Discoveries That Changed Cancer Treatment

What question was this research asking?

In colon cancer removed by surgery, does adding oxaliplatin to classic fluorouracil treatment reduce the chance of the disease coming back?

What did it find?

In stage III and selected high-risk patients, adding oxaliplatin lengthened the time without recurrence. The survival benefit is read separately by stage and by time point; not every early-stage patient needs the same regimen.

What did it change today?

Adjuvant (postoperative) FOLFOX and other oxaliplatin-containing regimens became the foundation of standard postoperative options in suitable colon cancer.

Who does this apply to?

Applies particularly to stage III and to selected high-risk stage II disease. In older, frail patients or those at high risk of neuropathy, duration and dose are individualized. It is not automatically applied to rectal cancer.

The story behind the gold star

MOSAIC is one of the key trials that shaped the long-term outcomes of adding oxaliplatin in surgically resected colon cancer. The role of oxaliplatin-based treatment was strengthened especially in the stage III population. Ten-year updates helped clarify the balance of benefit and toxicity. The IDEA and treatment-duration trials later addressed the separate question of ‘how much drug’. The message of MOSAIC is not to impose the same intensity on every early-stage patient, but to choose according to risk group.

What question was this research asking?

In operated stage III colon cancer with mismatch repair deficiency (dMMR), does adding atezolizumab to postoperative FOLFOX chemotherapy lengthen the time before the disease comes back (disease-free survival)?

What did it find?

At a median follow-up of about 41 months, the proportion of patients alive without recurrence at three years was 86.3% in the combination group and 76.2% in the control group (absolute difference about 10 percentage points; hazard ratio 0.50; p<0.001). This hazard ratio is a relative event rate; it does not mean a 50% reduction in absolute risk. Severe side effects (grade 3–4) occurred in 84.1% of the combination group and 71.9% of the control group. The difference in overall survival (total survival time) is not yet clear.

What did it change today?

It showed a disease-free survival benefit from adding immunotherapy after surgery in stage III dMMR colon cancer. With FDA approval — 8 October 2026 (United States), an approved adjuvant option now exists for this indication. Licensing / reimbursement in Turkey is separate.

Who does this apply to?

Valid only for stage III colon cancer with mismatch repair deficiency (dMMR). Overall survival data are not yet mature; the increase in side effects should be monitored. FDA approval applies to the United States; it is not automatically considered standard in Turkey and other countries.

The story behind the gold star

ATOMIC compared adding atezolizumab to adjuvant mFOLFOX6 with chemotherapy alone in surgically treated stage III dMMR colon cancer. At a median follow-up of 40.9 months, three-year disease-free survival was 86.3% vs 76.2% (HR 0.50; p<0.001). Grade 3–4 adverse events were more frequent in the combination arm. The gold-star rationale is that it established the era of biomarker-selected adjuvant immunotherapy with phase III DFS; OS has not yet clearly separated, and the result is not carried over to pMMR. The NICHE-2 neoadjuvant pCR question is separate.

What question was this research asking?

In locally advanced rectal cancer, does completing chemotherapy before surgery after short-course radiotherapy reduce disease-related treatment failure compared with classic long-course chemoradiotherapy?

What did it find?

In high-risk locally advanced disease, the RAPIDO approach reduced disease-related treatment failure. This does not mean the same plan for every rectal cancer; organ preservation and other TNT schedules are separate studies.

What did it change today?

In selected high-risk rectal cancer, options for intensive systemic treatment before surgery (total neoadjuvant therapy, TNT) were strengthened.

Who does this apply to?

Designed for high-risk locally advanced rectal cancer. It is not automatically generalized to early-stage or low-risk disease, or to patients whose only goal is organ preservation. The overall survival advantage is not the same in every analysis.

The story behind the gold star

RAPIDO made clinicians rethink the order of treatment in high-risk locally advanced rectal cancer. Moving systemic therapy before surgery after short-course radiotherapy strengthened a TNT model that reduces disease-related treatment failure. The primary endpoint should not be confused with DFS or OS. PRODIGE 23 and organ-preservation trials address different clinical questions. Patient selection and center experience remain critical.

