Neoadjuvant chemotherapy, also known as preoperative chemotherapy, induction chemotherapy, and initial chemotherapy, refers to the administration of systemic chemotherapy drugs prior to surgery. Neoadjuvant chemotherapy is not a new treatment, but refers to a different point in time from adjuvant chemotherapy in systemic treatment.
Neoadjuvant chemotherapy for breast cancer began in the 1970s. With the establishment of the status of adjuvant chemotherapy in breast cancer treatment, neoadjuvant chemotherapy began to be used in inoperable locally advanced breast cancer, shrinking the tumor through chemotherapy, thus giving inoperable patients the opportunity to receive surgical treatment and greatly improving the quality of life of these patients, and the application of neoadjuvant chemotherapy in this group of patients gained wide acceptance. The use of neoadjuvant chemotherapy in this group of patients has been widely recognized. Later on, neoadjuvant chemotherapy has also been proven in clinical trials to shrink tumors and thus achieve breast conservation. Since the 1980s, neoadjuvant chemotherapy has been applied in inoperable locally advanced breast cancer and has achieved good results.
The success of neoadjuvant chemotherapy in inoperable locally advanced breast cancer and in improving breast conservation rates, coupled with animal studies that reported that neoadjuvant chemotherapy seemed to have better systemic therapeutic effects, led to the question of whether the indications for neoadjuvant chemotherapy could be further expanded to include operable early-stage breast cancer. In order to confirm this question at the level of evidence-based medicine, a series of prospective randomized controlled studies have been conducted since the mid-1980s, the largest of which were the NSABP B-18 and B-27 trials [4]. cyclophosphamide (AC) preoperative neoadjuvant chemotherapy compared with postoperative adjuvant chemotherapy to improve disease-free survival (DFS) and overall survival (OS); (ii) whether the tumor response to neoadjuvant chemotherapy correlates with prognosis; and (iii) whether neoadjuvant chemotherapy can (3) whether neoadjuvant chemotherapy can improve the breast conservation rate. In the B-18 trial, 751 patients received neoadjuvant chemotherapy for AC and 742 patients received post-operative adjuvant chemotherapy for AC. The latest published data are the results of a study with a median follow-up of 16 years: there was no significant difference in DFS and OS between neoadjuvant and adjuvant chemotherapy, but the prognosis of patients who achieved pathologic complete response (pCR) in neoadjuvant chemotherapy was better than that of non-pCR patients; for patients who were ready for breast-conserving surgery before randomization, A total of 2,411 patients were enrolled in the B-27 trial and randomized to three groups: AC neoadjuvant chemotherapy followed by surgery (AC→surgery), AC sequential docetaxel (T) neoadjuvant chemotherapy followed by surgery (AC→T→surgery), and AC neoadjuvant chemotherapy followed by surgery and continued T adjuvant chemotherapy (AC→surgery→T). The latest published data are the results of a study with a median follow-up of 8.5 years: neoadjuvant chemotherapy regimens with T in addition to AC increased the pCR rate from 13% to 26%, but did not improve DFS and OS in patients. The results of a meta-analysis of 11 clinical trials with a total of 3,946 patients also showed that neoadjuvant chemotherapy did not improve patients’ DFS, OS, or distant metastasis-free survival compared with adjuvant chemotherapy, but increased the risk of local recurrence. Of course, the increased risk of local recurrence with neoadjuvant chemotherapy may be related to the increased rate of breast conservation and the fact that some patients in complete clinical remission (complete response, CR) underwent only radiotherapy without surgery. In conclusion, although there is a hypothesis that neoadjuvant chemotherapy may improve prognosis by enabling patients to receive systemic therapy earlier, there are still no large randomized controlled trials to confirm this hypothesis, so it is currently believed that there is no difference between neoadjuvant and adjuvant chemotherapy in terms of DFS and OS.
The advantages and disadvantages of neoadjuvant chemotherapy are still controversial. The advantages that have been basically agreed internationally are that it can shrink the tumor to facilitate surgery, improve the resection rate of inoperable locally advanced breast cancer, and increase the success rate of breast conservation for some patients with large tumor size; the disadvantages include prolonging the tumor carrying time in vivo, delaying the timing of surgery for those who are ineffective, diagnostic errors caused by limited sampling, better prognosis of The disadvantages include prolonged in vivo tumor carryover time, diagnostic errors due to limited sampling, overtreatment of better prognosis, and influence on prognostic judgment and protocol selection.
Neoadjuvant chemotherapy is a hot spot and focus of research in the field of breast cancer treatment, and every meeting that involves neoadjuvant chemotherapy can lead to intense discussions. Here are 10 hot issues about neoadjuvant chemotherapy that are frequently discussed in national meetings.
