Neoadjuvant Therapy For Prostate Cancer

What Are The Costs Of Adjuvant Therapy

Survivorship and patient-reported outcomes are increasingly recognized as important aspects of curative-intent treatment. For PC patients, one important question is whether adding systemic therapy increases the local morbidity of surgery and radiation i.e. effects on sexual, urinary, and bowel function. According to the Irish Clinical Oncology Research Group trial 97-01, duration of neoadjuvant ADT may not affect the risk of late toxicities. In this trial 276 men were randomly assigned to 4 months or 8 months of ADT followed by external beam radiation. There was no difference in erectile function at 5 years39. Additional reassuring data come from a single-arm study of adjuvant ADT and docetaxel after external beam radiation and brachytherapy for high-risk PC40. This intense regimen was associated with only 7.7% grade 2 late genitourinary and gastrointestinal toxicities, with a notable absence of grade 3 or 4 late toxicity after median follow-up of 5.6 years. More data are needed to adequately counsel patients about risks and benefits of systemic therapy as intensified multimodal regimens are used. The longer term effects of surgery and radiation on sexual function and urinary symptomatology are not encouraging and it is likely that incorporating ADT would make longer term sexual complications even worse41.

Treatment And Research Considerations

Many unanswered questions exist regarding the benefit of NADT. Current data are insufficient to support the routine recommendation of NADT. Until this ambiguity is clarified, the utility of NADT prior to RP will remain controversial.

In patients with clinically localized prostate cancer, the National Comprehensive Cancer Network strongly discourages the use of NADT before RP outside of a clinical trial. However, the NCCN notes that androgen deprivation therapy before, during, and/or after radiation prolongs survival in selected patients who are receiving radiation therapy only.

As with any therapy, the ultimate benefit of NADT in prostate cancer will be determined only through properly designed trials with long-term follow-up. Also, hormone therapy is associated with significant side effects, such as hot flushes and gynecomastia, as well as financial costs.

The decision to use hormone therapy should, therefore, be taken at a local level, between the patient, clinician, and policy maker, taking into account the clinical benefits, toxicity, and cost. More research is needed to guide the choice, the duration, and the schedule of hormone deprivation therapy and the impact of long-term hormone therapy with regard to toxicity and the patients quality of life.

There is a particularly strong need for neoadjuvant chemotherapy trials that will allow more rapid and less costly screening of new drugs and drug regimens. Research to date has identified some possible candidates.

Histopathologic Changes In Nadt

Androgen deprivation therapy produces distinct histopathologic changes in neoplastic and nonneoplastic prostate tissue. A pathologist who is not familiar with these alterations may misinterpret the specimen, resulting in inappropriate tumor grading or missed tumor foci. Thus, the urologist should convey to the pathologist any information regarding therapy that might cause histopathologic changes.

Civantos et al published the largest series on the pathology of androgen deprivation therapy for prostate cancer, and in the series of 173 patients who were treated with a luteinizing hormone-releasing hormone analogue and an antiandrogen prior to radical prostatectomy , atrophy was observed in benign and malignant tissue. Examination of noncancerous tissue revealed atrophy of secretory cells, with cytoplasmic clearing and vacuolization. Atrophy and disappearance of luminal cells resulted in basal cell prominence. Morphologic alterations induced by treatment were patchy the entire neoplastic tissue was affected in only 57% of the specimens. The poorly differentiated areas of tumors were affected less frequently.

Three types of changes in neoplastic tissue were reported in the Civantos study :

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Resistance To Neoadjuvant Therapy

24 February 2022

Neoadjuvant therapy usually refers to chemotherapy administered prior to definitive treatment such as surgery or radiation. In the context of prostate cancer neoadjuvant treatment can include androgen deprivation therapy . Although usually given in the context of a clinical trial, neoadjuvant ADT may be used to reduce the size of locally advanced tumours, facilitating surgical resection. It has also been shown to decrease the rates of cancer escaping the prostate capsule into surrounding tissues, increasing negative surgical margins and lowering the frequency of lymph node metastases after a radical prostatectomy. Till now researchers have been unable to demonstrate significant improvements in overall survival with nADT. A possible explanation is due to treatment resistance. Urologist, Niall Corcoran and his team from the University of Melbourne have reviewed the medical literature to explain some of these mechanisms of resistance as well as potential biomarkers to help determine which cancers will respond to nADT and which may be resistant.

