Second-line chemotherapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) in patients with advanced small bowel adenocarcinoma after failure of first-line platinum-based chemotherapy: a multicenter AGEO study

BACKGROUND:

Small bowel adenocarcinoma (SBA) is a rare tumor with poor prognosis. First‐line platinum‐based chemotherapy is active in patients with advanced SBA, but data regarding second‐line chemotherapy are lacking. The aim of this study was to evaluate the efficacy and tolerability of fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) as second‐line chemotherapy in patients with advanced SBA.

METHODS:

We analyzed all consecutive patients who received second‐line chemotherapy with FOLFIRI among 93 patients with advanced SBA included from 1996 to 2008 in a previous retrospective multicenter study. Progression‐free survival (PFS) and overall survival (OS) were estimated from the start of second‐line chemotherapy using the Kaplan‐Meier method. Cox models were applied for multivariate analyses.

RESULTS:

Among 51 patients who received second‐line chemotherapy, 28 patients (male, 57%; median age, 54 years; metastatic disease, 96%) were treated with FOLFIRI after progression (n = 24) or limiting toxicity (n = 4) to first‐line FOLFOX (n = 19) or LV5FU2‐cisplatin (n = 9). Grade 3‐4 toxicity was observed in 48% of patients (grade 3‐4 neutropenia, 37%). After a median follow‐up of 21.5 months, all patients had tumor progression, and 22 patients died. Objective response rate was 20%, and disease control rate was 52%. Median PFS and OS were 3.2 and 10.5 months, respectively. No clinical, biological, or tumor characteristics were associated with PFS or OS by multivariate analysis.

CONCLUSIONS:

Second‐line chemotherapy with FOLFIRI produced disease control in half of patients with advanced SBA after failure with first‐line platinum‐based chemotherapy. Nevertheless, the short median PFS warrants the evaluation of other treatments including targeted therapies. Cancer 2011. © 2010 American Cancer Society.     

Platinum/taxane‐based chemotherapy with or without radiation therapy favorably impacts survival outcomes in stage I uterine papillary serous carcinoma

BACKGROUND:

A study was undertaken to determine recurrence patterns and survival outcomes of stage I uterine papillary serous carcinoma (UPSC) patients.

METHODS:

A retrospective, multi‐institutional study of stage I UPSC patients diagnosed from 1993 to 2006 was performed. Patients underwent comprehensive surgical staging; postoperative treatment included observation (OBS); radiotherapy alone (RT); or platinum/taxane–based chemotherapy (CT) ± RT.

RESULTS:

The authors identified 142 patients with a median follow‐up of 37 months (range, 7‐144 months). Thirty‐three patients were observed, 20 received RT alone, and 89 received CT ± RT. Twenty‐five recurrences (17.6%) were diagnosed, and 60% were extrapelvic. Chemotherapy‐treated patients experienced significantly fewer recurrences than those treated without chemotherapy (P = .013). Specifically, CT ± RT patients had a lower risk of recurrence (11.2%) compared with patients who received RT alone (25%, P = .146) or OBS (30.3%, P = .016). This effect was most pronounced in stage IB/IC (P = .007). CT‐ and CT + RT–treated patients experienced similar recurrence. After multivariate analysis, treatment with chemotherapy was associated with a decreased risk of recurrence (P = .047). The majority of recurrences (88%) were not salvageable. Progression‐free survival (PFS) and cause‐specific survival (CSS) for chemotherapy‐treated patients were more favorable than for those who did not receive chemotherapy (P = .013 and .081). Five‐year PFS and CSS rates were 81.5% and 87.6% in CT ± RT, 64.1% and 59.5% in RT alone, and 64.7% and 70.2% for OBS.

CONCLUSIONS:

Stage I UPSC patients have significant risk for extrapelvic recurrence and poor survival. Recurrence and survival outcomes are improved in well‐staged patients treated with platinum/taxane–based chemotherapy. This multi‐institutional study is the largest to support systemic therapy for early stage UPSC patients. Cancer 2009. © 2009 American Cancer Society.     

The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers

BACKGROUND:

We assessed the efficacy of taxane chemotherapy in BRCA1‐ and BRCA2‐associated patients compared with sporadic metastatic breast cancer patients.

