Wikis
Quiz
Adjuvant therapy is a term used to describe the role of therapy relative to other cancer treatments.
The terms adjuvant and neoadjuvant have special meanings in oncology. Adjuvant therapy refers to additional treatment,[1] usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to occult disease. If known disease is left behind following surgery, then further treatment is not technically "adjuvant".
For example, radiotherapy or systemic therapy is commonly given as adjuvant treatment after surgery for a 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 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.
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Neoadjuvant therapy, in contrast to adjuvant therapy, is given before the main treatment. For example, systemic therapy that is given before removal of a breast is considered neoadjuvant chemotherapy. The most common reason for neoadjuvant therapy is to reduce the size of the tumor so as to facilitate more effective surgery.Neoadjuvant therapy, an adjunctive therapy given before the main therapy, has become an integral part of modern multidisciplinary cancer management. Organized by the primary organ involved by cancer, this review summarizes the outcomes of neoadjuvant therapy for common malignant solid tumors, based on large, randomized, controlled trials. In locally advanced rectal, laryngeal, and breast cancer, neoadjuvant therapy enables organ preservation; however, it does not improve overall survival when compared with definitive treament followed by adjuvant therapy. In locally advanced bladder and cervical cancer, patients who undergo neoadjuvant therapy before radical surgery appear to have better survival than those receiving definitive therapy alone; however, it is unclear if the neoadjuvant approach will be superior to definitive therapy followed by adjuvant therapy. To date, the survival benefits of neoadjuvant therapy for resectable non-small cell lung carcinoma, esophageal cancer, gastric cancer, and prostate cancer remains under investigation. Neoadjuvant therapy, an adjunctive therapy given before a definitive treatment, is an essential component of modern multidisciplinary cancer therapy. Although neoadjuvant or induction therapy does not contribute the most to the treatment outcome, it may improve the result substantially. For example, neoadjuvant therapy allows patients with large breast cancer to undergo breast-conserving surgery. It enables patients with locally advanced 'laryngeal cancer to have their vocal function preserved. Many patients with rectal cancer can avoid permanent colostomy and it's devastating psychosocial effects after undergoing this approach. In addition, in certain cancers, neoadjuvant therapy may improve long-term survival. Recent years have seen an increase in the popularity of this treatment technique. The number of clinical trials on this topic published from 2000 to 2003 exceeded the number published during the entire previous decade.[2]
The extensiveness of radical surgery, the main treatment modality for rectal cancer, is an important impetus for neoadjuvant therapy trials. Locally advanced, large, or lower rectal cancer usually necessitates an abdominoperineal resection (APR). APR will result in permanent colostomy and loss of anal function. In addition, after APR, patients whose pathologic findings indicate malignant invasion of rectal subserosa will need adjuvant chemotherapy and radiation to reduce the risk of cancer recurrence. Improved staging techniques, including the use of endoscopic ultrasonography, make it possible to preoperatively identify the patients who will need adjuvant therapy after surgery. In this group of patients who would ultimately need more therapy after surgery, administering adjunctive therapy before surgery appears an attractive option to avoid APR and to improve long-term survival.
Neoadjuvant therapy indeed can help avoid APR in many patients with large or lower rectal tumors. Anal sphincter-sparing surgery such as low-anterior resection is feasible in patients judged preoperatively to require APR-after tumor shrinkage from neoadjuvant therapy. Preoperative radiation or combined chemoradiation may offer an up to 75% chance of sphincter-preserving surgery at 6 to 8 weeks after completion of radiation; however, long-term survival of patients undergoing neoadjuvant therapy remains similar to those receiving surgery followed by adjuvant therapy.
Nevertheless, when compared with surgery alone, neoadjuvant therapy followed by surgery may improve overall survival. In a large prospective trial published in 1997, the Swedish investigators, using a 5-day course of radiation and a 1-week pause followed by surgery, demonstrated an increase in 5-year survival of patients with resectable rectal cancer from 48% to 58%. However, a subsequent study from the Dutch Colorectal Cancer Group, using the same neoadjuvant radiation, did not indicate a survival advantage of neoadjuvant therapy, although cancer recurrence rate significantly decreased. In this study, every patient also received a total mesorectal excision, a technique known to reduce cancer recurrence. In a meta-analysis of randomized, controlled trials on this topic, patients with resectable rectal cancer treated with neoadjuvant radiotherapy had significantly improved overall and cancer-specific survival compared with surgery alone, but the magnitude of the benefit was small.[3]
Surgery, a key treatment for resectable head and neck cancers, frequently results in disfigurement and loss of organ function. Although plastic reconstruction may restore cosmetic appearance, patients with advanced laryngeal or hypopharyngeal cancer will permanently lose their voice after total laryngectomy. Experiences indicate that head and neck tumors respond to chemotherapy and radiation. In fact, many patients who undergo surgery require adjuvant radiation and/or chemotherapy for residual or recurrent disease. The use of chemotherapy and radiation before surgery has been attempted to preserve the larynx and to improve long-term survival.
