The following represent additions to UpToDate since the last version of What’s New that were considered by the authors and editors to be of particular interest.
BREAST CANCER
Adjuvant trastuzumab for HER2-positive early breast cancer — Human epidermal growth factor receptor 2 (HER2) overexpression identifies patients with breast cancer who may benefit from treatments targeting HER2. A meta-analysis confirmed that the adjuvant use of trastuzumab-containing regimens for HER2-positive early breast cancer was associated with a significant benefit in disease-free and overall survival [1]. However, it also demonstrated a fivefold increased risk of heart failure and a twofold increased risk of left ventricular ejection fraction decline relative to non-trastuzumab-containing chemotherapy. For patients receiving adjuvant trastuzumab for HER2-positive breast cancer, we continue to recommend serial monitoring of cardiac function and left ventricular ejection fraction. (See "Adjuvant medical therapy for HER2-positive early stage breast cancer", section on 'Monitoring during treatment' and "Cardiotoxicity of trastuzumab", section on 'Cardiac monitoring'.)
Radiation therapy after breast conserving surgery — Radiation therapy (RT) is a standard component of the treatment of women who undergo breast conserving surgery (BCS) for breast cancer. The latest meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group confirmed long-lasting benefits of adjuvant RT after BCS [2]. Compared to BCS alone, the addition of RT after BCS was associated with reductions in the 10-year risk of recurrence and in the 15-year risk of breast cancer death. The benefits were consistently seen in both women with node-positive and node-negative breast cancer at diagnosis. (See "Role of radiation therapy in breast conservation therapy", section on 'Benefits'.)
Bevacizumab approval in metastatic breast cancer revoked — An initial trial suggested that the addition of bevacizumab to weekly paclitaxel for the initial treatment of metastatic breast cancer improved progression-free survival. However, subsequent studies have not confirmed this benefit. As a result, the US Food and Drug Administration revoked the approval of bevacizumab as a first-line treatment with paclitaxel for metastatic breast cancer in November 2011 [3]. While the combination of weekly paclitaxel and bevacizumab is still a reasonable option for women with metastatic breast cancer as suggested by the National Comprehensive Cancer Network, we prefer not to include bevacizumab in the treatment of women with metastatic breast cancer given the inability to select patients most likely to benefit it use, its toxicity risks, and the lack of overall survival seen when it is combined with chemotherapy. (See "Systemic treatment for metastatic breast cancer: Biologic therapy", section on 'Bevacizumab'.)
Dual HER2-directed antibody therapy for metastatic breast cancer — HER2 is an important prognostic and predictive factor in breast cancer and the use of the HER2 monoclonal antibody is part of the standard treatment for women with HER2-positive breast cancer. Like trastuzumab, pertuzumab also binds the HER2 receptor but at a different subdomain. A phase III trial enrolled women with untreated HER2-positive metastatic breast cancer and assigned them to therapy with standard treatment (trastuzumab plus docetaxel) with randomization to include pertuzumab or placebo [4]. Compared to placebo, combining standard treatment with pertuzumab improved the overall response rate and progression-free survival, with a trend towards improved overall survival. While pertuzumab is not approved for use in the United States, this data supports its use as a first-line treatment for women with HER2-positive breast cancer. (See "Systemic treatment for metastatic breast cancer: Biologic therapy", section on 'Pertuzumab'.)
Bisphosphonates and breast cancer outcomes — While bisphosphonates are recommended for women with osteoporosis or cancer treatment-induced bone loss to prevent skeletal related events, the use of bisphosphonates to prevent breast cancer recurrence continues to be the subject of clinical research. Three studies presented at the 2011 San Antonio Breast Cancer Symposium suggest that any benefit on breast cancer specific outcomes may be limited to newly diagnosed breast cancer patients who are either perimenopausal or postmenopausal [5-7]. We continue to reserve bisphosphonates for women with breast cancer who have other indications for their use. (See "Overview of the use of osteoclast inhibitors in early breast cancer", section on 'Prevention of breast cancer recurrence'.)
