Adjuvant Treatment Of Stage Research Articles

FC13 DERMA Phase III trial of MAGE-A3 immunotherapy as adjuvant treatment in stage III melanoma: MAGE-A3 gene expression frequency and baseline demographics

FC13 DERMA Phase III trial of MAGE-A3 immunotherapy as adjuvant treatment in stage III melanoma: MAGE-A3 gene expression frequency and baseline demographics

Stage II and Stage III Colon Cancer

Because of its frequency and mortality rate, colorectal cancer represents a major public health problem. Adjuvant chemotherapy has improved the prognosis. Six months of oxaliplatin and fluoropyrimidine in combination is the standard adjuvant treatment in stage III patients. Two monoclonal antibodies, bevacizumab targeting vascular endothelial growth factor and cetuximab targeting epidermal growth factor receptor 1, are being assessed in addition to chemotherapy in the adjuvant setting. Preliminary results of 2 trials have shown disappointing results. Duration of therapy is another other critical issue for the future. Adjuvant chemotherapy in patients with stage II colon cancer is still a subject of controversy. The potential biomarkers that can accurately select patients with stage II or III cancer who are at risk for recurrence to individualize therapy from microsatellite instability to gene signature are reviewed. Adjuvant therapy in elderly patients is another matter of debate due to the lack of survival advantage in the recent trials.

Abstract 2610: TYMS and XRCC1 gene polymorphisms as possible predictors for the addition of oxaliplatin to 5FU in the adjuvant treatment of stage II and III colorectal cancer

Abstract Background: The MOSAIC trial demonstrated that adding oxaliplatin to LV5FU2 significantly improved 5-year disease free survival (DFS) and 6-year overall survival (OS) in the adjuvant treatment of stage II/III colorectal cancer (CRC). However, oxaliplatin-related toxicities represent a problem when managing these patients. Genetic variants in TYMS and XRCC1 have shown to influence patients' outcomes in the metastatic setting. The purpose of the present study was to evaluate the influence of these polymorphisms on DFS and OS of stage II/III CRC patients treated with LV5FU2 +/- oxaliplatin in an adjuvant setting. Methods: We genotyped 216 patients (53.7% LV5FU2 and 46.3% FOLFOX4) from the MOSAIC trial. TYMS polymorphisms (5′TRP and 5′UTR SNP) and XRCC1-Arg399Gln were analyzed through PCR, RFLP and allelic discrimination respectively. According to TYMS 5′UTR SNP, genotypes were grouped as low expression (2R/2R, 2R/3RC, 3RC/3RC) or high expression (2R/3RG, 3RC/3RG, 3RG/3RG). Association of genetic variants with DFS and OS was investigated through Kaplan Meyer curves, log rank test and Cox regression models. Results: In our cohort 57.5% of patients were males; median age was 61 years (33-79); stage II/III tumors were equally distributed (50.2% and 49.8%). After 6 years of follow-up, 20.4% (38.6% FOLFOX4, 61.4% LV5FU2) of patients had relapsed and 15.4% (42.4% FOLFOX4, 57.6% LV5FU2) were dead. There were no statistical significant differences in DFS or OS according to individual genetic variants either in the whole group or by treatment. Therefore, they were analyzed jointly. TYMS high expression genotypes were considered as non-favorable for 5FU and XRCC1-399 Gln/Gln or Arg/Gln genotypes were considered as non-favorable for oxaliplatin. Patients in the FOLFOX4 group with non-favorable genotypes were more likely to relapse (28% vs. 11% for some favorable genotype; HR=2.7, 95% CI 1.00-7.34; Log rank p=0.04) or dying (17% vs. 5% for some favorable genotype; HR=2.7, 95% CI 0.92-8.17; Log rank p=0.06). Interestingly, these phenomena didn't occur in the LV5FU2 group of patients. Taken together, patients with some favorable genotype had better outcomes when receiving FOLFOX4 (87% vs. 78% for DFS, HR=0.63, 95% CI 0.28-1.43; p=0.07 and 95% vs. 89% for OS, HR=0.56, 95% CI 0.27-1.15; p=ns) after 6 years of follow-up. Inversely, FOLFOX4 was detrimental for those patients with non-favorable genotypes as compared with patients receiving LV5FU2 (68% vs. 78% for DFS, HR=2.5, 95% CI 0.60-11.1; p=ns and 83% vs. 89% for OS, HR=1.27, 95% CI 0.41-4; p=ns). Conclusion: TYMS 5′UTR SNP and XRCC1 Arg399Gln genotyping could help in the decision of adding or not oxaliplatin to LV5FU2 as adjuvant treatment in patients with stage II/III CRC and thus avoid undesirable oxaliplatin-related toxicities to these patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2610.

