Chemotherapy

Kate Middleton Reveals Cancer Diagnosis, Says She Is Undergoing Chemotherapy

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The news comes as speculations about her whereabouts reach new heights online.

preview for Kate Middleton reveals she's been diagnosed with cancer
  • Kate Middleton, 42, has been diagnosed with cancer.
  • The Princess of Wales revealed in a statement Friday that she is undergoing chemotherapy.
  • She is asking for “time, space, and privacy,” while she and her family navigate the diagnosis.

Kate Middleton, the Princess of Wales, has been diagnosed with cancer. The royal revealed in a statement Friday that she is undergoing chemotherapy treatments and asks for privacy during this difficult time. The news comes after weeks of speculation about her health reaches a fever pitch online, and after she underwent abdominal surgery in January.

While the specifics of the 42-year-old’s diagnosis are not yet known to the public (she did not specify the type of cancer nor the stage), she did make a statement.

“In January I underwent major abdominal surgery in London and at the time it was thought that my condition was non-cancerous. The surgery was successful, however, tests after the operation found cancer had been present,” the Princess of Wales said in a video updating fans on her health released by Kensington Palace.

She then explained that her medical team advised “a course of preventative chemotherapy,” which she is undergoing. “I am now in the early stages of that treatment,” she said in a palace statement. She asked for “time, space, and privacy” while finishing treatment.

The Princess noted that she, too, was surprised by the diagnosis. “This, of course, came as a huge shock, and William and I have been doing everything we can to process and manage this privately for the sake of our young family. As you can imagine, this has taken time. It has taken me time to recover from major surgery in order to start my treatment,” she said.

Depending on the type of cancer and surgery, which again, is unknown to the public at this time, it can take up to six weeks to heal, according to the Cleveland Clinic.

“But, most importantly, it has taken us time to explain everything to George, Charlotte, and Louis in a way that is appropriate for them, and to reassure them that I am going to be OK.”

Chemotherapy is a drug treatment that uses powerful chemicals to kill fast-growing cells in your body, and is most often used to treat cancer, since cancer cells grow and multiply much more quickly than other bodily cells, the Mayo Clinic notes. Many different chemotherapy drugs are available, and can be used alone or in combination to treat a variety of cancers.

The Princess relayed a message of hope to others affected by similar diagnoses. “At this time, I am also thinking of all those whose lives have been affected by cancer,” she said. “For everyone facing this disease, in whatever form, please do not lose faith or hope. You are not alone.”

The news comes soon after King Charles was diagnosed with cancer. Our thoughts are with the Princess, the King, and their families at this time.

Radiotherapy with or without chemotherapy for locally advanced head and neck cancer in elderly patients: analysis of the Head and Neck Cancer Registry of Japan

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Abstract

Background

Whether concurrent chemotherapy with radiotherapy (CRT) is effective for elderly patients with head and neck cancer is a controversial topic. This study aimed to analyze the effectiveness of CRT vs. radiation therapy (RT) among elderly patients in Japan.

Methods

Data from the Head and Neck Cancer Registry of Japan were extracted and analyzed. Patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, or larynx who received definitive CRT or RT between 2011 and 2014 were included.

Results

CRT was administered to 78% of the 1057 patients aged ≥ 70 years and 67% of the 555 patients aged ≥ 75 years. For the patients aged ≥ 75 years, the overall survival (OS) rate was significantly better in the CRT group than in the RT group (P < 0.05), while the progression-free survival (PFS) rate was not significantly different (P > 0.05). The add-on effect of CRT was significantly poor in elderly patients (P < 0.05), and it was not a significant factor in the multivariate analysis for patients aged ≥ 75 years. After propensity score matching, there were no significant differences in the OS and PFS rates between the patients aged ≥ 70 years and those aged ≥ 75 years (all, P > 0.05).

Conclusion

Although aggressive CRT is administered to elderly patients in Japan, its effectiveness is uncertain. Further prospective randomized trials are needed to verify whether CRT is superior to RT alone for elderly patients.