GASTROINTESTINAL CANCER
Oxaliplatin for elderly patients with resected node-positive colon cancer — Randomized trials have established the superiority of oxaliplatin-containing versus fluoropyrimidine alone chemotherapy regimens for adjuvant treatment of resected node-positive colon cancer, but few elderly patients were enrolled and the efficacy of oxaliplatin in this group has been questioned. A benefit of oxaliplatin in older patients is supported by an analysis of five observational community-based cohorts (the largest of which is the linked SEER-Medicare database) of patients treated for stage III colon cancer between 2004 and 2009 [8]. The benefits of oxaliplatin extended to a diverse group of patients, including the elderly and those with a Carlson Comorbidity Index of 2. These data support the view that oxaliplatin-based chemotherapy is an appropriate option for elderly patients with resected node-positive colon cancer who are sufficiently robust to tolerate the drug and who have an estimated life expectancy of at least five years. (See "Adjuvant therapy for resected colon cancer in elderly patients", section on 'Oxaliplatin-based regimens'.)
Adjuvant imatinib for resected GIST — The placebo-controlled ACOSOG Z9001 trial established treatment with at least 12 months of adjuvant imatinib as a standard approach for resected high-risk gastrointestinal stromal tumor (GIST) [9]. The benefit of longer duration therapy was addressed in the Scandinavian Sarcoma Group (SSG) XVIII trial, which compared 36 versus 12 months of imatinib in 400 patients with high-risk resected GIST [10]. As previously reported at the 2011 meeting of the American Society of Clinical Oncology, at a median follow-up of 54 months, prolonged treatment was associated with a significant 54 percent improvement in relapse-free survival and a significant 55 percent improvement in overall survival. Most adverse effects were mild.
These data establish at least 36 months of adjuvant imatinib as a new standard for patients with high-risk resected GIST, but questions remain as to whether patients with high-risk tumors should continue treatment for even longer. (See "Adjuvant and neoadjuvant imatinib for gastrointestinal stromal tumors", section on 'SSG XVIII trial'.)
Aspirin for chemoprevention in patients with Lynch syndrome — Individuals with Lynch syndrome have an 80 percent risk of developing colorectal cancer in their lifetime. While an earlier placebo-controlled trial (CAPP2) did not find a benefit for aspirin for adenoma or colon cancer prevention in patients with Lynch syndrome after a mean of 29 months of follow-up, a subsequent analysis found a marginally significant reduction in colorectal cancer incidence in the subset of patients treated with 600 mg aspirin per day for more than two years [11]. A secondary analysis found a decreased rate of overall Lynch cancers in the aspirin-treated group. Further studies are needed to validate this potentially important result and determine if the benefits associated with aspirin outweigh the risks. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and management of patients and families", section on 'Chemoprevention' and "NSAIDs (including aspirin): Role in prevention of colorectal cancer", section on 'Aspirin trials'.)
Risk of esophageal cancer with Barrett's esophagus — A 2010 meta-analysis estimated the incidence of esophageal adenocarcinoma in patients with Barrett’s esophagus to be 6.3 cases per 1000 person-years [12]. However, a subsequent large study using the Danish Cancer Registry reported a rate of 1.2 cases per 1000 person-years [13]. This more recent study suggests that the risk of esophageal adenocarcinoma in patients with Barrett's esophagus may be lower than previously suggested. (See "Management of Barrett's esophagus", section on 'Influence of Barrett's esophagus on mortality' and "Vitamin D and extraskeletal health", section on 'Cancer'.)
Vitamin D and colon cancer — The relationship between vitamin D deficiency and risk of cancer is controversial. In a meta-analysis of nine case-control studies, there was a link between poor vitamin D status and risk of colon cancer [14]. For each 4 ng/mL (10 nmol/L) increase in pre-diagnosis serum 25OHD concentration, there was a 6 percent reduction in colorectal cancer. (See "Vitamin D and extraskeletal health", section on 'Cancer'.)