Laryngeal preservation is possible after neoadjuvant therapy for patients with laryngeal or hypopharyngeal cancer who need total laryngectomy. In the late 1980s, the Veterans Affairs Cooperative Laryngeal Cancer Study Group randomly assigned patients with resectable glottic or supraglottic cancer to two treatment arms. One arm received neoadjuvant chemotherapy followed by radiation. If poor response to chemotherapy occurred, patients would proceed to surgery. The other arm received immediate total laryngectomy. Although there was no overall survival difference between the two arms, 64% of patients in the neoadjuvant arm had a functional larynx at 2 years as compared with none in the other arm. In resectable cancer of the piriform sinus or aryepiglottic fold, the same technique also allowed 35% of patients to have functional larynx at 5 years.[9] Recently, however, the use of concurrent chemoradiation has shown a better result when compared with chemotherapy followed by radiation. Concurrent treatment, though associated with greater toxicities, results in 88% of patients with a functional larynx at 2 years as compared with 74% in those receiving treatment in a sequential fashion.
Survival benefit of neoadjuvant therapy for resectable head and neck cancers, however, remains controversial. Many studies comparing neoadjuvant therapy followed by surgery with surgery alone in various sites of head and neck cancer have shown no improvement in long-term survival. A few trials, particularly in patients with cancer of the oropharynx or oral cavity, reported a modest improvement in survival outcome with neoadjuvant approach.[4]
Neoadjuvant therapy for locally advanced non-small cell lung cancer has evolved rapidly near the turn of the century. Historically, radiation used to be the only treatment for unresectable non-small cell lung cancer. In 1990, Dillman et al introduced the use of neoadjuvant cisplatin-based chemotherapy before radiation with better survival, and other chemotherapy regimens used in this fashion also yielded comparable results. Nevertheless, adding adjuvant chemotherapy after radiation provided no additional benefit. Subsequently, the use of neoadjuvant chemotherapy followed by radiation waned, when concurrent chemoradiation had been found to produce better survival outcome. Today, concurrent chemoradiation is the standard of care for patients with unresectable non-small cell lung cancer who have good performance status.
In certain situations, concurrent chemoradiation has transformed its role from a definitive treatment into a neoadjuvant treatment before radical resection. Concurrent chemoradiation may render some unresectable non-small cell lung cancers resectable. Although no data from randomized, controlled trials are available, it is evident that patients with superior sulcus tumor or pancoast tumor, after undergoing neoadjuvant radiation with or without concurrent chemotherapy, may become eligible for complete resection and achieve prolonged disease-free survival.
For patients with resectable but locally advanced non-small cell lung cancer, outcome of treatment with surgery alone is poor. Several small, randomized studies suggest that neoadjuvant chemotherapy before surgery improves overall survival when compared with surgery alone. One such study, for instance, using 3 cycles of chemotherapy followed by surgery, demonstrated an increase in median survival from 8 months in the surgery-alone arm to 26 months in the neoadjuvant arm. Subsequent larger studies, however, produced conflicting results. Other investigators have experimented with concurrent chemoradiation followed by surgery in comparison with chemoradiation alone. Preliminary data indicate that patients who respond well to chemoradiation may benefit from subsequent surgery, although long-term follow-up is still necessary.
Recently, Arriagada et al have demonstrated a survival benefit of postoperative chemotherapy for resectable non-small cell lung cancer. To date, however, no large, randomized trials between neoadjuvant and adjuvant therapy is available, leaving the role of neoadjuvant therapy in resectable non-small cell lung cancer inconclusive.[5]
The value of neoadjuvant therapy before esophagectomy, which is the definitive treatment for esophageal cancer, remains controversial. Two promising neoadjuvant modalities exist, chemoradiation or chemotherapy alone.
In 1996, Walsh et al published a randomized study of treatment with neoadjuvant chemoradiation followed by surgery or immediate surgery. The study included patients with resectable adenocarcinoma of the middle or distal esophagus. Treatment with neoadjuvant chemoradiation followed by surgery was associated with a significantly longer median survival: 16 months compared with 11 months among patients who underwent immediate surgery. However, a subsequent large study of neoadjuvant chemoradiation for patients with resectable squamous cell carcinoma of the esophagus did not confirm this benefit, showing a median survival of approximately 19 months in both arms. Another study including both the patients with squamous cell carcinoma and patients with adenocarcinoma also demonstrated no survival benefit from neoadjuvant chemoradiation when compared with immediate surgery.
The benefit of neoadjuvant chemotherapy without radiation in esophageal cancer is also debatable. Chemotherapy alone without radiation potentially reduces toxicity, particularly dysphagia. Some investigators have given chemotherapy both before and after esophagectomy. In a 1998 publication, Kelsen et al found no advantage of intensive treatment comprising neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy over surgery alone. A meta-analysis of randomized, controlled trials on this topic also suggested no survival benefit of neoadjuvant chemotherapy. Recently, however, investigators from the Medical Research Council Esophageal Cancer Working Group demonstrated in a large study that preoperative chemotherapy before surgery significantly increased median survival from approximately 13 months in the surgery-alone arm to 17 months in the neoadjuvant arm.
