Neoadjuvant Chemotherapy

Neoadjuvant therapy

 

  • Neoadjuvant treatment is an increasingly important part of early breast cancer management.
  • The main aims of neoadjuvant therapy are to treat occult metastases, decrease the bulk of the tumor and allow breast-conserving surgery.
  • In patients with large, operable breast tumors who are ineligible for Breast –Conserving Surgery (BCS), neoadjuvant therapy is a useful option for reducing the tumor size and for increasing the proportion of candidates for BCS
  • Multidisciplinary teams play a key role in the decision process for neoadjuvant treatment.
  • Expert discussion on current evidence to support neoadjuvant treatment decisions for patients is important.

 

 

In numerous occasions when cancer is found, the tumor is either too large or to risked to operate. The tumor size reduction would be ideal in order to be more assessable to surgery. The different modalities of treatment that are instituted in order to accomplish this shrinkage is the neoadjuvant therapies, and it can be given in the form of chemotherapy, radiotherapy, immunotherapy, and hormonal therapy.  Neoadjuvant, therapy has come to play an increasingly prominent role in the treatment of cancer. Potential advantages include improved local and distant control, direct evaluation, and organ-sparing treatment. Potential disadvantages include increased toxicity and cost, potential delay in effective treatment, and obscuring of pathologic staging.

 

 

Neoadjuvant therapy in cancer treatment may be viewed in three categories: tumors in which neoadjuvant treatment has been shown effective, thus becoming standard therapy; tumors in which it has been shown to facilitate organ-sparing, and tumors in which its utility has not been shown. For patients with osteogenic sarcoma, for example, preoperative chemotherapy and limb salvage therapy have become the standard of care. Response to chemotherapy, ascertained by histologic review of the surgical specimen, can be used to tailor postoperative chemotherapy. In patients with advanced laryngeal squamous cell carcinoma, neoadjuvant chemotherapy followed by radiation has permitted laryngeal preservation in a majority of patients without compromising overall survival.  Women with breast cancer have demonstrated promising results for neoadjuvant chemotherapy given before radiation therapy and/or surgery. For neoadjuvant therapy, as with other innovations in cancer treatment, it is crucial that a new strategy must be compared closely to standard therapy in terms of recurrence, survival, and impact on organ sparing, as well as the quality of life and treatment costs.

Neoadjuvant therapy is therapy given before surgery or radiotherapy.  Contrary, to adjuvant therapy that he is given after surgery or radiotherapy.  Neoadjuvant chemotherapy for breast, gastric, colon cancer, ovarian and head and neck cancer is a new multidisciplinary strategy that was introduced with the aim of reducing tumor size before surgery in the late 70’, but during the last 10 years has reemerged and established a prominent place in cancer treatment. The main rationale behind this type of treatment is to reduce the tumor size, make an inoperable tumor operable and of course, which is a new tendency allowing more conservative surgery and is now widely used, particularly for large tumors.  One of the advantages seen with neoadjuvant chemotherapy is the opportunity to observe tumors diminished in size or shrink both palpably and on imaging, and having a clinical oncologist can have a rapid assessment of clinical response.  This could help tests the progressive responses in vivo of the tumor to new drugs regimens, which could then could be used as adjuvant therapies. Neoadjuvant chemotherapy can shrink a breast large tumor,  enough so that lumpectomy plus radiation therapy becomes an option to mastectomy for those cases where breast preservation and aesthetics is important for the patient.

 

Role of neoadjuvant chemotherapy in breast cancer treatment

Breast cancer is now considered to be a systemic disease from the outset, with no correlation seen between the intensity of local treatment and survival or recurrence. Adjuvant therapy has clearly demonstrated a reduction in local and distant relapse; neoadjuvant therapy is similarly being assessed. It aims to treat occult metastases and decrease tumor bulk. Its use has demonstrated down-staging of the tumour with increased rates of breast-conserving surgery.

The management of breast cancer has gone through a significant change in the last few decades, with the super-radical mastectomy no longer a common entity. Breast cancer is now considered to be a systemic disease from the outset, with most patients with early breast cancer developing metastases whatever the treatment undertaken. Moreover, the intensity of local treatment does not correlate with survival and the risk of metastatic recurrence. A possible explanation to this may be the blood-borne micrometastases that are present at initial diagnosis. These observations have lead to a more conservative approach to surgical intervention in breast cancer and the concurrent use of medical therapy. A clear survival benefit has already been shown with adjuvant therapy, presumably by eradicating occult metastases. Neoadjuvant therapy is now being evaluated in this setting and has shown encouraging results.