Human papillomavirus vaccine for prevention of anal intraepithelial neoplasia — A quadrivalent vaccine has been shown to be effective in preventing infection with human papillomavirus vaccine (HPV) types 6, 11, 16, and 18 and to prevent the development of external genital lesions [15]. A planned substudy of that trial analyzed the impact of the vaccine on the development of anal intraepithelial neoplasia in 602 men who have sex with men [16]. Study subjects were aged 16 to 26 years, had no history or evidence of anal lesions, had five or fewer lifetime sexual partners, and were HIV negative. Administration of the HPV vaccine was associated with a significant decrease in the incidence of anal intraepithelial neoplasia. (See "Anal intraepithelial neoplasia: Diagnosis, screening, prevention, and treatment", section on 'Prevention'.)
GENERAL ONCOLOGIC ISSUES
Erwinia asparaginase approved in the United States — For patients who develop an anaphylactic reaction to pegylated asparaginase (pegaspargase), which is derived from Escherichia coli (E coli), continued therapy is possible in over 80 percent by switching to the Erwinia formulation. Cross reactivity is uncommon with the E coli and Erwinia derivatives of asparaginase, because the two are antigenically distinct. Erwinia asparaginase was approved in the United States in November 2011. (See "Infusion reactions to systemic chemotherapy", section on 'L-asparaginase'.)
Glucarpidase approved in the United States — High-dose methotrexate is used for central nervous system (CNS) prophylaxis in patients with leukemia and high-risk lymphoma, and for the treatment of leptomeningeal metastases, primary CNS lymphoma, and osteosarcoma. These otherwise lethal doses of methotrexate are followed by a two to three day period of leucovorin administration to terminate the toxic effects. Successful “rescue” by leucovorin depends on rapid elimination of methotrexate by the kidneys. Glucarpidase (recombinant carboxypeptidase G) is an enzyme that metabolizes antifolates such as methotrexate to inactive metabolites. In January 2012, the US Food and Drug Administration (FDA) approved glucarpidase injection (Voraxaze®) for the treatment of toxic plasma methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function. Continuation of leucovorin after glucarpidase administration is essential. (See "Therapeutic use of high-dose methotrexate", section on 'Glucarpidase (carboxypeptidase G2)'.)
Proton pump inhibitors in patients receiving high-dose methotrexate — The FDA has issued a warning about use of proton pump inhibitors (PPIs) in patients receiving methotrexate, particularly high-dose methotrexate [17]. Case reports and published population pharmacokinetic studies suggest that concomitant use of PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. (See "Therapeutic use of high-dose methotrexate", section on 'Use of proton pump inhibitors'.)
Brentuximab and progressive multifocal leukoencephalopathy — Brentuximab vedotin was granted accelerated approval by the FDA earlier this year for treatment of patients with relapsed refractory Hodgkin lymphoma or relapsed systemic anaplastic large cell lymphoma. Rare reports of progressive multifocal leukoencephalopathy (PML) prompted the FDA to add a black box warning to the drug label regarding this complication in January 2012 [18]. PML typically presents with subacute neurologic deficits which may include altered mental status, visual symptoms, weakness, ataxia and seizures. (See "Neurologic complications of cancer treatment with biologic agents", section on 'Brentuximab'.)
Panitumumab and pulmonary toxicity — Initial reports suggested that pulmonary toxicity was rare with panitumumab; only 2 of 1467 patients enrolled in clinical trials (<1 percent) developed pulmonary fibrosis [19]. However, an increased number of cases of fatal interstitial lung disease and pulmonary fibrosis have been reported during postmarketing surveillance, prompting the FDA to issue a warning in December 2011. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Agents targeting the EGFR'.)
