The development of new systemic cancer therapies has not only improved patient survival and quality of life but is now transforming surgical approaches to cancer treatment. The emergence of novel systemic therapies—those that travel throughout the body and treat cancer cells wherever they are—combined in new and better ways, is significantly changing cancer surgery.

ASCO’s selection of Refinement of Surgical treatment of Cancer as the 2020 Advance of the Year recognizes recent strides seen in the effectiveness of these treatments in reducing the amount of surgery, and even the need for it, while increasing the number of patients who can undergo surgery when needed. In particular, considerable advances have been seen in neoadjuvant therapies—those given before surgery—as reflected in the highlighted studies below. Progress in systemic therapies for pancreatic and kidney cancers, as well as melanoma, have helped reshape surgical treatment, making them some of this year’s most impressive research successes.

Neoadjuvant Combinations of Immunotherapies Pave the Way For More Successful, Less Invasive Surgery for Patients With Advanced Melanoma

For patients with locally advanced melanoma, surgery to remove the tumor along with radical lymph node dissection—the removal of most of the lymph nodes near the tumor—has long been the standard of care. The success of systemic treatment following lymph node dissection (known as adjuvant therapy) has set the stage for neoadjuvant therapy (therapy before surgery), including strategies using targeted therapies and immunotherapies. Two studies this past year examined the efficacy and safety of pre-surgery combination immunotherapy treatments. These studies are already changing practice, helping patients with locally advanced melanoma avoid surgery in many cases.

In the NeoCombi trial (ClinicalTrials.gov identifier: NCT01972347),10a Australian researchers examined the combination of two molecularly targeted drugs—dabrafenib and trametinib—given before surgery in patients with stage IIIC melanoma with the BRAFV600 mutation. Not only did the majority of the 35 patients (86%) on the trial respond by the time of resection, but almost half (46%) had a complete response, according to Response Evaluation Criteria in Solid Tumors (RECIST).

Treatment also made it easier to surgically remove the tumor and surrounding tissue in nearly half of patients (46%). Toxicities were generally similar to those that occur in patients treated with these therapies for metastatic disease. Most patients (80%) experienced fever. Just over half of patients (51%) had serious adverse events. Given the findings, neoadjuvant dabrafenib and trametinib should be considered for patients with stage IIIC melanoma twith the BRAFV600 mutation.

In a second trial, OpACIN-neo (ClinicalTrials.gov identifier: NCT02977052),11 researchers evaluated a less-toxic approach to combining two immunotherapies (treatments that help the body’s own immune system find and destroy cancer cells)—ipilimumab and nivolumab. Previous work has demonstrated the efficacy of adjuvant ipilimumab plus nivolumab for the treatment of locally advanced melanoma; however, this efficacy came at the cost of increased toxicity.

In OpACIN-neo, researchers evaluated several alternative dosing strategies. Patients with stage III melanoma that was still treatable with surgery who received 1 mg/kg ipilimumab and 3 mg/kg nivolumab every 3 weeks for two cycles had high radiologic objective and pathologic response rates (57% and 77%, respectively). Importantly, these patients were considered high risk, with disease that had spread to at least one lymph node near the tumor. While this regimen was effective, patients experienced fewer grade 3/4 adverse events in the first 12 weeks than standard dosing (ipilimumab 3 mg/kg plus nivolumab 1 mg/kg every 3 weeks for four cycles). Reduced neoadjuvant dosing of ipilimumab and nivolumab could make treatment more tolerable—yet still effective—in patients with advanced melanoma. Long-term outcomes are awaited to determine if this less-toxic approach can be recommended as a standard of care.

Targeted Therapy Provides Alternative to Immediate Surgery in Treatment of Renal Cell Carcinoma

In the absence of effective systemic therapies, surgical resection has traditionally been the primary treatment of many solid tumor cancers, including renal cell carcinoma (RCC). Landmark research from 2001 demonstrated improved survival with removal of the cancerous kidney (primary cytoreductive nephrectomy, or CRNx) followed by immunotherapy compared with immunotherapy alone (interferon alpha-2b). As a result of these data, thousands of individuals have since undergone CRNx. Results from two randomized controlled trials published this past year provide evidence for an alternate treatment approach that might eliminate the need for surgery.

The CARMENA trial (ClinicalTrial.gov identifier: NCT00930033)12 demonstrated that systemic therapy with sunitinib alone was comparable to cytoreductive nephrectomy followed by sunitinib in patients with metastatic RCC classified as poor or intermediate risk of survival. In this trial, 450 patients with metastatic RCC were randomly assigned to receive either nephrectomy followed by sunitinib or sunitinib alone. Nephrectomy was performed within 28 days of random assignment in the adjuvant treatment arm; sunitinib was started within 21 days of random assignment in the sunitinib-only group. 

