J Clin Oncol. 2023 Jul 11. IF: 50.717
Inconsistent Data Between Distant Relapse Events and Breast Cancer-Specific Death Events in India Lidocaine Trial.
Yu KD.
Shanghai Cancer Center and Cancer Institute, Fudan University, Shanghai, China.
Badwe et al conducted an open-label, multicenter randomized trial to test the impact of presurgical, peritumoral injection of 0.5% lidocaine on disease-free survival (DFS) and on overall survival (OS). At a median follow-up of 68 months, there were 255 DFS events and 189 deaths. In the local anesthetic (LA) and no-LA groups, 5-year DFS rates were 86.6% and 82.6% (hazard ratio [HR], 0.74; P = .017) and 5-year OS rates were 90.1% and 86.4% (HR, 0.71; P = .019), respectively. After reviewing the survival data, I am concerned about the inconsistency between recurrence and death events.
The LA group has 109 DFS events and 79 OS events. Among the 109 DFS events, 19 were locoregional events and 70 were distant events (with or without locoregional recurrence). Among the 79 OS events, 67 events were causes of death from breast cancer. Because locoregional were not life-threatening and most patients with locoregional relapses have a long OS time, the life-threatening events of breast cancer are mainly distant metastasis. Of note, this trial enrolled 67% of patients with ER/PgR-positive tumors. Although India may have poor social health security and a low use rate of HER2-targeted therapy, the ER/PgR-positive cases who received the first-line endocrine therapy still have 30-50 months OS even after using inexpensive and common aromatase inhibitors. However, in the India lidocaine trial, it is likely that 67 of 70 (96%) patients with distant events might die within the median 68-month follow-up duration. These data are similar in the no-LA group. In contrast, previous relevant data have shown that only about 65%-75% of cases with distant relapse might die because of breast cancer within a median follow-up of 60-85 months. Therefore, I am curious about the dynamics of recurrence and death timing in this trial. How about the time interval between the first diagnosis of distant recurrence and death from breast cancer? The detailed data would provide more solid and valid information to build up the conclusion's reliability.
PMID: 37433105
DOI: 10.1200/JCO.23.00976
J Clin Oncol. 2023 Jul 11. IF: 50.717
Painfully Absent.
Broens S, van Duijnhoven FH, Hollmann MW, Hemmes SNT.
The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Amsterdam University Medical Centers, Location "AMC," Amsterdam, the Netherlands.
With great interest we read the study by Badwe et al investigating the effect of peritumoral injection of lidocaine before breast cancer surgery on survival and cancer recurrence.
We would like to commend our colleagues with their great achievement in completing this large trial with lengthy follow-up. The authors provide a relevant contribution to the current controversial evidence on the effect of local anesthetics on metastatic spread of breast cancer. However, in our opinion, important aspects of perioperative analgesia were insufficiently addressed: the systemic effect of lidocaine and the effect on the surgical stress response and perioperative pain.
As mentioned by Higgins et al, surgical trauma and perioperative pain can affect the neuroendocrine and the immune system in complex ways, which could promote cancer proliferation and metastasis. Catecholamine and prostaglandin signaling suppress antitumor immunity and possibly facilitate progression of residual disease.
The current study focusses on the potential direct effect of lidocaine on malignant cells, of which the evidence is still inconclusive. Yet, there is strong evidence that systemic lidocaine can attenuate inflammation and the surgical stress response in diverse ways. Another clear benefit of local anesthetics is their analgesic properties. By dampening perioperative pain and its associated catecholamine release and immunosuppression, lidocaine could also have an effect on metastatic progression through this indirect pathway.
The dose of local lidocaine used for peritumoral infiltration (60 mL of lidocaine 0.5%, with a maximum dose of 4.5 mg/kg) in this study is high enough to be taken up into the circulation, resulting in plasma levels that are sufficient for a systemic analgesic and anti-inflammatory action. Consequently, a decrease in pain and/or opioid use in the local anesthetics (LA) group is expected. Unfortunately, the authors do not present any data on plasma levels of lidocaine, pain perception, and analgesic use of the patients.
