Liposomal anthracyclines: adjuvant and neoadjuvant therapy for breast cancer

Conventional anthracyclines, particularly doxorubicin, have played an important role in the treatment of patients with breast cancer for many decades. Conventional doxorubicin has shown excellent antitumor activity in the metastatic, neoadjuvant, and adjuvant settings. However, its clinical utility is limited due to acute and chronic toxicities, particularly cardiotoxicity, myelosuppression, nausea and vomiting, and alopecia. Liposomal doxorubicin formulations (liposomal doxorubicin [D-99] and pegylated liposomal doxorubicin) currently under investigation for the treatment of breast cancer have demonstrated similar efficacies and favorable toxicity profiles compared with conventional doxorubicin in patients with metastatic breast cancer. These agents have also shown efficacy and tolerability in several small studies as neoadjuvant therapy in patients with locally advanced breast cancer. While there are currently no studies with liposomal doxorubicin or pegylated liposomal doxorubicin as adjuvant therapy, their demonstrated activities and tolerabilities in the metastatic and neoadjuvant settings provide the rationale for the future study of these agents in adjuvant therapy for patients with early-stage breast cancer.     

Emerging modalities for adjuvant therapy of breast cancer: neoadjuvant chemotherapy

There is evidence from theoretical models and experimental studies that indicates that preoperative timing of chemotherapy (neoadjuvant treatment) may be a superior treatment strategy than its use postoperatively. We have shown in our pilot study of 43 premenopausal patients with newly diagnosed cancer of the breast that administration of one cycle of CMF chemotherapy preoperatively was safe. Subsequently, a randomized study of preoperative against postoperative adjuvant chemotherapy has been started and to the present time, 98 patients have been randomized. Preliminary assessment of the randomized study confirmed the safety of the adjuvant chemotherapy with one course of cyclophosphamide, methotrexate, and 5-fluorouracil given preoperatively and also showed that the interval between diagnosis and the first course of chemotherapy can be substantially reduced. In addition to the preoperative timing, other aspects of the neoadjuvant approach are discussed. They include a more frequent utilization of fine needle aspiration so that the tissue diagnosis of breast cancer can be obtained and also refinement of diagnostic techniques, used before the preoperative treatment for the selection of high-risk patients (the neoadjuvant staging). The purpose of our presentation is not to recommend presently preoperative chemotherapy routinely but rather to indicate a need for well-controlled studies testing its appealing theoretical rationale. Its use in adjuvant therapy of breast cancer represents a major departure from the conventional management and, therefore, if the cooperation of practitioners and cooperative groups is to be secured, its rationale and safety must be well-defined.     

赫赛汀在乳腺癌新辅助治疗与辅助治疗中的新进展

人源化单克隆抗体赫赛汀（herceptin）是第一个针对HER-2阳性乳腺癌的、以癌基因为靶的治疗药物。多项研究已证明,赫赛汀对治疗转移性乳腺癌有明显效果,单药治疗总有效率在25％左右。据Slamon等的Ⅲ期临床试验报道,将469例HER-2过度表达的女性转移性乳腺癌患者随机分为单用化疗组与化疗＋赫赛汀组,结果赫赛汀提高了肿瘤缓解率,延长了疾病进展时间（TTP））、中位缓解持续时间和整体生存时间。一组Ⅱ期随机对照研究（M77001）证明了赫赛汀联合泰索帝在一线治疗HER-2阳性转移性乳腺癌的地位。     

