Optimal Duration Of Adjuvant Therapy Research Articles

Immune Checkpoint Inhibitors for Solid Tumors in the Adjuvant Setting: Current Progress, Future Directions, and Role in Transplant Oncology

The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk-benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice.

Assessing the predictive value of ctDNA on relapse in patients with resected stage IB-IIIA NSCLC treated with adjuvant chemotherapy plus concomitant atezolizumab followed by atezolizumab: BTCRC LUN 19-396.

TPS8592 Background: A standard of care treatment for most patients with stage II and III non-small cell lung cancer (NSCLC) and a PD-L1 > 1% is surgery followed by adjuvant (adj) histology-specific chemotherapy followed by 1 year of atezolizumab. The benefit of adding atezolizumab concomitantly to chemotherapy in the adj setting has not been reported. In addition, the optimal duration of adjuvant therapy is undefined. Emerging data have demonstrated the potential for ctDNA to predict clinical recurrence in patients with surgically resected lung, breast, and colon cancer. The current study explores the predictive value of ctDNA for early relapse in patients treated with adj chemotherapy plus atezolizumab. Methods: The LUN19-396 is a phase II biomarker study that enrolls pts with resected NSCLC stage IB (tumors ≥ 4cm), IIA, IIB, and select IIIA (T3N1-2, T4N0-2). The ctDNA will be assessed within 60 days post-surgery and then every 3 months up to 12 months. All pts will receive treatment with 4 cycles of Cisplatin 60-75mg/m2 + Docetaxel 60-75mg/m2 + Atezolizumab 1200mg IV on day 1 q 3w (for patients with squamous cell cancer) or Cisplatin 60-75mg/m2 + Pemetrexed 500mg/m2 + Atezolizumab 1200mg on day 1 IV q 3w (for patients with non-squamous cell), followed by up to 13 additional cycles of Atezolizumab 1200mg IV every 3w. This trial will enroll a total of 100 pts to achieve more than 80% power. The primary objective is to estimate the percentage of pts with detectable ctDNA after surgery who have clearance of ctDNA at designated time points during adjuvant therapy. The key secondary objective is to estimate the 1-year disease-free survival in pts with undetectable ctDNA after 4 cycles of adj chemotherapy plus atezolizumab who had detectable ctDNA after surgery. This trial has enrolled 17 pts as of February 8, 2022. Clinical trial information: NCT04367311.

The Optimal Duration of Adjuvant Therapy for Stage III Colon Cancer: the European Perspective

The International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration was created to pool data from different studies worldwide in order to assess whether a shorter duration of adjuvant treatment in colon cancer could maintain the expected benefit while reducing toxicity. The results of the IDEA trials were clinically relevant. They confirmed a two- to sixfold reduction in neurotoxicity for the shorter duration across trials. Overall, the 3-year disease-free survival was very similar: only 0.9% lower for the 3months group. However, the results were partially unexpected, because they revealed a difference among chemotherapy regimens (CAPOX better than FOLFOX) and risk groups within stage III. The similar outcome between 3 and 6months of CAPOX coupled with the substantial reduction in toxicity makes us use the CAPOX regimen for 3months for most stage III patients. An exception to this general rule is the patient with very high risk, i.e., either T4N1b-T4anyN2 or anyTN2b where we use 6months of CAPOX. Our take from the trial results is also that FOLFOX should never be given for 3months and preferably not used at all in the adjuvant setting. The conduction of the IDEA enterprise was truly global. The European contribution was major with three fourths of patients enrolled in the four European trials. Herein, we review the results of the "3 versus 6" trials and the literature regarding the interpretation of the collected data in Europe and in the rest of the world.

Duration of extended adjuvant therapy with neratinib in early-stage HER2+ breast cancer after trastuzumab-based therapy: Exploratory analyses from the phase III ExteNET trial.

524Background: The optimal duration of adjuvant therapy with targeted agents remains a question of ongoing relevance in oncology. ExteNET, an international, randomized, placebo-controlled phase III...

Optimizing Endocrine Therapy for Breast Cancer.

Endocrine therapy has significantly improved outcomes for patients with early- and advanced-stage hormone-receptor (HR)-positive breast cancer. Despite the success of adjuvant endocrine therapy, some patients with early-stage disease will experience relapse. Additionally, all patients with advanced disease will eventually experience disease progression on endocrine therapy due to resistance. Improved understanding of the mechanisms associated with resistance to endocrine agents has recently led to the approval of new therapeutics. Multiple questions remain unanswered, including the optimal duration of adjuvant therapy, the role of ovarian ablation in early-stage breast cancer in premenopausal women, and how to best incorporate targeted agents with endocrine therapy in the metastatic setting. This article reviews the optimization of endocrine therapy in patients with HR-positive breast cancer, focusing on these controversial areas.