What question was this research asking?

In locally advanced rectal cancer with mismatch repair deficiency (dMMR), can dostarlimab (a PD-1 inhibitor immunotherapy) given before surgery make the tumor disappear completely on examination and imaging?

What did it find?

In all of the first 12 patients who completed treatment, complete disappearance of the tumor on examination and imaging (clinical complete response) was reported.

What did it change today?

It created a pioneering paradigm signal for a biomarker (dMMR)-based, non-operative organ-preservation approach. AZUR-1 is cross-linked as confirmatory / supporting evidence; it is not a second star.

Who does this apply to?

In the first report the number of patients is very small and follow-up is limited; the results cannot be generalized to all rectal cancer patients. Valid only for patients with mismatch repair deficiency (dMMR).

The story behind the gold star

The pioneering MSK NCT04165772 cohort reported a clinical complete response in all of the first 12 patients who completed neoadjuvant dostarlimab for dMMR locally advanced rectal cancer. The gold-star rationale is the pioneering paradigm signal that opened a biomarker-based organ-preservation approach. The evidence is a small cohort; long-term follow-up and multicenter confirmation are read together with AZUR-1. AZUR-1 is a clinical milestone — not a second gold star. The result is not carried over to pMMR rectal cancer.

What question was this research asking?

In resectable gastric or esophagogastric junction cancer, is FLOT chemotherapy before and after surgery better than the older ECF/ECX regimen?

What did it find?

Median overall survival was reported as 50 months in the FLOT group and 35 months in the ECF/ECX group (hazard ratio [HR] 0.77). This does not mean every patient will live 50 months; FLOT4 did not compare FLOT with CROSS.

What did it change today?

In suitable resectable gastric / GEJ cancer, perioperative FLOT became the reference chemotherapy in many centers.

Who does this apply to?

For patients who are operable and in good performance status. It is not the same as metastatic disease or East Asian adjuvant approaches. Side-effect management and nutritional support are critical. The comparison with CROSS is in ESOPEC.

The story behind the gold star

FLOT4 became one of the most influential Western trials to change the standard of perioperative treatment in resectable gastric and gastroesophageal junction cancer. Compared with ECF/ECX, FLOT improved median overall survival. Because it is an intensive regimen, performance status, nutrition and side-effect management are critical. Later trials adding immunotherapy (e.g., MATTERHORN) are a separate line of development; they do not automatically erase FLOT4.

What question was this research asking?

In advanced gastric / gastroesophageal junction (GEJ) / esophageal adenocarcinoma, does adding nivolumab to chemotherapy prolong survival?

What did it find?

With a PD-L1 combined positive score (CPS) of 5 or higher, median survival was 14.4 vs 11.1 months. With CPS 1 or higher it was 14.0 vs 11.3 months; in all randomized patients it was 13.8 vs 11.6 months. The clearest evidence is in the CPS ≥5 group.

What did it change today?

In suitable advanced HER2-negative upper gastrointestinal adenocarcinoma, first-line nivolumab plus chemotherapy (especially with PD-L1 combined positive score [CPS] ≥5) became a standard option.

Who does this apply to?

HER2-negative adenocarcinoma. PD-L1 combined positive score (CPS) strata are read separately. It is not confused with perioperative FLOT / MATTERHORN or with esophageal squamous cell carcinoma (CM-648).

The story behind the gold star

CheckMate-649 compared nivolumab + chemotherapy with chemotherapy alone in previously untreated advanced gastric, GEJ and esophageal adenocarcinoma (HER2-negative). Dual primary endpoints: OS and PFS in PD-L1 CPS ≥5. In CPS ≥5, median OS was 14.4 vs 11.1 months (HR 0.71). An OS advantage was also shown hierarchically in the CPS ≥1 (median OS 14.0 vs 11.3 months; HR 0.77) and all-randomized (13.8 vs 11.6 months; HR 0.80) populations; the strength of evidence is clearest in CPS ≥5. The gold-star rationale is that it established the era of first-line nivolumab + chemotherapy in advanced upper-GI adenocarcinoma.