The main aims of neoadjuvant therapy are to treat occult metastases, decrease the bulk of the tumor and allow breast-conserving surgery. It seems to have the potential of improving the results in more advanced cancers, for instance, in cancers with local fixity. Neoadjuvant therapy trials also offer a means for evaluating the effectiveness of the systemic agents compared to the adjuvant setting. The biological rationale for neoadjuvant therapy in breast cancer has been provided by Fisher and his colleagues. In a mice cancer model, they demonstrated that tumor excision was associated with an increase in metastases and that preoperative chemotherapy prevented these changes.3

Originally neoadjuvant therapy was a means to downstage patients with inoperable locally advanced breast cancer and neoadjuvant therapy is now integral to the treatment of patients with early-stage disease. Large clinical trials such as EORTC 10902 and NSABP B-18 have shown no differences between the same systemic therapy given pre- or post-surgery on disease-free (DFS) and overall survival Other benefits (i.e. the conversion of patients requiring mastectomy to breast-conserving surgery [BCS]) and some potential concerns have been investigated and are well

Several treatment modalities have been assessed as neoadjuvant therapy. Most trials have been on neoadjuvant chemotherapy, although more recently, neoadjuvant endocrine therapy and neoadjuvant trastuzumab have also been assessed.

What is a role of breast-conserving surgery and neoadjuvant chemotherapy for breast cancer treatment?

Breast-conserving surgery (BCS) is an attractive option for many patients with early-stage breast cancer, because it provides a better cosmetic outcome than modified radical mastectomy while reducing surgical morbidity. In patients with large, operable breast tumors who are ineligible for BCS, neoadjuvant therapy is a useful option for reducing the tumor size and for increasing the proportion of candidates for BCS. In patients with endocrine-responsive tumors, neoadjuvant endocrine therapy with either tamoxifen or an aromatase inhibitor (AI; anastrozole, letrozole, or exemestane) provides an alternative to neoadjuvant chemotherapy. Clinical trials have demonstrated the superiority of neoadjuvant AIs over tamoxifen in achieving a clinical response and increasing the frequency of BCS. In addition, adjuvant endocrine therapy with AIs, whether used as initial therapy instead of tamoxifen, in a switching strategy after 2-3 years of tamoxifen, or as extended adjuvant therapy after 5 years of adjuvant tamoxifen, has been shown in several randomized clinical trials to improve disease-free survival, reduce distant metastases and, in some cases, improve overall survival. The availability of the AIs for effective and well-tolerated neoadjuvant and/or adjuvant endocrine therapy represents an important advance in breast cancer treatment.

Neoadjuvant therapy improves patient outcomes substantially by increasing the rate of breast-conserving surgery. Following primary surgery, women with hormone-sensitive early breast cancer remain at risk for loco-regional and systemic recurrence. The most common relapse event, distant metastases, is associated with the poorest outcomes. As a neoadjuvant therapy, anastrozole, letrozole, and exemestane have been investigated and have shown efficacy in this setting. All three aromatase inhibitors (AIs) significantly improved the rate of breast-conserving surgery. As initial adjuvant therapy, the third-generation AIs anastrozole and letrozole more effectively reduce recurrence risk compared with tamoxifen following surgery, especially in the first 2 years, when the risk is greatest

Neoadjuvant therapy for HER2-positive breast cancers

HER-2, the human epidermal factor receptor, is over-expressed in 15%–25% of breast cancers.2 Several studies have shown a survival benefit of trastuzumab, a HER-2 receptor antibody, in metastatic breast cancer in combination with chemotherapy. There are several small trials that have shown a benefit of using trastuzumab in the neoadjuvant setting. One of the trials with trastuzumab had to be closed early due to its significant superiority in the group in which this was used. In this randomized study by Buzdar et al., . In the M.D. Anderson Cancer Centre (MDACC. The study showed a marked superiority in the trastuzumab plus chemotherapy arm with a pCR of 65% compared to a pCR of 26% in the other arm. Cardiac toxicity remains one of the main drawbacks of its use. Its optimal duration of administration and its impact on long-term outcome await further details, with several trials in progress. For HER2-positive breast cancers, neoadjuvant therapy usually includes trastuzumab and pertuzumab.

Trastuzumab

If you have neoadjuvant trastuzumab, you will likely also have trastuzumab after surgery (adjuvant trastuzumab). Trastuzumab is not usually given at the same time as anthracycline-based chemotherapy in either setting.