Long-term Results of Adjuvant Imatinib Mesylate in Localized, High-Risk, Primary Gastrointestinal Stromal Tumor

To conduct the first adjuvant trial of imatinib mesylate for treatment of gastrointestinal stromal tumor (GIST). GIST is the most common sarcoma. Although surgical resection has been the mainstay of therapy for localized, primary GIST, postoperative tumor recurrence is common. The KIT protooncogene or, less frequently, platelet-derived growth factor receptor alpha is mutated in GIST; the gene products of both are inhibited by imatinib mesylate. This was a phase II, intergroup trial led by the American College of Surgeons Oncology Group, registered at ClinicalTrials.gov as NCT00025246. From September 2001 to September 2003, we accrued 106 patients who had undergone complete gross tumor removal but were deemed at high risk for recurrence. Patients were prescribed imatinib 400 mg per day for 1 year and followed with serial radiologic evaluation. The primary endpoint was overall survival (OS). After a median follow-up of 7.7 years, the 1-, 3-, and 5-year OS rates were 99%, 97%, and 83%, which compared favorably with a historical 5-year OS rate of 35%. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 96%, 60%, and 40%. On univariable analysis, age and mitotic rate were associated with OS. On multivariable analysis, the RFS rate was lower with increasing tumor size, small bowel site, KIT exon 9 mutation, high mitotic rate, and older age. Adjuvant imatinib in patients with primary GIST who are at high risk of recurrence prolongs OS compared with that of historical controls. Optimal duration of adjuvant therapy remains undefined. (NCT00025246).

New fronts in the adjuvant treatment of GIST

To review the prognostic factors and stratification systems used to determine the need for adjuvant therapy in the treatment of gastrointestinal stromal tumors (GIST), and to review recent clinical advances in investigation of the efficacy and safety of adjuvant imatinib mesylate treatment. Recent data from clinical trials of various durations of adjuvant imatinib in GIST are reviewed, with emphasis on key results from the Phase III American College of Surgeons Oncology Group (ACOSOG) Z9001 trial and the Scandinavian Sarcoma Group XVIII/Arbeitsgemeinschaft Internistische Onkologie (SSGXVIII/AIO) trial. Complete surgical resection remains the standard of treatment for localized GISTs; however, disease recurrence occurs in up to 50% of patients who undergo complete resection. The ACOSOG Z9001 trial established that 1year of adjuvant imatinib reduces the risk of recurrence in patients with resected GIST. The SSGXVIII/AIO trial further demonstrated that 3-year adjuvant imatinib improves both recurrence-free survival and overall survival compared with 1-year therapy in patients at high risk of recurrence after surgery. Considering risk factors associated with tumor recurrence is essential for identifying the patients who are most likely to benefit from adjuvant imatinib. Although the optimal duration of adjuvant therapy remains to be determined, results from these pivotal trials provide firm evidence that adjuvant imatinib improves recurrence-free survival and improved overall survival of patients in the SSGXVIII/AIO trial. Ongoing studies may shed further light on the benefits and harms of adjuvant therapy, as well as the most appropriate patient candidates for adjuvant imatinib treatment.

Adjuvant Therapy for High-Risk Gastrointestinal Stromal Tumour

One randomized trial has found that adjuvant treatment with imatinib for gastrointestinal stromal tumour (GIST) 3 cm or larger in diameter prolongs recurrence-free survival, and another trial has reported that 3 years of adjuvant imatinib improves both recurrence-free and overall survival compared with 1 year of imatinib in high-risk GIST. The US National Comprehensive Cancer Network now recommends consideration of adjuvant imatinib for at least 3 years for patients with a high risk of GIST recurrence. Estimation of the risk of GIST recurrence is mandatory when considering adjuvant therapy. The risk varies greatly from negligible risk (tumours smaller than 1 cm) to 90% or greater risk (large tumours with frequent mitoses). The risk of recurrence can be estimated using one of the three validated risk stratification schemes, the National Institutes of Health (NIH) consensus risk criteria, the Armed Forces Institute of Pathology criteria or the modified NIH criteria, which have roughly similar prognostic accuracy, or with nomograms or prognostic contour maps. Patients with an intermediate risk may pose a problem when considering adjuvant therapy because few research data are available. The decision about whether or not to treat these patients with adjuvant imatinib can be solved using the modified NIH risk stratification criteria, since, with these criteria, patients with intermediate risk have similar outcomes to those with low risk, leaving only patients with high risk for consideration of adjuvant therapy. Analysis of tumour tissue for KIT and PDGFRA mutations is recommended to exclude patients with imatinib-insensitive mutations from adjuvant therapy (notably patients with PDGFRA substitution mutation D842V), and those with neurofibromatosis-1-associated wild-type GIST. The standard daily dose of adjuvant imatinib is 400 mg, but it is unknown whether this dose is optimal. Some patients, such as those with KIT exon 9 mutation, might benefit from a higher dose. While the optimal duration of adjuvant therapy is also unknown, 3 years of adjuvant imatinib is currently a reasonable choice. Early detection and management of imatinib side effects is likely important for achieving high compliance. Repeat imaging of the abdomen with CT or MRI during adjuvant imatinib and after its completion is also likely to be beneficial, since most patients whose GIST recurs after adjuvant treatment respond to reinstitution of imatinib, and the presence of a small tumour burden when imatinib is reinstituted may reduce the likelihood of rapid emergence of a second mutation that confers imatinib resistance.