Antioxidant Use During Chemo Risky.

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Breast cancer patients who take the dietary supplements known as antioxidants, as well as iron, vitamin B12, and omega-3 fatty acids, during chemotherapy may be at increased risk of disease recurrence and death, according to new study results appearing in the Journal of Clinical Oncology.

Led by researchers at the SWOG Cancer Research Network, a cancer clinical trials network funded by the National Cancer Institute (NCI) through the National Institutes of Health, the study confirms previous medical guidance advising cautious use of any supplements, other than a multivitamin, for cancer patients undergoing chemotherapy.

A small but growing body of research in the last 20 years shows that, despite their cancer-fighting reputation, antioxidants such as vitamin E, beta-carotene, and selenium can actually increase risk of some cancers, cause some cancers to return after treatment, or interfere with the effects of chemotherapy. As part of the nation’s oldest and largest publicly-funded cancer research network, SWOG has conducted some of this work. Its landmark Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed that vitamin E supplementation increases the risk of prostate cancer in healthy men.

What’s unique about the new study, led by Christine B. Ambrosone, PhD, of Roswell Park Comprehensive Cancer Center, is that it is the first investigation of the effects of supplement use during breast cancer treatment, and only the second to investigate the effects of supplement use during any kind of cancer treatment. The first was conducted by Charles Fuchs, MD, MPH, the director of Yale Cancer Center, who found that vitamin C may be helpful for people undergoing chemotherapy treatment for colorectal cancer.

“Although this is an observational study and the number of users of supplements was fairly small, the results are compelling,” said Ambrosone, chair of the Department of Cancer Prevention and Control at Roswell Park. “Patients using any antioxidant before and during chemotherapy had an increased risk of their breast cancer returning and, to a lesser degree, had an increased risk of death. Vitamin B12, iron, and omega-3 fatty acid use was also associated with poorer outcomes.”

Ambrosone conducted her study as part of S0221, a randomized phase III SWOG trial determining the best dose and schedule for using three chemotherapy drugs – doxorubicin, cyclophosphamide, and paclitaxel – as adjuvant therapy for high-risk, early-stage breast cancer. In its first iteration, the trial enrolled 2,716 patients between 2003 and 2010. Patients were followed for a median of six years to identify any side effects from the chemotherapy combinations tested and to measure how long, if ever, it took for their breast cancer to return.

Whether vitamin and mineral supplements, in particular the type known as antioxidants, help or hurt cancer patients is a matter of debate and dueling research findings. Some evidence suggests that antioxidants can interfere with the cancer-killing effects of chemotherapy. That’s because these chemical treatments cause oxidative stress, a chemically-triggered reaction in the body, which in turn kills cancer cells. But antioxidants fight oxidative stress, which means they can blunt the effects of chemotherapy. At the same time, a few studies, such as Fuchs,’ show benefits to cancer patients who take dietary supplements.

To better understand the role supplements might play in chemotherapy response, Ambrosone and her team asked every woman and man randomized onto S0221 whether they would answer detailed questionnaires about their use of dietary supplements – first at the time they were assigned to a treatment group, then again six months after their chemotherapy was complete. Of the 2,014 patients eligible for this part of the study, 1,607 – or 80 percent – agreed.

In the end, 1,134 patients completed both surveys, and of these, 18 percent used at least one antioxidant daily, while 44 percent took multivitamins. Here’s what researchers found:

  • Patients who reported taking any antioxidant – vitamins A, C, E and carotenoids and Coenyzme Q10 – were 41 percent more likely to have their breast cancer return when they took the supplements both before and during chemotherapy treatment
     
  • Patients had a similar, but weaker, increased risk of death when taking those antioxidants
     
  • Patients taking vitamin B12, iron, and omega-3 fatty acid supplements were at significantly greater risk of breast cancer recurrence and death
     
  • Patients taking multivitamins showed no signs of poorer or better outcomes after chemotherapy

Ambrosone cautions that her study results are not definitive enough to influence how doctors treat cancer patients. To do that, she notes, the research community would need to run a larger, randomized trial testing groups who do and do not take supplements to get a clear and strong connection. However, she said the results do support the current cautious approach to supplement use for people undergoing chemotherapy.

