cisplatin arm
compared with control (P.05) and a 31% reduction (HR, 0.69; 95% CI, 0.50 to
0.96) for the docetaxel arm (P .01). These corresponded to 2.5% and 11.1% improvements
in 2-year DFS relative to control. There was a 28% reduction (HR, 0.72; 95% CI,
0.50 to 1.03) in the death rate for the cisplatin arm relative to control
(P.04) and a 44% reduction (HR, 0.56; 95% CI, 0.39 to 0.82) for the docetaxel
arm (P .001).15 It was
concluded that docetaxel based radiosensitization needs to be studied further.
Subsequently
a randomised study was done at TMH comparing docetaxel with RT to RT alone in
these group of patients. The study recruited 356 patients. The 2-year DFS was
30.3% (95% CI, 23.6 to 37.4) versus 42% (95% CI, 34.6 to 49.2) in the RT and
Docetaxel-RT arms, respectively (hazard ratio, 0.673; 95% CI, 0.521 to
0.868; P value = .002). The
corresponding median overall survival (OS) was 15.3 months (95% CI, 13.1 to
22.0) and 25.5 months (95% CI, 17.6 to 32.5), respectively (log-rank P value = .035). The 2-year OS was
41.7% (95% CI, 34.1 to 49.1) versus 50.8% (95% CI, 43.1 to 58.1) in the RT and
Docetaxel-RT arms, respectively (hazard ratio, 0.747; 95% CI, 0.569 to
0.980; P value = .035).
There was a higher incidence of grade 3 or above mucositis (22.2% v 49.7%; P < .001), odynophagia (33.5% v 52.5%; P <
.001), and dysphagia (33% v 49.7%; P = .002) with the addition of
docetaxel.
This suggested the need to develop
safer alternative therapy in this segment.
Rationale for
the study
Cisplatin
based CTRT is associated with absolute survival benefit of magnitude of more
than 10%. However unfortunately 15-20% of patients in routine practice are
unfit for it. Currently radical RT or Radical RT with carboplatin or radical RT
with docetaxel or Radical Rt with cetuximab is administered in this setting.
cetuximab is not logistically feasible in most of the patients
(>99%).Docetaxel has shown promise as radiosensitizer in both adjuvant and
radical settings. This benefit is claimed on the basis of meta analysis and
Phase 2 RTOG study. The meta analysis had incorporated lot of single arm studies. The PK-PD of
docetaxel makes this drug administerable in many of the settings where
cisplatin is contraindicated or likely to cause high morbidity. We have safety
data from TMH establishing the role of docetaxel.
Currently
docetaxel based CTRT is used as part of routine care in TMH. But considering
the toxicity there is a need to develop safer alternative. There is no Phase 3
data in this setting for physicians guidance for other alternative safer
therapy. Hence this study is planned to study the impact of this safe,
alternative drug carboplatin as radiosensitizer in patients undergoing radical
or adjuvant CTRT but are unfit for cisplatin.