neoadjuvant chemotherapy

Neoadjuvant nivolumab treatment improves survival rates in NSCLC patients

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Bottom line:Patients with resectable non-small cell lung cancer (NSCLC) who were treated with neoadjuvant nivolumab had improved five-year recurrence-free and overall survival rates compared with historical outcomes.

Background:NSCLC is the most common type of lung cancer and is a leading cause of cancer-related death worldwide. Despite strides in treating metastatic NSCLC, new treatments for earlier-stage disease have only recently emerged, according to Forde.

Rosner added that there is great interest in optimizing neoadjuvant strategies for earlier-stage NSCLCs that are eligible for surgical resection. Rosner is a medical oncology fellow at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and a member of Forde’s research group.

Forde, Rosner, and colleagues previously reported safety and efficacy results from a phase II clinical trial in which patients with stage I-III resectable NSCLC were treated with two doses of neoadjuvant nivolumab. Major pathological responses were observed in 45 percent of patients, independent of tumor PD-L1 expression, and 73 percent of patients whose tumors were surgically resected were recurrence-free 18 months following surgery.

The latest publication reports the final analyses from this trial, including five-year recurrence-free and overall survival rates for the 20 patients who underwent surgical resection.

“To our knowledge, this is the longest follow-up to date for a PD-1/PD-L1 inhibitor in the neoadjuvant setting for any solid tumor,” said Forde.

Results:Among the 20 patients who underwent surgical resection, 12 patients (60 percent) remained recurrence-free five years after surgery, and 16 patients (80 percent) were alive, exceeding the 36 to 68 percent five-year survival rate historically observed for patients with stage I-III NSCLC, Rosner noted. Forde added that the observed patient outcomes after neoadjuvant nivolumab were better than those historically observed among patients treated with neoadjuvant chemotherapy.

The authors also identified major pathologic response after neoadjuvant nivolumab as a potential predictive biomarker of recurrence-free and overall survival. Of the nine patients who had a major pathological response after neoadjuvant nivolumab, eight were alive and cancer-free five years after treatment. One patient experienced a recurrence within the first 10 months after treatment but has since been disease-free after definitive chemoradiation. The one death in this subgroup was unrelated to cancer.

In contrast, six of the 11 patients who did not have a major pathological response experienced disease recurrence, and three of these patients died due to their cancer. These results indicate that a major pathological response following neoadjuvant nivolumab may be associated with a lower risk of disease recurrence and death, although the authors caution that these results are preliminary and require further validation in larger studies.

Neoadjuvant nivolumab did not lead to surgical delays, and there was only one late-onset immune-related adverse event, which occurred 16 months after nivolumab treatment and was successfully managed, the authors noted.

Author’s comments:“The results from the five-year follow-up analysis indicate that neoadjuvant nivolumab was safe in long-term follow-up and led to encouraging survival in this patient cohort,” said Forde. “The long-term safety and efficacy data from this study provide further support for the use of nivolumab in the neoadjuvant setting.”

Neoadjuvant nivolumab in combination with chemotherapy was approved by the U.S. Food and Drug Administration in March 2022 for the treatment of lung cancer. “Further studies will help us determine whether select patients may benefit from immunotherapy alone,” Forde noted.

“An interesting finding from the analysis was the difference in outcomes between patients with and without a major pathological response,” said Rosner. “Although the sample size was small, the results illustrate the potential power of pathological response as a predictive biomarker.”

AI can predict the effectiveness of neoadjuvant chemotherapy in breast cancer patients

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Engineers at the University of Waterloo have developed artificial intelligence (AI) technology to predict if women with breast cancer would benefit from chemotherapy prior to surgery.

The new AI algorithm, part of the open-source Cancer-Net initiative led by Dr. Alexander Wong, could help unsuitable candidates avoid the serious side effects of chemotherapy and pave the way for better surgical outcomes for those who are suitable.

“Determining the right treatment for a given breast cancer patient is very difficult right now, and it is crucial to avoid unnecessary side effects from using treatments that are unlikely to have real benefit for that patient,” said Wong, a professor of systems design engineering.

“An AI system that can help predict if a patient is likely to respond well to a given treatment gives doctors the tool needed to prescribe the best personalized treatment for a patient to improve recovery and survival.”

In a project led by Amy Tai, a graduate student with the Vision and Image Processing (VIP) Lab, the AI software was trained with images of breast cancer made with a new magnetic image resonance modality, invented by Wong and his team, called synthetic correlated diffusion imaging (CDI).