As mentioned in previous blogs prostate cancer growth is reliant on the effects of testosterone. Testosterone is largely produced in the adrenal gland and attaches to receptors on prostate cancer cells signalling a pathway of changes within the cell to allow the cancer to grow.

References

About the Author

Kalli SpencerMBBCh, FC Urol , MMed , Dip.Couns

Staging And Clinical Activity

Surgical variables were recorded implying the functional outcome. Continence was defined as the use of no pads and erectile function using the erection hardness score . Adverse events were registered according to Common Terminology Criteria , including dose reductions and treatment deferrals. Additional hematologic analyses were performed one week after docetaxel application.

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What Are The Side Effects Of Hormone Therapy For Prostate Cancer

Because androgens affect many other organs besides the prostate, ADT can have a wide range of side effects , including:

• loss of interest in sex

How Will I Know That My Hormone Therapy Is Working

Doctors cannot predict how long hormone therapy will be effective in suppressing the growth of any individual mans prostate cancer. Therefore, men who take hormone therapy for more than a few months are regularly tested to determine the level of PSA in their blood. An increase in PSA level may indicate that a mans cancer has started growing again. A PSA level that continues to increase while hormone therapy is successfully keeping androgen levels extremely low is an indicator that a mans prostate cancer has become resistant to the hormone therapy that is currently being used.

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How Does Hormone Therapy Work Against Prostate Cancer

Early in their development, prostate cancers need androgens to grow. Hormone therapies, which are treatments that decrease androgen levels or block androgen action, can inhibit the growth of such prostate cancers, which are therefore called castration sensitive, androgen dependent, or androgen sensitive.

Most prostate cancers eventually stop responding to hormone therapy and become castration resistant. That is, they continue to grow even when androgen levels in the body are extremely low or undetectable. In the past, these tumors were also called hormone resistant, androgen independent, or hormone refractory however, these terms are rarely used now because the tumors are not truly independent of androgens for their growth. In fact, some newer hormone therapies have become available that can be used to treat tumors that have become castration resistant.

Advantages And Disadvantages Of Nadt

Neoadjuvant androgen deprivation offers the following potential advantages:

• Rate of positive margins is reduced
• Organ-confined disease is increased
• Serum PSA level is reduced
• Prostate size is reduced.

The following disadvantages of NADT have been identified:

• Clinical trials have not demonstrated unequivocal improvement in disease-free survival rates
• NADT has an unknown therapeutic effect on microscopic local or metastatic disease
• Poorly differentiated areas of tumor are altered minimally
• Tumor is rarely completely eradicated
• Risk of androgen-independent clonal proliferation exists with prolonged NADT
• Ability to evaluate the extent of the tumor at surgical resection may be compromised
• Pathologic interpretation may be obscured
• Increased difficulty occurs at surgery due to periprostatic fibrosis
• Cost of therapy is a disadvantage
• Adverse effects are a potential disadvantage
• Treatment of the tumor is delayed
• Likelihood of requiring blood transfusion during surgery is increased

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Adjuvant Ht After Radiation Therapy

The use of adjuvant HT for locally advanced prostate cancer or high-risk patients after RT is well established. The RTOG 85-31 trial randomized 977 patients with locally advanced prostate cancer to receive adjuvant ADT indefinitely after definitive RT. After a follow-up of 7.6 years, a significant increase in the 10-year OS , and significant decreases in local failure rate , incidence of distant metastases , and disease-specific mortality were observed, favoring the adjuvant group. This study had some limitations because 139 patients received prior RP and, in addition, the trial was conducted in the pre-PSA era, making it difficult to translate it to current practice.

A subsequent landmark trial, EORTC trial 22863, reported by Bolla and colleagues, enrolled 415 node negative patients with T3 or T4 tumors or high-grade T1 or T2 tumors, and randomized them to either adjuvant HT with goserelin for a total of 3 years or observation after definitive RT. At a median follow-up of 66 months, a significant benefit was observed for the adjuvant group in 5-year OS , cancer-specific survival , and clinical DFS .

Selection Of Candidates For Nadt

High-risk patients with localized prostate carcinoma are likely to benefit most from effective neoadjuvant therapy. However, heterogeneous definitions of high-risk disease render trial-to-trial comparisons difficult.