1. B-18 and B-27 have confirmed that neoadjuvant chemotherapy can improve survival by achieving pCR, so pCR is the goal we are pursuing?
Both the B-18 and B-27 trials found that those who achieved pCR in neoadjuvant chemotherapy had a significantly better prognosis than those who did not. Therefore, some scholars believe that patients who achieve pCR can improve survival and pCR should be the goal to pursue in neoadjuvant chemotherapy, and as long as patients have the possibility to achieve pCR, neoadjuvant chemotherapy should not be stopped.
The first point to understand this issue is that both pCR and non-pCR patients involved in the comparison received neoadjuvant chemotherapy, that is, the comparison is between the two subgroups of neoadjuvant chemotherapy, not between neoadjuvant chemotherapy and adjuvant chemotherapy, therefore, the comparison between pCR and non-pCR cannot be used to conclude which is better or worse.
The B-18 and B-27 trials also confirmed that there was no difference in DFS and OS between neoadjuvant and adjuvant chemotherapy. There are two possibilities to understand whether pCR patients have improved survival with neoadjuvant chemotherapy. One possibility is that patients who achieved pCR did improve survival with neoadjuvant chemotherapy, but the overall survival of patients did not change, so the result can only be that non-pCR patients had a lower survival due to neoadjuvant chemotherapy. If someone benefits, then someone must be impaired to ensure that there is no change overall. If the above reasoning holds, then the benefit to pCR patients is based on the detriment of the majority of non-pCR patients. Another possible scenario is that for the patients who were awarded pCR in neoadjuvant chemotherapy themselves, the postoperative chemotherapy was just as good and their own survival did not change. In this sense, neoadjuvant chemotherapy is only a screening trial that selects patients who are sensitive to chemotherapy and have a good prognosis, and this group of patients can also benefit from adjuvant chemotherapy; neoadjuvant chemotherapy does not increase the number of people who survive.
Ethically, the second scenario is preferred, because “do no harm” is the primary principle of medical practice. Moreover, the clinical trials suggest that patients with pCR also benefit from adjuvant chemotherapy and that increasing the pCR rate does not improve overall survival. In the B-27 trial, the second group had AC→T→surgery and the third group had AC→surgery→T. The second group had a pCR rate of 26% due to the addition of T to the neoadjuvant chemotherapy regimen, while the third group used T for adjuvant chemotherapy and only AC for neoadjuvant chemotherapy, and had a pCR rate of 13%. Although the second group had a 1-fold higher pCR rate than the third group, both groups had an 8-year DFS of 62% and This suggests that the increased pCR rate in the second group was due to the addition of the more effective T. Patients who used T in adjuvant chemotherapy also benefited, and pCR did not improve overall survival.
The goal of breast cancer treatment is to improve the quality of life and survival of patients. Whether patients can obtain pCR is determined by the intrinsic characteristics of the tumor to the drug, not all pCR patients will not recur, and not all non-pCR patients will recur. pCR does not represent DFS and OS, so the ultimate goal of breast cancer treatment is not pCR, and pCR “does not need to be pursued”!
2. Can all breast cancers suitable for adjuvant chemotherapy be treated with neoadjuvant chemotherapy?
The statement “neoadjuvant chemotherapy can be given to all breast cancers suitable for adjuvant chemotherapy” was first made by the International Expert
Panel) in 2006. The International Expert Panel meeting is held every two years, and the experts attending the meeting are mainly from Europe, the United States and other developed countries, and the consensus formulated at the meeting is mainly based on the experts’ views.
First, are the indications for adjuvant chemotherapy and neoadjuvant chemotherapy the same? According to the latest NCCN guidelines, the indications for adjuvant chemotherapy are patients with tumor > 1 cm or lymph node metastasis or high-risk patients with tumor size of 0.6~1 cm. The St Gallen consensus suggests that the indications for adjuvant chemotherapy are intermediate-risk or high-risk patients. According to the latest NCCN guidelines and the St Gallen consensus, the indications for neoadjuvant chemotherapy are patients with inoperable locally advanced disease or those with breast-conserving expectations but whose tumors are too large to be conserved. This shows that the indications for adjuvant chemotherapy and neoadjuvant chemotherapy are completely different. Secondly, it is very difficult to determine whether adjuvant chemotherapy is needed before surgery. It is impossible to accurately determine the status of lymph node metastasis preoperatively, the results of coarse needle aspiration may not be representative, and it is impossible to determine the status of vascular aneurysm embolism. Some tumors that are large in size but predominantly carcinoma in situ may not require adjuvant chemotherapy postoperatively.