METHODS:

Response rates (RRs) to and progression‐free survival (PFS) after taxane chemotherapy of 35 BRCA1‐associated and 13 BRCA2‐associated metastatic breast cancer patients were compared with those outcomes in 95 matched (1:2) sporadic patients. Matching was performed for age at and year of diagnosis of primary breast cancer, year of metastatic disease, and line of therapy (first vs second or third).

RESULTS:

Among BRCA1‐associated patients, the RR was worse (objective response [OR], 23% vs 38%; progressive disease [PD], 60% vs 19%; P < 0.001); and the median PFS shorter (2.2 vs 4.9 months; P = 0.04) compared with sporadic patients. In the subgroup of hormone receptor (HRec)‐negative patients, BRCA1‐associated patients (n = 20) had a worse RR (OR, 20% vs 42%, respectively; PD, 70% vs 26%, respectively; P = 0.03) and a shorter PFS (1.8 vs 3.8 months; P = 0.004) compared with sporadic patients (n = 19). These outcomes in HRec‐positive patients were similar in BRCA1‐associated (n = 11) and sporadic (n = 61) patients (OR, 36% vs 38%; PD, 28% vs 20%; median PFS, both 5.7 months). In BRCA2‐associated patients, who were mainly HRec‐positive, the OR was higher than in sporadic patients (89% vs 38%, respectively; P = 0.02), whereas the median PFS was not significantly different (7.1 vs 5.7 months, respectively).

CONCLUSIONS:

BRCA1‐associated, HRec‐negative metastatic breast cancer patients were less sensitive to taxane chemotherapy than sporadic HRec‐negative patients. HRec‐positive BRCA1‐ and BRCA2‐associated patients had a sensitivity to taxane chemotherapy similar to that of sporadic patients. Cancer 2012;. © 2011 American Cancer Society.     

Germline polymorphisms in patients with advanced nonsmall cell lung cancer receiving first-line platinum-gemcitabine chemotherapy: a prospective clinical study

BACKGROUND:

The authors assessed the impact of germline polymorphisms on clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC) who received platinum‐gemcitabine (PG) chemotherapy.

METHODS:

In total, 137 patients with stage IIIB/IV NSCLC were included who received first‐line PG chemotherapy (74% of patients received cisplatin, and 26% received carboplatin). Twenty‐three germline polymorphisms that were identified in peripheral blood samples were analyzed for progression‐free survival (PFS), treatment response, overall survival (OS), and toxicity.

RESULTS:

The median PFS was 5.8 months, the median OS was 10.2 months, and 44 patients (32%) had a partial treatment response. Carriers of the excision repair cross‐complementation group 1 (ERCC1) mutant thymine (T) allele had a lower treatment response rate (29% vs 52%; P = .02), shorter PFS (adjusted hazard ratio [HR], 1.60; P = .04), and shorter OS (adjusted HR, 1.54; P = .05) compared with carriers of the wild‐type cytosine/cytosine (CC) genotype. The xeroderma pigmentosum group A member 10 (XPD10) mutant adenine (A) allele (adjusted HR, 0.64; P = .04) and the x‐ray cross‐complementing group 1 (XRCC1) mutant guanine (G) allele (adjusted HR, 0.51; P = .02) also were independent predictors of OS. Carriers of the mutant adenosine triphosphate‐dependent DNA helicase Q1 (RECQ1) C allele or the mutant cytidine deaminase (CDA) C allele were more likely to experience severe leukocytopenia (26% vs 10% [P = .03] and 28% vs 11% [P = .02], respectively) compared with wild‐type genotype carriers. Patients who carried the homozygous mutant glutathione S‐transferase π 1(GSTP1) GG genotype were at considerable risk for severe platinum‐associated polyneuropathy (18% vs 3% in wild‐type vs heterozygous mutant patients, respectively; P = .01).

CONCLUSIONS:

To the authors' knowledge, this is the first prospective study to date in patients with advanced NSCLC describing predictive germline polymorphisms not only for the clinical activity of PG chemotherapy (ERCC1, XPD10) but also for its toxicity (GSTP1, RECQ1, CDA). Nonplatinum‐containing chemotherapy in carriers of the ERCC1 T allele or the XPD10 G allele should be studied prospectively. Cancer 2012;. © 2011 American Cancer Society.     

Upfront observation versus radiation for adult pilocytic astrocytoma

BACKGROUND:

Although pilocytic astrocytoma accounts for up to 40% of all childhood brain tumors, it is a rare disease in adults. Consequently, there are few mature data on the impact of up‐front treatment options after surgery that include observation or adjuvant radiotherapy.