“People diagnosed with any cancer should talk with their doctors about whether they should be taking vitamins or other supplements,” she said. “I’d recommend that they try to get their vitamins and minerals – including antioxidants – from food. With a healthy and balanced diet, you can get all the nutrients your body needs, even while undergoing chemo.”

If changes in taste or loss of appetite related to the effects of cancer treatment are making whole vegetables, fruits, and grains unappealing or difficult to eat, Ambrosone advises, patients should seek out guidance from their medical team or a dietician to find out ways to incorporate these foods into their diets.

Long-Term Update on Neoadjuvant Pembrolizumab Plus Chemotherapy in Early-Stage Triple-Negative Breast Cancer

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Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab has yielded improvements in pathologic complete response and event-free survival in patients with early-stage triple-negative breast cancer. In a study presented at the 2023 San Antonio Breast Cancer Symposium (SABCS; Abstract LBO1-01), Peter Schmid, MD, PhD, of Barts Cancer Institute, Queen Mary University, London, and colleagues reported that after a median follow-up of approximately 5 years, 145 patients (18.5%) in the pembrolizumab group and 108 patients (27.7%) in the placebo group had an event-free survival event, defined as disease progression that precluded definitive surgery.

A total of 1,174 eligible patients with early-stage triple-negative breast cancer were randomly assigned on a 2:1 basis to receive pembrolizumab (n = 784) or placebo (n = 390) groups. Both groups received four cycles of paclitaxel plus carboplatin, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab or placebo for nine cycles or until disease recurrence or unacceptable toxicity. The dual primary endpoints were pathologic complete response and event-free survival.

Findings revealed the 60-month event-free survival rate was 81.3% (95% confidence interval [CI] = 78.4%–83.9%) vs 72.3% (95% CI = 67.5%–76.5%), respectively, with and without neoadjuvant pembrolizumab. The benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant chemotherapy alone was consistent with the primary event-free survival results in all five sensitivity analyses. In a prespecified, nonrandomized, exploratory analysis, the 5-year event-free survival rates in the pembrolizumab and placebo groups were 92.2% vs 88.2% in patients with a pathologic complete response and 62.6% vs 52.3% in patients without a pathologic complete response.

Automated Liquid Biopsy Detects CNS Tumor Cells in Children

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Physicians treating CNS tumors with surgery, chemotherapy, radiation, or a combination of these therapies have relied on a series of magnetic resonance imaging (MRI) scans to monitor whether treatment is working or not. But MRI scans can’t detect microscopic disease that could indicate whether cancer cells remain or have returned.

To fill this gap, researchers have been looking for reliable, tumor-specific biomarkers. They know from previous studies in adults that primary tumors shed circulating tumor cells (CTCs) into a patient’s bloodstream and that CTCs could be reliable biomarkers for CNS tumors.

Pediatric researchers at the University of Texas MD Anderson Cancer Center wanted to know whether a liquid biopsy tool that relies on detecting vimentin, a structural protein on the surface of many cancer cells, would work to capture and isolate CTCs in blood samples taken from children with CNS tumors.

The researchers who published their study in Cancers also wanted to know whether automating the CTC capture method would improve their previously validated manual method.

The researchers’ liquid biopsy approach captures cells with cell-surface vimentin (CSV) to isolate CTCs from patients’ blood, which can provide information about their cancer and monitor their ongoing treatment.

The study authors had previously found that the manual liquid biopsy approach detected CTCs in adults with different types of cancer. In the current study, the researchers wanted to automate their method to boost its sensitivity and to capture CTCs from CNS tumors.