Single dose rasburicase for prevention of tumor lysis syndrome — Rasburicase, recombinant urate oxidase, is an effective agent for lowering serum uric acid levels in patients receiving chemotherapy for leukemia, lymphoma, and some high-risk solid tumors who are at high risk for tumor lysis; the FDA approved dosing schedule is once daily for up to five days. A randomized trial of single dose versus five daily doses in patients at high to intermediate risk of tumor lysis syndrome demonstrated that single dose therapy was effective in most patients with only a small subset requiring a second dose [20]. Single dose rasburicase therapy with close monitoring of serum uric acid levels and additional doses if needed is a reasonable option for high-risk patients. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Dosing and administration'.)
Antineoplastic agents and thyroid dysfunction — Newer antineoplastic agents, such as targeted therapies and immunotherapies, are associated with thyroid dysfunction. Oral tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib) used for the treatment of gastrointestinal stromal tumors, renal cell carcinoma, hepatocellular cancer, chronic myeloid leukemia, and in other cancers can cause hypothyroidism in patients with previously normal function and increase thyroid hormone requirements in patients with preexisting hypothyroidism [21]. Hypophysitis and panhypopituitarism, including central hypothyroidism, may also occur as a complication of ipilimumab (anti-CTLA-4) immunotherapy used for the treatment of metastatic melanoma. Hyperthyroidism may occur after treatment with denileukin diftitox, ipilimumab, and alemtuzumab. Possible mechanisms include changes in thyroid hormone clearance, impaired iodine uptake, or destructive thyroiditis. (See "Drug interactions with thyroid hormones", section on 'Drugs that cause hypothyroidism' and "Drug interactions with thyroid hormones", section on 'Drugs that cause hyperthyroidism'.)
GENITOURINARY ONCOLOGY
Axitinib for renal cell cancer — Patients with advanced renal cell cancer (RCC) have a poor long term prognosis. However, a better understanding of the molecular pathogenesis of clear cell renal cell cancer has lead to the approval of several targeted agents to treat this disease. Axitinib is an orally available potent inhibitor of the VEGF receptors 1, 2, and 3. A phase III trial of axitinib versus sorafenib in patients who had progressed on first-line treatment demonstrated improved outcomes associated with axitinib [22]. In January 2012, axitinib was approved by the US Food and Drug Administration for the treatment of advanced RCC after one systemic therapy. We recommend axitinib over other molecularly targeted agents in patients who have progressed after one prior therapy for advanced RCC. (See "Molecularly targeted therapy for advanced renal cell carcinoma", section on 'Axitinib'.)
GYNECOLOGIC ONCOLOGY
BRCA mutations and ovarian cancer prognosis — A meta-analysis of 26 observational studies found that BRCA gene mutation carriers with ovarian cancer, particularly BRCA2 mutation carriers, have a significantly better prognosis than noncarriers [23]. The five-year all-cause mortality rate for noncarriers was 47 percent compared with 45 percent for BRCA1 mutation carriers and 36 percent for BRCA2 mutation carriers.
HPV testing and cervical cancer screening — A 2011 systematic review of HPV screening, prepared for the US Preventive Services Task Force (USPSTF), concluded that although primary HPV screening for women over age 30 detected more cases of CIN3 or cancer than cytology, evidence to date is too limited to determine the net benefit of HPV testing strategies [24]. The review did not find evidence that the combination of cytology plus HPV testing was more effective than primary HPV screening alone. The authors concluded that primary HPV testing was “very promising” as a screening strategy, but that data from ongoing randomized trials are needed to determine the balance of benefits and harms from an HPV testing strategy, including the potential for overdiagnosis and excess colposcopy. Revised cervical cancer screening guidelines are in draft form [25]. (See "Screening for cervical cancer: Rationale and recommendations", section on 'HPV testing'.)
Discontinuing cervical cancer screening — Another review prepared for the US Preventive Services Task Force, focusing on risk factors for cervical cancer, noted a decline in the incidence of cervical cancer and that evidence supports discontinuing cervical cancer screening in women aged 65 and older who have had adequate screening and are not at high risk [26]. (See "Screening for cervical cancer: Rationale and recommendations", section on 'Stopping age'.)