METHODS:

Ten women and 20 men were identified who were diagnosed with pilocytic astrocytoma from 1971 to 2007 and were retrospectively reviewed. The median patient age was 30 years (range, 18‐64 years), and the median follow‐up was 87 months (range, 16‐420 months). Initial surgery included biopsy (10% of patients), subtotal resection (57% of patients), or gross‐total resection (33% of patients). Nineteen patients were observed postoperatively, whereas 11 patients received up‐front postoperative adjuvant radiotherapy (50 grays in 25 fractions). No patient received adjuvant or concurrent chemotherapy. Progression‐free survival (PFS) and overall survival (OS) were calculated using the Kaplan‐Meier method. Differences between survival curves were analyzed with the log‐rank test.

RESULTS:

For the entire cohort, the 5‐year and 10‐year OS rates were 95% and 85%, respectively, and the 5‐year and 10‐year PFS rates were 63% and 35%, respectively. The median PFS was 8.4 years. Initial radiation, compared with observation, did not have an impact on OS but significantly improved PFS. The 5‐year PFS rate for patients who were observed versus those who received radiation was 42% versus 91%, respectively; and, at 10 years, the PFS rate was 17% versus 60%, respectively (P = .005). Patients who progressed after observation (11 of 19 patients) received various salvage therapies, resulting in a 2‐year PFS rate of 68% compared with 33% for patients who progressed after initial radiation (3 of 11 patients) and were salvaged with either chemotherapy or surgery (P = .1).

CONCLUSIONS:

Adjuvant radiotherapy for pilocytic astrocytoma significantly prolonged PFS at both 5 years and 10 years compared with observation. However, equivalent OS was observed, which reflected the efficacy of salvage therapies. Cancer 2011;. © 2011 American Cancer Society.     

Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases

BACKGROUND.

The current study evaluated the effect of bevacizumab added to fluoropyrimidine‐plus‐oxaliplatin (5FU/OX) chemotherapy for colorectal liver metastases (CLM) on the pathologic response and nontumorous liver histology.

METHODS.

A total of 105 consecutive patients treated preoperatively with 5FU/OX chemotherapy with (n = 62) or without (n = 43) bevacizumab were analyzed. The response to chemotherapy was evaluated by pathologic analysis of tumor viability (percentage of viable tumor in relation to tumor surface area). The incidence and grade of hepatic sinusoidal dilation were also investigated.

RESULTS.

Bevacizumab‐containing regimens significantly reduced the degree of tumor viability compared with 5FU/OX‐only chemotherapy (32.9% vs 45.3%; P = .02). After stratification according to the magnitude of tumor viability, a higher proportion of patients treated with bevacizumab than without had <25% residual viable tumor cells (45% vs 23%; P = .02). However, the addition of bevacizumab to 5FU/OX did not appear to increase the incidence of complete pathologic response (11.3% vs 11.6%; P = .59). The incidence and severity of sinusoidal dilation was lower in patients treated with bevacizumab than in those treated with 5FU/OX only (any grade: 27.4% vs 53.5%; moderate or severe: 8.1% vs 27.9%; both P < .01).

CONCLUSIONS.

In patients treated with 5FU/OX chemotherapy, bevacizumab improves the pathologic response, as demonstrated by a reduction of the degree of tumor viability, and reduces the incidence and severity of hepatic injury. This retrospective study provides additional evidence supporting the use of bevacizumab in combination with 5FU/OX for CLM. Cancer 2007. © 2007 American Cancer Society.     

Docetaxel and irinotecan in recurrent or metastatic head and neck cancer

BACKGROUND:

Docetaxel and irinotecan have single‐agent antitumor activity in squamous cell carcinoma of the head and neck (SCCHN). The authors sought to evaluate their combination in the treatment of patients with recurrent or metastatic SCCHN.

METHODS:

Eligibility criteria included recurrent or metastatic SCCHN with measurable disease, good performance status, and adequate laboratory parameters. Patients received docetaxel 35 mg/m² and irinotecan 60 mg/m², intravenously, on Days 1 and 8, every 21 days, until disease progression. The authors assessed UGT1A1 genotype, vascular endothelial growth factor (VEGF) in serum, and cyclooxygenase‐2 and VEGF in baseline tumor tissue.

