Adjuvant therapies and markers of post-surgical minimal residual disease. II. Adjuvant therapies of the various primary tumors.
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Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous liver cancer with a poor prognosis. Improved stratification is needed to guide postoperative therapy. In this study, we applied integrative multiomics analysis to classify iCCA and identify biomarkers predictive of adjuvant treatment benefit. Using publicly available datasets (including whole exome sequencing, RNA sequencing, proteomics, and phosphoproteomics from FU-iCCA cohort and a transcriptomic cohort GSE244807), we defined 3 robust molecular subtypes of iCCA. These subtypes exhibited distinct genomic alterations, pathway activation, and immune microenvironments, with significant differences in overall survival (OS). Through protein-protein interaction network analysis and consensus feature selection using 10 clustering algorithms, we prioritized 8 marker genes distinguishing the subtypes. A Cox proportional-hazards model constructed from these markers stratified patients into high- and low-risk groups. High-risk iCCA, characterized by elevated expression of markers such as CLDN18, MUC1, and MUC5AC, had significantly worse OS in the absence of adjuvant therapy. Notably, in an independent validation of 174 patients with iCCA who underwent resection (single-center cohort), high expression of any of these 3 markers were associated with markedly prolonged OS in patients who received adjuvant chemotherapy or chemoembolization, compared with those who did not. In contrast, marker-negative patients showed no clear benefit from adjuvant therapy. In conclusion, our multiomics approach identified a high-risk, mucin-enriched subtype of iCCA. CLDN18, MUC1, and MUC5AC emerge as candidate predictive biomarkers for adjuvant chemotherapy benefit in iCCA, warranting prospective validation to improve personalized postoperative management.
Over the past three decades, adjuvant therapy for solid tumours has evolved from treatment based predominantly on anatomical recurrence risk towards strategies informed by tumour biology, treatment response, and molecular residual disease. Cytotoxic chemotherapy and endocrine therapy established the curative potential of postoperative systemic treatment, while targeted agents and immunotherapy expanded its efficacy across malignancies. However, matching a drug to tumour biology does not establish whether residual cancer remains, and many patients receive treatment despite having been cured by surgery alone. This Perspective examines the transition from empirical risk reduction towards selective intervention against residual disease. Response-adapted perioperative strategies provide a dynamic assessment of treatment sensitivity and support postoperative escalation or omission in defined settings. Circulating tumour DNA offers a complementary approach, but its strong prognostic value must be distinguished from evidence that biomarker-directed treatment improves outcomes. Contrasting findings from randomised trials demonstrate that neither de-escalation after a negative result nor escalation after a positive result can be generalised across clinical contexts. Future studies should integrate anatomical risk, tumour genomics, pathological response, and longitudinal molecular assessment while prioritising absolute benefit, mature survival outcomes, irreversible toxicity, patient-reported outcomes, and equitable access. They should also distinguish durable eradication from temporary suppression and evaluate treatment omission with the same rigour as intensification. Progress in adjuvant oncology should ultimately be measured by additional cures achieved with less avoidable harm, through the smallest effective intervention supported by validated evidence.
Adequate surgical resection is the most effective primary treatment of potentially curable cancer of the colon and rectum. Radiation therapy, immunotherapy, and chemotherapy are being evaluated in clinical trials to see if they should be recommended for adjuvant therapy.
Co-operative investigation of clinical therapy for cancer is used to test hypotheses developed in single institutions and in animal research laboratories. The present studies in a large co-operative organization, the Central Oncology Group, are being conducted in seven major solid tumors in adults; in these studies patients with a poor surgical prognosis are being treated with preoperative or postoperative chemotherapy, preoperative radiotion therapy of these modalities. Results of studies currently underway or recently completed in 1,278 patients are summarized. In most instances, the research has demonstrated little or no apparent improvement in the disease free interval or the survival time from adjuvant therapy, although only on of the studies has been completed and fully evaluated thus far. In carcinoma of the colon and rectum and melanoma, mild toxicity from drug therapy has been associated with statistically significant improvement in survival times. These studies have produced base line information on disease free intervals, time to progression and survival time in patients with cancer who are seen in the participating institutions. These observations are expected to useful in the planning of future adjuvant studies.
Our initial experience with weekly high dose methotrexate with leucovorin rescue (MTX-LCV), in advanced recurrent or metastatic squamous cell carcinoma of the head and neck with a 77% tumor response rate and high therapeutic index, prompted a trial of MTX-LCV as initial adjuvant therapy in high risk nonmetastatic patients. Results in 11 patients are presented and confirm the high response rate to MTX-LCV and the low incidence of myelotoxicity and mucositis, when concurrent urinary alkalinization is employed. Initial MTX-LCV administrations has not compromised subsequent optimum aggressive combinations of surgery and radiation therapy. Cytoreduction with MTX-LCV may be safely used initially in combined therapy for high risk squamous cell carcinoma of the head and neck.