Radiation therapy as adjuvant treatment after radical prostatectomy

Between 1977 and 1984, adjuvant radiation therapy was administered after radical prostatectomy to 71 patients at high risk for recurrence of carcinoma of the prostate. In 35 patients, tumor remained at the surgical margin (stage C2 disease) and/or the disease had invaded the seminal vesicles (stage C3). Thirty-six patients had microscopic metastases in the pelvic lymph nodes (stage D1a). Radiation therapy was administered only after full recovery from surgery, which included full recovery of continence. The average period between surgery and initiation of radiation therapy was 3 months. Serious or long-term complications attributable to irradiation occurred in 7% of the patients. Tumor recurred locally in only 2 patients. Five-year actuarial survival, disease-related survival, and disease-free survival for patients with stage C2 and C3 disease were 86%, 96%, and 80%, respectively. These survival values for patients with stage D1a disease were 74%, 90%, and 69%, respectively. Our results suggest a greater therapeutic benefit from radical prostatectomy and adjuvant radiation therapy than from radical prostatectomy alone for stages C2 and C3 disease or from radical prostatectomy alone or radiation therapy alone for stage D1a disease; however, the length of follow-up, number of patients treated, and problems in comparing our results with those from historical controls do not allow us to draw firm conclusions about the benefits of this combined therapy. Controlled, randomized studies clearly are required. The serum levels of prostate-specific antigen, but not prostatic acid phosphatase, were invariably elevated in patients at the time of clinical detection of disease recurrence and predicted recurrence up to 4 years before the event.(ABSTRACT TRUNCATED AT 250 WORDS)     

Importance of node dissection in relation to neoadjuvant and adjuvant therapy

Since the advent of effective chemotherapeutic regimens for treating transitional cell carcinoma, multimodal therapy has become part of the contemporary management of patients with muscle-invasive bladder cancer. However, radical cystectomy with pelvic lymphadenectomy remains the cornerstone of treatment for patients with localized and regionally advanced muscle-invasive disease. The effectiveness of chemotherapy models in bladder cancer can depend greatly on the quality of surgery. Unfortunately, without sufficient level I data, the boundaries of lymphadenectomy and the diagnostic and therapeutic ramifications of variations in the pelvic lymph node dissection remain undetermined. This article examines the role of pelvic lymph node dissection during perioperative chemotherapy and discusses the current challenges in establishing standards for lymphadenectomy in patients undergoing treatment for muscle-invasive bladder cancer.     

When to consider adjuvant/neoadjuvant therapy for adult soft-tissue sarcoma

In patients with adult soft-tissue sarcoma (ASTS), the use and timing of adjuvant chemotherapy or chemoradiotherapy remains controversial. The appropriate target population is generally accepted as International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) stage III extremity or trunk sarcomas (i.e., >5 cm, grade 3/4, located deep to the superficial fascia, with no evidence of metastases). After definitive local treatment, the 5-year disease-free and overall survival rates in this population are approximately 52% and 56%.     

Neoadjuvant or adjuvant therapy for gastric cancer

Currently, there is no international consensus on the best treatment regimen for patients with advanced resectable gastric carcinoma. In the United States, where a limited lymph-node dissection is frequently performed, adjuvant chemoradiotherapy after surgery is the standard treatment. In Europe, intensified perioperative chemotherapy is commonly administered. In Japan and South Korea, postoperative S-1-based adjuvant chemotherapy after surgery with D2 lymph-node dissection is the standard treatment. Several ongoing trials are currently evaluating the optimal sequence of chemotherapy, radiotherapy, and surgery, as well as the place of targeted therapeutic agents in the treatment of advanced gastric carcinoma.     

Radiation therapy (RT) after prostatectomy: The case for salvage therapy as opposed to adjuvant therapy

Patients with pathologic stage T3 or T4 prostate cancer who have undetectable PSA levels following radical retropubic prostatectomy (RRP) have a substantial risk of recurrence. Radiotherapy (RT) can be administered immediately following the RRP (immediate adjuvant RT) or may be postponed until the PSA level has risen to a level that is indicative of residual or recurrent prostate cancer (salvage RT). Immediate adjuvant RT can significantly reduce the risk of relapse, but does not appear to increase the rate of survival. Approximately two-thirds of patients with rising PSA levels after RRP can be salvaged with RT alone. This result was achieved in patients treated with an adequate dose of radiation before the PSA rose to > 1.1 ng/ml. While no one can be certain which approach (adjuvant or salvage RT) is better, future studies should examine this issue. Whether immediate postoperative adjuvant RT is of value to patients is the subject of two randomized prospective studies. The benefit of adjuvant RT is a matter of controversy. Salvage RT treats only those patients with proven residual prostate cancer. The salvage RT approach has several advantages. This approach spares approximately 40% of patients who have had an RRP for T3 or T4 prostate cancer and eliminates the risks and costs associated with adjuvant RT. Additionally, it appears that the results of immediate adjuvant RT are similar to those achieved with early salvage RT.     

Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer

Mature outcomes from adjuvant endocrine therapy trials in estrogen receptor-positive breast cancer have enabled comparisons with neoadjuvant clinical trials that have parallel randomizations of treatment in terms of the response of disseminated disease versus the local response within the breast. Imprecise end points, such as 'clinical response', have produced inconsistent results regarding the relationship between neoadjuvant and adjuvant endocrine therapy outcomes. However, the proliferation marker Ki-67, measured during neoadjuvant treatment, has predicted accurately and consistently the results of much larger studies in the adjuvant setting. In this Review, we summarize these trials and discuss the implications for the design of future adjuvant endocrine therapy trials. We conclude that there is sufficient evidence supporting the view that the degree of Ki-67 suppression is a reliable short-term surrogate for the adjuvant potential of endocrine drugs, at least in postmenopausal women. We propose that adjuvant endocrine therapy trials should only be conducted once adequately-powered neoadjuvant studies have indicated superior Ki-67 suppression in patients receiving experimental endocrine treatment versus the standard treatment.     

Survival benefit of adjuvant chemotherapy following neoadjuvant therapy and oesophagectomy in oesophageal adenocarcinoma

BackgroundThe evidence assessing the additional benefits of adjuvant chemotherapy (AC) following neoadjuvant therapy (NAT; i.e. chemotherapy or chemoradiotherapy) and oesophagectomy for oesophageal adenocarcinoma (EAC) are limited. This study aimed to determine whether AC improves long-term survival in patients receiving NAT and oesophagectomy.MethodsPatients receiving oesophagectomy for EAC following NAT from 2004 to 2016 were identified from the National Cancer Data Base (NCDB). To account for immortality bias, patients with survival ≤3 months were excluded to account for immortality bias. Propensity score matching (PSM) and Cox regression was performed to account for selection bias and analyze impact of AC on overall survival.ResultsOverall, 12,972 (91%) did not receive AC and 1,255 (9%) received AC. After PSM there were 2,485 who did not receive AC and 1,254 who did. After matching, AC was associated with improved survival (median: 38.5 vs 32.3 months, p < 0.001), which remained after multivariable adjustment (HR: 0.78, CI_95%: 0.71–0.87). On multivariable interaction analyses, this benefit persisted in subgroup analysis for nodal status: N0 (HR: 0.85, CI_95%: 0.69–0.96), N1 (HR: 0.66, CI_95%: 0.56–0.78), N2/3 (HR: 0.80, CI_95%: 0.66–0.97) and margin status: R0 (HR: 0.77, CI_95%: 0.69–0.86), R1 (HR: 0.60, CI_95%: 0.43–0.85). Further, patients with stable disease following NAT (HR: 0.60, CI_95%: 0.59–0.80) or downstaged (HR: 0.80, CI_95%: 0.68–0.95) disease had significant survival benefit after AC, but not patients with upstaged disease.ConclusionAC following NAT and oesophagectomy is associated with improved survival, even in node-negative and margin-negative disease. NAT response may be crucial in identifying patients who will benefit maximally from AC, and thus future research should be focused on identifying molecular phenotype of tumours that respond to chemotherapy to improve outcomes.     

Effect of adjuvant trastuzumab among patients treated with anti-HER2-based neoadjuvant therapy

Purpose:

To study the impact of adjuvant trastuzumab among patients achieving a pathologic complete response (pCR) after trastuzumab-based neoadjuvant systemic therapy (NST).

Patients and methods:

Patients with primary HER2-positive breast cancer treated with trastuzumab-based NST were categorised according to adjuvant trastuzumab administration and pCR status. Adjuvant trastuzumab became standard of care in 2006, this was the main reason patients in our cohort did not receive adjuvant trastuzumab. Kaplan–Meier was used to estimate survival. A test for interaction between adjuvant trastuzumab and pCR was completed.