What question was this research asking?

In operable gastric / gastroesophageal junction (GEJ) cancer, does adding durvalumab to FLOT improve outcomes?

What did it find?

Lancet 2026 final overall survival (OS): hazard ratio (HR) for death 0.78 (95% confidence interval [CI] 0.63–0.96). An event-free survival (EFS) benefit had also been reported earlier (2-year EFS 67.4% vs 58.5%). It does not mean automatic immunotherapy for all gastric cancer patients; licensing is separate by country (US FDA November 2025).

What did it change today?

In suitable resectable patients, perioperative FLOT plus durvalumab was strengthened as an option.

Who does this apply to?

Resectable gastric / GEJ adenocarcinoma. Not to be confused with metastatic CheckMate 649 or with thoracic squamous cell carcinoma. Immune-related toxicity; access in Turkey / EMA (European Medicines Agency) is not automatically equal to FDA approval.

The story behind the gold star

MATTERHORN compared adding durvalumab to perioperative FLOT with placebo + FLOT in resectable gastric or gastroesophageal junction adenocarcinoma. The primary endpoint was event-free survival: two-year EFS was 67.4% vs 58.5% (HR 0.71). In the Lancet 2026 final overall survival analysis, OS HR was 0.78 (P=0.021); 36-month OS was 69% vs 62%; median OS had not been reached in either arm. The gold-star rationale is that it established the era of perioperative FLOT+IO with EFS and final OS; EFS and OS are not confused.

What question was this research asking?

In pancreatic cancer removed by surgery, does the four-drug regimen mFOLFIRINOX prolong survival compared with gemcitabine?

What did it find?

In the first publication, median overall survival (OS) was 54.4 vs 35.0 months; at long-term follow-up it was 53.5 vs 35.5 months (different time points). Disease-free survival (DFS) and OS both improved; the regimen is intensive and may not be suitable for every patient.

What did it change today?

In selected patients in good condition, adjuvant mFOLFIRINOX became a preferred option in many guidelines.

Who does this apply to?

Applies to patients with adequate general condition after surgery who meet the eligibility criteria. It is not generalized to metastatic / inoperable disease or to neoadjuvant borderline-resectable questions.

The story behind the gold star

PRODIGE-24 / CCTG PA.6 redefined the intensity of adjuvant treatment in resected pancreatic cancer. mFOLFIRINOX improved DFS and OS compared with gemcitabine (initial publication median OS 54.4 vs 35.0 months; long-term 53.5 vs 35.5 months — different follow-up periods). Toxicity is high; the result does not extend to metastatic or unresectable disease. Neoadjuvant strategies for borderline/locally advanced disease are separate trials.

What question was this research asking?

In esophageal cancer that can be operated on, does giving chemotherapy and radiotherapy together before surgery prolong survival?

What did it find?

NEJM 2012 median overall survival (OS) ~49 vs 24 months; 10-year OS (JCO 2021) 38% vs 25%. Adenocarcinoma and squamous cell results should not be considered identical; CROSS is not a direct comparison with FLOT.

What did it change today?

In many operable esophageal and gastroesophageal junction cancers, chemoradiotherapy before surgery became a paradigm-changing standard option.

Who does this apply to?

Results are for patients who can be operated on. Histology subgroups are read separately; in adenocarcinoma, the choice of FLOT after ESOPEC is also being discussed.

The story behind the gold star

CROSS showed, with long-term survival, the superiority of neoadjuvant chemoradiotherapy over surgery alone in resectable esophageal and gastroesophageal junction cancer. Preoperative treatment with carboplatin–paclitaxel and 41.4 Gy improved median and ten-year survival. This is the paradigm-changing evidence that established neoadjuvant chemoradiotherapy as the standard in Western practice. In adenocarcinoma, later ESOPEC results individualize the choice; the historical and clinical place of CROSS is preserved.