The researchers enrolled 62 participants in their study: 58 children (median age 13 years) who were diagnosed with CNS tumors and four healthy adolescents (median age 16 years) who made up the comparison group. Forty-five of the participants with cancer had malignant tumors, including seven whose cancer had metastasized.

The researchers took blood samples from all the participants to isolate and capture the tumor cells. After removing denser cells unlikely to contain CTCs, the researchers loaded the samples onto a machine that is equipped with a microchip. This microchip is coated with an antibody that recognizes CSV, which causes the CTCs to attach to it, but allows other types of cells to flow away. The cells on the chip were then stained so that they could be counted and identified.

The automated method successfully captured CTCs in 50 of the 58 pediatric patients (86%). There were no significant differences in CTC detection based on patient characteristics, such as gender, age, disease status, or type of cancer therapy.

Overall, the automated CSV-CTC capture tool was highly accurate in identifying patients with and without CNS tumor cells (meaning that the test was both sensitive and specific). The tool was also highly accurate in predicting the presence of CNS tumor cells, but it only predicted their absence about one-third of the time.

“This is the first study to demonstrate the detection of CTCs using CSV as a biomarker in pediatric CNS tumors, including ones that are malignant and have metastasized,” said Shulin Li, PhD, principal investigator of this study and professor of pediatrics at UT Anderson Cancer Center.

Also, compared to the researchers’ previous manual CTC capture and identification process, the automated CTC isolation process increased the sensitivity of CTC detection rates by about 10% and decreased sample processing times.

“This study also showed the value of automating the CSV-CTC capture process with a microchip. This tool could make it easier to monitor patients’ response to treatment and identify cancer relapse earlier,” said Shawn Mulvaney, PhD, a health science administrator in the NIBIB Division of Applied Science & Technology (Bioimaging).

The research team also wanted to show that they could identify a specific mutation that has been associated with worse prognosis among patients with midline gliomas. When they analyzed the CTCs captured from patients with these types of tumors, they were able to detect this mutation among 75% of the samples.

The main study limitations were the small sample size and the fact that the microchip technology required additional steps to confirm the identification of CTCs. While larger studies are needed to validate the findings in this study, the detection of CTCs in patients with CNS tumors can potentially be used to confirm the diagnosis of inoperable, difficult-to-biopsy tumors such as brainstem gliomas and optic pathway gliomas.

“Our tool also has the potential to help physicians know early on which patients will respond to treatment. When they know a tumor isn’t responding, they could enroll the patient in a clinical trial with innovative therapy,” said Wafik Zaky, MD, lead author and associate professor of neuro-oncology at the University of Texas MD Anderson Cancer Center.

Can AI save breast cancer patients from unnecessary chemotherapy treatments?

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Will expert pathologists still have a job in the near future? Possibly not, thanks to the development of a new artificial intelligence (AI) tool that scientists say will be more capable than human doctors at predicting the outcome of breast cancer.

Perhaps it will not quite be as severe as that, with expert pathologists being able to work alongside the AI tool to help patients classified as intermediate- or high-risk to survive longer with less of a need for chemotherapy treatments.

According to new research out of Northwestern Medicine in Chicago, the new AI tool could help cancer doctors to better protect patients against harmful side effects by reducing the need for as much chemotherapy or radiation.

Published in the journal Nature Medicine, the paper highlights how pathologists currently only evaluate cancerous cells in a patient’s tissue in order to select a course of treatment. The AI tool would allow for non-cancerous cells to also be looked at and used to predict patient outcomes.

“Our study demonstrates the importance of non-cancer components in determining a patient’s outcome,” said Lee Cooper, an associate professor of pathology at the Northwestern University Feinberg School of Medicine.

“The importance of these elements was known from biological studies, but this knowledge has not been effectively translated to clinical use.”

Watch below as Mike Adams talks about a new open-source, downloadable AI chatbot currently in production that aims to democratize humanity’s knowledge about nutrition and natural health:

https://www.brighteon.com/embed/226d0aa7-a172-45b0-bd52-07a9049636c0

(Related: Did you know that there exists demon-possessed AI that is being “taught” how to use synthetic biotechnology to construct artificial “superhuman” biological systems?)

