Robotic surgery using the Intuitive da Vinci Surgical System was introduced nearly 2 decades ago. The platform allows the surgeon an ergonomically comfortable position to perform the operation, a magnified 3-dimensional view, and “wristed” instruments that mimic the movements of the surgeon’s hand, often in tight spaces in the human body. It was expected that this technology would lead to more precise surgery, translating into better patient outcomes, and the robotic platform was adopted rapidly, crossing 5 million total surgeries performed and 4409 robotic systems installed worldwide by the end of 2017.

One would expect that robotic surgery would have been put through the scientific process of rigorous clinical trials before such widespread adoption. However, this was not the case and no adequately powered, prospective multicenter randomized trials were performed comparing it with the open approach in any surgical specialty. Only a small number of single-center randomized trials were conducted, with endpoints focused on perioperative recovery and not on oncologic outcomes.

Surgical techniques are particularly important in bladder cancer, which is among the most common cancers in both men (4th) and women (11th) in the United States, with an estimated 81,190 new patients diagnosed with bladder cancer and 17,240 deaths attributable to it in 2018.

 Invasive disease is treated surgically with radical cystectomy and urinary diversion. Traditionally, this has been a formidable procedure, with significant morbidity and even mortality, but it does provide patients with the best oncological survival. A laparoscopic approach to radical cystectomy was attempted in order to improve perioperative outcomes, but it was a very time-consuming procedure with a large learning curve and was never widely adopted.

With the advent of the surgical robot, it was believed that the disadvantages of traditional laparoscopy could be overcome and that a truly minimally invasive alternative to open cystectomy was available. Retrospective studies and case series suggested that the robotic approach was indeed technically feasible and reproducible, and that it had potential perioperative benefits in terms of reduced blood loss, complication rates, and length of hospital stay. Two single-center pilot studies and 1 small singlecenter randomized trial comparing open with robotic cystectomy found no difference between the procedures in oncological surrogates such as positive margins and lymph node yield, with similar complication rates. The study findings also noted better perioperative outcomes, including reduced blood loss and length of hospital stay, in the robotic group.

However, there were questions regarding the lack of tactile feedback available with the robot, and how that would affect the complete removal of locally advanced tumors. Further concerns were raised after uncommon locations of cancer recurrence, such as peritoneal carcinomatosis, were observed following robotic cystectomy in certain studies. It was believed that these 2 concerns could compromise the oncological efficacy of robotic cystectomy.

Given that no prospective randomized study had compared oncological outcomes between robotic and open cystectomy, investigators in the Sylvester Comprehensive Cancer Center’s Department of Urology, at the University of Miami Miller School of Medicine in Florida, led the design of the RAZOR trial. Patients with clinical stage T1-T4, N0-N1, M0 bladder cancer were randomized to receive robotic versus open cystectomy. The noninferiority study had a primary endpoint of 2-year progression- free survival (PFS) after radical cystectomy for invasive bladder cancer (NCT01157676).

The trial was a multicenter phase III randomized study performed across 15 centers in the United States between 2011 and 2017. The trial was funded by a grant from the National Cancer Institute. All participating centers were high-volume academic centers with experienced surgeons performing both robotic and open cystectomy. All patients with invasive bladder cancer who were candidates for radical cystectomy were eligible for inclusion except those who had previous abdominal surgery or comorbid conditions that would make pneumoperitoneum difficult to tolerate.

Relevant intraoperative and perioperative data were collected, and patients were followed with axial imaging at predefined intervals for a minimum of 2 years after surgery to assess disease recurrence. The 2-year interval was chosen because the majority of bladder cancer recurrences appear within this time and this is an excellent marker for 5-year survival. Any recurrence or death within 2 years was considered as progression.

To obtain 80% power at a 1-sided α error of 

 = .025 and take dropouts into account, a total of 350 patients were randomized between July 1, 2011, and November 18, 2014. Following exclusions and dropouts, a total of 150 patients were available for analysis in the robotic group and 152 in the open group (302 in total). Patients in both groups were well matched for demographic and tumor variables.