What question was this research asking?

In patients who had chemoradiotherapy before surgery and still have residual tumor after surgery, does nivolumab delay the return of the disease?

What did it find?

Median disease-free survival (DFS) was 22.4 vs 11.0 months (hazard ratio [HR] 0.69). It applies to the population with neoadjuvant chemoradiotherapy (CRT) + R0 resection + pathological residual disease; it is not automatically generalized to pathological complete response (pCR) or to a different perioperative strategy. The 2025 overall survival (OS) analysis was not statistically significant.

What did it change today?

In suitable patients, postoperative nivolumab became the standard option that improves DFS in residual disease.

Who does this apply to?

Only for neoadjuvant chemoradiotherapy (CRT) + R0 resection + residual pathological disease. An overall survival advantage was not statistically demonstrated in 2025.

The story behind the gold star

CheckMate-577 compared adjuvant nivolumab with placebo in residual pathologic disease after neoadjuvant chemoradiotherapy and R0 resection. The primary endpoint, disease-free survival, was clearly prolonged. In the 2025 long-term update, the DFS benefit persisted, while the overall survival difference did not meet the threshold for statistical significance. The gold-star rationale is therefore the DFS paradigm change; an OS advantage is not claimed.

What question was this research asking?

In advanced esophageal cancer, does adding pembrolizumab to chemotherapy in first-line treatment prolong survival?

What did it find?

Median survival was about 12 months in the group with pembrolizumab added and about 10 months in the chemotherapy-alone group. The proportions of patients alive after five years were 10.6% and 3.0%. The benefit was clearer especially in squamous cell cancers with high PD-L1 levels.

What did it change today?

Adding immunotherapy to first-line treatment in advanced-stage patients became a widely used option, depending on PD-L1 and cell type.

Who does this apply to?

Only for advanced, inoperable or metastatic disease; it should not be confused with adjuvant or neoadjuvant studies in operable disease. PD-L1 level and cell type are important for the decision.

The story behind the gold star

KEYNOTE-590 compared first-line pembrolizumab + chemotherapy with placebo + chemotherapy in unresectable or metastatic esophageal squamous cell carcinoma or adenocarcinoma, and in Siewert type I GEJ adenocarcinoma. In the ITT population, median OS was about 12.4 vs 9.8 months (HR ~0.73); five-year OS was 10.6% vs 3.0%. The benefit was more pronounced especially in the PD-L1 CPS ≥10 squamous cell subgroup. The gold-star rationale is that it established the era of first-line IO + chemotherapy in advanced esophageal/GEJ cancer; distinctions by histology and PD-L1 are preserved.

What question was this research asking?

In advanced squamous cell esophageal cancer, is first-line nivolumab (with chemotherapy or with ipilimumab) better than chemotherapy alone?

What did it find?

In patients with a PD-L1 value of 1% or higher, median survival was 15.4 months with nivolumab plus chemotherapy, 13.7 months with nivolumab plus ipilimumab, and 9.1 months with chemotherapy alone. In all patients too, both nivolumab approaches were associated with longer survival than chemotherapy. A significant benefit in time without disease progression was seen especially in the nivolumab plus chemotherapy arm; the two immunotherapy arms were not compared with each other for superiority.

What did it change today?

In advanced squamous cell cancer, first-line nivolumab plus chemotherapy and nivolumab plus ipilimumab became established as standard options showing an overall survival (OS) advantage over chemotherapy.

Who does this apply to?

Only for advanced squamous cell carcinoma. PD-L1, general condition and suitability for chemotherapy determine the choice of regimen; for adenocarcinoma, different evidence such as KEYNOTE-590 is used.