The use of preoperative nomograms that incorporate clinical T classification, serum PSA level, and biopsy Gleason grade can enhance prediction of the risk of PSA recurrence and selection of a relatively homogeneous population. The percentage of cancer in biopsy cores and the number of positive biopsy cores, as well as the incorporation of biomarkers , may further improve predictive accuracy.

Although a relatively high threshold of PSA recurrence to determine eligibility is reasonable, it may negatively affect accrual. In addition, investigators may determine that radiotherapy, instead of prostatectomy, is the optimal treatment in such high-risk patients. Conversely, setting a lower threshold of recurrence may result in unnecessary treatment, a reduction in the event rate, and an increase in the number of patients required.

It may be reasonable to hypothesize that patients with a relatively high risk of recurrence may be optimal candidates for cytotoxic chemotherapy, whereas those with a lower risk of recurrence may be optimal candidates for more tolerable biologic agents and immunotherapy.

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Neoadjuvant Strategies Before Radical Prostatectomy For High Risk Prostate Cancer In The Era Of New Hormonal Agents

Volume 22, Issue 1, 2021

21 June, 2020

Page: Pages: 9

Abstract

Prostate cancer is a hormone-dependent disease, including several different patternsfrom indolent and clinically meaningless to aggressive and lethal disease. Among non -metastatic PCa,high-risk disease represents a therapeutical challenge, given the unfavorable oncological outcomes afterexclusive local therapy. Deprivation therapy in the neoadjuvant setting is not recommended prior toradical prostatectomy since it did not provide any survival advantage, although reducing tumor volume,surgical margins rate, local and nodal stage. However, in the few recent years, new hormonaltreatments for metastatic PCa emerged and showed a relevant increase of overall survival concerningstandard androgen deprivation therapy . Thus, neo-adjuvant regimens of ADT based on thesenovel molecules are now under investigation and the results of ongoing clinical trials are expected inorder to provide a definitive answer on the real role of neoadjuvant hormonal therapy in the treatmentof high-risk localized prostate cancer. In this narrative review, we underline the role of neoadjuvanttherapy before radical prostatectomy in high-risk PCa patients considering the impact of the newavailable hormonal agents.

Referenceset al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al.

How Is Hormone Therapy Used To Treat Hormone

Hormone therapy may be used in several ways to treat hormone-sensitive prostate cancer, including:

Early-stage prostate cancer with an intermediate or high risk of recurrence. Men with early-stage prostate cancer that has an intermediate or high risk of recurrence often receive hormone therapy before, during, and/or after radiation therapy, or after prostatectomy . Factors that are used to determine the risk of prostate cancer recurrence include the grade of the tumor , the extent to which the tumor has spread into surrounding tissue, and whether tumor cells are found in nearby lymph nodes during surgery.

The use of hormone therapy before prostatectomy has not been shown to be of benefit and is not a standard treatment. More intensive androgen blockade prior to prostatectomy is being studied in clinical trials.

Relapsed/recurrent prostate cancer. Hormone therapy used alone is the standard treatment for men who have a prostate cancer recurrence as documented by CT, MRI, or bone scan after treatment with radiation therapy or prostatectomy.

Hormone therapy is sometimes recommended for men who have a “biochemical” recurrencea rise in prostate-specific antigen level following primary local treatment with surgery or radiationespecially if the PSA level doubles in fewer than 3 months.

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Neoadjuvant And Adjuvant Therapies In Prostate Cancer

Prostate cancer is the most common cancer in men in the United States and the second leading cause of cancer death. Advances in surgical therapies have paralleled advances in radiation therapy and chemotherapy for metastatic disease. There is a great interest in neoadjuvant and adjuvant therapies for patients at intermediate and high risk of recurrence and prostate cancerspecific death. Because high-risk prostate cancer patients can be readily identified by clinical criteria, many studies have attempted to use local and systemic adjuvant therapy to reduce the risk of recurrence. This review discusses neoadjuvant and adjuvant therapies in prostate cancer, including hormonal therapy, chemotherapy, and postoperative radiotherapy.