Self-collected HPV testing for cervical cancer screening in resource-limited settings — Self-collected human papilloma virus (HPV) testing was compared with clinic-based cervical cytology in a randomized trial of over 12,000 women in Mexico [27]. Acceptability of self-collected HPV testing was high; nearly all women in this group performed the testing. Sensitivity of HPV testing was 2.9-fold higher for detection of a high-grade cervical intraepithelial lesion (CIN) or more severe disease and 3.6-fold higher for detection of invasive cervical cancer. The disadvantage of HPV testing was that many more women underwent unnecessary colposcopy. For a diagnosis of high-grade CIN or more severe disease, the positive predictive value of HPV testing was 12.2 percent compared with 90.5 percent for cytology. (See "Screening for cervical cancer in resource-limited settings", section on 'Self-collected samples'.)
Ultrasound for ovarian cancer screening — A large prospective study with follow-up to 20 years evaluated annual transvaginal ultrasonography for the detection of ovarian cancer in over 37,000 asymptomatic women (aged 50 and older or aged 25 and older with a documented family history of ovarian cancer) [28]. The specificity and positive predictive value for primary invasive epithelial ovarian cancer were 98.5 and 8.9 percent, respectively; 11.1 operations were performed per primary ovarian cancer detected. Seventy percent of the 47 screen-detected invasive cancers were stage I or II. The five-year survival rate for women with screen-detected invasive ovarian cancer was higher than for ovarian cancers in unscreened women at the same institution; whether this difference reflects a true mortality difference or biases related to nonrandomized studies (lead time, length time, and healthy volunteer effects) cannot be determined. Additionally, these results reflect findings from a center with high expertise in ultrasound and are not likely to be reproducible in the general community. UpToDate does not recommend screening average risk women for ovarian cancer. (See "Screening for ovarian cancer", section on 'Pelvic ultrasonography'.)
Bevacizumab plus chemotherapy for newly diagnosed epithelial ovarian cancer — Most women with newly diagnosed epithelial ovarian cancer (EOC) are treated with surgery followed by platinum- and taxane-based chemotherapy. Despite this, the majority will relapse within three years. The Gynecologic Oncology Group trial 218 (GOG 218) and the Gynecologic InterGroup trial (ICON7) randomly assigned women with newly diagnosed EOC to treatment using standard chemotherapy with or without the angiogenesis inhibitor bevacizumab [29,30]. Both studies showed that incorporation of bevacizumab significantly improved progression free survival, but did not impact overall survival. Despite this improvement in progression free survival, we continue to suggest not adding bevacizumab routinely until there is longer follow-up on quality of life and overall survival outcomes. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, or peritoneal cancer", section on 'Incorporation of angiogenesis inhibitors'.)
HEAD AND NECK CANCER
Oropharyngeal cancer and HPV infection — Despite the decrease in tobacco use, the incidence of oropharyngeal cancer has been increasing due to human papillomavirus (HPV) related cancers arising in the base of the tongue and the tonsillar region. A cross-sectional study of men and women aged 14 to 69 years found that the overall prevalence of HPV DNA in oral exfoliated cells was 6.9 percent, and the prevalence of HPV16 was 1.0 percent [31]. HPV prevalence was approximately three-fold more common in men compared with women (10.1 versus 3.6 percent), consistent with the observed sex distribution for HPV associated oropharyngeal cancer. (See "Human papillomavirus associated head and neck cancer", section on 'Epidemiology'.)
Cetuximab approval for first-line therapy of head and neck cancer — Cetuximab was approved by the US Food and Drug Administration for first-line treatment of patients with metastatic or recurrent head and neck cancer in combination with platinum-based therapy plus 5-fluorouracil [32]. Approval was based upon results of a phase III trial, which demonstrated a significantly improved overall survival compared with chemotherapy alone [33]. (See "Treatment of metastatic and recurrent head and neck cancer", section on 'Anti-EGFR monoclonal antibodies plus platinum-based chemotherapy'.)