The story behind the gold star

CheckMate-648 covers only advanced esophageal squamous cell carcinoma (ESCC); adenocarcinoma is not part of this trial. Three arms: nivolumab + chemotherapy, nivolumab + ipilimumab, and chemotherapy alone — the two IO regimens are each tested against chemotherapy, not against one another. In PD-L1 TPS ≥1%, median OS was 15.4 months with nivolumab + chemotherapy, 13.7 months with nivolumab + ipilimumab, and 9.1 months with chemotherapy. The gold-star rationale is that it established first-line IO as the standard in advanced ESCC; the histology limit and the separation of arms are mandatory.

What question was this research asking?

In esophageal adenocarcinoma, is FLOT chemotherapy given before and after surgery better than chemotherapy plus radiotherapy before surgery (CROSS)?

What did it find?

3-year overall survival (OS) 57.4% (FLOT) vs 50.7% (CROSS); hazard ratio (HR) 0.70; median OS ~66 vs ~37 months. It is not generalized to squamous cell esophageal cancer or to all gastric cancers.

What did it change today?

In resectable esophageal adenocarcinoma, perioperative FLOT became the option showing an overall survival advantage over CROSS; it is not generalized to squamous cell cancer.

Who does this apply to?

Valid only for esophageal adenocarcinoma; it does not address squamous cell carcinoma or the FLOT4 gastric question.

The story behind the gold star

ESOPEC directly compared perioperative FLOT with CROSS chemoradiotherapy in resectable esophageal adenocarcinoma. Three- and five-year survival and progression-free survival were better in the FLOT arm than with CROSS. This result is paradigm-changing evidence that alters treatment selection in adenocarcinoma. It cannot be carried over to squamous cell cancer; patient selection, tolerance and surgical quality remain critical.

What question was this research asking?

In early breast cancer, does removing the whole breast prolong survival compared with removing only the tumor and keeping the breast?

What did it find?

In suitable early-stage patients, breast-conserving surgery plus whole-breast radiotherapy gave similar survival to removing the entire breast. The risk of local recurrence may differ somewhat, but this does not necessarily mean that survival is shorter.

What did it change today?

In selected patients, breast-conserving surgery became established as an equivalent option to mastectomy; not everyone has to lose the breast.

Who does this apply to?

Applies only to patients with a suitable tumor size, safe surgical margins and a radiotherapy plan. It cannot be generalized to locally advanced disease or to situations in which radiotherapy cannot be given.

The story behind the gold star

For years it was assumed that the more extensive the breast cancer operation, the better the outcome. NSABP B-06 tested this assumption systematically. In suitable patients, no clear difference in overall survival was shown between breast-conserving surgery and mastectomy; radiotherapy played a critical role in reducing recurrence in the same breast. This trial became a historical turning point in moving breast cancer surgery toward more limited procedures and in making the radiotherapy plan central to patient selection. The results strengthened the idea that not every patient must lose her breast; however, suitable tumor characteristics and safe surgical margins must be maintained.

What question was this research asking?

In patients planned for breast-conserving surgery and radiotherapy who have one or two positive sentinel nodes, is it necessary to remove all the lymph nodes in the armpit?

What did it find?

In selected patients, completion axillary dissection did not clearly improve overall survival or disease-free survival. As a result, in many patients the larger armpit operation can now be omitted.

What did it change today?

In suitable early-stage disease, routine completion axillary dissection has largely been abandoned; the aim is to reduce the risk of arm swelling while maintaining oncologic safety.

Who does this apply to?

Depends on breast-conserving surgery plus whole-breast radiotherapy and on limited sentinel node involvement. It is not automatically extended to mastectomy, to more than three positive nodes, or to patients who do not receive radiotherapy.

The story behind the gold star

After a positive sentinel node, completion axillary dissection was long considered routine. ACOSOG Z0011 questioned this routine in selected patients with one or two positive sentinel nodes who were planned for breast-conserving surgery and whole-breast radiotherapy. Under trial conditions, sentinel biopsy alone was not inferior to axillary dissection in terms of overall survival. As a result, the larger armpit operation could be avoided in many suitable patients. This result does not answer the same clinical question as SOUND or AMAROS; it cannot be carried beyond its selection criteria.