P-0123 Outcome of Gist's with Imatinib Mesylate: An Indian Experience.

ABSTRACT Introduction GIST represents an uncommon form of malignancy and one of best paradigms of molecularly targeted therapy. While the natural history of GIST following treatment with imatinib mesylate is relatively well known from various series in western literature, rarely any series from developing world has been published in this regard. Methods Forty four GISTs cases diagnosed and treated with imatinib between 2003 and 2009 were retrieved from the Department of Medical Oncology database, KMIO, Bangalore. Their clinical, histopathological data and treatment outcome were analysed. Kaplan Meier survival analysis was done. Anatomic site, tumor size, mitotic activity and extent of resection were correlated with overall survival using the Log Rank test. Results Median age was 56 years (range 21-68 years) with a male : female ratio of 2:1.Stomach (52%) was the most commonly involved site followed by small intestine (36%). Twenty nine cases had disease localized to a single site and 15 cases were metastatic at presentation. Mean tumor size was 10.5 cm (range 4–18cm) and mitotic rate of 6 (range 4-9)/50 HPF. NIH 2002,” Fletchers” criteria was applied for non metastatic disease, none had very low risk, 1 case (3%) had low risk, 10 (34%) intermediate and 18 (65%) belonged to high risk. All cases underwent upfront surgery with R0 resection (84%), R1 (13%) and R2 resection in 3%cases followed by imatinib (400 mg/day) for duration of one year. Metastatic sites in descending frequency of involvement were liver (85%), peritoneum (13%), omentum (6%) and lungs (1%). None had lymph node or soft tissue involvement. In the adjuvant group, median follow-up was 42 months (m) (range 10-70 m).Estimated recurrence free survival (RFS) and overall survival (OS) at 42 m were 59.9 % and 80.6 % respectively. In metastatic group, median follow up was 28 months (range 2-54 m). The median progression free survival (PFS) and OS were 18m [95 %CI 8.65m – 27.34 m] and 28m [95 %CI 17.90 m-38.09 m] respectively. Estimated PFS and OS at 28 months were 38.7% and 46.7% respectively. Non gastric GIST, R2 resection, tumor size (> 10 cm) and mitotic rate>5 (per 50 HPF) were associated with negative impact on survival Conclusion Non gastric GISTs, R1, R2 resection, tumor size (> 10cm) and mitotic rate>5/50 HPF had a negative impact on survival. However, one limitation of our study is the small sample size. This obviates the need for larger prospective studies to determine the optimal duration of adjuvant therapy across various risk groups.

Reduced Chemotherapy Duration: A Good Idea?

Over the past three decades, survival outcomes of high-risk stage II and stage III colon cancer have improved with the use of adjuvant chemotherapy. Oxaliplatin and fluoropyrimidine combination regimens, given for 6 months, are the current standard of care. However, chronic peripheral neuropathy can result as a side effect of oxaliplatin use. Investigators have questioned whether the recommended duration of adjuvant therapy is necessary. This review discusses the history of adjuvant therapy for colon cancer and provides a rationale for an ongoing clinical trial collaboration addressing the optimal duration of adjuvant therapy.

Extended duration temozolomide in patients with glioblastoma multiforme.