Pertuzumab. Pertuzumab is only used in neoadjuvant therapy and is not usually given after surgery

 

Pathological response after Neoadjuvant chemotherapy

When you have when you have been subjected to neoadjuvant therapy, normally, a pathologist checks the breast tissue removed during surgery for a pathologic response.

The Pathologic response describes how much of the tumor is left in the breast and lymph nodes after neoadjuvant therapy.

Pathologic complete response

In some cases, when the neoadjuvant therapy has been an effective function, shrinking the tumor so much that the pathologist can’t find any remaining cancer. This is called a pathologic complete response (pCR). A pCR can give some information about prognosis, but it doesn’t change your treatment plan. Although a pCR is encouraging, it doesn’t mean the cancer will never return. And, many people who do not have a pCR will still do very well.

The pCR rates to neoadjuvant chemotherapy are highest among women with:

  • High-grade tumors
  • Hormone receptor negative (estrogen receptor-negative and/or progesterone receptor-negative) tumors
  • HER2-positive tumors (when the neoadjuvant treatment plan includes trastuzumab and pertuzumab)

However, neoadjuvant chemotherapy can be effective in treating tumors of any grade and hormone receptor status.

What is next after neoadjuvant therapy ends?

To check the response to neoadjuvant therapy, you may have several tests, including a physical examination, including a breast exam; a mammogram; breast MRI and/or a breast ultrasound, and a PET CT scan.

Surgery is then planned much in the same way as if you did not have neoadjuvant therapy.

Sentinel node biopsy and neoadjuvant therapy

Axillary lymph node status is regarded as a prognostic indicator in invasive breast cancer. Sentinel lymph node biopsy (SLNB) is being used increasingly in patients with early breast cancer in predicting node status. The remainder of the axilla can be considered to be tumor free when the sentinel lymph node is negative. SLNB has an identification rate of 86–93% and a false negative rate of 7–13%.

 A sentinel node biopsy will be done either before neoadjuvant therapy begins or after neoadjuvant therapy (at the time of your breast surgery). A sentinel node biopsy checks for cancer in the lymph nodes in the underarm area (axillary nodes).

 SLNB assessment becomes difficult in the neoadjuvant setting due to the histological changes which may alter the accuracy of SLNB and lead to an increase in false negative results. Several small studies have examined the efficacy of SLNB in this setting. One of the largest of these, the NSABP B-27, involved 428 patients from several centers that underwent SLNB and axillary lymph node dissection following neoadjuvant therapy. The sentinel lymph nodes were successfully identified and removed in 85% of the patients. The false negative rate was 11%, not far from the false negative rate of SLNB in the normal clinical setting. Charfare et al. have combined the results of 14 studies and describe an overall detection rate of SLNB in 89% of the patients with a false negative rate of 11%. These figures are almost comparable to those obtained prior to neoadjuvant therapy and suggest that sentinel lymph node biopsy may be applicable in the neoadjuvant setting.

The timing of SLNB in the neoadjuvant setting is also controversial, with advocates for both pre- and post-neoadjuvant SLNB. Performing the SLNB in the pre-neoadjuvant scenario may provide a more definite node status at presentation and provide the therapists with an opportunity to tailor the treatment based on the node status. However, it exposes the patients to a further surgical procedure. The number of positive lymph nodes may be altered by the neoadjuvant therapy and may alter further treatment plans in the axilla. In the NSABP B-18 trial, axillary down-staging has been described following neoadjuvant chemotherapy (41% node positive in the neoadjuvant group compared to 57% in the adjuvant group). In patients where there has been a significant reduction in lymph node disease, a pre-neoadjuvant SLNB may subject them to an unnecessary axillary lymph node dissection later on. The other alternative may be to perform the SLNB after neoadjuvant therapy. This has also been met with several controversies. Though this may mean a reduction in the surgical procedure for the patient as this can be combined with the surgical procedure on the breast, the identification rates may not be as good compared to when done before neoadjuvant therapy. Moreover, performing the SLNB after adjuvant therapy may be technically more demanding and involve a significant learning curve.

It’s unclear whether it’s better to have a sentinel node biopsy before or after neoadjuvant therapy. There are pros and cons to each and the best timing is still under study.  Discuss the timing of the sentinel node biopsy with your surgeon before you start neoadjuvant therapy.

What is the Role of radiotherapy after neoadjuvant therapy?