With knowledge gleaned from CDI images of old breast cancer cases and information on their outcomes, the AI can predict if pre-operative chemotherapy treatment would benefit new patients based on their CDI images.

Known as neoadjuvant chemotherapy, the pre-surgical treatment can shrink tumors to make surgery possible or easier and reduce the need for major surgery such as mastectomies.

I’m quite optimistic about this technology as deep-learning AI has the potential to see and discover patterns that relate to whether a patient will benefit from a given treatment.”

Dr. Alexander Wong, Director of the VIP Lab and the Canada Research Chair in Artificial Intelligence and Medical Imaging

A paper on the project, Cancer-Net BCa: Breast Cancer Pathologic Complete Response Prediction using Volumetric Deep Radiomic Features from Synthetic Correlated Diffusion Imaging, was recently presented at Med-NeurIPS as part of NeurIPS 2022, a major international conference on AI.

The new AI algorithm and the complete dataset of CDI images of breast cancer have been made publicly available through the Cancer-Net initiative so other researchers can help advance the field.

Intravesical Mitomycin in Treatment of Non-Muscle-Invasive Bladder Cancer

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Neoadjuvant instillation without TURBt is reasonable option in patients motivated to avoid invasive procedures

In recent years the management of non-muscle-invasive bladder cancer has undergone radical changes. Intravesical Bacillus Calmette-Guérin (BCG) has long been established as the therapeutic standard when superiority was demonstrated in carcinoma in situ and stage Ta urothelial cancer of the bladder. For decades after the approval of intravesical BCG, no other effective therapies were available for this disease. Valrubicin received FDA approval but had only modest efficacy and was not widely adopted or utilized. Recently, a number of novel therapies have demonstrated efficacy in BCG-failure bladder cancer such as systemic intravenous pembrolizumab, intravesical gemcitabine alternating with docetaxel, and intravesical gene therapy with nadofaragene firadenovec-vncg (Adstiladrin).

Mitomycin is an antitumor antibiotic that inhibits DNA synthesis by producing DNA cross-links that halt cell replication and eventually cause cell death. Intravesical mitomycin has long been used in the treatment of intermediate-risk superficial bladder cancer. The standard regimen involves instillations into the bladder through a catheter weekly for 6 weeks.

A recent study by Lindgren et al. evaluated a neoadjuvant intensive regimen of intravesical mitomycin instilled three times a week for 2 weeks, and compared the outcomes with the standard weekly regimen for 6 weeks. The study was conducted in patients with relapsed/recurrent NMIBC, and the majority of patients (70%) had a history of low-grade disease.

Interestingly, there was no statistically significant difference in recurrence-free survival; however, in the neoadjuvant intensive regimen group 29% of patients were able to avoid invasive procedures such as transurethral resection of bladder tumor (TURBt) as compared with the standard arm of all patients receiving TURBt followed by mitomycin instillation.

The study concludes that avoiding invasive procedures is a goal worthy of achieving in this patient population with a change in the regimen, especially as no safety risk was incurred.

Bladder cancer is a disease of the elderly. The risks of anesthesia and postoperative infections, bleeding, and hospitalizations are magnified in patients of advanced age and multiple comorbidities. The study raises an important management endpoint for clinical trial design: Decreasing the requirement for invasive procedures is an especially important goal in this patient population.

If cancer control is not compromised, then reducing the hassle, cost, and morbidity of invasive procedures is a practically useful endpoint. However, the advancement of technology has resulted in urine-based genomic tests that have reasonable sensitivity and specificity to detect relapse. The cost of these tests is considerable and maybe they would be best applied to the patients with a history of high-grade NMIBC where management would involve consideration of multiple other therapies and the risk of progression to muscle-invasive disease is substantially higher.

In conclusion, the neoadjuvant instillation of intravesical mitomycin without doing TURBt is a reasonable option to consider in patients motivated to avoid invasive procedures but committed to close cystoscopy monitoring and surveillance. Careful selection of patients with a history of low- to intermediate-grade NMIBC, and a minimum treatment-free interval of at least 2 years after intravesical BCG, is required.

Neoadjuvant Chemo Reduces Disease Recurrence in Operable Colon Cancer

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Consider it now “an option” for locally advanced disease, editorialists say

A photo of a mature woman wearing a head scarf and receiving chemotherapy.

Six weeks of neoadjuvant chemotherapy for patients with operable colon cancer is safe and results in downstaging, increased complete resection rates, and better disease control at 2 years, according to results from the randomized FOxTROT trialopens in a new tab or window.

