Peritumoral Anesthetic Infiltration Impacts Survival in Early Breast Cancer

Dr. Shannon Westin, Dr. Rajendra Badwe, and Dr. Alastair Thompson discuss the JCO paper "Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer." TRANSCRIPT The guests on this podcast episode have no disclosures to declare.  Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, gynecological oncologist by trade, but serve as our JCO Social Media Editor. And I'm super excited to talk to you about a paper that was just published online, April 6, 2023, entitled “The Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer.”   Before we start, I just note that our guests have no conflicts of interest.   And so I'm accompanied by two greats in the field. First is the principal investigator on this trial, Dr. Rajendra Badwe, who is the Director and Head of Surgical Oncology Division at the Tata Memorial Center in Mumbai.  Welcome. Dr. Rajendra Badwe: Thank you. Dr. Shannon Westin: And then, of course, I'm joined by Dr. Alastair Thompson, Co-Director of the Lester and Sue Smith Breast Center and the Section Chief for Breast Surgery at Baylor College of Medicine here in Houston, Texas. We should have met in person. Dr. Alastair Thompson: Great to be with you today, both of you. Thank you. Dr. Shannon Westin: So this is an exciting topic, and of course, as a surgeon, I'm super intrigued. So let's get started. First, I would love for you all to tell me about the rationale for modulating events at the time of surgery to improve survival in any cancer, but specifically in breast cancer as it was in this study. Dr. Rajendra Badwe: So we have been working on events at the time of surgery for quite some time. And for the first time, when I walked through the gynae OPD in Guy's Hospital, there was this cartoon of the cell being extruded for ovulation, and I felt a cell moving from one organ to the other is actually metastasis. And that's how we started working on it. And in the past few years, we have been—a decade or so, we have been publishing changes induced by event of surgery.   So what we did earlier before beginning this trial is picking up a core biopsy before I start surgery. So it's normoxic, well-ventilated as well as well-nutrition-provided tumor, and I do a core biopsy and send it for expression profile on next-generation sequencing. Then, when 50% of the tumor surface is denuded from the opposite side, which is not denuded, I do other core biopsy. And the third core biopsy is when the tumor is in my hand in breast conservation surgery.  So first was normoxic, second was hypoxic, and the last was completely anoxic tumor. And we found that the middle sample, which has never been studied, all our understanding of biology of breast cancer is based on the first core biopsy or the whole tumor sample post-surgery. The middle sample had approximately 800 genes going up and down on the next-generation sequencing mRNA, and majority of these were epithelial-mesenchymal transition, proliferation, invasion, motility. You name the hallmark of metastases, and they were up in the middle of surgery at least in 30% of the tumor. Now, if the cell surface on one side in a three-centimeter tumor ring to the cell at the other end of the tumor as to some invasion has happened, how quickly can it happen? The difference between the two biopsies was just about five minutes.  Obviously, it was some kind of an electrical stimulus that went across the tumor. That's what our assumption was. And if it was to happen through the voltage-gated channels, the downstream effect of voltage-gated channel being depolarized was the same channels that I mentioned, the hallmarks of metastases that I mentioned. And if we were to block it, it was easiest possible by local anesthetic. So that's how this trial was originated. And we did in 1600 patients local anesthetic, half of them randomly allocated to receive lidocaine 0.5% versus not. Dr. Shannon Westin: That is so intriguing. I have to look up this work. I definitely agree with you. We do a lot of pre-biopsies and post-biopsies, but the intra-tumor biopsy is so novel with being able to study the anoxic tissue. I'm so interested. And you kind of started to get into this. Can you dig in a little bit more around that role or how the mechanism of action of this peritumoral anesthetic infiltration might work in preventing metastasis and preventing some of the changes that you were able to see? Dr. Rajendra Badwe: So if adequate amount of local anesthetic injected would paralyze or block the voltage-gated channels, sodium channels, and if the sodium is not allowed to get inside the cell as a gush, the first depolarization does not happen. And the downstream effect of such voltage-gated channels being stimulated is induction of proliferation, induction of invasion, and increased motility of the cell, everything that is necessary for metastases to set in. In fact, somewhere close to about 200 genes that belong to the pathway that allows a cell to express epithelial-mesenchymal transition were upregulated during this hypoxic episode. And hypoxia also is known to produce these changes. So we now, out of these 1583 patients, in about 100 patients, we also have the middle sample. And that's being looked at on the