Will AI medicine actually be safe?

In Europe right now, female breast cancer is the most commonly diagnosed form of cancer. In 2020, more than 355,000 women were diagnosed, accounting for 13.3 percent of all cancer diagnoses across the continent.

Many of these patients were put on a course of chemotherapy, but far fewer would have been had the AI tool been ready back then, we are told.

Right now, the job of a pathologist involves reviewing cancerous tissue to determine the look of abnormal tissue. Based on the tissue’s appearance, a treatment protocol is then selected.

The problem is that many breast cancer biology studies have shown that non-cancerous cells are sometimes involved in either sustaining or inhibiting cancer cell growth, despite being technically benign.

Cooper and his team used this knowledge to build an AI model that is capable of evaluating breast cancer tissue from digital images. It is able to measure the appearance of both cancerous and non-cancerous cells, as well as how these cells interact with one another.

“These patterns are challenging for a pathologist to evaluate as they can be difficult for the human eye to categorize reliably,” Cooper said. “The AI model measures these patterns and presents information to the pathologist in a way that makes the AI decision-making process clear to the pathologist.”

The AI tool reportedly looks at 26 different properties of a patient’s breast tissue in order to generate a prognostic score. It also generates individual scores for not just cancer but also immune and stromal cells to extrapolate the overall score.

The information collected from this analysis can then be used to develop customized treatment plans for each individual patient, utilizing more accurate risk assessments than what is currently available.

Cooper and his colleagues trained their AI model using hundreds of thousands of human-generated annotations of cells and tissue structures found in the digital images of tissue samples collected from patients. This process took a number of years to fine-tune, and is now being unveiled.

Bevacizumab Added to FTD-TPI in Third-Line Therapy for Metastatic Colorectal Cancer

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A phase 3, randomized, placebo-controlled trial shows benefits, including in overall survival and progression-free survival.

Trifluridine-tipiracil (FTD-TPI) is an approved late-line therapy in chemotherapy-refractory metastatic colorectal cancer. Bevacizumab is combined with first- and second-line chemotherapy, but its continued use in later-line therapy has not been clearly supported in clinical trials. Investigators now report results of the SUNLIGHT trial, a global, open-label, industry-sponsored, randomized, phase 3 trial evaluating the use of standard-regimen FTD-TPI, given with or without bevacizumab (5 mg/kg) every 2 weeks, in chemotherapy-refractory colorectal cancer.

Of the 492 patients treated, 72% had left-sided primary tumors, 92% had received two prior chemotherapy regimens, 72% had received prior anti–vascular endothelial growth factor (VEGF) therapy, 20% received bevacizumab as part of first- and second-line chemotherapy, and of the 31% with RAS wild-type cancers, 94% had received prior epidermal growth factor (EGFR)–targeted therapy.

At a median follow-up of 14 months, the primary endpoint of median overall survival was significantly longer with the addition of bevacizumab (10.8 vs. 7.5 months; hazard ratio, 0.61). Overall survival at 6 months and at 12 months were also better with bevacizumab added (77% vs. 61% and 43% vs. 30%, respectively). Progression-free survival was significantly longer with bevacizumab (5.6 vs. 2.4 months; HR for disease progression or death, 0.44), and response rate was also better (6.1% vs. 1.2%). No new safety signals were observed; hypertension and neutropenia were more common with bevacizumab.

Comment

The SUNLIGHT trial is practice changing and indicates that bevacizumab should be continued into late-line treatment with FTD-TPI, as the addition of bevacizumab was associated with clinically meaningful improvements in all treatment endpoints. Although a cleaner trial comparison would have included only patients with prior first- and second-line bevacizumab therapy, most patients received at least two lines of prior chemotherapy, and nearly all had prior treatment with EGFR or anti-VEGF agents.