Findings:

Of 589 patients, 203 (34.5%) achieved a pCR. After surgery, 109 (18.5%) patients in the entire cohort did not receive adjuvant trastuzumab. Among patients achieving a pCR, 31.3% received adjuvant trastuzumab compared with 68.8% among those who did not achieve a pCR (P=0.0006). Among patients achieving pCR, adjuvant trastuzumab did not further improve overall survival (OS) or relapse-free survival (RFS) (P=0.35 and P=0.93, respectively). Any benefit of adjuvant trastuzumab in OS and RFS among patients without a pCR did not achieve statistical significance (P=0.3 and P=0.44, respectively).

Conclusions:

In this cohort, patients treated with trastuzumab-based NST who achieved a pCR have excellent outcome regardless of whether they received adjuvant trastuzumab.     

Chemotherapy for invasive bladder cancer: neoadjuvant versus adjuvant

The treatment of a patient with an invasive bladder tumor is based on the original urologic assessment. The global recommendation of a single treatment plan such as radical surgery, chemotherapy, radiation, or variations thereof, for all patients is clearly an antiquated approach. Case selection criteria for each single or multimodality approach need to be defined. Neoadjuvant therapy has the advantage of an in vivo response evaluation and the potential for bladder preservation. However, before treatment, the therapeutic goal--bladder preservation, treatment of micrometastases, or both--should be outlined. Patients with T2 or T3a tumors can be considered for bladder salvage by chemotherapy alone, chemotherapy plus radiation therapy or, chemotherapy followed by partial cystectomy. For those with higher stage tumors, therapy is directed more to the treatment of micrometastases, with bladder preservation as a secondary goal. In most cases additional therapy directed at the primary is required and clinical understaging remains significant. For some patients, initial surgery with the definition of the prognosis on firm pathologic grounds, may represent a better strategy. Those with positive nodes should be offered chemotherapy in the postoperative setting. Refinements in the techniques of ileo neo-bladders are of importance in improving quality of life, but when used alone will not alter the natural history of the disease. Drug resistance remains a major therapeutic obstacle. More effective agents, and the prospective identification of intrinsic or acquired resistance, invasion, and metastatic potential are required to optimize therapy for an individual patient. Ultimately, large scale randomized trials will be required to negate the heterogeneity of this patient population. Only then will individualization of treatment be possible.     

Clinical outcomes for hilar and extrahepatic cholangiocarcinoma with adjuvant,definitive, or liver transplant-based neoadjuvant chemoradiotherapy strategies: a single-center experience

BackgroundWe report our experience with 3 strategies for treating hilar and extrahepatic cholangiocarcinoma (CCA) including chemoradiotherapy: neoadjuvant chemoradiotherapy (nCRT) and orthotopic liver transplant, surgical resection and adjuvant chemoradiotherapy (aCRT), and definitive chemoradiotherapy (dCRT).MethodsWe included patients treated from 1998 through 2019. Kaplan-Meier estimates, log-rank testing, and univariate/multivariate Cox models were used to assess outcomes (local progression-free survival, disease-free survival, and overall survival).ResultsSixty-five patients (nCRT, n=20; aCRT, n=16; dCRT, n=29) met inclusion criteria [median (range) age 65 years (27–84 years)]. Median posttreatment follow-up was 19.1 months (0.8–164.8 months) for all patients and 38.6, 24.3, and 9.0 months for the nCRT, aCRT, and dCRT groups, respectively. At 3 and 5 years, overall survival was 78% and 59% for the nCRT group; 47% and 35%, aCRT group; and 11% and 0%, dCRT group. Compared with the dCRT group, the nCRT group (hazard ratio =0.13, 95% CI: 0.05–0.33) and the aCRT group (hazard ratio =0.29, 95% CI: 0.14–0.64) had significantly improved overall survival (P<0.001). The 5-year local progression-free survival (50% nCRT vs. 30% aCRT vs. 0% dCRT, P<0.001) and 5-year disease-free survival (61% nCRT vs. 30% aCRT vs. 0% dCRT, P=0.01) were significantly better for strategies combined with surgery.ConclusionsOutcomes for patients with extrahepatic CCA were superior for those who underwent nCRT/orthotopic liver transplant or postsurgical aCRT than for patients treated with dCRT. The excellent outcomes after nCRT/orthotopic liver transplant provide additional independent data supporting the validity of this strategy. The poor survival of patients treated with dCRT highlights a need for better therapies when surgery is not possible.