In patients treated with neoadjuvant chemotherapy and mastectomy, post-mastectomy radiation has been shown to lower the rate of loco-regional recurrence. Huang et al. performed a retrospective analysis of 542 patients who were treated in six prospective trials within the same institution and compared the data with 134 patients with similar treatment but without radiation. They demonstrated a reduced loco-regional recurrence rate in irradiated patients (10-year recurrence rate 11% vs. 22%.). The benefit was more in patients with clinical T3 & T4 stage, a tumor size of >5.1 cm and in those with more than four positive nodes. This led to their recommendation that patients with locally advanced disease at presentation or with four or more positive lymph nodes should be considered for radiation after neoadjuvant chemotherapy and mastectomy. Based on their review, it remains unclear whether patients with stage II breast cancer with less than three positive lymph nodes would benefit from radiation therapy in a similar setting.

 

New clinical practice guideline advises neoadjuvant chemotherapy
for certain women with ovarian cancer

Ovarian cancer remains the most deadly gynecologic malignancy in the United States. What are the practical implications of recent research results on screening, neoadjuvant chemotherapy, and an investigational agent that targets recurrent ovarian cancer?

Neoadjuvant chemotherapy, in which chemotherapy is administered prior to surgical cytoreduction (surgical removal), challenges the traditional treatment paradigm for advanced stage ovarian cancer. Several randomized controlled trials have reported equivalent survival for primary surgical cytoreduction and NACT. Importantly, women who received NACT had fewer complications and were more likely to have optimal cytoreduction at the time of surgery. These
studies have limitations, however, and the role of NACT remains uncertain. To help guide clinicians, the Society of
Gynecologic Oncology and the American Society of Clinical Oncology convened an expert panel to provide recommendations and guidance on the evaluation of women and the use of NACT in the setting ofadvanced ovarian cancer.

Strong clinical evidence supports that all women with suspected stage IIIC or stage IV ovarian cancer should be evaluated by a gynecologic oncologist prior to the initiation of therapy. The evaluation should include at least a computed tomography scan of the chest, abdomen, and pelvis to assess the extent of disease and resectability.
A preoperative risk assessment should be performed to assess risk factors for increased morbidity and mortality.
Women who have a high perioperative risk profile or a low likelihood of achieving surgical reduction  to 1 cm or less of the residual tumor should receive NACT. Prior to the initiation of NACT, histologic confirmation of ovarian cancer should be obtained.

For women diagnosed with ovarian cancer, treatment paradigms for the initial management of the disease have shifted dramatically. Based on data from multiple randomized controlled trials, neoadjuvant chemotherapy (NACT) is being used more frequently. The American Society of Clinincal Oncology and the Society of Gynecologic Oncology developed consensus recommendations for the appropriate use of NACT and primary cytoreductive surgery for women with ovarian cancer.

Patients who are appropriate candidates for NACT should be treated with a platinum and taxane doublet and should
receive interval cytoreduction(surgical removal) following 3 to 4 cycles of therapy if a favorable response is noted. Patients whose disease progresses despite NACT have a poor prognosis, and there is little role

 

CONCLUSION

Neoadjuvant therapy offers several benefits. It gives an opportunity to assess the tumor response to the agent in vivo by tumor size assessment at regular intervals. It also provides a unique opportunity to study the biology of the tumor. Several modalities of neoadjuvant therapy have been examined and have all shown a variable success. Neoadjuvant chemotherapy has demonstrated a down-staging of the tumors which provides an opportunity for more breast-conserving surgery. Though no difference in survival has been demonstrated in trials comparing neoadjuvant with adjuvant chemotherapy, neoadjuvant chemotherapy seems to be associated with an increase in loco-regional recurrence. Neoadjuvant hormone therapy and trastuzumab have also shown promising results. The role of sentinel lymph node biopsy and radiotherapy in this setting is evolving.

Clinical trials for new drugs and novel combinations increasingly exploit neoadjuvant use and will be key to improving treatment of patient subgroups. Particularly, the opportunity for individualized molecular assessment during neoadjuvant therapy will further enhance scientific understanding of breast cancer biology and behavior.

 

The information in this document does not replace a medical consultation. It is for personal guidance use only. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of the disease.

Sources:

  • American Cancer Society
  • The National Cancer Institute
  • National Comprehensive Cancer Network
  • American Academy of Gastroenterology
  • National Institute of Health
  • MD Anderson Cancer Center
  • Memorial Sloan Kettering Cancer Center
  • American Cancer Society

 

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