Preoperative Chemotherapy Without Radiotherapy for Locally Advanced Rectal Cancer

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Patients with clinical stage T2N1 or T3N0–1 rectal cancers who are eligible for sphincter-sparing surgery might be able to avoid preoperative radiotherapy if given induction FOLFOX prior to surgery.

Total neoadjuvant therapy for patients with locally advanced rectal cancer — whereby chemoradiotherapy and chemotherapy are administered prior to surgery — offers the potential for enhanced treatment tolerance and delivery, improvements in pathologic response at surgery, and nonoperative management for colostomy candidates who achieve a clinical complete response. However, for patients with high- or mid-rectal cancers undergoing total mesorectal excision, the role of neoadjuvant radiotherapy has been increasingly questioned.

To test the concept of avoiding neoadjuvant radiotherapy in this setting, investigators conducted a multicenter, noninferiority, randomized, phase 3 trial (PROSPECT) involving 1128 patients with clinical stage T2N1 or T3N0–1 high- or mid-rectal cancer who were candidates for sphincter-sparing surgery. Most patients were male, half had T3N1 cancers, 91% had T3N0–1 cancers, and 64% had cancers 5 to 10 cm from the anal verge. Half of patients received conventional neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy. The other half received induction chemotherapy with 6 cycles of FOLFOX, and those with a ≥20% reduction in the primary tumor proceeded to surgery without radiotherapy and received adjuvant chemotherapy.

At 5 years, disease-free survival was noninferior with induction FOLFOX versus chemoradiotherapy (80.8% vs. 78.6%; hazard ratio, 0.92, P=0.005), meeting the primary endpoint. Rates of local recurrence were similar with FOLFOX or chemoradiotherapy (1.8% and 1.6%, respectively), as were 5-year overall survival (89.5% and 90.2%) and pathologic complete response (21.9% and 24.3%). Nearly 90% of patients treated with FOLFOX avoided radiotherapy; 9.1% required neoadjuvant chemoradiotherapy after FOLFOX, and 1.4% required postoperative chemoradiotherapy. No new safety signals were observed.

Comment

The large, well-conducted trial indicates that the vast majority of patients with clinical stage T2N1 or T3N0–1 rectal cancers who are eligible for sphincter-sparing surgery can avoid the use of preoperative radiotherapy if given induction FOLFOX. This trial will change practice. The use of radiotherapy preoperatively will increasingly be relegated to more advanced rectal cancers or to patients requiring a permanent colostomy.

Olanzapine Improves Weight Gain in Patients with Advanced Cancer on Chemotherapy

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Among patients with newly diagnosed advanced gastric, hepatopancreaticobiliary, or lung cancers starting chemotherapy, low-dose daily olanzapine improved appetite and weight gain.

Patients with advanced cancer often present with anorexia and weight loss. Poor nutritional status is associated with myriad adverse outcomes in this population. Medical management options have been limited, although corticosteroids and progesterone analogs (e.g., megestrol acetate) are commonly used. These investigators evaluated olanzapine — an antipsychotic agent that increases appetite and decreases nausea — for the treatment of chemotherapy-related anorexia in patients with locally advanced or metastatic gastric, hepatopancreaticobiliary, or lung cancer.

In the randomized, double-blind study, 124 adult patients received olanzapine (2.5 mg daily) or placebo for 12 weeks, starting on the first day of the first chemotherapy cycle. A significantly higher percentage of patients in the olanzapine arm than the placebo arm had weight gain >5% (60% vs. 9%; P<.001) and improved appetite (43% vs. 13%; P<.001) — the primary outcomes. The olanzapine arm also had significantly improved quality of life and nutritional status, as well as less chemotoxicity ≥ grade 3 (12% vs. 37%; P=.002). Adverse events attributable to olanzapine included mild, limited drowsiness.

Comment

This study fills an important gap in the literature, helping clinicians better support patients with advanced cancer who have cancer-associated weight loss and anorexia.