In findings reported in Lancet, the 2-year PFS was 72.3% (95% CI, 64.3%-78.8%) in the robotic cystectomy group and 71.6% (95% CI, 63.6%-78.2%) in the open cystectomy group for a difference of 0.7% (95% CI, —9.6% to 10.9%; overall 

 This fell within the predefined 15% margin for noninferiority, thereby proving the noninferiority of robotic cystectomy. This margin was chosen based on the available data at the time regarding alternatives to open cystectomy and the consensus of trial investigators who were all experts in the field of bladder cancer.

Estimated blood loss during robotic cystectomy was less than half that of open cystectomy, with a corresponding significantly lower transfusion rate for robotic surgery. The median length of stay was a day less in patients undergoing robotic surgery (6 days versus 7 days), with 29% of them hospitalized fewer than 5 days compared with only 18% of those undergoing open surgery. There was no significant difference between the 2 groups with respect to overall or major complication rates as measured using the Clavien-Dindo classification system (

Similarly, the quality-of-life questionnaires showed no difference between the 2 groups. Importantly, the study showed no difference in positive margin rates, lymph node yield, or patterns of recurrence between robotic and open cystectomy, providing further evidence that the robotic approach did not compromise oncological safety.

Table. Comparison of Clinical Outcomes With Surgical Techniques

Unfortunately, we were not able to obtain reliable cost data from the participating institutions to perform a meaningful comparison between open and robotic cystectomy. Whether the increased equipment, disposable costs, and/ or time costs of robotic surgery will be offset by its improved perioperative recovery remain a matter for debate. In today’s era of ever-burgeoning healthcare costs, this remains a valid potential criticism of robotic surgery and one that needs to be investigated.

We believe that this is the first phase III multicenter trial comparing robotassisted technology with open surgery for any surgical site and, as such, marks a notable landmark in the surgical literature. Our data suggest that robotic cystectomy is not inferior to open cystectomy with regard to oncological outcomes. We believe that this trial reinforces the fact that surgical trials are possible and should be attempted across other surgical specialties.

Although it is essential that high-quality trials should be performed prior to adoption of any new surgical technology, Buxton’s law provides an excellent explanation for why this is often not the case. It states that it is always too early for rigorous assessment of a new technique—until it suddenly becomes too late.

The reason, Buxton’s law continues, is that new procedures usually have a learning curve, making surgeons reluctant to participate in trials early on. Later on, the technique becomes widely adopted and trials cannot be done because it is deemed unethical to deny patients what is already perceived as cuttingedge care, and the chance to thoroughly evaluate surgical innovations is missed. The successful completion of this trial should serve an encouragement to surgeon-scientists that such studies can be performed.

These findings finally provide high-level evidence to inform discussion between patients and physicians regarding potential benefits and risks of various approaches for a complex and often morbid surgery, such as radical cystectomy

Intuitive Surgical hits 2018 priorities. blows past Q1 expectations. Medtech[y] website. medtechy.com/the-ticker/articles/2018/intuitive-surgical-hits-2018-priorities.-blows-past-q1-expectations. Published April 18, 2018. Accessed November 19, 2018.

Atlanta, GA: American Cancer Society; 2018. cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed November 18, 2018.

Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3 non-inferiority trial. 

. 2018;391(10139):2525-2536. doi: 10.1016/S0140-6736(18)30996-6.

Vivek Venkatramani, MD, and Dipen J. Parekh, MD, discuss the evolution of surgery in bladder cancer.

Landmark Trial Puts Robotic Surgery to the Test in Bladder Cancer

Dipen J. Parekh, MD

Dipti Gupta, MD, MPH,  Memorial Sloan Kettering Cancer Center

Dirk Arnold, MD, director, Department of Medical Oncology at Klinik für Tumorbiologie, Freiburg, Germany, discusses the phase IIIb CONSIGN study, which looked at treatment with regorafenib for previously treated patients with metastatic colorectal cancer (mCRC).

The CONSIGN trial reported on 2,872 patients from more than 180 institutions; it is a truly worldwide initiative, said Arnold. In this "real world" experience, the median treatment duration with regorafenib was 2.5 months. Patients received a median of 3 cycles of regorafenib (range, 1—33) at a median daily dose of 160mg (range, 74–166).

The trial was a follow-up to the phase III CORRECT trial, which demonstrated a median progression-free survival (PFS) of 2.0 months with regorafenib compared with 1.7 months with placebo (HR, 0.49; 95% CI, 0.42-0.58; 

 <.0001). Based on findings from this study, the FDA approved regorafenib in September 2012. 

