# Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer

Source: https://onco.cc/key-papers/paper-scagliotti-cisplatin-pemetrexed-histology-jco-2008/  
OnCo record `paper-scagliotti-cisplatin-pemetrexed-histology-jco-2008` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

1,725 patients, two chemotherapy combinations, identical survival overall. But split by what the tumour looked like down a microscope, one drug was better for adenocarcinoma and the other for squamous cancer. Histology started choosing the drug.

## Summary

Scagliotti, Parikh, von Pawel and colleagues randomised 1,725 chemotherapy-naive patients with advanced non-small-cell lung cancer to cisplatin with gemcitabine (863) or cisplatin with pemetrexed (862) for up to six cycles, in a non-inferiority design.

The overall result was non-inferiority, which by itself would have changed little. The pre-specified histology analysis is what changed practice: pemetrexed was better in adenocarcinoma and large-cell carcinoma and worse in squamous cell carcinoma, a difference attributed to thymidylate synthase expression. This is the first phase 3 trial in lung cancer to show survival differences by histological type, and the reason a pathologist's subtype now has to be recorded before chemotherapy is chosen.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Tags: lung-evidence
- Journal: Journal of Clinical Oncology
- Year: 2008
- DOI: 10.1200/JCO.2007.15.0375
- Authors: Scagliotti GV, Parikh P, von Pawel J, et al.
- Findings: Overall survival for cisplatin and pemetrexed was non-inferior to cisplatin and gemcitabine: median 10.3 against 10.3 months, hazard ratio 0.94 (95 percent confidence interval 0.84 to 1.05).; In adenocarcinoma (847 patients) survival was superior with pemetrexed: 12.6 against 10.9 months.; In large-cell carcinoma (153 patients) survival was superior with pemetrexed: 10.4 against 6.7 months.; In squamous cell histology (473 patients) survival was superior with gemcitabine: 10.8 against 9.4 months.; Cisplatin and pemetrexed caused less grade 3 or 4 neutropenia, anaemia and thrombocytopenia, less febrile neutropenia and less alopecia; nausea was more common.; The first prospective phase 3 study in non-small-cell lung cancer to show survival differences based on histological type.
- What it means: The moment lung cancer stopped being one disease for treatment purposes. Before this trial the pathology report said cancer or not cancer; after it, the subtype chose the drug, and the tissue had to be preserved well enough to answer the question.
- Caveats: The histology effects were subgroup analyses within a non-inferiority trial, and the biological explanation (thymidylate synthase) was proposed rather than measured prospectively.; Predates molecular testing, so the adenocarcinoma arm mixes EGFR-mutant, ALK-positive and driver-negative disease.; Cross-trial comparison with modern regimens is not valid: these patients received neither maintenance therapy nor immunotherapy.

## Sources

- J Clin Oncol 2008: https://doi.org/10.1200/JCO.2007.15.0375
- PubMed: https://pubmed.ncbi.nlm.nih.gov/18506025/
- JCO 2023 reprint: https://europepmc.org/article/MED/37146426

## Connected records

- roadmaps: [Chemotherapy roadmap: mustard gas → curative combinations → the warhead inside smarter drugs](https://onco.cc/roadmaps/chemotherapy-roadmap/)
- key papers: [Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer](https://onco.cc/key-papers/paper-schiller-ecog-1594-four-chemotherapy-regimens-nejm-2002/), [KEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation](https://onco.cc/key-papers/paper-keynote-189-nejm-2018/), [Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer](https://onco.cc/key-papers/paper-sandler-ecog-4599-bevacizumab-nsclc-nejm-2006/)
- cancers: [Adenocarcinoma of the lung](https://onco.cc/cancers/lung-adenocarcinoma/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Squamous cell carcinoma of the lung](https://onco.cc/cancers/lung-squamous-cell-carcinoma/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/)
- drugs: [Cisplatin](https://onco.cc/drugs/cisplatin/), [Gemcitabine](https://onco.cc/drugs/gemcitabine/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/)
- terms: [Histology](https://onco.cc/terms/histology/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)
- journals: [Journal of Clinical Oncology](https://onco.cc/journals/jco/)

---
JSON: https://onco.cc/api/v1/entities/paper-scagliotti-cisplatin-pemetrexed-histology-jco-2008.json