Patients allocated to neoadjuvant chemotherapy followed by 18 weeks of postoperative chemotherapy had a 16.9% risk of residual or recurrent disease within 2 years, compared with a 21.5% risk in patients who received the standard 24 weeks of postoperative chemotherapy only, reported Laura Magill, PhD, of the University of Birmingham in England, and colleagues.

This difference in favor of neoadjuvant therapy translated to a 28% relative reduction in 2-year recurrence (rate ratio [RR] 0.72, 95% CI 0.54-0.98, P=0.037), meeting the trial’s primary endpoint.

“FOxTROT results indicate that [neoadjuvant chemotherapy] then [adjuvant chemotherapy] may be superior to conventional postoperative chemotherapy,” Magill and co-authors wrote in the Journal of Clinical Oncologyopens in a new tab or window.

Relative reductions in colon cancer-specific and all-cause mortality appeared similar, but did not reach statistical significance:

  • Colon cancer-specific mortality: RR 0.74 (95% CI 0.52-1.05)
  • All-cause mortality: RR 0.76 (95% CI 0.55-1.06)

Initial results of the trial presented at the 2019 annual meeting of the American Society of Clinical Oncologyopens in a new tab or window, and reported as negative, showed a 2-year recurrence rate favoring neoadjuvant chemotherapy (13.6% vs 17.2%) that failed to reach statistical significance, owing to a lower-than-expected event rate in the control arm.

Still, in 2019, as well as with this updated report, trial investigators suggested that neoadjuvant chemotherapy should be considered a therapeutic option for locally advanced colon cancer.

In FOxTROT, patients with radiologically staged T3-4, N0-2, M0 colon cancer were randomly allocated (2:1) to 6 weeks of oxaliplatin-fluoropyrimidine preoperatively plus 18 weeks of therapy postoperatively (n=699), or 24 weeks postoperatively (n=354). Patients with RAS-wild-type tumors could also be randomly assigned 1:1 to receive panitumumab (Vectibix) or not during neoadjuvant chemotherapy.

Patients in the study had a median age of 63. Baseline CT suggested T4 disease in 25% of patients, and lymph-node involvement in 75%. The median follow-up was 3.1 years.

Of the patients allocated to have preoperative chemotherapy, 96% started and 87% completed therapy. Overall, 98.1% of patients in the neoadjuvant group and 99.2% of the patients in the adjuvant-only group underwent surgery.

Magill and co-authors also found:

  • Resection was more often histopathologically complete with neoadjuvant chemotherapy compared with adjuvant-only chemotherapy: 94% vs 89% (P<0.001)
  • Neoadjuvant chemotherapy produced significant T and N downstaging and histologic tumor regression (P<0.001)
  • Panitumumab did not enhance the efficacy of neoadjuvant chemotherapy in RAS-wild-type patients

Regarding tolerability, chemotherapy toxicity was comparable whether given before or after surgery, while surgical complications “were, if anything, less in the neoadjuvant chemotherapy group,” the authors reported.

In an editorial accompanying the studyopens in a new tab or window, Julien Taieb, MD, PhD, and Mehdi Karoui, MD, PhD, both of the Georges Pompidou European Hospital, Université Paris Cité, suggested that the question the gastrointestinal oncology community now needs to address is whether neoadjuvant chemotherapy represents a new standard for patients with locally advanced colon cancer.

The answer, Taieb and Karoui wrote, is that FOxTROT comes with several limitations, and that neoadjuvant chemotherapy should be considered “not a standard but an option.”

They emphasized that results from FOxTROT were initially reported as negative and have since become positive. This they attributed to “new statistical analyses incorporating new events mainly because of integration of data generated with CT scans done a bit later than 2 years.”

Moreover, while disease-free survival “has been accepted for 20 years as the most relevant endpoint for adjuvant CC [colon cancer] trials,” FOxTROT used a primary endpoint — the 2-year recurrence-free rate — that is not standard for adjuvant trials, Taieb and Karoui said.

Finally, they pointed out that staging preoperatively with a CT scan is associated with up to one-third of patients being overtreated for what is actually low-risk disease.

However, despite these and other limitations, “FOxTROT remains an important research effort,” the editorialists wrote. “The results convince us that [neoadjuvant chemotherapy] is feasible and safe and certainly not detrimental for patients. This opens a new avenue for preoperative treatments in patients with resectable CC.”

Neoadjuvant chemotherapy for patients with locally advanced penile cancer: an updated evidence

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887093/#:~:text=The%20most%20commonly%20used%20chemotherapy,cisplatin%2C%20methotrexate%2C%20and%20bleomycin.