Even if we ignore the possible systemic effect of lidocaine in this study, data on the perioperative analgesia and postoperative pain in both groups would have been insightful, given the potential influence of pain and stress on cancer recurrence.
We encourage the authors to elaborate on perioperative analgesic management and consecutive pain scores in the study groups since both are potential confounders of the primary outcome.
Finally, future research might consider to use the analgesic and anti-inflammatory properties of systemically administered local anesthetics or to use local anesthetics in local nerve blocks of the breast. For example, a field block for breast surgery consists of a straightforward technique in which local anesthetics are infiltrated on a deep subcutaneous level around the breast. This block combines the placement of LA relatively near to the tumor, in contrast to a paravertebral block, with effective analgesia.
PMID: 37433120
DOI: 10.1200/JCO.23.01063
J Clin Oncol. 2023 Jul 11. IF: 50.717
Reply to S. Broens et al and K.-D. Yu.
Badwe RA, Joshi S, Hawaldar R, Gupta S.
We thank Broens et al and Yu for their interest in our study and their comments.
We agree with Broens et al1 that surgical stress and pain could have immune-modulatory effects which may affect the development of metastatic disease. They contend that the obtundation of surgical stress and inflammatory response by systemically absorbed lidocaine, which was injected in peritumoral location, could be responsible for the beneficial effect of this local anesthetic agent in this study. This is unlikely because almost all lidocaine-containing tissue was excised within 20-30 minutes of injection in patients who underwent breast-conserving surgery and within 35-45 minutes in those who underwent mastectomy. Hence, it is unlikely that enough amounts of lidocaine were systemically absorbed to be able to inhibit systemic stress response. Furthermore, most patients in both arms received injectable diclofenac at the time of anesthesia reversal and oral diclofenac (or another nonsteroidal anti-inflammatory drug) for at least 24 hours after surgery. Thus, use of nonsteroidal analgesics was evenly matched between the two arms. Opioids were not routinely used in this patient population as per standard practice in participating institutions. Notably, the study of regional anesthesia using ropivacaine failed to improve outcomes in patients with breast cancer compared with general anesthesia. This suggests that the survival benefit of the amide local anesthetic agent lidocaine is likely to be due to local effects on tumor rather than analgesic or systemic anti-inflammatory effects.
Dr Yu states that an overwhelming majority of patients with distant metastases (96% by his calculation in the lidocaine arm) died of their disease within the reported median follow-up of this study (68 months) compared with 65%-75% deaths in 60-85 months in patients with distant relapse in the references cited by him. He contends that postrelapse deaths are higher in our distant relapse patients compared with other cohorts, especially since 67% of our study population had ER-positive disease. He acknowledges that postdistant relapse deaths are comparable between the two arms of our study. In response, we would like to make the following points. First, in the 70 patients with distant (including distant plus locoregional) relapse as the first event in the local anesthetic (LA)-arm, there were 40 (57.1%) with triple-negative or human epidermal growth factor receptor 2 (HER2)-positive disease and 53 (75.7%) deaths, and in the 94 patients with distant (including distant plus loco-regional) relapse as the first event in no-LA arm, there were 50 (53.2%) with triple-negative or HER2-positive disease and 75 (79.8%) deaths, at the time of data analysis. This suggests that the majority of patients with distant relapse had triple-negative or HER2-positive breast cancer, and the outcome after distant relapse is in keeping with several Indian studies where median overall survival of patients with metastatic breast cancer has been reported to be 20-24 months. Second, the data quoted by Yu are from studies conducted predominantly in Western population where the prognostic characteristics of patients was different. For example, there was a higher proportion of ER-positive disease (77%-81% in the Del Mastro study, 80% in the NSABP B-38 trial, and 78.3% in BCIRG-005) in all three studies referred to by Yu compared with 67% in our study. It is likely that other characteristics such as tumor burden at relapse and visceral involvement would also have been different in these studies. Third, to our knowledge, none of the three studies quoted by Yu have specifically reported the postrelapse survival of patients with distant relapse. Therefore, we see no inconsistency between distant relapse and breast cancer deaths in our full study population as well as in each arm.
PMID: 37433099
DOI: 10.1200/JCO.23.01209
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