For gastric cancer, preoperative therapy remains investigational. Neoadjuvant chemotherapy typically yields a low response rate, and no large trial to date has demonstrated a clear benefit on patient's survival or resectability rate of the cancer. However, neoadjuvant radiation followed by surgery may improve survival in some patients with cancer of the cardia of the stomach when compared with surgery alone. Currently, surgery followed by adjuvant chemoradiation remains the standard of care in high-risk patients with cancer of the stomach or gastroesophageal junction.This adjuvant approach has been demonstrated in a large phase III, randomized trial to help improve patient's survival when compared with surgery alone.[6]
Neoadjuvant therapy has a therapeutic role for patients with bulky, locally advanced cervical cancer. Preoperative chemotherapy can induce tumor shrinkage and render radical excision possible in a high percentage of cases. In a large, prospective study, Italian investigators randomly assigned patients with locally advanced cervical cancer to receive neoadjuvant chemotherapy followed by surgery or to undergo a standard treatment with definitive radiation. At 5 years, there was a 10% to 15% survival advantage observed among patients who received neoadjuvant therapy and surgery. Patients with tumor a size less than 4 cm, however, did not appear to benefit from this approach, since the tumors were generally amenable to radical resection at presentation.
Another effective treatment for locally advanced cervical cancer is definitive concurrent chemoradiation. Some gynecologists also choose to perform extrafascial or nonradical hysterectomy after chemoradiation. Because chemoradiation contributes the most to the treatment outcome, in this situation, surgery may be considered an adjuvant therapy. Weekly infusions of cisplatin during radiation, followed by hysterectomy, reduce the risk of disease recurrence and death in women with bulky, locally advanced cervical cancers when compared with radiation alone followed by hysterectomy.[7]
Finally, concomitant or concurrent systemic 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 reoccurrence. In breast cancer, adjuvant therapy may consist of chemotherapy (doxorubicin, herceptin, paclitaxel, docetaxel, cyclophosphamide, 5-fu, and methotrexate) and radiotherapy, especially after lumpectomy, and hormonal therapy (tamoxifen, femra). 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, reoccurrence occurs in 1–3 months. Adjuvant therapy does not improve prognsis in stage I, II, and III renal cell carcinoma, with the possible exception of radiotherapy, which lowered the risk of local reoccurrence 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 chemotheraputic agents, and adjuvant radiotherapy is administered to either the lung (to prevent a local reoccurrence) 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)[8] However, it has been found a single dose of carboplatin is as effective as EBRT] in stage 11 testicular cancer, with only mild side effects (transeint myelosuppressive action vs severe and prolonged myelosuppresive neutropenic illness in normal chemotherapy, and much less vomiting, diarrhea, mucositis, and no alopecia in 90% of cases,according to cancerconsultants.com)Adjuvant therapy is particularly 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,and just 10% if no adjuvant chemotherapy or craniospinal irradiation is used.prophylatic cranial irradation for ALL is technically adjuvant, and most experts agree that cranial irradation decreases risk of CNS relapse in ALL and possibly AML,but it can cause severe side effects,and adjuvant intrathecal methotrexate and hydrocortisone may be just as effective as cranial irraditon,without severe late effects,such as developmental disability,dementia,and increased risk for second malignancy.
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, myelosuppresion particularly neutropenia,sometimes resaulting in septicaemia.some chemotheraputic agents can cause acute myeloid leukaemia, in particular the alkylating agents. Rarely, this risk may outweigh the risk of reoccurrence of the primary tumor. Depending on the agent(s)used, side effects such as neuropathy,leukoencephalopathy, bladder damage, constipation or diarrhea, hemorrhage, or neurocognitive changes, often colloquially called chemobrain. 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 causes memory loss, headache, alopecia, and radiation necrosis of the brain. If the abdomen or spine is irradiated, nausea, vomiting, diarrhea, and dysphasgia can occur. If the pelvis is irradiated, prostitis, procitis, dysuria, metritis, diarrhea, and abdominal pain can occur. Adjuvant hormonal therapy for prostate cancer may cause cardiovascular disease, and other, possibly severe, side effects.
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 reoccurrence.since then,however,some doctors have argued that interferon treatment does not prolong survival or decrease the rate of relapse,but only causes harmfull 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, contrary to some peoples thoughts, a chemotherapy resistant malignancy. Dacarbizine, 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 reoccurence 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 statisticaly significant survival benefit.
adjuvant chemotherapy is effective in preventing the metastatic spread of localy advanced colorectal cancer. fluorouracil is one effective agent.
it has been known for at least 30 years the adjuvant chemotherapy decreases the risk of metastatic recurrence of breast cancer in woman with localized node-positive breast carcinoma.agents used include:
giving 2 or more chemotheraputic agents at once may decrease the chances of reoccurence of the cancer,and increase overall survival in patients with breast cancer.commonly used combination chemotherapy regimines used include:
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