Brachytherapy for Stage I Endometrial Cancer: Survival Results from the SEER Registry

Purpose: Vaginal cuff brachytherapy (VCB) is an alternative to whole pelvic irradiation (WPRT) in the adjuvant treatment of Stage I endometrial cancer with an elevated risk of recurrence. The SEER registry is queried to determine the effect of VCB on overall survival, with and without WPRT.

Ethnicity, Age, and Employment Associated with Persistent Symptoms in Breast Cancer Survivors.

Abstract Background: Increases in breast cancer survival rates have prompted research on the quality of life (QOL) of breast cancer survivors, but relatively few studies have included nonwhite women or women who do not speak English.Patients and Methods: We administered a survey to patients who were ≥3 months post-completion of their adjuvant treatment for stage 0-III breast cancer at Columbia University Medical Center. The questionnaire asked patients about their experience of 16 physical and emotional symptoms in the last 7 days. Univariate analysis was performed to compare differences in each symptom measure by clinical, demographic, and treatment-related factors. Factor analysis is a statistical tool used to describe the covariance relationships among many inter-related variables in terms of a few underlying factors. Maximum likelihood factor analysis of the 16 symptoms using a varimax rotation identified 4 underlying symptom clusters that we termed depression-related, chemotherapy-related, hormone-related, and pain-related based on our clinical impression of the symptom clusters. We then used analyses of variance (ANOVA) to evaluate the associations of each of the sociodemographic and clinical characteristics (race, age, income, education, language, employment, years since diagnosis, and stage) individually with each of the four factors and multiple linear regression analysis to evaluate the associations of all of the sociodemographic and clinical characteristics with each of the four factors.Results: Of 139 patients surveyed, 58 were white, 63 Hispanic, and 18 black. Most women were <5 years post-diagnosis. The symptom most commonly reported was fatigue (76%). The most common severe symptom was muscle aches (40%). Most patients (70%) complained of ≥6 symptoms. Hispanic women were more likely than others to report >10 symptoms (chi2 11.8, df: 4, p<0.05), chemotherapy-related symptoms (beta 1.06±0.465; p<0.05) and pain-related symptoms (beta 0.778±0.362; p<0.05). Unemployed women were more likely than employed women to report chemotherapy-related symptoms (beta 0.472±0.228; p<0.05). Women <45 years old were less likely than women >65 years old to report chemotherapy (beta -0.883±0.364; p<0.05) and pain-related symptoms (beta -0.569±0.283; p<0.05).Conclusions: The majority of women in this population of breast cancer survivors, especially those who were Hispanic, elderly, or unemployed, were burdened by symptoms, most commonly fatigue. As the number of breast cancer survivors increases, and the U.S. population diversifies, it is important to identify, characterize and alleviate perceived post-treatment physical and emotional symptoms in women of different backgrounds. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1064.

Incidence of KRAS status in ongoing adjuvant trials in colon cancer

The current standard for adjuvant treatment of stage III colon cancer is chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin for 6 months. Cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is effective and safe in combination with an oxaliplatin-based regimen in patients with metastatic colorectal cancer. Based on these data, two large randomized, multicenter, phase 3 trials opened in 2005 to compare the efficacy of cetuximab combined with chemotherapy with that of chemotherapy alone in curatively R0 resected stage III colon cancer. The primary end point of these two trials is disease-free survival. The recent findings on tumor KRAS mutational status and efficacy of cetuximab in the metastatic setting have led to amendments to the protocols of both trials to enroll only patients with wild-type KRAS tumors. As a consequence, the sample sizes have increased and both trials will enroll more than 6000 patients in nine European countries and the United States. The first interim analyses are planned for 2011. This review summarizes current knowledge regarding stage III colon cancer adjuvant therapy, anti-EGFR therapy, KRAS status and its prognostic and predictive value in advanced colorectal cancer, and how to deal with these new scientific paradigms in the adjuvant setting.

