Adjuvant therapy

For adjuvant substances, see adjuvant.

Adjuvant therapy, also known as adjunct therapy, add-on therapy, and adjuvant care, is therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. The surgeries and complex treatment regimens used in cancer therapy have led the term to be used mainly to describe adjuvant cancer treatments. An example of such adjuvant therapy is the additional treatment usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to the presence of undetected disease. If known disease is left behind following surgery, then further treatment is not technically adjuvant.

An adjuvant agent modifies the effect of another agent, so adjuvant therapy modifies other therapy.

History

The term "adjuvant therapy," derived from the Latin term adjuvāre, meaning "to help," was first coined by Paul Carbone and his team at the National Cancer Institute in 1963. In 1968, the National Surgical Adjuvant Breast and Bowel Project (NSABP) published its B-01 trial results for the first randomized trial that evaluated the effect of an adjuvant alkylating agent in breast cancer. The results indicated that the adjuvant therapy given after the initial radical mastectomy "significantly decreased recurrence rate in pre-menopausal women with four or more positive axillary lymph nodes."

The budding theory of using additional therapies to supplement primary surgery was put into practice by Gianni Bonadonna and his colleagues from the Instituto Tumori in Italy in 1973, where they conducted a randomized trial that demonstrated more favorable survival outcomes that accompanied use of Cyclophosphamide Methotrexate Fluorouracil (CMF) after the initial mastectomy.

In 1976, shortly after Bonadonna's landmark trial, Bernard Fisher at the University of Pittsburgh initiated a similar randomized trial that compared the survival of breast cancer patients treated with radiation after the initial mastectomy to those who only received the surgery. His results, published in 1985, indicated increased disease-free survival for the former group.

Despite the initial pushback from the breast cancer surgeons who believed that their radical mastectomies were sufficient in removing all traces of cancer, the success of Bonadonna's and Fisher's trials brought adjuvant therapy to the mainstream in oncology. Since then, the field of adjuvant therapy has greatly expanded to include a wide range of adjuvant therapies to include chemotherapy, immunotherapy, hormone therapy, and radiation.

Neoadjuvant therapy

Neoadjuvant therapy, in contrast to adjuvant therapy, is given before the main treatment. For example, systemic therapy for breast cancer that is given before removal of a breast is considered neoadjuvant chemotherapy. The most common reason for neoadjuvant therapy for cancer is to reduce the size of the tumor so as to facilitate more effective surgery.

In the context of breast cancer, neoadjuvant chemotherapy administered before surgery can improve survival in patients. If no active cancer cells are present in a tissue extracted from the tumor site after neoadjuvant therapy, physicians classify a case as “pathologic complete response” or "pCR." While response to therapy has been demonstrated to be a strong predictor of outcome, the medical community has still not reached a consensus in regard to the definition of pCR across various breast cancer subtypes. It remains unclear whether pCR can be used as a surrogate end point in breast cancer cases.

Adjuvant cancer therapy

For example, radiotherapy or systemic therapy is commonly given as adjuvant treatment after surgery for breast cancer. Systemic therapy consists of chemotherapy, immunotherapy or biological response modifiers or hormone therapy. Oncologists use statistical evidence to assess the risk of disease relapse before deciding on the specific adjuvant therapy. The aim of adjuvant treatment is to improve disease-specific symptoms and overall survival. Because the treatment is essentially for a risk, rather than for provable disease, it is accepted that a proportion of patients who receive adjuvant therapy will already have been cured by their primary surgery.

Adjuvant systemic therapy and radiotherapy are often given following surgery for many types of cancer, including colon cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, and some gynaecological cancers. Some forms of cancer fail to benefit from adjuvant therapy, however. Such cancers include renal cell carcinoma, and certain forms of brain cancer.

Hyperthermia therapy or heat therapy is also a kind of adjuvant therapy that is given along with radiation or chemotherapy to boost the effects of these conventional treatments. Heating the tumor by Radio Frequency (RF) or Microwave energy increases oxygen content in the tumor site, which results in increased response during radiation or chemotherapy. For example, Hyperthermia is added twice a week to radiation therapy for the full course of the treatment in many cancer centers, and the challenge is to increase its use around the world.

Concomitant or concurrent systemic cancer therapy

Concomitant or concurrent systemic cancer therapy refers to administering medical treatments at the same time as other therapies, such as radiation. Adjuvant hormonal therapy is given after prostate removal in prostate cancer, but there are concerns that the side effects, in particular the cardiovascular ones, may outweigh the risk of recurrence.