IMMUNOCOMPROMISED HOST
Malignancy following solid organ transplantation — An increased risk of a wide range of cancers is associated with solid organ transplantation, with specific cancer risk varying with the organ transplanted. A cohort study analyzed the frequency of malignancy in over 175,000 solid organ transplant recipients [34]. The standardized incidence ratio for developing cancer was 2.1 compared with the general population, with an excess absolute risk of 719 cases per 100,000 person-years. The biggest relative increases were seen for Kaposi sarcoma, nonmelanoma skin cancer, non-Hodgkin lymphoma, and cancers of the liver, anus, vulva, and lip. Lung cancer, kidney cancer, colorectal cancer, pancreatic cancer, Hodgkin lymphoma, and melanoma also contributed significantly to the excess risk. (See "Development of malignancy following solid organ transplantation", section on 'General epidemiology'.)
MELANOMA AND OTHER SKIN CANCER
Long-term response to ipilimumab in advanced melanoma — Only a minority of patients with advanced melanoma achieve a complete response to treatment with ipilimumab. However, such responses appear to be durable and of prolonged duration in most cases. In a series from the National Institutes of Health, about 9 percent of 177 patients treated between 2002 and 2005 experienced a complete response of which all but one have lasted between 54 and 99 months [35]. (See "Anti-CTLA-4 immunotherapy in advanced melanoma", section on 'Long-term duration of response'.)
Vismodegib for basal cell carcinoma — Vismodegib, an inhibitor of the sonic hedgehog pathway, was approved by the US Food and Drug Administration for the treatment of metastatic and locally advanced basal cell carcinoma that is not amenable to treatment with surgery or radiation therapy. The approval was based upon clinically significant activity in a single arm phase II study of 104 patients [36]. (See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas", section on 'Vismodegib'.)
NEUROONCOLOGY
Diagnosis-specific prognostic assessment for brain metastases — Survival results following treatment for brain metastases are highly heterogeneous and depend in part upon the primary tumor site. Multivariate analysis of almost 4000 patients led to the development of separate prognostic criteria for patients with lung cancer (both non-small cell and small cell), melanoma, renal cell carcinoma, breast cancer, and gastrointestinal cancer. Factors that were variably incorporated into these criteria include age, Karnofsky performance score, the presence or absence of extracranial metastases, number of brain metastases, and cancer subtype for those with breast cancer (table 1). (See "Overview of the clinical manifestations, diagnosis, and management of patients with brain metastases", section on 'Diagnosis-specific graded prognostic assessment'.)
PROSTATE CANCER
Androgen deprivation therapy and cardiovascular disease — No randomized trials have prospectively addressed the risks of cardiovascular disease associated with androgen deprivation therapy (ADT), although retrospective studies have suggested that risks may be increased. A meta-analysis of over 4000 patients who were enrolled in eight multicenter randomized phase III trials found that the incidence of cardiovascular death was not significantly different in those assigned to ADT compared with placebo [37]. (See "Managing the side effects of androgen deprivation therapy", section on 'Cardiovascular disease and diabetes'.)
SARCOMA
Pazopanib for advanced soft tissue sarcoma — In April 2012, pazopanib was approved by the US Food and Drug Administration for treatment of advanced soft tissue sarcoma in patients who have received prior anthracycline-containing chemotherapy. Approval was based upon a preliminary report of the placebo-controlled phase III PALETTE trial, which demonstrated significantly improved progression-free survival with pazopanib [38]. Benefit was consistent across all histologic subtypes, although patients with liposarcoma or gastrointestinal stromal tumor (GIST) were excluded from the trial. For patients with advanced or metastatic soft tissue sarcoma (other than liposarcoma or GIST) who progress after an anthracycline-containing regimen, we recommend pazopanib. (See "Systemic treatment of metastatic soft tissue sarcoma", section on 'Antiangiogenic therapy'.)
All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.
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