The CONSIGN trial confirmed the results of the CORRECT trial, demonstrating a median PFS of 2.7 months (95% CI, 2.6-2.7). Adverse events were also similar between the two studies. Overall, 87% of patients required dose modifications, with 46% experiencing an adverse event that required a dose reduction.

View more from the 2015 European Cancer Congress

Dirk Arnold, MD, Director Department of Medical Oncology at Klinik fÃ¼r Tumorbiologie, Freiburg, Germany, Arnold Discusses the CONSIGN Study.


Dr. Dirk Arnold Discusses the CONSIGN Study

Dirk Arnold, MD

Dirk Arnold, MD, PhD,  Instituto CUF de Oncologia

Dirk Arnold, MD, PhD,  KTB Klinik fur Tumorbiologie GmbH & Co. KG

Dirk Arnold, MD, PhD, Tumor Biology Center

Dirk De Ruysscher, MD, PhD,  Maastricht University Medical Center

Dirk Schadendorf, MD, head of department for Dermatology, Venerology and Allergology, University Hospital Essen, Germany, discusses sequencing agents in melanoma.

Schadendorf says that it is currently unclear whether administering combination therapy upfront or beginning with targeted therapy and maintaining response by using a checkpoint blockade is more beneficial. There are ongoing clinical trials evaluating these strategies, but there is a waiting period.

Dirk Schadendorf, MD, head of department for Dermatology, Venerology and Allergology, University Hospital Essen, Germany, discusses sequencing agents in melanoma.
 

Dr. Schadendorf Discusses Sequencing Agents in Melanoma

Dirk Schadendorf, MD

Dirk Schadendorf, MD, PhD,  West German Cancer Center at University Hospital Essen

 Dirk, at the end, we want to discuss the recent releases from ASCO [the American Society of Clinical Oncology annual meeting] 2020. There was a release on lifileucel, an LN-122, adoptive T-cell transfer…dealing with tumor-infiltrating lymphocytes [TILs]. It had a promising response rate of 38%, but I know that at least, in part, you would disagree, in patients who were heavily pretreated with 1 to 9 lines of previous treatment. What is your expectation on the further development of lifileucel?

 It is an interesting concept that had been proposed nearly 30 years ago by Steven Rosenberg, MD, PhD already.

It was in 1985 in The New England Journal of Medicine.

You see? It has been 35 years now. The concept of using T cells, and we know from the IOs [immune-oncology] that T cells are the critical component of the immune system to control the disease. To infuse TILs in principle, is a good starting point. 

On the other hand, one has to say that taking such a mass of tumor out of the body is already a selection. A patient who has survived 7 lines of treatment needs to have a certain biology of the disease to make it to this line of treatment.

There are certain selection biases that drive this response rate. Nevertheless, for those patients who are achieving a complete response that is long lasting, hopefully for years, that is a benefit. Whether this is something that would shift the standard of care, I am still a bit doubtful.

Dirk, these are excellent responses. My last question is this: what is your expectation for the next positive, statistically significant positive phase 3 clinical trial in the year 2021 or may I say 2021 and 2022? Which drug can make it to the market? Which is the most promising one?

After the lesson that it is not so easy to combine different modes of action to improve outcome of our patients, we need to rethink our strategy. That is my personal belief. To think that we have chosen the wrong drug and that we just must take another drug and combine it with PD-1 or whatever will lead to the next breakthrough, I am not very hopeful.

In that sense, I am a bit skeptical about the breakthroughs in 2021 and 2022. We are expecting 2 clinical trial results over the next 2 years. The first is the MASTERKEY-265 trial, which is pembrolizumab plus or minus TVEC [talimogene laherparepvec]. It is whether an injectable is producing a systemic immune response that is even better than what we get with PD-1 monotherapy. It is an interesting question.

The second similar avenue is the bempegaldesleukin study, which is a combination with nivolumab that is in clinical phase 3 testing, which is liposomal encapsulated IL-2 [interleukin-2], which is also a revival introduced by Steven Rosenberg over 30 years-plus back.

 Dirk, I would like to thank you very much, and I will sum up now. The adjuvant treatment of melanoma has completely changed in the last 3 years. We now have very effective anti–PD-1 antibodies in dabrafenib and trametinib as a targeted therapy available for our patients, but all of them are leading to a 50% improvement of relapse-free survival.