Improved Overall Survival With Oxaliplatin, Fluorouracil, and Leucovorin As Adjuvant Treatment in Stage II or III Colon Cancer in the MOSAIC Trial

PURPOSE Three-year disease-free survival (DFS) was significantly improved in patients who had undergone resection with curative intent for stage II or III colon cancer who received bolus plus continuous-infusion fluorouracil plus leucovorin (LV5FU2) with the addition of oxaliplatin (FOLFOX4). Final results of the study, including 6-year overall survival (OS) and 5-year updated DFS, are reported. PATIENTS AND METHODS A total of 2,246 patients were randomly assigned to receive LV5FU2 or FOLFOX4 for 6 months. The primary end point was DFS. Secondary end points were OS and safety. Results Five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups, respectively (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.93; P = .003). Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 and LV5FU2 groups, respectively (HR = 0.84; 95% CI, 0.71 to 1.00; P = .046); corresponding 6-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively (HR = 0.80; 95% CI, 0.65 to 0.97; P = .023). No difference in OS was seen in the stage II population. The incidence of second noncolorectal cancers was 5.5% and 6.1% in the FOLFOX4 and LV5FU2 groups, respectively. Among patients receiving oxaliplatin, the frequency of grade 3 peripheral sensory neuropathy was 1.3% 12 months after treatment and 0.7% at 48 months. CONCLUSION Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease.

Palonosetron for prevention of acute and delayed nausea and vomiting induced by moderately emetogenic adjuvant folfox-4 regimen in colorectal cancer (CRC) patients: A phase II study of the Gruppo Oncologico dell’ Italia Meridionale (GOIM)

IntroductionFolfox-4 is the standard adjuvant treatment in stage III colon cancer and is also recommended in high-risk stage II colon cancer. Oxaliplatin-based regimens are considered moderately emetogenic therapies. Palonosetron, a new selective inhibitor of 5-HT3 receptors, in combination with dexhametasone showed a high antiemetic activity in pivotal trials enrolling patients treated with moderately or high emetogenic regimens. Considering these data, the GOIM started a multicentre phase II trial aiming to evaluate the activity and safety of palonosetron plus dexhametasone in patients affected by radically resected colorectal cancer and treated with adjuvant folfox-4.Materials and methodsPatients with stage III or high-risk stage II colorectal cancer and receiving folfox-4 as adjuvant treatment entered into the trial. Informed written consent was required. A single pretreatment dose of palonosetron 0.25mg (intravenous) i.v. followed by dexamethasone 8mg i.v. was administered. Nausea and vomiting were evaluated on day 1 and over the following 4d, with a patient diary including vomiting episodes, daily nausea and use of rescue medications. The main end-point of the study was the absence of vomiting in the entire period (5d) at the first cycle. The absence of moderately or severe nausea and vomiting on days 1–5 was the secondary end-point. Adverse events were evaluated according to the NCI-CTC criteria.ResultsEighty-five patients entered into the study and were all evaluable for activity and safety. The absence of vomiting on the study period (days 1–5) was observed in 82 (96.5%) patients: one patient on the 1st and two on the 2nd day experienced mild vomiting. With respect to the secondary end-point, the complete control during the acute phase was 96.5% while during the late phase was 92%. The complete responses during the acute and delayed phases were 99% and 89.5%, respectively. The main side-effects (G1 grade) were: constipation 13%, headache 10%, vertigo and insomnia 2%.ConclusionsPalonosetron is a very active antiemetic drug for the prevention of nausea and vomiting induced by folfox-4 regimen.

Adjuvant therapy of stage II colorectal cancer – who will benefit from treatment?

Adjuvant treatment of stage II colon cancer remains an issue of controversy. Though there is evidence indicating that adjuvant therapy is associated with a limited survival benefit, large clinical trials published so far did not provide enough evidence to regard adjuvant therapy of stage II colon cancer as standard of care. The ultimate clinical decision should be based on the presence of high-risk prognostic features, the evidence supporting treatment, the anticipated side effects and morbidity of treatment as well as patient preferences. Considering all these circumstances, regimen containing oxaliplatin together with 5-FU/leukovorin may be regarded as standard therapy. Stage II rectal cancer represents an excellent example for the need of close collaboration between both surgeons and medical oncologists together with radiation oncologists. The combination of radiotherapy and chemotherapy given in the neoadjuvant or adjuvant setting can be regarded as standard therapy. The potential benefit of the addition of oxaliplatin is currently under investigation. The goal of ongoing studies is to investigate whether combination of chemotherapy with therapeutic antibodies such as cetuximab or bevacizumab will become standard of care in the adjuvant setting.

Is capecitabine a cost-effective adjuvant treatment of stage III colon cancer in Ontario?

