Progression-free Survival In Stage Research Articles

Neutrophil gelatinase-associated lipocalin immunoexpression in colorectal carcinoma: A stage-specific prognostic factor?

TNM post-surgical staging is considered to be one of the most powerful prognosticators for colorectal carcinoma. Although patient survival mostly decreases concomitantly to stage increase, in a percentage of cases TNM stage appears only to express the anatomic extent of the neoplasia with no correlation with clinical outcome. Thus, the identification of additional prognostic markers for colorectal cancer is required. Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein that appears to play an important role in colorectal cancer progression. In order to evaluate whether NGAL expression may be considered as a predictor of colorectal cancer progression, we analyzed its correlation with clinicopathological characteristics, as well as with patient progression-free survival in a series of surgically resected colorectal carcinomas. A variable NGAL immunoexpression was found in 24 out of the 64 analyzed cases. When only the positive cases were considered, a significant association was found between a high NGAL expression and the presence of distant metastases or high tumor stage. In addition, the presence of NGAL was a significant negative prognostic marker correlated with a shorter progression-free survival in stage I colorectal carcinoma, but not in the remaining TNM stages. If our findings are confirmed in more extensive analyses on stage I colorectal carcinoma, NGAL assessment may be used in order to select those patients with a higher progression risk and to submit them to adjuvant therapies useful to prevent adverse outcome.

Phase II induction cetuximab (C225), paclitaxel (P), and carboplatin (C) followed by chemoradiation with C225, P, C, and RT 68-72Gy for stage III/IV head and neck squamous cancer: Primary site organ preservation and disease control at 2 years (ECOG, E2303).

5513 Background: C225 plus RT improved survival vs. RT alone (Bonner, 2009). E2303 evaluated C225 with induction CT plus C225 and RT (CRT) in stage III/IV head and neck SCC with focus on event free survival, pathologic complete response (pCR) and toxicity. Restaging biopsy showed high pCR after C225/CRT 50 Gy w/ low toxicity. We now report 2-yr disease control and organ preservation rates. Methods: IRB consented resectable stage III/IV (21/42) patients (pts) sites- (oropharynx, 61%, larynx 22% other 16%) had triple endoscopy, gastrostomy, CT/MRI. Induction CT was C225 (400mg/m2 wk1, then 250mg/m2), P 90mg/m2, C (AUC=2)/ wk × 6. Restaging primary site (PS) biopsy (bx) was done wk 8, if the pt had a clinical CR and at wk 14 if disease persisted after CRT (C225 250mg/m2, P 30mg/m2, C (AUC=1) wkly × 6, 50 Gy). If PS bx was negative wk 14 pts completed CRT (68-72 Gy); If positive, the pt had surgery. Results: Of 74 enrolled pts, 70 had induction and 68 pts CRT. (13% < 70 Gy, 87% ≥70Gy ): 63 pts were eligible for analysis. Of 41 pts (59%) with clinical CR after induction, PS bx was neg. in 24 (59% pCR); Re-bx at wk 14 after chemo-RT (50Gy) in 34 pts (15 previous bx'd and 19 initial non-responders) was neg in 33 pts (97%). Thus 57 of 60 (95%) re biopsied pts and 91% of all eligible 63 pts had pCR. Neck dissection (n=34) was positive in 11 pts (32%). Pattern of failure was noted as: Local recurrence 11 (17.5%), regional 5 (8%), distant 5 (8%). Primary disease control at 2yr was 83%. Overall survival (OS): 1yr 97%, 2yr 82%; progression free survival (PFS) was 1yr 82%, 2 yr 66%. 2 yr PFS in stage III was 62%; in stage IV it was 68%. Conclusions: Induction C225 and CT followed by C225 plus CRT induces a 95% primary site path CR in biopsied pts and 91% response in eligible pts with a 2 yr OS of 82%, and PFS of 66%. This therapy and management approach produced promising local control, organ site preservation, and 2-yr survival. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, GenMab AACR, ASCO, IMER, NCCN, Pfizer Amgen, Bristol-Myers Squibb

