ASCO Names Refinement of Surgical Treatment of Cancer as Advance of the Year

Howard A. "Skip" Burris, III, MD, FACP, FASCO

Following significant progress made in the development of novel systemic therapies for patients with cancer, the role of surgery in oncology continues to evolve. To this end, ASCO has selected the refinement of surgical treatment of cancer as its Advance of the Year.¹

ASCO made the announcement as part of Clinical Cancer Advances 2020: ASCO’s Annual Report on Progress Against Cancer. The organization’s annual update on advances made with oncology treatments spotlights pivotal clinical research milestones and policy developments that have been made over the past year. The report also highlights areas of opportunity to address unmet needs with future research.

“It is fair to say that cancer treatment began with surgery, with accounts dating back to ancient times. In recent years, other treatments like systemic therapy emerged, changing the role of surgery in cancer care,” said ASCO president Howard A. “Skip” Burris III, MD, FACP, FASCO in a press release. “ASCO’s 2020 Advance of the Year recognizes the way systemic cancer therapies have improved the effectiveness of surgery, minimized the extent of surgery required for many patients, and even eliminated the need for surgery for some patients.”

Over the past few years, substantial progress has been made in the understanding and development of systemic therapies in cancer care; however, the impact of these advancements on surgical care has only come to light recently, according to ASCO.

Neoadjuvant Immune-Based Combos Lead to Less-Invasive Surgery in Melanoma

In locally advanced melanoma, surgery to remove the cancer along with radical lymph node dissection has been the standard of care. The efficacy with adjuvant therapy following lymph node dissection paved the way for neoadjuvant therapy, which consists of targeted therapies and checkpoint inhibitors.

In the past year, 2 practice-changing studies evaluated the safety and effectiveness of neoadjuvant immunotherapy combinations: the NeoCombi trial (NCT01972347) and the OpACIN-neo trials (NCT02977052).

In the phase II NeoCombi trial, investigators examined the use of the BRAF inhibitor dabrafenib (Tafinlar) in combination with the MEK inhibitor trametinib (Mekinist) administered prior to surgery in patients with resectable stage IIIc melanoma who harbor BRAF V600 mutations. Results showed that 86% of the 35 patients on the trial achieved a RECIST response to treatment by the time of resection and 46% achieved a complete response.²

The phase II OpACIN-neo trial evaluated a dual immunotherapy approach comprised of neoadjuvant ipilimumab (Yervoy) and nivolumab (Opdivo) in patients with stage III melanoma. Although prior research demonstrated efficacy with this combination when used in the adjuvant setting, it was found to result in increased toxicities.

As such, in OpACIN-neo, investigators compared various alternative dosing strategies. High radiologic objective and pathologic response rates (57% and 77%, respectively) were observed in patients with resectable disease who received 1 mg/kg of ipilimumab and 3 mg/kg of nivolumab every 3 weeks for 2 cycles.³ Fewer grade 3/4 adverse events (AEs) were reported in the first 12 weeks with this regimen compared with standard dosing.

As such, reduced dosing of this neoadjuvant combination could prove to be a safe and effective option for this patient population; however, long-term data are needed before it could be considered a standard of care.

TKIs Are Alternative to Cytoreductive Nephrectomy in Kidney Cancer

Historically, surgical resection served as the primary treatment option for patients with renal cell carcinoma (RCC) or other solid tumors. Research reported in 2001 showed that primary cytoreductive nephrectomy followed by immunotherapy could improve survival outcomes compared with immunotherapy alone. Based on these results, primary cytoreductive nephrectomy was integrated into clinical practice.

However, 2 trials have demonstrated effectiveness supporting an alternative option that might allow patients to avoid surgery altogether: the CARMENA and the SURTIME trials.

In the phase III CARMENA study, investigators compared standard cytoreductive nephrectomy followed by sunitinib (Sutent) with sunitinib alone in patients with metastatic RCC. Results showed that outcomes with patients who received sunitinib alone were more favorable than those who underwent surgery followed by sunitinib.

Specifically, patients given sunitinib alone experienced a longer median overall survival (OS) compared with surgery plus sunitinib, at 18.4 months versus 13.9 months, respectively.⁴ The same held true for patients who were determined to be of intermediate- or poor-risk, at 23.4 months versus 19.0 months and 13.3 months versus 10.2 months, respectively. With longer-term follow-up at 61.5 months, the median OS in the intent-to-treat population was 15.6 months with cytoreductive nephrectomy/sunitinib versus 19.8 months with sunitinib alone (HR, 0.97; 95% CI, 0.79-1.19).⁵

Furthermore, data from the phase III SURTIME trial demonstrated that a surgery-first approach failed to result in an improvement in the progression-free survival (PFS) rate versus delayed cytoreduction post-sunitinib treatment in patients with primary clear cell metastatic RCC.