RESULTS:

Fifty‐two patients were analyzable: 20 chemotherapy naive (Group A) and 32 previously treated with 1 chemotherapy regimen (Group B); 73% of patients had distant metastasis, and 60% were paclitaxel‐exposed. In Group A, 3 (15%) patients achieved a partial response; in Group B, 1 (3%) patient achieved a partial response. Median progression‐free survival (PFS) and overall survival were 3.3 and 8.2 months in Group A and 1.9 and 5.0 months in Group B, respectively. Common serious toxicities were diarrhea, fatigue, and anorexia. Patients with high serum VEGF had a median PFS of 2.8 months versus 1.7 months for patients with low VEGF (P = .085).

CONCLUSIONS:

Docetaxel and irinotecan had acceptable toxicities, but efficacy results in unselected patients with recurrent or metastatic SCCHN did not suggest an advantage over docetaxel alone or platinum‐based regimens. Cancer 2009. © 2009 American Cancer Society.     

Capecitabine monotherapy as salvage treatment after failure of chemotherapy containing oxaliplatin and irinotecan in patients with metastatic colorectal cancer

Aim: There has been limited data on capecitabine monotherapy in metastatic colorectal cancer (CRC) patients who were previously treated with both oxaliplatin/5‐fluorouracil(FU)/leucovorin (FOLFOX) and irinotecan/5‐FU/leucovorin (FOLFIRI). Methods: We analyzed 20 patients between August 2002 and March 2008 with metastatic CRC who had been treated with capecitabine monotherapy after the failure of FOLFOX and FOLFIRI. Results: Overall, one partial response was observed (overall response rate, 5%) and stable disease was observed in 11 patients (55.0%). The disease control rate was 60.0%. The median progression‐free survival (PFS) was 2.3 months (95% CI 1.9–2.7) and the median overall survival (OS) was 5.3 months (95% CI 4.6–6.0). Patients without ascites had longer PFS than those with ascites (P = 0.02). Patients with more than three metastatic sites had poorer OS than those with less than two (P = 0.01). Grade 3 or 4 non‐hematological toxicities included hand–foot syndrome in one patient. There were no grade 3 or 4 hematological toxicities or treatment‐related deaths. Conclusion: The capecitabine monotherapy had a moderate disease control rate and a tolerable toxicity profile as third‐line or fourth‐line treatment for metastatic CRC patients who were refractory to standard chemotherapy with no further treatment options.     

A double-blind, randomized, placebo-controlled, phase 2 study of maintenance enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab after first-line therapy for metastatic colorectal cancer

BACKGROUND:

Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5‐fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC).

METHODS:

Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first‐line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5‐fluorouracil/leucovorin (leucovorin 400 mg/m² intravenously [IV], 5‐fluorouracil 400‐mg/m² bolus, 5‐fluorouracil 2400 mg/m² IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression‐free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first‐line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events.

RESULTS:

Fifty‐eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84‐2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first‐line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86‐2.23; P = .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin‐related death occurred because of arrhythmia.

CONCLUSIONS:

Enzastaurin combined with bevacizumab‐based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab‐based therapy alone. Cancer 2012. © 2011 American Cancer Society.     

Xeroderma pigmentosum complementation group C single-nucleotide polymorphisms in the nucleotide excision repair pathway correlate with prolonged progression-free survival in advanced ovarian cancer

BACKGROUND:

The nucleotide excision repair (NER) pathway is the principal DNA repair pathway for removing bulky platinum DNA adducts. Suboptimal DNA repair may lead to improved response to platinum agents. The objective of this study was to determine whether single‐nucleotide polymorphisms (SNPs) in NER pathway genes could be markers of platinum response in ovarian cancer.

METHODS:

The authors identified patients with advanced‐stage, papillary serous ovarian cancer who underwent primary cytoreductive surgery followed by platinum‐based chemotherapy. DNA was isolated from peripheral blood specimens. Twenty‐two SNPs within NER genes (xeroderma pigmentosum [XP] complementation group A [XPA], XPB/excision repair cross‐complementing rodent repair deficiency, complementation group 3 [ERCC3], XPC, XPD/ERCC2, XPF/ERCC4, XPG/ERCC5, Cockayne syndrome group B protein [CSB]/ERCC8, ERCC1) were genotyped using polymerase chain reaction analysis.