Many studies consider biochemical recurrence as an end point to evaluate the efficacy of the neoadjuvant and adjuvant therapies, but this should be done cautiously. Prostate cancer is a disease of older men and usually has a long course. Thus a significant proportion of patients who experience biochemical recurrence may not progress or die of prostate cancer because other competing causes of death also increase with age. Therefore, careful attention to the defining characteristics of the study population and the outcomes of interest are crucial when assessing the efficacy of the adjuvant treatment options.

Adjuvant Vs Neoadjuvant Androgen

Sequencing of androgen-deprivation therapy with radiotherapy has a significant impact on long-term outcomes in localized prostate cancer, according to data presented during the virtual edition of the 2020 American Society for Radiation Oncology Annual Meeting.1

Pooled individual patient analysis of two phase III randomized trials has shown, for the first time, that the addition of adjuvant androgen-deprivation therapy to prostate-alone radiotherapy leads to superior outcomes when compared with a neoadjuvant approach. Findings demonstrated significantly improved progression-free survival, biochemical recurrence, distant metastasis, and metastasis-free survival with an adjuvant androgen-deprivation therapy sequence with radiotherapy, and this was accomplished without an increase in observed rates of toxicity.

We believe this analysis currently serves as the highest level of evidence to support the importance of sequencing of androgen-deprivation therapy with radiotherapy, said lead study author, Daniel E. Spratt, MD, of the University of Michigan Rogel Cancer Center, Ann Arbor.

Daniel E. Spratt, MD

As Dr. Spratt explained, the timing of systemic therapy in relation to radiotherapy is important in most malignancies. However, androgen-deprivation therapy has largely been investigated in relation to its duration rather than its sequencing with radiotherapy.

Study Methods

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Asco : The Role Of Neoadjuvant Therapy For Patients With Localized Prostate Cancer

For patients with high risk localized prostate cancer, 15-year prostate cancer survival ranges from 20-38%. However, unlike other tumor types where neoadjuvant therapy has been shown to improve overall survival outcomes , there remains a paucity of randomized data showing improved long-term outcomes with neoadjuvant therapy for prostate cancer. Current NCCN, AUA, and ASCO guidelines do not recommend neoadjuvant therapy outside of a clinical trial. Prior studies, such as CALGB 90203 did not show improvement in 3-year PSA PFS .

More recently, neoadjuvant studies have been conducted with second-generation androgen antagonists such as abiraterone and enzalutamide, and this has demonstrated that 6 months of neoadjuvant ADT + enza can achieve pathologic complete response in some patients.1 Prior analysis by Rana R. McKay, MD has shown that a pathologic response can correlate with PSA recurrence.2These two studies presented at this ASCO evaluate the safety and pathologic responses to intensive neoadjuvant hormonal therapy with combination apalutamide and leuprolide with or without abiraterone.Abstract 5503: Results of a Phase II Trial of Intense Androgen Deprivation Therapy Prior to Radical Prostatectomy in Men with High-Risk Localized Prostate Cancer:

The first study randomized patients with high-risk prostate cancer to either abiraterone + prednisone + apalutamide + leuprolide or abiraterone + prednisone + leuprolide for a total of 6 cycles , followed by radical prostatectomy.

Neoadjuvant Hormone Therapy: The Canadian Trials

Journal Article

The Canadian Urologic Oncology Group has carried out three studies of neoadjuvant hormonal therapy in prostate cancer. The first, a study of 3 months of cyproterone acetate 100 mg TID in patients undergoing external-beam radiation therapy, showed a benefit with respect to time to biochemical progression. There are no survival or clinical progression data available from this study. The second study involved 3 months of CPA prior to radical prostatectomy compared with radical prostatectomy alone and enrolled 200 patients. The probability of biochemical progression at 36 months was similar in the two groups . More recently, we have carried out a randomized trial of 3 v 8 months of leuprolide plus flutamide prior to radical prostatectomy in 547 patients. Patients were stratified by clinical stage, Gleason grade, and serum prostate specific antigen concentration. In the 3- and 8-month groups, presurgery PSA concentrations were < 0.1 ng/mL in 35% v 73%, and > 0.3 ng/mL in 37% v 10%, respectively. In the 3- and 8-month groups, the positive margin rates were 17% and 5% and the organ-confined rates 71% and 91% . One-year follow-up is now available on the entire cohort. Data regarding time to biochemical and clinical progression and overall and disease-specific survival will be required to determine whether this change in the pathologic findings translates into a patient benefit.

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