In fact, the 2008 International Expert Committee Consensus has been revised to consider the indications for neoadjuvant chemotherapy for patients who are inoperable or have breast-conserving expectations but the tumor is too large to be breast-conserving, which is consistent with the current NCCN guidelines and the St Gallen Consensus.
3. Should triple negative breast cancer be treated with neoadjuvant chemotherapy?
Triple negative breast cancer (TNBC) is the most common form of breast cancer,
As most of TNBC are basal-like breast cancer, the prognosis is poor, and chemotherapy is the main treatment currently, and the pCR rate of neoadjuvant chemotherapy for TNBC is high [9]. There are no prospective studies comparing neoadjuvant chemotherapy with adjuvant chemotherapy for TNBC. However, some studies have shown that although patients with pCR in TNBC have a better prognosis, the majority of patients with non-pCR are lost to surgery due to faster tumor progression [9]. If pCR patients in TNBC “benefit” from neoadjuvant chemotherapy, their “benefit” comes at the cost of ineffectiveness or rapid progression in some patients! In fact, TNBC is only one of the factors affecting the pCR rate. Patients with pCR in TNBC are sensitive to chemotherapy and do well with postoperative adjuvant chemotherapy. Moreover, not all patients with TNBC can achieve pCR, and there are also a large proportion of non-pCR or even ineffective patients, and these patients progress more rapidly than non-pCR patients with other types of tumors; therefore, TNBC cannot be used as an indication for neoadjuvant chemotherapy.
Some scholars believe that human epidermal growth factor receptor 2 (HER-2) positive breast cancer patients with poor prognosis and high pCR rate should also be treated with neoadjuvant chemotherapy, and there is the same misconception as TNBC. Poor prognosis and high pCR rate are not indications for neoadjuvant chemotherapy.
4. Neoadjuvant chemotherapy is a collision between the latest treatment concept and the old treatment model of breast cancer?
Although neoadjuvant chemotherapy has the word “new” in it, it does not mean that it is a “newest treatment concept”. With the establishment of cyclophosphamide + methotrexate + fluorouracil (CMF) chemotherapy in the 1970s, neoadjuvant chemotherapy has been used in patients with inoperable locally advanced breast cancer. Neoadjuvant chemotherapy regimens have also been updated with the emergence of targeted agents such as anthracyclines, paclitaxel, and trastuzumab in adjuvant chemotherapy. Neoadjuvant chemotherapy and adjuvant chemotherapy are both important elements of the comprehensive treatment of breast cancer, and neoadjuvant chemotherapy is not the “latest treatment concept”, nor is adjuvant chemotherapy the “old treatment model”.
5. Neoadjuvant chemotherapy is better than adjuvant chemotherapy because it treats patients systemically as early as possible?
Fisher et al. found in animal models that excision of the primary lesion of breast cancer leads to the release of “tumor growth factor”, which promotes the growth of distant “metastases”, while local radiotherapy or systemic chemotherapy or endocrine therapy given before excision of the primary lesion can suppress this “tumor growth factor”. Local radiotherapy or systemic chemotherapy or endocrine therapy given before resection of the primary site can inhibit the release of this “tumor growth factor” and suppress the growth of the “metastases”. Therefore, some people believe that neoadjuvant chemotherapy is more effective than adjuvant chemotherapy because it targets systemic micrometastases earlier, and some people even believe that neoadjuvant chemotherapy can “lower the risk” and that people with high risk of recurrent metastases should receive neoadjuvant chemotherapy. So, does this conclusion obtained in experimental animals apply to clinical practice? Can neoadjuvant chemotherapy reduce the risk of recurrence and metastasis better than adjuvant chemotherapy?
In fact, in Fisher’s animal model, different numbers of tumor cells were planted in the left and right legs of nude mice, resulting in graft tumors of 5-7 mm in the right leg and 3-5 mm in the left leg, and defining the larger graft tumor in the right leg as the “primary site” and the smaller graft tumor in the left leg as the “metastatic site” or “metastatic site”. The larger graft on the right leg was defined as the “primary focus”, while the smaller graft on the left leg was defined as the “metastasis” or “residual lesion”, and then the right leg was excised to observe the proliferation of the graft on the left leg [10]. Therefore, the so-called “metastases” are not formed by the metastasis of the “primary site” and do not correspond to the actual clinical situation of the patient.