Treatment of colorectal cancer – ASCO 2009

Colorectal cancer is a curable disease in stage II and stage III with higher cure rates if adjuvant chemotherapy is administered and that in most cases is treated with palliative intention in stage IV. Addition of bevacizumab, a vascular endothelial growth factor (VEGF) antibody, prolongs progression-free survival in stage IV when added to chemotherapy. Results of the NSABP study C-08 show that bevacizumab does not improve outcome when added to adjuvant chemotherapy in stage II and stage III colon cancer. Oxaliplatin led to a prolongation of progression-free survival and to improved response rates when added to 5-FU in stage IV colorectal cancer. In contrast, addition of oxaliplatin to 5-FU-based radiotherapy in neoadjuvant treated locally advanced rectal cancer did not improve the response rate. Survival results with adjuvant oxaliplatin in rectal cancer need to be awaited. Th e addition of oxaliplatin to 5-FU-based adjuvant chemotherapy in stage II (high risk) and stage III colon cancer became a standard of care after results of two randomized studies had been published. Current results suggest that the benefi t of adding oxaliplatin in patients >70 years is vanishing and 5-FU/folonic acid alone should be considered the standard of care in the adjuvant treatment of elderly patients. Cetuximab and panitumumab are two epidermal growth factor receptor (EGFR) directed monoclonal antibodies with proven activity in stage IV colorectal cancer. K-Ras mutations indicate resistance to anti-EGFR-directed antibodies. New molecular markers like the expression of the EGFR ligands epiregulin and amphiregulin, the expression of insulin-like growth factor-1 (IGF-1) and mutations of b-RAF and n-RAS may complement the panel of markers for the selection of patients who benefi t from anti-EGFR treatment.

Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study

Background:This study investigated the potential clinical utility of circulating free DNA (cfDNA) as a source of BRAF mutation detection in patients enrolled into a phase II study of AZD6244, a specific MEK1/2 inhibitor, in patients with advanced melanoma.Methods:BRAF mutations were detected using Amplification Refractory Mutation System allele-specific PCR. BRAF mutation status was assessed in serum-derived cfDNA from 126 patients enrolled into the study and from 94 matched tumour samples.Results:Of 94 tumour samples, 45 (47.9%) were found to be BRAF mutation positive (BRAF+). Serum-derived cfDNA was BRAF+ in 33 of 126 (26.2%) samples, including in five samples for which tumour data were unavailable. Of BRAF+ tumours, 25 of 45 (55.6%) were BRAF+ in cfDNA. In three cases in which the tumour was negative, cfDNA was BRAF+. Progression-free survival (PFS) of patients with BRAF+ tumour and cfDNA was not significantly different compared with tumour BRAF+ but cfDNA BRAF-negative patients, indicating that cfDNA BRAF detection is not associated with poorer prognosis on PFS in stage III/IV advanced melanoma.Conclusions:These data demonstrate the feasibility of BRAF mutation detection in cfDNA of patients with advanced melanoma. Future studies should aim to incorporate BRAF mutation testing in cfDNA to further validate this biomarker for patient selection.

The impact of aggressive debulking surgery and cisplatin-based chemotherapy on progression-free survival in stage III and IV ovarian carcinoma.

Forty consecutive patients with stage III and IV invasive ovarian carcinoma were treated on a phase II protocol consisting of optimal debulking surgery, induction cisplatin, cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy, 6-month interval laparoscopy, reinduction cisplatin, PAC chemotherapy, and second-look procedure. All 40 patients have either disease progression or have completed the 12-month protocol. Eighty-seven percent of the patients (35) underwent optimal (less than or equal to 2 cm residual) debulking surgery before chemotherapy, in spite of the fact that 50% (20) were referred to Roswell Park Memorial Institute (RPMI) as inoperable after initial surgery elsewhere. There were no postoperative deaths and chemotherapy was started in less than or equal to 14 days in 97% of the patients. Of the 40 patients, 30% (12) achieved a pathologic complete remission (11) or a clinical complete remission (one patient refused second-look surgery). The estimated 3-year survival rate was 62%, but the 3-year progression-free survival rate was only 29%. The median survival time was 48 months. The estimated 3-year progression-free survival rate was 31% for residual disease less than or equal to 2 cm. For the five patients with residual disease greater than 2 cm, four died within 3 years. The median survival time of patients with less than or equal to 2 cm residual disease was 48 months, as compared with 21 months for those with greater than 2 cm residual disease. Although the estimated 3-year survival rate of 62% is noteworthy, the 3-year progression-free survival rate of only 29% is probably indicative that in spite of extensive debulking surgery and cisplatin-based chemotherapy as used in this protocol, the long range proportion of patients "cured" will remain small.