RESULTS:

In total, 139 patients with stage III and IV papillary serous ovarian cancer were genotyped. The XPC (reference SNP 3731108 [rs3731108]) adenosine‐guanine (AG)/AA genotype versus the GG genotype was associated with prolonged a progression‐free survival (PFS) of 21.3 months versus 13.4 months (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.42‐0.95; P = .03). The XPC (rs1124303) guanosine‐thymidine (GT)/GG genotype versus the TT genotype was associated with a prolonged PFS of 22.8 months versus 14.9 months (HR, 0.47; 95% CI, 0.24‐0.94; P = .03). The XPC poly(AT) (PAT) (?/+)/(?/?) genotype versus the (+/+) genotype was associated with a prolonged PFS of 17 months versus 11.6 months (HR, 0.56; 95% CI, 0.36‐0.89; P = .01). The XPF/ERCC4 (rs12926685) cytidine‐thymidine (CT)/CC genotype versus the TT genotype was associated with a prolonged PFS of 16.7 months versus 12.4 months (HR, 0.63; 95% CI, 0.41‐0.95; P = .03). On multivariate analysis adjusting for breast cancer (BRCA) gene and cytoreductive surgery status, the XPC SNPs remained significantly associated with prolonged PFS.

CONCLUSIONS:

The current results indicated that XPC is a key component of the NER pathway that participates in DNA damage repair. SNPs in the XPC gene may represent novel markers of ovarian cancer response to platinum‐based chemotherapy. Cancer 2012;. © 2011 American Cancer Society.     

Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study

BackgroundSmall-bowel adenocarcinoma (SBA) is a rare tumor of poor prognosis. Data on the efficacy of chemotherapy for advanced SBA are scarce.Patients and methodsAll patients with advanced SBA who received frontline chemotherapy from 1996 to 2008 were eligible for this retrospective multicenter study.ResultsNinety-three consecutive patients were included. In the entire population, the median progression-free survival (PFS) and overall survival (OS) times were 6.6 and 15.1 months, respectively. Median PFS times among patients treated with LV5FU2 (n = 10), FOLFOX (n = 48), FOLFIRI (n = 19) and LV5FU2-cisplatin (n = 16) were 7.7, 6.9, 6.0 and 4.8 months, respectively, while median OS times were 13.5, 17.8, 10.6 and 9.3 months, respectively. In multivariate analysis, World Health Organization performance status (PS) (P < 0.0001) and elevated serum levels of carcinoembryonic antigen (CEA) (P = 0.02) and carbohydrate antigen 19-9 (CA 19-9) (P = 0.03) were the only variables significantly associated with poor OS. In the subgroup of patients treated with platinum-based chemotherapy, multivariate analysis showed that LV5FU2-cisplatin was associated with poorer PFS (P < 0.0001) and OS (P = 0.02) compared with FOLFOX.ConclusionsThis is the largest study of chemotherapy in advanced SBA. Baseline PS and CEA and CA 19-9 levels were the main prognostic factors. FOLFOX seems to be the most effective platinum-based chemotherapy regimen.     

Gene polymorphisms predict toxicity to neoadjuvant therapy in patients with rectal cancer

BACKGROUND

Toxicity from neoadjuvant chemoradiation therapy (NT) increases morbidity and limits therapeutic efficacy in patients with rectal cancer. The objective of this study was to determine whether specific polymorphisms in genes associated with rectal cancer response to NT were correlated with NT‐related toxicity.

METHODS

One hundred thirty‐two patients with locally advanced rectal cancer received NT followed by surgery. All patients received 5‐fluorouracil (5‐FU) and radiation (RT), and 80 patients also received modified infusional 5‐FU, folinic acid, and oxaliplatin chemotherapy (mFOLFOX‐6). Grade ≥3 adverse events (AEs) that occurred during 5‐FU/RT and during combined 5‐FU/RT + mFOLFOX‐6 were recorded. Pretreatment biopsy specimens and normal rectal tissues were collected from all patients. DNA was extracted and screened for 22 polymorphisms in 17 genes that have been associated with response to NT. Polymorphisms were correlated with treatment‐related grade ≥3 AEs.