What question was this research asking?

In early-stage triple-negative breast cancer, does adding pembrolizumab to chemotherapy before and after surgery control the disease better?

What did it find?

In high-risk early triple-negative disease, adding pembrolizumab to chemotherapy increased the likelihood that the tumor disappeared completely at surgery and reduced events (recurrence or death). This does not mean immunotherapy for every triple-negative patient.

What did it change today?

In suitable high-risk early triple-negative breast cancer, perioperative pembrolizumab plus chemotherapy became an important option.

Who does this apply to?

For early-stage, high-risk triple-negative patients who meet the protocol criteria. The same result cannot be assumed for metastatic disease or low-risk early disease. The side-effect profile is assessed separately.

The story behind the gold star

Triple-negative breast cancer is a subtype that lacks hormone-receptor and HER2 targets. KEYNOTE-522 tested adding pembrolizumab to chemotherapy in high-risk early-stage disease. The trial became one of the key pieces of evidence that moved perioperative immunotherapy into the standard options for this selected population. The side-effect profile and patient selection remain critical. This result does not mean automatic immunotherapy for every patient diagnosed with triple-negative breast cancer.

What question was this research asking?

In advanced melanoma, does nivolumab (± ipilimumab) prolong survival compared with ipilimumab alone?

What did it find?

10-year overall survival (OS) was 43% (nivolumab plus ipilimumab), 37% (nivolumab) and 19% (ipilimumab). Dual immunotherapy toxicity is higher; nivolumab plus ipilimumab vs nivolumab was not a primary superiority test.

What did it change today?

In advanced melanoma, PD-1 ± CTLA-4 inhibition became the first-line standard.

Who does this apply to?

Metastatic / unresectable disease. It is not confused with adjuvant questions.

The story behind the gold star

CheckMate 067 compared three arms in previously untreated advanced/metastatic melanoma: nivolumab + ipilimumab, nivolumab, and ipilimumab. With a minimum follow-up of ten years, ten-year overall survival was approximately 43% (nivolumab + ipilimumab), 37% (nivolumab) and 19% (ipilimumab); median OS was 71.9 / 36.9 / 19.9 months. The primary comparisons are the superiority of the nivolumab-containing arms over ipilimumab. The difference between nivolumab + ipilimumab and nivolumab is descriptive; an OS superiority of the combination over monotherapy is not presented as separately proven in this trial. Dual-IO toxicity is markedly higher. It is not confused with adjuvant/neoadjuvant questions.

What question was this research asking?

In BRAF-mutant stage III melanoma, does dabrafenib plus trametinib after surgery reduce recurrence?

What did it find?

At five years, the recurrence-free rate was 52% vs 36%. Final overall survival (OS) in the overall population was not statistically significant (P=0.06).

What did it change today?

In suitable BRAF V600-positive patients, adjuvant dabrafenib plus trametinib became one of the standard options.

Who does this apply to?

Only BRAF V600E/K. Note that OS was not significant (NS); it is not a head-to-head comparison with PD-1 inhibitors.

The story behind the gold star

COMBI-AD compared 12 months of dabrafenib + trametinib with placebo in completely resected, high-risk stage III melanoma with a BRAF V600E/K mutation. At five years, recurrence-free survival was 52% vs 36% and distant-metastasis-free survival was 65% vs 54%. In the final overall survival analysis, HR was 0.80 and P=0.06 — it did not meet the threshold for statistical significance in the overall population. The gold-star rationale is that adjuvant BRAF+MEK therapy became a standard option in a mutation-selected population based on RFS/DMFS; the OS claim is not overstated and the result is not carried over to BRAF-negative patients.

What question was this research asking?

In a suitable melanoma patient whose sentinel lymph node is positive, does immediate completion lymph node dissection reduce the risk of death from melanoma compared with close observation?

What did it find?

At three years, melanoma-specific survival was the same in both groups (about 86%). Regional control was better in the dissection arm, but lymphedema was more frequent. The gain in regional control did not translate into a gain in melanoma-specific survival. Therapeutic dissection is not abandoned entirely.