e12538 Background: Standard treatment for glioblastoma multiforme (GBM) includes surgical resection, temozolomide (TMZ) with radiotherapy, and adjuvant TMZ. Phase III data has shown that patients treated with 6 months of adjuvant TMZ had a median overall survival (OS) of 14.6 months with a 26.9% PFS and 61.1% OS at 1 year. The optimal duration of adjuvant therapy and whether additional agents may improve outcome is a matter of intense study. Methods: From 2002 to 2009, consecutive patients from a regional cancer center were assessed. To be eligible, patients required histological confirmation of GBM, a good performance status, and must have received concurrent radiation and TMZ. Each patient went on to receive up to 30 cycles of TMZ (150-200 mg/m2) concurrent with cis-retinoic acid (CRA) (50 mg/m2 BID). Treatment was stopped or changed if there was intolerance to therapy or clinical/radiologic evidence of progression. TMZ was continued if patients were intolerant only to the side effects of CRA. Results: Of the 79 patients that were included, mean age was 57 and 63.3% were male. The mean number of cycles of TMZ given was 8.5, with 2 patients receiving 30 cycles and 7 receiving 24 cycles. 18 patients (22.7%) received at least 12 cycles of TMZ. The mean number of TMZ cycles given concurrently with CRA was 6.7, with 15 patients (19%) receiving at least 12 concurrent cycles. No patients discontinued TMZ due to intolerance. Median OS was 17.1 months, and median progression-free survival (PFS) on TMZ was 9.6 months. The 12 month PFS was 36.7% and OS was 70.9%. Multivariable analysis determined that the extent of surgery (biopsy: HR 4.1, p = 0.003; partial resection: HR 2.3, p = 0.027) and age (HR 1.03, p = 0.006) were independently associated with survival. Survival did not improve over time. Conclusions: Extended duration TMZ is a well- tolerated treatment for up to 30 cycles. Patients treated in this manner had favorable survival compared to standard therapy. The combination of TMZ and CRA given monthly until progression or intolerance should be studied in a prospective randomized trial in the adjuvant setting. No significant financial relationships to disclose.

Optimising Hormone Therapy in Localised and Early Disease

Prostate cancer (PCa) is being diagnosed at an earlier age, and at an earlier stage of disease. Increasing numbers of relatively young patients (<60 years) with localised and early disease are receiving radical therapy. The addition of hormonal therapy in an adjuvant and/or neoadjuvant setting is widely used in clinical practice. The key issue when dealing with optimising hormone therapy in localised and early disease is to identify the patients who will benefit from this form of treatment, and optimise the timing of initiation as well as duration of the treatment. The current literature was reviewed to address this issue. Traditionally, most patients diagnosed with localised disease receive radical therapy, either radiation therapy or radical prostatectomy. However, many men have indolent PCa and may not require radical therapy. In contrast, patients with aggressive disease benefit from local therapy. As a consequence, the main clinical challenge is the stratification of patients with localised disease into good risk patients and intermediate-to-high risk patients in order to offer the patient a tailored treatment strategy. Patients diagnosed with good risk disease (stage T1c–T2a, Gleason score ≤6, small volume of disease on biopsy and prostate specific antigen (PSA) ≤10 ng/mL) can be closely monitored with periodic biopsies and measurement of the PSA doubling time (DT). Patients diagnosed with an aggressive form of disease (intermediate-to-high risk disease) need immediate curative therapy. Both radical prostatectomy and radiotherapy are currently used in combination with neoadjuvant and/or adjuvant hormonal therapy. Neoadjuvant therapy prior to radical prostatectomy has failed to demonstrate an improvement in PSA progression in numerous randomised trials. However, one trial showed a benefit in high risk patients (PSA >20 ng/mL) after 3 months of neoadjuvant therapy, based on retrospective stratification analysis. Overall, some practitioners recommend neoadjuvant therapy for patients with high risk localised PCa. Adjuvant hormonal therapy after surgery has not, to date, demonstrated an improvement in overall or disease specific survival, but does delay PSA progression. The significance of this remains uncertain. Neoadjuvant hormonal therapy prior to radiation therapy is recommended for patients with intermediate-to-high risk disease. The optimal duration of neoadjuvant hormone therapy is not yet defined. However, a 3 to 6 month course of neoadjuvant therapy prior to radiation is widely utilised. Adjuvant hormonal therapy after radiotherapy is also widely used in patients with intermediate-to-high risk disease. The optimal duration of adjuvant therapy is between 6 months and 3 years. For patients with biochemical failure, androgen deprivation therapy is appropriate for those whose clinical and pathologic parameters indicate that local recurrence is unlikely. For such patients who are at high risk (Gleason ≥8, or PSA DT <1 year), androgen deprivation should be implemented when the PSA is between 5 and 10 ng/mL. For lower risk patients, or those who have secondary failure after initial attempt at salvage radiation, there is no evidence that early androgen deprivation enhances survival or time to androgen independent progression. These patients should be monitored and treated upon clinical progression or rapid biochemical progression.

Systemic therapy for breast cancer.

Currently available information suggests that the optimal duration of adjuvant therapy for breast cancer patients with no involved axillary nodes is 5 years, though controversy about this recommendation persists. In postmenopausal patients, disease-free survival appears to be improved by the addition of combination chemotherapy to tamoxifen. Recently reported studies indicate that there is no benefit to dose escalation of cyclophosphamide in adjuvant therapy and that the risk of secondary leukemia may be increased. The combination of paclitaxel and doxorubicin has been reported in single-institution studies to produce high response rates but may also be cardiotoxic. Recent reports indicate that a pharmacokinetic interaction between these two drugs may cause these clinical findings. New agents that may be of utility in the management of advanced or primary breast cancer include novel hormonal agents, notably the aromatase inhibitors, and the bisphosphonates.