Hopefully, all of them will one day show an overall survival improvement as well. This has been shown for dabrafenib/trametinib alone now. For stage IV disease, we heard that there are already some failures, although in the last 10 years, most of the trials have been positive.

Professor Schadendorf was pointing out that he is still hopeful for at least some drugs, and we need to go back to the laboratory if I understand him correctly. We must go back to the bench to find the right concept, not only for combination treatments but eventually for intelligent sequential treatment as well. 

With this, I would like to thank you very much for your attention. It was a great pleasure that we could discuss the recent developments in adjuvant and stage IV melanoma treatment with you. I wish all the best for you.

Future Directions in Metastatic Melanoma 

Dirk Schadendorf, MD, University Hospital Essen

Dirk Schadendorf, MD,  West German Cancer Center

In the interest of time, I’m going to move on to our second case, and we’re going to talk briefly about non-clear cell [cancer].

This is a 42-year-old woman who presents to clinic with new onset gross hematuria, fatigue, and flank pain. Past medical history is just well-controlled hypertension and occasional smoking for her social history. On CT scan imaging, she has a nearly 8-cm infiltrated left renal mass and some small nonpathologically enlarged retroperitoneal nodes. [She has] normal labs and a performance status of one. This patient undergoes a left radial nephrectomy, which confirms renal cell carcinoma [RCC], but it’s a fumarate hydratase or FH-deficient tumor. So non-clear cell, a relatively rare tumor. It’s grade 3, no sarcomatoid features, pathologic stage T3aN0. And she’s referred appropriately for genetic testing given her age and her histology, and is actually found to have a germline pathogenic variant, which is then confirmed to be present in family members. So, unfortunately, [this patient doesn’t] get adjuvant therapy; this is non-clear cell disease, this patient undergoes imaging post nephrectomy 6 months and has, unfortunately, recurrent metastatic disease, mediastinal lymph nodes, and hepatic metastasis. So [Dr Jonasch], I’m going to start with you, FH-deficient kidney cancer. Do you see a lot of this? I don’t.

I have several, I have a number of cases, and my go-to treatment for these patients is bevacizumab-erlotinib, based on the NCI [National Cancer Institute] data. And I’ve had some pretty dramatic and sustained responses with that combination.

[Dr Berg], any experience here? Maybe just [with] non-clear cell in general. We’re talking about germline variant, so I don’t want to get too down the rabbit hole here. But either this or just non-clear cell, a papillary patient who comes in, which is obviously far more common.

 Variant histology is always challenging. The [PAPMET] data that [Sumanta “Monty” K. Pal, MD] started through SWOG was, I think it did establish cabozantinib...for papillary was the best. And we know about chromophobe not really reacting to immunotherapy, medullary cancer. We know it doesn’t really react in normal kidney cancer types. But I think it is something where I’m a go-to of cabozantinib for a lot of the variants. And sometimes now we have a lot of doublets that I’ve been looking at for pap.

That was going to be my next question. There are some phase 2 data of IO-TKI [immuno-oncology/tyrosine kinase inhibitor] combinations. Some presented at ASCO [American Society of Clinical Oncology annual meeting] and if people know numbers, feel free to chime in, but there’s clear activity to IO-TKI combinations. To me it looks like more activity than TKI monotherapy, separate trials of course. Do you give TKI monotherapy or IO-TKI or both, or how do you decide?

 Since with everything coming out now, I’ve switched to just treating [non-clear cell] like a clear cell to actually giving a doublet therapy.

 Yes. FH-deficient [cancer] obviously is very rare, and I agree with the bevacizumab [plus] erlotinib, but I think there’s that proper classification, once we know it’s a variant histology, is so important, and getting pathology review and getting second opinions, sequencing, things like that are giving us what these unclassifieds used to be and giving us an in to them. Because I think, we always see these trials, like what are these unclassifieds? What does that even mean anymore? We really need to start defining these, and there’s even, in the WHO [World Health Organization] classification, there are new entities that are coming out that have different variants.

They seem to come out with another 12 classifications.

 Yes, exactly. So having that pathology is really important.

Academic center pathology review, hugely important. You mentioned genetics and genomics in these, and I couldn’t agree more. [Dr Plimack], what’s your approach? You can either comment on this or just on non-clear stuff in general.