What did it change today?

In suitable sentinel-positive patients, close surveillance with ultrasound and, if needed, therapeutic dissection became widespread instead of routine completion dissection.

Who does this apply to?

For suitable sentinel-positive patients. Therapeutic dissection for macroscopic nodal involvement or for recurrence during surveillance is a separate indication.

The story behind the gold star

MSLT-II compared routine completion dissection with ultrasound surveillance in suitable patients with sentinel-node-positive melanoma. Three-year melanoma-specific survival was the same in both arms (86%). Dissection improved regional nodal control but increased lymphedema. The paradigm message is this: an advantage in regional control does not automatically translate into a gain in melanoma-specific survival; routine completion dissection is therefore withdrawn. Therapeutic dissection performed for clinical recurrence or macroscopic disease is not ‘abandoned altogether’ by this trial.

What question was this research asking?

In high-risk stage III melanoma that has been completely removed by surgery, does pembrolizumab delay the return of the disease and its distant spread?

What did it find?

At seven years, the recurrence-free rate was 50% vs 36%; the distant-metastasis-free rate was 54% vs 42%. These are not overall survival.

What did it change today?

In suitable high-risk stage III disease, adjuvant pembrolizumab became a widely used standard option.

Who does this apply to?

Completely resected high-risk stage III. Recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) are not confused with overall survival (OS).

The story behind the gold star

KEYNOTE-054 compared adjuvant pembrolizumab with placebo in completely resected high-risk stage III melanoma. In the seven-year analysis, recurrence-free survival was 50% vs 36% and distant-metastasis-free survival was 54% vs 42%. This trial is one of the cornerstones of the adjuvant PD-1 era. Recurrence-free and distant-metastasis-free survival are not overall survival; an OS benefit is not presented as proven in this summary.

What question was this research asking?

In resectable melanoma, is it better to start pembrolizumab before surgery?

What did it find?

The two-year event-free rate was 72% in the group treated before and after surgery, and 49% in the group treated only after surgery. This is not a survival rate.

What did it change today?

The neoadjuvant PD-1 approach was strengthened in selected patients.

Who does this apply to?

Resectable stage III–IV; phase II. It differs from the NADINA combination regimen.

The story behind the gold star

SWOG S1801 is one of the pioneering randomized trials that strengthened the place of neoadjuvant immunotherapy in clinical practice, showing that a neoadjuvant-plus-adjuvant pembrolizumab approach improved event-free survival compared with adjuvant treatment alone in resectable high-risk melanoma. Two-year event-free survival was 72% vs 49%. This result is not overall survival (OS). NADINA is a different regimen (ipilimumab + nivolumab) and a phase III trial; the two trials are read together without claiming direct superiority.

What question was this research asking?

In macroscopic stage III disease, is giving ipilimumab plus nivolumab before surgery better than operating first and then giving nivolumab?

What did it find?

The two-year event-free rate was 77.3% vs 55.7%. Serious side effects were more frequent in the neoadjuvant group (~31% vs ~16%). Event-free survival (EFS) is not overall survival (OS); OS maturity is followed separately.

What did it change today?

In selected macroscopic stage III disease, neoadjuvant ipilimumab plus nivolumab with response-guided adjuvant therapy became a strong option.

Who does this apply to?

Macroscopically resectable stage III. Serious immune-related toxicity; overall survival is not yet mature.

The story behind the gold star

NADINA compared neoadjuvant ipilimumab + nivolumab, followed by surgery and a response-adapted adjuvant strategy, with surgery first followed by adjuvant nivolumab in macroscopically resectable stage III melanoma. In the 2025 update, two-year event-free survival was 77.3% vs 55.7%. Distant-metastasis-free survival also favored the neoadjuvant arm. Serious (grade ≥3) treatment-related adverse events occurred in about 31% in the neoadjuvant arm and about 16% in the comparator arm. The gold-star rationale is the EFS paradigm change; EFS is not presented as OS, and toxicity is not hidden.