third-generation—next-generation expression profile to see whether the effects that I mentioned just now, are they abrogated by local anesthetic as the underlying mechanism of reducing the metastatic potential or upregulating pro-metastatic pathways in cancer cells. Dr. Shannon Westin: It's so intriguing. I guess I wonder if you or Dr. Thompson can speak a little bit about the results of any studies looking at peritumoral anesthetic infiltration prior to the work that we're going to discuss today. Were there smaller studies that looked at this? Dr. Alastair Thompson: There have been a number of studies over the years, particularly some small studies from the Republic of Ireland, which have suggested that the use of local anesthetic in breast surgery might be beneficial. And then there have been some other larger studies really more thinking about the block of the surgical stimulus to the surgical site, for example, using paravertebral blocks. And we are aware that what is given as an anesthetic, whether it's an agent, intravenous agent, like propofol, or a gaseous agent, may also have some effect on the metabolic response to the trauma of surgery. So there's quite a building logical background to this particular trial. But to my knowledge, this is a unique trial which a group of surgeons have been able to implement a fairly simple technique, taking a very short period of time, but with almost as much impact as some of the major drug trials in terms of disease freedom and overall survival.  Dr. Shannon Westin: Great. So, yeah, let's get into—do you want to take us through the design of the study, Dr. Badwe? Dr. Rajendra Badwe: Yes, thank you. We had 1583 patients who were randomly allocated. These are women with early breast cancer, so essentially, T1, T2 breast cancer with or without lymphadenopathy in the armpit, and metastatic, disease-wise, M0. And these individuals, these patients, were randomly allocated on table to receive local anesthetic versus not. 796 women received local anesthetic, and 804 women did not receive local anesthetic. The adequacy of this local anesthetic was 0.5% of lidocaine being injected on all surfaces of the tumor as if from one pole of the tumor, I would open an umbrella, a needle going in all directions all around the tumor from one side and then from the other side. And if the tumor was larger than being covered by these injections, additional points of injections were done on all surfaces of the primary tumor. The adequacy was tested by inability of the surgeon to use electrical diathermy for dissection. So the surgeon had to use knife to get the tumor out. Because of so much of water content in the tissues, the diathermy would not work. And if it worked, that would mean the amount of local anesthetic injected was inadequate. So that was the quality control parameter.  Postoperatively, patients received standard treatment. We had assessment of the hormone receptors, HER2 receptors. And postoperatively, they received standard chemotherapy, which is—in great majority, was epirubicin or Adriamycin with cyclophosphamide, four cycles, followed by 12 weekly paclitaxel injections. And those who were hormone receptor-positive, premenopausal received tamoxifen, and postmenopausals received either letrozole or Arimidex. All patients who were more than four centimeter positive in tumor size or had lymph nodes positive received postoperative radiotherapy, irrespective of whether they had conservation or mastectomy. And all individuals who had conservation received postoperative radiation, which was the standard protocol.  Talking about those with HER2 positive or triple-negative or ER/PR positive, their distribution on either side was identical, very, very close, no different at all. 35% of those who were HER2 3+ or FISH positive received trastuzumab for a year on either side, but two-thirds of them did not receive trastuzumab because of the cost constraints in India. But the distribution of those who received versus not was identical on both sides. So that's the kind of general demographics of the women who were on the study. Dr. Shannon Westin: Great. I think now—I think everyone's ready for the good news. So how did the infiltration impact outcomes in these patients? Dr. Rajendra Badwe: The primary endpoint was disease-free survival. There were a total of 255 events, 109 events in local anesthetic arm and 146 events in the no local anesthesia arms. That gave us a 26% reduction, a relative reduction of 26%, which reached statistical significance at P 0.01. And at the same time, for overall survival, which was the secondary endpoint, there was a 29% relative reduction in deaths related to breast cancer, and majority of the patients who died died of breast cancer. The other cause of mortality was very little—to be precise, less than 1.5%, and that was also equally distributed on—identically distributed on both sides. So approximately 4% reduction in disease-free survival absolute and a similar 4% reduction in overall survival and the number of deaths. So this was the first trial that looked at preventing metastases than treating micrometastases. Dr. Shannon Westin: Yeah, and I think I would just call on Dr. Thompson here because I think you already started saying this. I mean, when you look at the simplicity of the intervention and the low-cost nature of the intervention and the impact as opposed to some of our “incremental benefits” that we see with different very expensive targeted therapies and immunotherapies, I'd love just to get your thoughts on that. Dr. Alastair Thompson: So, of course. I think this is an extraordinarily well-designed, very balanced trial. Yes, you can say that not all patients are treated the same way around the world. But there's been a rigor about this which is very attractive, and I think it's one of the reasons the Journal of Clinical Oncology has published it.  