Sunitinib alone was no worse than surgery followed by sunitinib. Median overall survival was longer for patients receiving only sunitinib—18.4 months compared with 13.9 months. Median overall survival was also longer for patients classified as intermediate or poor risk with sunitinib only compared with surgery plus sunitinib—23.4 months v 19.0 months and 13.3 v 10.2 months, respectively. Grade 3 or greater adverse events were slightly higher in the sunitinib-only arm (42.7%), compared with nearly a third of patients (32%) in the nephrectomy-sunitinib arm. These included physical weakness/lack of energy, hand-foot syndrome, anemia, and neutropenia.

Results from the SURTIME trial (ClinicalTrials.gov identifier: NCT01099423)13 indicate that a surgery-first approach did not improve the progression-free survival rate compared with delaying cytoreduction until after treatment with sunitinib for patients with primary clear cell metastatic RCC. A total of 99 patients were included, with a median follow up of more than 3 years. At 28 weeks, the progression-free survival was comparable for the two arms (42%-43%). Median overall survival, however, was 32.4 months for those who received sunitinib first and delayed surgery, compared with 15 months for those who went immediately to surgery. The results of an exploratory analysis suggest that patients with disease that progressed despite pretreatment with sunitinib had worse prognosis and were less likely to have good results following nephrectomy.

Both studies highlight the evolving role of systemic treatment in patients with metastatic RCC.

Upfront Treatments Make Surgery Possible for More Patients With Pancreatic Cancer

While surgical resection offers the best chance of survival for patients with pancreatic cancer, many either have tumors that are surgically difficult to remove entirely (borderline resectable) or cannot be removed at all (locally advanced). Two preliminary studies suggest that more patients may be eligible for surgery following upfront treatment, though confirmation is needed with randomized trials. One treatment approach, published in the past year, combined a chemotherapy regimen, called FOLFIRINOX for short, with radiotherapy and has already shown promise in making patients eligible for surgery. FOLFIRINOX consists of three chemotherapy drugs: folinic acid (also known as leucovorin), fluorouracil (along with leucovorin), irinotecan, and oxaliplatin. In a similar study published in 2019, the addition of the blood pressure treatment losartan to the FOLFIRINOX/radiotherapy combination showed even better results.

In a single-arm phase II study (ClinicalTrials.gov identifier: NCT01591733),13a researchers investigated neoadjuvant FOLFIRINOX plus radiotherapy in 48 patients with borderline resectable pancreatic ductal adenocarcinoma. Following FOLFIRINOX, patients were restaged. Those with resolution of vascular involvement received a short course of proton radiation with capecitabine. Patients with persistent vascular involvement received standard radiotherapy with fluorouracil or capecitabine.

Surgery was performed either 1-3 weeks after a short course of radiotherapy or 4-8 weeks after a long course for patients who met the requirements for surgery. Among 31 patients who underwent surgery, more than two-thirds (67%) of the patients had negative margins (no cancer cells seen on pathologic examination). Median progression free survival for all patients in the trial was 14.7 months, and overall survival was 37.7 months. Among those patients who were able to undergo resection, however, progression-free survival was significantly improved (48.6 months). Median overall survival had not been reached for this group, but overall survival at 2 years was 72% (compared with 56% for all patients). Grade 3 or higher adverse events occurred in 19% of patients, with diarrhea, neutropenia, and peripheral neuropathy being the most common severe events. This study was funded, in part, by the NCI.

Another study explored the benefit of adding the common blood pressure medicine losartan to neoadjuvant FOLFIRINOX and radiation in adults with locally advanced pancreatic cancer. The renin-angiotensin-aldosterone (RAA) system plays roles in cell proliferation, metabolism, and growth and regulates blood pressure, electrolyte, and fluid levels and cardiac output. Because losartan works by mediating the RAA system, researchers speculated that the therapy could help further reduce the size of pancreatic tumors, allowing more patients to undergo surgery.

In a single-arm phase II study (ClinicalTrials.gov identifier: NCT01821729),14 all patients with locally advanced pancreatic cancer received FOLFIRINOX and losartan, and those with radiographically resectable tumors received short course proton radiotherapy and capecitabine. Patients with persistent vascular involvement received standard long course radiotherapy with fluorouracil or capecitabine. This approach resulted in more than half of patients (61%) going on to surgery and surgical margins (the tissue surrounding the removed tumor) that were free of cancer cells.

Surgery was performed either 1-3 weeks after a short course of radiotherapy or 4 to 8 weeks after a long course. Overall, median progression-free survival was 17.5 months for the 49 patients in the federally funded study, and overall survival was 31.4 months. In comparison, among the 34 patients who were able to undergo resection, progression free survival and overall survival were 21.3 and 33 months, respectively.

The results with the addition of losartan compared favorably to a similar trial published in 2018. That study was also single-arm, phase II trial and included 48 patients with newly diagnosed, previously untreated, localized pancreatic cancer determined to be borderline resectable. Grade 3 or higher adverse events occurred in 51% of patients, with neutropenia, thrombocytopenia, diarrhea, and nausea/vomiting being the most common severe events. Grade 1/2 peripheral neuropathy was also common. This study was funded, in part, by the NCI.

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