In fact, the systemic treatment time of neoadjuvant chemotherapy is not much earlier than that of adjuvant chemotherapy. Obtaining pathological evidence (core needle aspiration biopsy or McMerton biopsy and hematoxylin-eosin staining of tumor tissue and immunohistochemical analysis) prior to neoadjuvant chemotherapy usually takes 1 week, and may take longer if an anterior lymph node biopsy is performed. In contrast, with postoperative adjuvant chemotherapy, postoperative recovery and wound removal takes 2 weeks, with a maximum difference of only 1 week between the two. Neoadjuvant chemotherapy, however, delays local treatment. Neoadjuvant chemotherapy usually takes several months, even six months or longer, which significantly prolongs the time the body carries the tumor and likewise increases the chance of tumor cells being released into the blood from the primary focus. Moreover, patients with ineffective neoadjuvant chemotherapy may lose the chance of surgery and cure forever. More importantly, the results of large-scale randomized controlled clinical trials B-18, B-27 and meta-analysis clearly confirm that there is no difference in DFS and OS between neoadjuvant and adjuvant chemotherapy, and neoadjuvant chemotherapy does not “reduce risk” [4]. Therefore, the statement that neoadjuvant chemotherapy is better than adjuvant chemotherapy is inappropriate.
6. neoadjuvant chemotherapy is the best means of in vivo drug sensitivity testing, and patients can benefit from it, especially those who failed the first regimen?
The notion that neoadjuvant chemotherapy, in contrast to adjuvant chemotherapy, has foci where efficacy can be assessed and therefore in vivo drug sensitivity testing can be performed sounds fascinating and is an important reason why some scholars choose neoadjuvant chemotherapy.
However, current clinical trials have shown that “in vivo drug sensitivity testing” for neoadjuvant chemotherapy is not feasible in practice. In the GeparTrio trial, a prospective study conducted in Germany with 2,090 subjects, all subjects received 2 courses of neoadjuvant chemotherapy with docetaxel + doxorubicin + cyclophosphamide (TAC), followed by an efficacy assessment, and those who failed to respond to TAC were randomized to 2 groups. Patients were randomized into 2 groups, one group continued 4 courses of TAC and the other group switched to vincristine + capecitabine (vinorelbine + capecitabine, NX) without cross-resistance. The results showed that for patients who did not respond to 2 courses of TAC, the overall efficacy rate (CR + partial response, PR) assessed by the best means (ultrasound or physical examination) could still reach 69.5% with a pCR rate of 5.3%, while the overall efficacy rate after switching to NX was 62.5% with a pCR rate of 6%, with no There was no statistical difference between the two. There was also no difference in breast conservation rate. This result suggests that patients who are not responding to initial treatment may still be effective if they continue with the original regimen, but are still likely to be ineffective even if they switch to a regimen without cross-resistance. In the Aberdeen trial, another prospective study of neoadjuvant chemotherapy drug sensitivity trials conducted in the UK, all subjects first received 4 courses of cyclophosphamide + vincristine + doxorubicin + prednisone (cyclophosphamide + vincristine + doxorubicin + prednisone, CVAP) after Those who were ineffective were switched to doxorubicin, and those who were effective were randomized to doxorubicin or continued CVAP chemotherapy for 4 courses, followed by surgery. The results showed that for patients with effective initial treatment, the pCR rate increased from 15% to 31% after switching to doxorubicin, which means that patients with effective original regimen may be more effective after switching to other regimen; while patients with failed CVAP, even after switching to doxorubicin, the pCR rate was still only 2%, which is also consistent with the results of Gepartrio. Moreover, the Aberdeen trial also found that patients with effective initial treatment with CVAP who continued neoadjuvant chemotherapy with the original regimen had an overall efficiency of only 64%, and 3.5% of patients even had progression disease (PD), meaning that 1/3 of patients with effective initial treatment would become ineffective or even develop PD if they continued with the original regimen. The above two prospective studies confirm with conclusive data that in vivo drug sensitivity testing of neoadjuvant chemotherapy sounds good, but it does not work in clinical practice.
7. Can neoadjuvant chemotherapy avoid over-chemotherapy and ineffective chemotherapy?
The disadvantage of adjuvant chemotherapy is that there is no target lesion and efficacy assessment is difficult, which is the advantage of neoadjuvant chemotherapy. However, previous analyses have shown that neoadjuvant chemotherapy “drug sensitivity testing” does not guide clinical practice to avoid ineffective or inefficient chemotherapy regimens. In fact, neoadjuvant chemotherapy is more blind than adjuvant chemotherapy. First, preoperative sampling may not be representative, and the status of lymph nodes and vascular tumor emboli are unknown, which leads to preoperative diagnostic errors; second, in order to pursue efficiency, neoadjuvant chemotherapy usually uses a combination of anthracyclines + paclitaxel, which results in overtreatment for some patients with good prognosis and tumors mainly in ductal carcinoma; third, neoadjuvant chemotherapy changes the original information of the tumor, which affects the prognosis and subsequent treatment plan. It affects the prognosis judgment and the choice of subsequent treatment plan. In contrast, adjuvant chemotherapy can obtain more accurate pathological staging and tumor biological characteristics to develop a more individualized treatment strategy.