What question was this research asking?

In advanced liver cancer that cannot be removed by surgery, does atezolizumab plus bevacizumab prolong survival compared with sorafenib?

What did it find?

Overall survival (OS) and progression-free survival (PFS) improved (updated median OS 19.2 vs 13.4 months; hazard ratio [HR] 0.66). Bevacizumab is not suitable for every patient because of bleeding / varices risk; Child-Pugh A liver function and a suitable performance status are typical.

What did it change today?

It became one of the main first-line systemic treatment options for many suitable patients with advanced HCC.

Who does this apply to?

For unresectable HCC with no prior systemic therapy; variceal screening is critical. No head-to-head superiority claim is made over other first-line immunotherapy regimens.

The story behind the gold star

IMbrave150 is one of the landmark phase III trials that opened the immunotherapy era in advanced HCC. Atezolizumab + bevacizumab improved survival compared with sorafenib and changed first-line practice. Because of the anti-VEGF component, assessment for varices and management of bleeding risk are mandatory. HIMALAYA and other IO options offer alternative paths; there is no claim of a ‘single correct regimen’.

What question was this research asking?

In stage III ovarian cancer, does adding cisplatin hyperthermic intraperitoneal chemotherapy (HIPEC) to the clearing operation after chemotherapy prolong life?

What did it find?

Median progression-free survival was 14.3 months in the group with HIPEC added and 10.7 months with surgery alone. Median survival was found to be 44.9 vs 33.3 months (hazard ratio [HR] 0.70; 95% confidence interval 0.53–0.92; P=0.011). This is the interval pathway; it is not primary cytoreductive surgery (CRS).

What did it change today?

In the suitable interval ovarian pathway, cisplatin HIPEC was strengthened as an option (local guidelines / licensing).

Who does this apply to?

Stage III epithelial ovarian cancer, interval CRS after neoadjuvant chemotherapy. Cisplatin 100 mg/m². The primary CRS setting is OVHIPEC-2. It is not generalized to peritoneal metastasis of colorectal or gastric origin.

The story behind the gold star

OVHIPEC-1 compared adding cisplatin HIPEC to interval cytoreductive surgery after neoadjuvant chemotherapy in selected advanced epithelial ovarian cancer with CRS alone. In the long-term analysis, median overall survival was 44.9 vs 33.3 months; HR 0.70 (95% CI 0.53–0.92), P=0.011. The gold-star rationale is positive survival evidence: in a specific interval pathway, cisplatin HIPEC can improve survival. This result is not the same question as colorectal PRODIGE 7; the primary-CRS setting and platinum-sensitive recurrence (CHIPOR) are separate trials.

What question was this research asking?

In high-risk colon cancer, does preventive hyperthermic intraperitoneal chemotherapy (HIPEC) after surgery reduce peritoneal recurrence?

What did it find?

Peritoneal metastasis-free survival at 18 months ≈81% vs 76%; there was no significant difference (P=0.28). High risk alone is not an automatic reason for HIPEC.

What did it change today?

Routine prophylactic HIPEC is not supported.

Who does this apply to?

T4 / perforation; no peritoneal metastasis (PM). The question of therapeutic cytoreductive surgery (CRS) in existing PM is separate. It is not the same clinical question as PRODIGE 7 (therapeutic colorectal HIPEC).

The story behind the gold star

COLOPEC is an important negative randomized trial that could not demonstrate a peritoneal-metastasis-free survival benefit from routine preventive oxaliplatin-HIPEC in high-risk colon cancer, and that has guided clinical practice toward avoiding unnecessary treatment. At eighteen months, peritoneal-metastasis-free survival was about 81% vs 76%; there was no significant difference. The five-year update likewise showed no advantage. This question differs from PRODIGE 7, which adds HIPEC to CRS in existing peritoneal metastasis, and from PROPHYLOCHIP, which tests a second-look + HIPEC package after adjuvant chemotherapy; the three are not confused.