Since 1958 there has been intense efforts in adjuvant systemic therapy for colorectal cancer. Peri-operative chemotherapy with HN2, TSPA + FUDR produced no clear-cut prolongation of disease-free survival. Short-term (two courses) and long-term (18 months) therapy with 5-FU by the Veterans Administration surgical Adjuvant Group is reported to give marginal increases (7--9%) in survival at 5 years. These findings are confirmed by the COG study of prolonged 5-FU which shows prolongation of disease-free survival of borderline statistical significance for Dukes' C colon (P = 0.051) + rectum (P = 0.016). Short-term benefit to 18 months was conferred by prolonged 5-FU in the VASAG + COG studies, for patients who have had a palliative resection. Combination chemotherapy might be more active, but no results are available from the controlled trials utilizing 5-FU + MeCCNU or immunotherapy. Preoperative irradiation in the VASAG studies resulted in downstaging in terms of operative findings of lymph node involvement and was of survival benefit in those patients have an AP resection for cure or palliation of rectal cancer (P less than 0.02). More intensive preoperative radiation programs are ongoing, as well as postoperative radiation with and without chemotherapy. Further progress awaits the discovery of truly active chemotherapy programs, as well as better techniques of radiation enhancement.
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Premenopausal women with hormone receptor-positive (HR+)/HER2-negative early breast cancer represent a clinically distinct population, characterized by more aggressive tumor biology, unique survivorship concerns, and complex treatment decision-making. Although evidence from dedicated trials and subgroup analyses is available, management remains challenging because data are heterogeneous, evolving, and often extrapolated from broader populations that include predominantly postmenopausal women. Adjuvant endocrine therapy, with the addition of CDK4/6 inhibitors in selected higher-risk patients, remains the cornerstone of treatment; however major uncertainties persist regarding the optimal use of ovarian function suppression, the interpretation of genomic assays to inform chemotherapy decisions, the selection of candidates for extended endocrine therapy, and the management of adherence, treatment-related toxicities, pregnancy-related issues, and survivorship concerns. Here, we synthesize current evidence across these domains and propose a pragmatic clinical framework to support individualized treatment strategies and optimize care for this population in the contemporary therapeutic landscape.
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Seventeen consecutive patients with osteogenic sarcoma participated in a prospective study to ascertain first, whether postoperative adjuvant chemotherapy or chemoimmunotherapy could reduce the incidence of distant metastases and second, whether in situ tumor cell destruction could be achieved with preoperative chemotherapy and radiation therapy. To date 14 of 17 patients (85%) are alive and free of disease for a median survival time of 11 months. Three patients developed recurrent disease, one with local recurrence in the tibia and two with pulmonary metastases. Limb salvage was attained in 12 patients by cadaver allografts and in one patient by radiation alone at 6 months.
A randomized study compared the effects of combination chemotherapy (high-dose methotrexate, adriamycin, and vincristine) with immunotherapy in the form of transfer factor in the adjuvant treatment of patients with nonmetastatic osteogenic sarcoma after apparent complete surgical ablation of the primary tumor. Thirty-two patients were evaluated. Of 22 patients who received chemotherapy, three died of drug-related complications and six were alive without disease recurrence between 260 and 673 days after operation. Ten patients in the transfer factor group converted their markers, and of these, five were alive without recurrence 420--753 days after operation. Neither treatment program was considered superior with respect to disease-free survival.
In view of the discouraging results that have been obtained so far with the use of cytotoxic chemotherapy as an adjunct to surgery, a double-blind placebo-controlled evaluation of the adjuvant use of levamisole was conducted in 211 resectable lung cancer patients, following these patients for 2 years after their operation. Levamisole (or the placebo) was given for 3 days every 2 weeks and the dose level ranged 1.1--3.8 mg/kg per day (a fixed dose of 3 x 50 mg was given to all patients). It appeared that recurrences and carcinomatous deaths had occurred significantly less often in patients who had received a high dose (i.e., 2.1--3,8 mg/kg: patients weighing 70 kg or less) but not in the patients who received a lower dose. Patients who had more advanced cancers at the time of surgery seemed to have profited more from the treatment, but the results did not seem to depend upon the histologic type of the tumor or on the immune status of the patients as estimated from the skin test reactivity at the start. There was also suggestive evidence that levamisole may be more effective in preventing hematogenous dissemination than in inhibiting recurrences in the lung or the mediastinal tissues. Levamisole, if dosed adequately, appears to be a very suitable adjuvant treatment in resectable lung cancer patients as judged from its efficacy and its lack of troublesome side-effects.
Retrospective pathological classification of 213 patients with malignant melanoma identified a group at high risk of recurrence (25% developed recurrence in 12 months, 50% by 5 years) after resection for apparent cure. Using these criteria, 70 patients were identified after resection of all apparent disease as being at high risk for recurrent melanoma. They were randomly assigned to one of the three adjuvant treatment arms: chemotherapy with dimethyl triazeno imidazole carboxamide (DTIC), immunotherapy with bacillus Calmette-Guerin (BCG), or combined chemoimmunotherapy. Six of 20 patients receiving DTIC developed recurrence (30%) and four died (20%). Five of 28 patients receiving BCG developed recurrence (18%) and two died (7.5%). There have been no recurrences or deaths in 22 patients receiving combined chemoimmunotherapy. In the prevention of early recurrence, the combined therapy arm was significantly superior to both the immunotherapy arm (p less than 0.05) and the chemotherapy arm (p less than 0.01). In terms of survival, combined therapy also was superior to chemotherapy alone (p less than 0.05).
Fifty-three patients with colorectal cancer Dukes' B2 and C were randomized after surgery. One group was treated by radio-and/or chemotherapy and the second by radio-and/or chemotherapy and MER. After 24 and 36 months a significant longer disease free interval, lower recurrence rate and better survival was found in the group treated by radio-chemo- and immunotherapy. Treatment was well tolerated and there were few local side effects from the MER injections. The long time efficacy of this adjuvant treatment whether it increases the cure rate or only delays recurrence does require longer follow-up.
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