In breast cancer, adjuvant therapy may consist of chemotherapy (doxorubicin, herceptin, paclitaxel, docetaxel, cyclophosphamide, fluorouracil, and methotrexate) and radiotherapy, especially after lumpectomy, and hormonal therapy (tamoxifen, femara). Adjuvant therapy in breast cancer is used in stage one and two breast cancer following lumpectomy, and in stage three breast cancer due to lymph node involvement.

In glioblastoma multiforme, adjuvant chemoradiotherapy is critical in the case of a completely removed tumor, as with no other therapy, recurrence occurs in 1–3 months.

Adjuvant therapy does not improve prognosis in stage I, II, and III renal cell carcinoma, with the possible exception of radiotherapy, which lowered the risk of local recurrence from 41% to 22% in one study. As a result of this resistance to chemotherapy, targeted therapies, including nexavar, sutent, rapamycin and interleukin 2 that are known to be effective in stage IV renal cell carcinoma, have been studied in the adjuvant setting, without good results.

In early stage one small cell lung carcinoma, adjuvant chemotherapy with gemzar, cisplatin, paclitaxel, docetaxel, and other chemotherapeutic agents, and adjuvant radiotherapy is administered to either the lung, to prevent a local recurrence, or the brain to prevent metastases.

In testicular cancer, adjuvant either radiotherapy or chemotherapy may be used following orchidectomy. Previously, mainly radiotherapy was used, as a full course of cytotoxic chemotherapy produced far more side effects then a course of external beam radiotherapy (EBRT). However, it has been found a single dose of carboplatin is as effective as EBRT in stage II testicular cancer, with only mild side effects (transient myelosuppressive action vs severe and prolonged myelosuppressive neutropenic illness in normal chemotherapy, and much less vomiting, diarrhea, mucositis, and no alopecia in 90% of cases.

Adjuvant therapy is particularly effective in certain types of cancer, including colorectal carcinoma, lung cancer, and medulloblastoma. In completely resected medulloblastoma, 5-year survival rate is 85% if adjuvant chemotherapy and/or craniospinal irradiation is performed, and just 10% if no adjuvant chemotherapy or craniospinal irradiation is used. Prophylactic cranial irradiation for acute lymphoblastic leukemia (ALL) is technically adjuvant, and most experts agree that cranial irradiation decreases risk of central nervous system (CNS) relapse in ALL and possibly acute myeloid leukemia (AML), but it can cause severe side effects, and adjuvant intrathecal methotrexate and hydrocortisone may be just as effective as cranial irradiation, without severe late effects, such as developmental disability, dementia, and increased risk for second malignancy.

Dose-Dense Chemotherapy

Dose-dense chemotherapy (DDC) has recently emerged as an effective method of adjuvant chemotherapy administration. DDC uses the Gompertz curve to explain tumor cell growth after initial surgery removes most of the tumor mass. Cancer cells that are left over after a surgery are typically rapidly dividing cells, leaving them the most vulnerable to chemotherapy. Standard chemotherapy regimens are usually administered every 3 weeks to allow normal cells time to recover. This practice has lead scientists to the hypothesis that the recurrence of cancer after surgery and chemo may be due to the rapidly diving cells outpacing the rate of chemotherapy administration. DDC tries to circumvent this issue by giving chemotherapy every 2 weeks. To lessen the side effects of chemotherapy that can be exacerbated with more closely administered chemotherapy treatments, growth factors are typically given in conjunction with DDC to restore white blood cell counts. A recent 2018 meta-analysis of DDC clinical trials in early stage breast cancer patients indicated promising results in premenopausal women, but DDC has yet to become the standard of treatment in clinics.

Specific cancers

Malignant melanoma

The role of adjuvant therapy in malignant melanoma is and has been hotly debated by oncologists. In 1995 a multicenter study reported improved long-term and disease-free survival in melanoma patients using interferon alpha 2b as an adjuvant therapy. Thus, later that year the U.S. Food and Drug Administration (FDA) approved interferon alpha 2b for melanoma patients who are currently free of disease, to reduce the risk of recurrence. Since then, however, some doctors have argued that interferon treatment does not prolong survival or decrease the rate of relapse, but only causes harmful side effects. Those claims have not been validated by scientific research.

