The main evidence for this protocol comes from the 2010 West Japan Thoracic Oncology Group trial WJTOG 0105.r The aim of study was to compare newer 3rd generation regime with standard second generation regime. 456 patients were randomised to 1 of 3 arms. Arm A mitomycin/vindesine/cisplatin at full doses for 3 cycles, concurrent with 69 Gy. Arm B- carboplatin/irinotecan weekly with 60 Gy followed by 2 cycles full dose carboplatin/irinotecan. Arm C weekly paclitaxel and carboplatin with 60 Gy followed by 2 cycles full dose carboplatin/paclitaxel. With patients followed for more than 3 years, 5 year overall survival was equivalent as was median survival for the 3 arms. Toxicity slightly favoured carboplatin/paclitaxel.
A randomised phase III controlled trial reported by Carter et al 2012 compared the effects of either maintenance therapy with weekly paclitaxel or observation which involved no additional chemotherapy. This was preceded by combined modality regimen involving 2 cycles of induction therapy of paclitaxel and carboplatin and then concurrent paclitaxel, carboplatin and radiation therapy in both arms for patients with locally advanced inoperable non-small cell lung cancer (NSCLC).r
A randomised phase II study reported by Wang et al 2012 compared the cisplatin and etoposide (PE) concurrent with radiation therapy regimen with weekly paclitaxel and carboplatin (PC) concurrent with radiation therapy in patients with unresectable stage III NSCLC. Both arms were followed by consolidation treatment which consisted of either a platinum-based doublet chemotherapy regimen or a single agent chemotherapy regimen.r
All studies had at least 2 cycles of full dose neoadjuvant/consolidation carboplatin and paclitaxel when carboplatin and paclitaxel was used concurrent with radiation therapy.r,r,r
Further evidence in support of this protocol is provided by the RTOG 0617r trial which compared standard dose versus high dose conformal radiation therapy with concurrent and consolidation carboplatin and paclitaxel with or without cetuximab. Between November 2007 and November 2011, 166 patients were randomised to receive standard dose chemoradiation therapy, 121 to high-dose chemoradiation therapy, 147 to standard chemoradiation therapy with cetuximab and 110 to high dose chemoradiation therapy plus cetuximab. Median overall survival was 25.0 months (95% CI 20.2-30.5) for those receiving cetuximab and 24 months (19.8-28.6) for those who did not, at a median follow up of 21.3 months. Neither the addition of cetuximab nor increased RT dose improved outcomes compared with carboplatin and paclitaxel and standard radiation fractionation.
An analysis of 1842 Veterans Health Administration datar demonstrated no difference in treatment outcomes for those treated with cisplatin and etoposide (HR 0.97; 95% CI, 0.85 to 1.10) and those treated with carboplatin and paclitaxel. Patients had similar overall survival, but cisplatin and etoposide was associated with increased morbidity.
A systematic review comparing the concurrent use of either carboplatin and paclitaxel or cisplatin etoposide with thoracic radiation in patients with stage III NSCLC found the regimens to be of similar efficacy with fewer toxicities in those treated with carboplatin and paclitaxel.r
WJTOG 0105 demonstrated median survival of 20.5, 19.8 and 22.0 months with 5 year OS of 17.5%, 17.8% and 19.8%. There was no significant difference between the 3 arms.r
© J Clin Oncol 2010
In the Carter study the median overall survival for the maintenance arm was 16.1 months and 26.9 months for the observation arm. The median progression-free survival was 8.2 months for the maintenance arm and 10.2 months for the observation arm.r
A: Overall Survival; B: Progression Free Survival
Maintenance: weekly paclitaxel 70 mg/m2 x 3 weeks followed by 1 week of rest for 6 months.
Observation: observation for a 6-month period.
© Clin Lung Cancer 2012
The median survival time was 20.2 months in the PE arm and 13.5 months in the PC arm. The overall survival at 1,2,3 years respectively was 65.6%, 36.4%, 33.1% in the PE arm and 54.5%, 16.2%, 13% in the PC arm.
The progression-free survival at 1,2,3 years respectively was 46.9%, 21.9%, 21.9% in the PE arm and 42.4%, 13.6%, 10.2% in the PC arm.
As the overall survival and progression-free survival were significantly higher in the PE arm than the PC arm the PC weekly regimen is not recommended over the PE regimen according to this study.r
© Lung Cancer 2012
The following table demonstrates the toxicity of WJTO 0105r
© J Clin Oncol 2010
There were 11 treatment related deaths. Arm C (carboplatin/ paclitaxel and radiation therapy) had significantly less haematological, infection, febrile neutropenia and gastrointestinal toxicity than the standard arm A (mitomycin, vindesine and cisplatin) but more neuropathy.r
Carter et alr reported grade 3 or 4 neutropenia in 23%, fatigue in 11%, thrombocytopenia in 7% and leukopenia in 6% of patients receiving concurrent chemoradiation therapy.
Wang et alr reported grade 3 or 4 neutropenia as being higher in the PE arm than the PC arm, however the rate of grade 2 or greater radiation pneumonitis was higher in the PC arm than the PE arm.
The systematic review reported less haematological toxicities with carboplatin paclitaxel compared with cisplatin etoposide.r The incidence of greater than grade 3 toxicities associated with cisplatin etoposide v carboplatin paclitaxel for neutropenia were 54% v 23% (P<0.001), thrombocytopenia 14% v 8% (P<0.001), anaemia 14% v 9% (P=.15). Patients receiving cisplatin and etoposide experienced more nausea and vomiting than those receiving carboplatin etoposide (20% v 11% P=.03) There was no significant difference in the rates of pneumonitis (12% v 9% P=.12) or oesophagitis (23% v 21% P=.27).