At 28 weeks, PFS rates were comparable between the 2 arms, at 42% with immediate surgery and 43% with delayed cytoreduction.⁶ However, median OS was more than doubled in those who were given sunitinib first with delayed surgery compared with immediate surgery, at 32.4 months versus 15.0 months, respectively.

Earlier Systemic Treatment Permits Higher Resection Rate in Pancreatic Cancer

For patients with pancreatic cancer, surgical resection offers the best chance of survival. However, many patients have either borderline resectable or locally advanced disease, making the procedure either difficult to perform or not possible. However, data from 2 preliminary studies indicated that upfront treatment options may allow for more patients to eventually undergo surgery.

In a single-arm phase II trial, investigators examined neoadjuvant FOLFIRINOX in combination with radiation in patients with borderline resectable pancreatic ductal adenocarcinoma. After receiving the chemotherapy regimen, patients were restaged. Patients exhibiting resolution of vascular involvement were then given a short course of proton radiation plus capecitabine.

Those who still had vascular involvement following chemotherapy received standard radiotherapy with either fluorouracil or capecitabine (Xeloda). Patients who received a short course of radiotherapy underwent surgery 1 to 3 weeks after treatment, while those given a longer course of treatment and met requirements for surgery underwent the operation 4 to 8 weeks posttreatment.

More than two-thirds (67%) of the 31 patients who underwent surgery had negative margins. Furthermore, the median PFS was 14.7 months for all patients on the trial, and the median OS was 37.7 months.⁷ Notably, patients who were able to undergo resection experienced a significant improvement in PFS at 48.6 months, and the median OS was not reached. The 2-year OS rate was 72% for patients who underwent resection versus 56% for all enrolled patients.

Another single-arm phase II study examined the benefit of adding losartan (Cozaar), a blood pressure medication, to neoadjuvant FOLFIRINOX in adult patients with locally advanced pancreatic cancer. Patients with radiographically resectable disease underwent a short course of proton radiotherapy plus capecitabine, while those with persistent vascular involvement were given a standard long course of radiotherapy with either fluorouracil or capecitabine.

Results showed that this approach led to an R0 resection rate of 61% (n = 34) among all eligible patients.⁸ Those who received a short course of radiotherapy underwent surgery 1 to 3 weeks posttreatment, while those who were given the long course went to surgery 4 to 8 weeks posttreatment.

Overall, in the 49 patients enrolled on the study, the median PFS was 17.5 months, and the median OS was 31.4 months. Furthermore, in those who were able to undergo resection, the median PFS was 21.3 months and the median OS was 33.0 months.

Despite this early promise, findings from these trials must be confirmed in randomized later-phase trials, according to ASCO.

The Fight Continues

With the number of new cancer cases in the United States expected to rise by about one-third over the next decade, continued investment into research efforts at the national level is imperative, according to Burris. More work needs to be done to propel progress further in the prevention, screening, diagnosis, and treatment of patients with cancer.

“While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can’t rest on our laurels,” wrote Burris in a message to the public.⁹ “We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge.”

References

1. American Society of Clinical Oncology. Clinical cancer advances 2020 at a glance. bit.ly/2Sl1zd9. Accessed February 4, 2020.
2. Long GV, Saw RPM, Lo S, et al. Neoadjuvant dabrafenib combined with trametinib for resectable stage IIIb-c, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol. 2019;20(7):961-971. doi: 10.1016/S1470-2045(19)30331-6.
3. Rozeman EA, Menzies AM, van Akkooi ACJ, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicenter, phase 2 randomised, controlled trial. Lancet Oncol. 2019;20(7):948-960. doi: 10.1016/S1470-2045(19)30151-2.
4. Renner A, Samtani S, Marin A, et al. Is cytoreductive nephrectomy still a standard of care in metastatic renal cell carcinoma? J Kidney Cancer VHL. 2019;6(1):1-7. doi: 10.15586/jkcvhl.2019.114.
5. Méjean A, Thezenas S, Chevreau C, et al. Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): update on CARMENA trial with focus on intermediate IMDC-risk population. J Clin Oncol. 2019;37(suppl 15; abstr 4508). doi: 10.1200/JCO.2019.37.15_suppl.4508.
6. Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 2019;5(2):164-170. doi: 10.1001/jamaoncol.2018.5543.
7. Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2018;4(7):963-969. doi: 10.1001/jamaoncol.2018.0329.
8. Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial. JAMA Oncol. 2019;5(7):1020-1027. doi: 10.1001/jamaoncol.2019.0892.
9. American Society of Clinical Oncology. A message from ASCO’s president. bit.ly/2RX7JkD. Accessed February 4, 2020.