Adjuvant chemotherapy has been used in malignant melanoma, but there is little hard evidence to use chemotherapy in the adjuvant setting. However, melanoma is not a chemotherapy-resistant malignancy. Dacarbazine, temozolomide, and cisplatin all have a reproducible 10–20% response rate in metastatic melanoma.; however, these responses are often short-lived and almost never complete. Multiple studies have shown that adjuvant radiotherapy improves local recurrence rates in high-risk melanoma patients. The studies include at least two M.D. Anderson cancer center studies. However, none of the studies showed that adjuvant radiotherapy had a statistically significant survival benefit.

A number of studies are currently underway to determine whether immunomodulatory agents which have proven effective in the metastatic setting are of benefit as adjuvant therapy for patients with resected stage 3 or 4 disease.

Colorectal cancer

Adjuvant chemotherapy is effective in preventing the outgrowth of micrometastatic disease from colorectal cancer that has been removed surgically. Studies have shown that fluorouracil is an effective adjuvant chemotherapy among patients with microsatellite stability or low-frequency microsatellite instability, but not in patients with high-frequency microsatellite instability.

Lung Cancer

Non-small cell lung cancer (NSCLC)

In 2015, a comprehensive meta-analysis of 47 trials and 11,107 patients revealed that NSCLC patients benefit from adjuvant therapy in the form of chemotherapy and/or radiotherapy. The results found that patients given chemotherapy after the initial surgery lived 4% longer than those who did not receive chemotherapy. The toxicity resulting from adjuvant chemotherapy was believed to be manageable.

Breast cancer

It has been known for at least 30 years that adjuvant chemotherapy increases the relapse-free survival rate for patients with breast cancer

Agents used include:

Cyclophosphamide Methotrexate Fluorouracil Doxorubicin

Docetaxel Paclitaxel Epirubicin

However, ethical concerns have been raised about the magnitude of benefit of this therapy since it involves further treatment of patients without knowing the possibility of relapse. Dr. Bernard Fisher, among the first to conduct a clinical trial evaluating the efficacy of adjuvant therapy on patients with breast cancer, described it as an "value judgement" in which the potential benefits must be evaluated against the toxicity and cost of treatment and other potential side effects.

Ovarian Cancer

Roughly 15% of ovarian cancers are detected at the early stage, at which the 5-year survival rate is 92%. A Norwegian meta-analysis of 22 randomized studies involving early-stage ovarian cancer revealed the likelihood that 8 out of 10 women treated with cisplatin after the initial surgery were overtreated. Patients diagnosed at an early stage who were treated with cisplatin immediately after surgery fared worse than patients who were left untreated. An additional surgical focus for young women with early-stage cancers is on the conservation of the contralateral ovary for the preservation of fertility.

Most cases of ovarian cancers are detected at the advanced stages, when the survival is greatly reduced.

Combination adjuvant chemotherapy for breast cancer

Giving two or more chemotheraputic agents at once may decrease the chances of recurrence of the cancer, and increase overall survival in patients with breast cancer. Commonly used combination chemotherapy regimines used include:

• Doxorubicin and cyclophosphamide
• Doxorubicin and cyclophosphamide followed by docetaxel
• Doxorubicin and cyclophosphamide followed by cyclophosphamide, methotrexate, and fluorouracil
• Cyclophosphamide, methotrexate, and fluorouracil.
• Docetaxel and cyclophosphamide.
• Docetaxel,[doxorubicin, and cyclophosphamide
• Cyclophosphamide, epirubicin, and fluorouracil.

Side effects of adjuvant cancer therapy

Depending on what form of treatment is used, adjuvant therapy can have side effects, like all therapy for neoplasms. Chemotherapy frequently causes vomiting, nausea, alopecia, mucositis, myelosuppression particularly neutropenia, sometimes resulting in septicaemia. Some chemotheraputic agents can cause acute myeloid leukaemia, in particular the alkylating agents. Rarely, this risk may outweigh the risk of recurrence of the primary tumor. Depending on the agents used, side effects such as chemotherapy-induced peripheral neuropathy, leukoencephalopathy, bladder damage, constipation or diarrhea, hemorrhage, or post-chemotherapy cognitive impairment. Radiotherapy causes radiation dermatitis and fatigue, and, depending on the area being irradiated, may have other side effects. For instance, radiotherapy to the brain can cause memory loss, headache, alopecia, and radiation necrosis of the brain. If the abdomen or spine is irradiated, nausea, vomiting, diarrhea, and dysphagia can occur. If the pelvis is irradiated, prostatitis, proctitis, dysuria, metritis, diarrhea, and abdominal pain can occur. Adjuvant hormonal therapy for prostate cancer may cause cardiovascular disease, and other, possibly severe, side effects.

See also

• Analgesic adjuvant