15024 Background: The cost-effectiveness of capecitabine, as adjuvant treatment for Stage III colon cancer was explored. Phase III clinical trials show that capecitabine improves disease-free survi...

Progress and challenges in the adjuvant treatment of stage II and III colon cancers

Whereas the benefit of adjuvant 5-fluorouracil and leucovorin have been well established in resected stage III colon cancer, a significant benefit for patients with stage II disease has been more difficult to demonstrate. More recently, oxaliplatin-based chemotherapy with regimens such as oxaplatin plus 5-fluorouracil/leucovorin have been shown to improve disease-free and overall survival in these stage III patients. This review will discuss the development of adjuvant chemotherapy in colon cancer, focusing on recent progress and particular topical issues related to its use in this disease, such as the use of surrogate end points for overall survival in contemporary clinical trials.

Redefining adjuvant chemotherapy in patients with stage III colon cancer: X-ACT trial

The current standard adjuvant chemotherapy for suitable patients with stage III colon cancer is the combination of oxaliplatin and 5-fluorouracil plus folinic acid (5-FU/LV). However, until recently and for many years prior to this, the accepted standard adjuvant chemotherapy was 6–8 months of bolus 5-FU/LV. However, bolus treatment was associated with significant toxicity, namely stomatitis, diarrhea and neutropenia, in addition to multiple hospital visits for drug administration for patients. The X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) compared traditional bolus 5-FU/LV (as per the Mayo Clinic regimen) with capecitabine, in the adjuvant treatment of 1987 stage III colon cancer patients. The main safety, efficacy and pharmacoeconomic results have all been published, and the updated 5-year efficacy results have also recently been presented. This trial demonstrated that capecitabine was at least as effective as bolus 5-FU/LV in terms of disease-free and overall survival, with trends towards superiority for both. Moreover, there was much less toxicity associated with capecitabine, apart from hand–foot syndrome which was significantly more prevalent. On the basis of the X-ACT trial, capecitabine was approved by the US FDA, the National Institute for Clinical Excellence and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer.

Cetuximab plus FOLFOX-4 for fully resected stage III colon carcinoma: scientific background and the ongoing PETACC-8 trial

The standard adjuvant treatment for stage III colon cancer in Europe is the 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX-4) regimen, given for 6 months. Cetuximab, a monoclonal antibody directed against the EGF receptor, appears to be effective and safe when combined with oxaliplatin-based regimens, including FOLFOX-4, in patients with metastatic colorectal cancer. PETACC-8, a randomized, multicenter, European Phase III trial, is comparing the efficacy of cetuximab plus FOLFOX-4 with that of FOLFOX-4 alone in patients with stage III colon cancer. The study began in December 2005 and approximately 2000 patients are to be enrolled in nine European countries. The primary end point is disease-free survival time, analyzed after a minimum follow-up of 3 years per patient. Secondary end points include overall survival, treatment compliance, safety and pharmacogenomic parameters.

2040 POSTER Increased prevalence of hypothyroidism after adjuvant treatment for stage II/III breast cancer

2040 POSTER Increased prevalence of hypothyroidism after adjuvant treatment for stage II/III breast cancer

32 INVITED Adjuvant treatment of stage II colon cancer

32 INVITED Adjuvant treatment of stage II colon cancer

33 INVITED Adjuvant treatment of stage III colon cancer

33 INVITED Adjuvant treatment of stage III colon cancer

Successful desensitization to oxaliplatin with incorporation of calcium gluconate and magnesium sulfate

Since the results of the MOSAIC trial demonstrated an improved disease-free survival in stage III colorectal patients treated with oxaliplatin combined with 5-fluorouracil and folinic acid when they were compared with those treated with 5-fluorouracil and folinic acid alone, the addition of this organoplatin to 5-fluorouracil and folinic acid has become first-line adjuvant treatment for stage III colorectal cancer. Unfortunately, there is a small population of patients who develop grade III/IV hypersensitivity reactions to oxaliplatin which, until recently, have interfered with further treatment with oxaliplatin-containing regimens. Successful oxaliplatin desensitization protocols for patients having severe oxaliplatin hypersensitivity reactions have been reported. However, none of these protocols, have incorporated magnesium and calcium salts. Retrospective data has suggested that pretreating colorectal cancer patients with magnesium sulfate and calcium gluconate before the administration of oxaliplatin may reduce the incidence of neurotoxicities induced by this drug. Therefore, we modified a previously published oxaliplatin-desensitization protocol by incorporating intravenous calcium gluconate and magnesium sulfate, and report a patient with stage IIIc colorectal cancer and prior severe hypersensitivity reactions to oxaliplatin who underwent successful oxaliplatin desensitization using this protocol.

Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: A final report

4050 Background: We conducted a prospective randomized trial to define the optimal sequence of chemotherapy and radiotherapy of postoperative adjuvant treatment in stage II and III rectal cancer. Methods: Three hundred eight patients were enrolled onto the study. We randomly assigned 155 to arm I (early radiotherapy group) and 153 to arm II (late radiotherapy group). Treatment included eight cycles of chemotherapy at 4-week intervals and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on day 1 of the first chemotherapy cycle in arm I and on day 1 of the third chemotherapy cycle in arm II. The chemotherapy regimen consisted of fluorouracil 375 mg/m2/d and leucovorin 20 mg/m2/d. Chemotherapy was administered for 3 days per cycle in two cycles during the period of radiotherapy and for 5 days per cycle in the remaining six cycles. (J Clin Oncol 2002 20:1751- 8) Results: Twenty patients in arm I and 14 in arm II were not eligible. We included 274 patients in the analysis. With a median follow-up of 94 months for surviving patients, there was a trend for improved disease-free survival(DFS) in arm I compared with arm II, although it was not reached statistical significance (72% v. 63% at 7 years; P =.157). Especially, in patients who received abdominoperineal resection (APR), DFS was prolonged in arm I compared with arm II (66% v. 41% at 7 years; P=.033) Thirty six recurrences (26.7%) occurred in arm I and 49 (35.3%) in arm II (P =.151). Overall survival was not significantly different between arms I and II (71% v. 68% at 7 years; P =.855). Conclusions: With a long-term follow-up, this study failed to show a significant survival advantage for early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer. In patients with APR, significant improvement in DFS for arm I was observed. No significant financial relationships to disclose.

VEGF and VEGF receptor-2 (VEGFR2) gene polymorphisms predict tumor recurrence in stage II and III colon cancer

4004 Background: Despite recent advances in the treatment of metastatic colorectal cancer, tailoring adjuvant treatment of stage II and III colon cancer patients remains controversial. Identifying a reliable panel of prognostic and predictive markers for tumor recurrence is critical in selecting an individualized and tailored chemotherapy. Tumor angiogenesis plays an important role in tumor development, progression and metastasis. In this retrospective study, we tested whether a specific pattern of 40 functionally significant polymorphisms in 37 genes involved in angiogenesis and tumor microenvironment will predict the risk of tumor recurrence in stage II and III colon cancer patients treated with adjuvant chemotherapy. Methods: Between 1999 and 2006 blood specimens from 140 patients (69 females and 71 males with a median age of 59 years; range=28–86) were obtained at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC). Sixty-three patients had stage II and 77 had stage III colon cancer. The median follow-up was 5.4 years (range=2.0–16.8). 51 of 140 patients (36.4%) developed tumor recurrence with a 5-year probability of 0.28 ± 0.06 for stage II and 0.40 ± 0.06 for stage III colon cancer patients. Genomic DNA was extracted from peripheral blood and genotypes were determined using PCR based RFLP. Results: Polymorphisms in VEGF (C936T; p=0.009, log-rank) and VEGFR2 (+4422 AC- repeat; p=0.04, log-rank and +1416 T/A; p=0.0009, log-rank) were associated with risk of tumor recurrence in stage III colon cancer patients (n=77). VEGFR2 AC-repeat polymorphisms were additionally associated with risk of recurrence in Stage II colon cancer patients (n=63, p=0.02, log-rank). Conclusion: VEGF C936T and VEGFR2 (+4422 AC-repeat and +1416 T/A) polymorphisms may help to identify Stage II and III colon cancer patients who are at increased risk for developing tumor recurrence. Angiogenesis seems to play a crucial role in tumor recurrence, thus targeting VEGF and VEGFR2 may be of clinical benefit for stage II and stage III colon cancer patients. Large prospective trials are needed to validate these preliminary data. No significant financial relationships to disclose.

INV 25 Adjuvant treatment in stage II disease: how much the changing of stage II criteria and new trial results should affect our approach?

Spitler, Lynn1; Weber, Robert1; Lutzky, Jose2; Rose, Madalene1; Trautvetter, Sharon1; Nunez, Yvonne2; Swiger, Susan1; Allen, Robert1; Meyer, John1; Gillette, Lisa1 Author Information