8.Does neoadjuvant chemotherapy need a full course of treatment to achieve its purpose?
There are still many controversies about the course of neoadjuvant chemotherapy, some scholars believe that neoadjuvant chemotherapy needs 6~8 courses or even longer to achieve the goal. The goal of breast cancer treatment should be to increase survival and improve quality of life. This issue was also investigated in the previously mentioned GeparTrio trial [11]. In the GeparTrio trial those who were effective with 2 courses of TAC were randomized into 2 groups and continued with 4 courses of TAC or extended to 6 courses to determine if pCR rates or breast conservation rates could be improved with more courses. The results of the study showed that extending the course of neoadjuvant chemotherapy did not improve the pCR rate and breast conservation rate, but increased the chemotherapy toxicity and affected the patients’ surgery and postoperative recovery. For patients who can achieve pCR with neoadjuvant chemotherapy, the same efficacy can be obtained from chemotherapy in postoperative adjuvant chemotherapy, even if the preoperative course is insufficient and pCR is not achieved. However, unnecessarily prolonging the course of treatment may lead to secondary resistance in some of the tumor cells that have started to be sensitive to chemotherapy, causing the already shrinking tumor to grow again and even losing the opportunity for surgery. The “purpose” of neoadjuvant chemotherapy is not pCR, but to improve the surgical resection rate and increase the breast conservation rate. Therefore, once the tumor shrinks to the extent that surgery or breast conservation is possible, neoadjuvant chemotherapy should be stopped for surgery, and the course of treatment should be continued in the postoperative adjuvant chemotherapy.
9. There is no difference between the effect of neoadjuvant chemotherapy and adjuvant chemotherapy, so neoadjuvant chemotherapy can be chosen?
Although there is no difference in DFS and OS between neoadjuvant and adjuvant chemotherapy, for individual patients, once the tumor progresses after neoadjuvant chemotherapy, breast conservation or surgery will be lost, early breast cancer will become locally advanced and even metastasis will occur, and unnecessary neoadjuvant chemotherapy increases the complexity of pathological staging and subsequent treatment. “Do no harm (do no harm)” is the foremost and most fundamental principle of the Hippocratic Oath. Why should patients take the risk of losing breast-conserving or surgical opportunities and delaying treatment when they are unlikely to benefit compared to postoperative chemotherapy?
Moreover, the current doctor-patient relationship is tense, and the “proof is reversed”. For early-stage operable breast cancer, once the tumor progresses during neoadjuvant chemotherapy or even metastases, how to “prove”? Especially for the grassroots hospitals, the legal problems that may be brought by blind neoadjuvant chemotherapy also need to be paid great attention.
10. Is neoadjuvant chemotherapy the best means to compare two different treatment options?
The ultimate goal of breast cancer treatment should be to improve OS, but the follow-up of OS takes more than ten years or even decades, which is too time-consuming and costly. DFS can be used as a proxy for OS in adjuvant chemotherapy, but DFS data also require several years of follow-up. In neoadjuvant chemotherapy, pCR can be used as a surrogate indicator of OS, and pCR data can be obtained in a few months, which greatly improves efficiency and saves cost. These advantageous conditions make neoadjuvant chemotherapy an optimal testing ground for screening therapies. However, there are still some issues that need to be taken into account. First, as a clinical trial, it is necessary to pass the ethics committee’s consent, inform about the risks, and obtain the patients’ informed consent. Second, not all patients who obtain pCR will not relapse, and not all who do not have pCR will relapse. Therefore, pCR cannot replace OS, and the OS results of neoadjuvant chemotherapy screened treatment regimens need to be confirmed by long-term follow-up.
In summary, the indications for neoadjuvant chemotherapy should be: (1) inoperable locally advanced breast cancer, used to improve the resection rate; (2) operable early-stage breast cancer, where the patient has a strong desire for breast conservation and all other conditions except tumor size meet the criteria for breast conservation, used to improve the success rate of breast conservation; and (3) well-designed clinical trials that conform to formal procedures. These are also the principles of the current latest NCCN guidelines and St Gallen consensus on neoadjuvant chemotherapy. For neoadjuvant chemotherapy, one must keep a clear head, follow the principles strictly, do not abuse them, and do not let those who can operate lose the opportunity to operate and those who can conserve breast lose the opportunity to conserve breast.