 My comment on this is kudos to whoever picked up the FH deficiency, because it’s not necessarily apparent on pathology. You do need to send them for germline testing. I think the teaching point here is that any papillary that’s young, it’s a good idea to send them because [of] that match to bevacizumab [plus] erlotinib. I have a handful of patients too, and some of the best responses of any of my patients have occurred with that combination in these FH-deficient patients. So that’s something. And then to [Dr Berg’s] point, I think there’s chromophobe, which is treated one way, and papillary, that’s treated another. I tend to go to [lenvatinib plus pembrolizumab] based on the data at ESMO [European Society for Medical Oncology] that Laurence Albiges [MD, PhD] presented. And then there’s medullary, which is a chemotherapy-treated disease. If you can just separate those three out and consider them completely separate, that would be great. Unfortunately, the trials don’t do that for us, so we’re sort of subsetting those data.

 [A patient with] typical metastatic papillary [cancer] who comes in, what do you give them?

[Dr Bastos], what do you think, either this case or just more broadly, non-clear cell, papillary being the most common when [a case] comes in, what are you reaching to?

 I have a patient also with FH deficiency, and the erlotinib [plus] bevacizumab is the treatment that I’m using for this patient. They are responding very well, and there is a family history, but there is also some interesting discussion about how this was picked up, because there are data in undeveloped countries that don’t have access to NGS [next generation sequencing]. How to train the pathologist, how to triage which pathology cases: you should refer to NGS. They’re using AI [artificial intelligence] also on this pathology, to help this pathologist to triage better the NGS. That’s very important because as you see, there are two family members, and there is a 15% to 20% risk of developing RCC in this patient population. They need to be monitored very closely. So that’s very important. And then if it’s not a genetic-related tumor like this one, I think I’m tending to treat more like a clear cell now, with IO-TKI because just a TKI by itself [is] obsolete right now, and we should incorporate better strategies on this, definitely.

So it seems like in non-clear cell we go back and forth between, oh, we want special treatments [and] oh, we’ll just treat them like clear cell. They want special treatments, we treat them like clear cell. But I agree, I tend to do IO-TKI in your average papillary, whether it’s a cabozantinib [plus] nivolumab or lenvatinib [plus] pembrolizumab based on some recent ASCO data. Again, I think it’s the same as our discussion in clear cell, pick your favorite.

Focusing their discussion on a real-world patient scenario, expert panelists discuss treatment options in the setting of advanced non-clear cell renal cell carcinoma.

Selecting Optimal Therapy for Advanced Non-Clear Cell RCC

Discussant: Brian I. Rini, MD, Cleveland Clinic

Discussant: Daniel J. George, MD, DukeÂ

Discussant: David J. Dabbs, MD, Pittsburgh

Discussant: Francisco J. Esteva, MD, PhD, NYU

Discussant: H. Jack West, MD

Discussant: Kenneth Anderson, MD, Dana-Farber

Discussant: Kenneth Anderson, MD, Dana-FarberÂ

Discussant: Nicholas J. Vogelzang, MD

Diwakar Davar, MD, assistant professor of medicine, Department of Medicine, Hematology/Oncology, University of Pittsburgh, discusses the rationale for the combination of anti-TIM-3 and anti-PD-1 in multiple tumor types.

In a phase 1 study presented at the 2018 SITC Annual Meeting, Davar presented preliminary results of TSR-022, an anti-TIM-3 monoclonal antibody, in combination with TSR-042, an anti-PD-1 agent, in patients with colorectal cancer (CRC), post-PD-1 non—small cell lung cancer, and melanoma.

TIM-3 is highly coexpressed alongside PD-1 and may represent a resistance mechanism, especially in patients who do not respond to checkpoint blockade, says Davar. TIM-3 coexpression has been noted in several cancers, including melanoma and lung cancer. This serves as proof-of-concept to evaluate TIM-3 and PD-1 dual blockade in patients who have PD-1—refractory tumors.

The combination is also being evaluated in patients with CRC, although data from that cohort has yet to report. However, Davar notes that promising data were presented at the 2018 SITC meeting from the melanoma and lung cancer cohorts. According to Davar, investigators noted a positive relationship between dosing and efficacy with the combination in those patient subsets.

Authors