What is perhaps astonishing is that if we try to first do no harm, we're actually doing a very simple intervention, low cost, relatively easy. The patient is asleep, so it's not painful in any way. It's not toxic at the sort of levels of local anesthetic being administered. And yet we're managing that for every 25 patients who have this addition to their procedure, one of them is going to be disease free and one of them is going to be alive as a consequence in the relatively short term. So, in terms of balancing the issues of trying to implement something versus the benefits to a patient population, the balance is very much in favor of this really quite minor change in practice to give us quite a major, by modern standards, difference in outcomes.  Dr. Shannon Westin: Yeah, I think it's incredibly exciting, and I think, to your point around is it applicable, is it generalizable, I'd love to hear what you all think. I mean, is this something that we should be implementing across the globe? Dr. Alastair Thompson: Well, I think sometimes, we don't always do in our own practices what has been led and demonstrated to be effective elsewhere. And we need to really pause and, I would suggest, think hard whether such a simple intervention could be implemented on our next working day.  Now, many of us do use local anesthesia in the setting of breast surgery, whether it's mastectomy, axillary lymph node surgery, or lumpectomy. But the difference might be that instead of putting this local anesthesia towards the end of the operation, thinking about doing things up front and maybe, therefore, having an even bigger impact than simply good quality pain control and good quality patient care.  Dr. Shannon Westin: I would love also, just as we're kind of coming to a close here, to get both of your thoughts about how we might implement this. And again, this is coming from a somewhat selfish standpoint. How could we implement this in other solid tumors? So is there a way to replicate? Obviously, breast has a very local disease spread pattern. Is there a way to potentially replicate this in other cancer types?  Dr. Rajendra Badwe: So we have begun a similar study in my hospital for squamous cell carcinoma, as well as lung cancer. And I'm sure there will be efforts to replicate in many other cancers where it is possible to inject local anesthetic all around before we start the resectional procedure. But at the same time, we need studies to confirm that this is actually happening. If I were to take a step further and wait for the expression profile of those who have received local anesthetic versus not in this trial, and if it shows that the abrogation of effects related to the downstream stimulation of VGSC, the voltage-gated sodium channels, then it might just be a good idea to use something else. Because if local anesthetic is effective to the extent, say, about x amount, cannabis has about 200x effect on stabilization of voltage-gated channels. So that could be another intervention that can be explored in trials in any site. Dr. Alastair Thompson: So that's a good point. Where do we go from here? And I would suggest that perhaps thinking about which local anesthetic to inject—would a longer-acting local anesthetic be just as effective from a prevention of shedding of metastatic cells, would that give longer additional pain relief? Would it be possible to think about other tumor sites where we're doing a local reception, for example, in the gastrointestinal tract, elsewhere in the body, including lung, for resections? There's just a huge amount of potential which this landmark, practice-changing trial has really pointed us to. And I would envisage that in future podcasts, Shannon, you're probably going to have a lot of people talking with you about other trials that have followed on from this. Dr. Shannon Westin: I hope so because that will mean we're impacting our patients in a positive way. I'm just so thrilled to have the two of you here. This was such a fascinating discussion. It went by so fast, and I hate to bring it to a close. But I encourage our listeners to definitely read this incredibly important manuscript and communicate with us online on how we can move this forward.   Again, this has been JCO After Hours, and we've been discussing “The Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer,” published online April 6, 2023. I'm so thrilled that you joined us today on the podcast, and I hope you'll check out our other podcast offerings. Have a wonderful day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. 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