As noted in a recent ASCO Guideline Rapid Recommendation Update on cancer cachexia, daily low-dose olanzapine should be offered to patients with advanced cancer to support appetite and weight gain, along with nutritional support (J Clin Oncol 2023; 41:4178). For patients unable to tolerate olanzapine, a short-term trial of a corticosteroid or progesterone analog may be considered. Although the Update applies to all adult patients with advanced cancer, the majority of evidence derives from patients with gastrointestinal or lung malignancies and those receiving cytotoxic chemotherapy.

The use of mirtazapine for cancer-associated weight loss and anorexia should be limited, as a recent study found it to be no better than placebo (J Pain Symptom Manage 2021; 62:1207). Importantly, there are no FDA-approved medications for cancer cachexia.

Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma

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BACKGROUND: IMvigor130 demonstrated statistically significant investigator-assessed progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial carcinoma. Overall survival was not improved in interim analyses. Here we report the final overall analysis for group A versus group C.

METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged =18 years) with previously untreated locally advanced or metastatic urothelial cancer and who had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), with a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin risk factor score, and investigator’s choice of platinum-based chemotherapy, to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo (ie, group A and group C) and atezolizumab monotherapy (group B) was open label. For groups A and C, all patients received gemcitabine (1000 mg/m2 intravenously; day 1 and day 8 of each 21-day cycle), plus investigator’s choice of carboplatin (area under curve 4·5 mg/mL per min or 5 mg/mL per min; intravenously) or cisplatin (70 mg/m2 intravenously), plus either atezolizumab (1200 mg intravenously) or placebo on day 1 of each cycle. Co-primary endpoints of the study were investigator-assessed progression-free survival and overall survival for group A versus group C in the intention-to-treat (ITT) population (ie, all randomised patients), and overall survival for group B versus group C, tested hierarchically. Final overall survival and updated safety outcomes (safety population; all patients who received any amount of any study treatment component) for group A versus group C are reported here. The final prespecified boundary for significance of the overall survival analysis was one-sided p=0·021. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting.

FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 851 were assigned to group A (n=451) and group C (n=400). 338 (75%) patients in group A and 298 (75%) in group C were male, 113 (25%) in group A and 102 (25%) in group C were female, and 346 (77%) in group A and 304 (76%) in group C were White. At data cutoff (Aug 31, 2022), after a median follow up of 13·4 months (IQR 6·2-30·8), median overall survival was 16·1 months (95% CI 14·2-18·8; 336 deaths) in group A versus 13·4 months (12·0-15·3; 310 deaths) in group C (stratified hazard ratio 0·85 [95% CI 0·73-1·00]; one-sided p=0·023). The most common grade 3-4 treatment-related adverse events were anaemia (168 [37%] of 454 patients who received atezolizumab plus chemotherapy vs 133 [34%] of 389 who received placebo plus chemotherapy), neutropenia (167 [37%] vs 115 [30%]), decreased neutrophil count (98 [22%] vs 95 [24%]), thrombocytopenia (95 [21%] vs 70 [18%]), and decreased platelet count (92 [20%] vs 92 [24%]). Serious adverse events occurred in 243 (54%) patients who received atezolizumab plus chemotherapy and 196 (50%) patients who received placebo plus chemotherapy. Treatment-related deaths occurred in nine (2%; acute kidney injury, dyspnoea, hepatic failure, hepatitis, neutropenia, pneumonitis, respiratory failure, sepsis, and thrombocytopenia [n=1 each]) patients who received atezolizumab plus chemotherapy and four (1%; unexplained death, diarrhoea, febrile neutropenia, and toxic hepatitis [n=1 each]) who received placebo plus chemotherapy.

INTERPRETATION: Progression-free survival benefit with first-line combination of atezolizumab plus platinum-based chemotherapy did not translate into a significant improvement in overall survival in the ITT population of IMvigor130. Further research is needed to understand which patients might benefit from first-line combination treatment. No new safety signals were observed.