RESULTS

Overall, 27 of 132 patients (20%) had grade ≥3 AEs; 18 patients had a complication associated only with 5‐FU/RT, 3 patients experienced toxicity only during mFOLFOX‐6, and 6 patients had grade ≥3 AEs associated with both treatments before surgery. Polymorphisms in the genes x‐ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), xeroderma pigmentosum group D (XPD), and tumor protein 53 (TP53) were associated with grade ≥3 AEs during NT (P < .05). Specifically, 2 polymorphisms—an arginine‐to‐glutamine substitution at codon 399 (Q399R) in XRCC1 and a lysine‐to‐glutamine substitution at codon 751 (K751Q) in XPD—were associated with increased toxicity to 5‐FU/RT (P < .05), and an arginine‐to‐proline substitution at codon 72 (R72P) in TP53 was associated with increased toxicity to mFOLFOX‐6 (P = .008).

CONCLUSIONS

Specific polymorphisms in XRCC1, XPD, and TP53 were associated with increased toxicity to NT in patients with rectal cancer. The current results indicated that polymorphism screening may help tailor treatment for patients by selecting therapies with the lowest risk of toxicity, thus increasing patient compliance. Cancer 2013. © 2012 American Cancer Society.     

Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas

BACKGROUND:

The authors report on the local control and toxicity of stereotactic body radiotherapy (SBRT) for patients with unresectable pancreatic adenocarcinoma.

METHODS:

Seventy‐seven patients with unresectable adenocarcinoma of the pancreas received 25 gray (Gy) in 1 fraction. Forty‐five patients (58%) had locally advanced disease, 11 patients (14%) had medically inoperable disease, 15 patients (19%) had metastatic disease, and 6 patients (8%) had locally recurrent disease. Nine patients (12%) had received prior chemoradiotherapy. Sixteen patients (21%) received between 45 to 54 Gy of fractionated radiotherapy and SBRT. Various gemcitabine‐based chemotherapy regimens were received by 74 patients (96%), but 3 patients (4%) did not receive chemotherapy until they had distant failure.

RESULTS:

The median follow‐up was 6 months (range, 3‐31 months) and, among surviving patients, it was 12 months (range, 3‐31 months). The overall rates of freedom from local progression (FFLP) at 6 months and 12 months were 91% and 84%, respectively. The 6‐ and 12‐month isolated local recurrence rates were 5% and 5%, respectively. There was no difference in the 12‐month FFLP rate based on tumor location (head/uncinate, 91% vs body/tail, 86%; P = .52). The progression‐free survival (PFS) rates at 6 months and 12 months were 26% and 9%, respectively. The PFS rate at 6 months was superior for patients who had nonmetastatic disease versus patients who had metastatic disease (28% vs 15%; P = .05). The overall survival (OS) rates at 6 months and 12 months from SBRT were 56% and 21%, respectively. Four patients (5%) experienced grade ≥2 acute toxicity. Three patients (4%) experienced grade 2 late toxicity, and 7 patients (9%) experienced grade ≥3 late toxicity. At 6 months and 12 months, the rates of grade ≥2 late toxicity were 11% and 25%, respectively.

CONCLUSIONS:

SBRT for pancreatic adenocarcinoma was effective for local control with associated risk of toxicity and should be used with rigorous attention to quality assurance. Efforts to reduce complications are warranted. Distant metastases account for the vast majority of disease‐related mortality. Cancer 2009. © 2008 American Cancer Society.     

Clinical impact of anti-epidermal growth factor receptor monoclonal antibodies in first-line treatment of metastatic colorectal cancer: meta-analytical estimation and implications for therapeutic strategies

BACKGROUND:

Antiepidermal growth factor receptor (anti‐EGFR) monoclonal antibodies (MoAbs) are indicated for the treatment of metastatic colorectal cancer patients, but some scientific issues concerning their efficacy are currently unsolved.

METHODS:

A literature‐based meta‐analysis was conducted. Hazard ratios (HRs) were extracted from randomized trials for progression‐free survival (PFS) and overall survival (OS); the event‐based risk ratio was derived for response. Sensitivity analyses to look for interactions according to KRAS status and chemotherapy association regimens were performed.

RESULTS:

Eight trials (6609 patients) were identified. A significant interaction according to KRAS status was found for PFS (wild type vs mutant, P = .001) and response rate (wild type vs mutant, P < .0001). The addition of an anti‐EGFR MoAb to first‐line chemotherapy increased PFS in the KRAS wild‐type population (HR, 0.91; 95% confidence interval [CI], 0.84‐0.99; P = .03), and had a detrimental effect in the KRAS mutant population (HR, 1.13; 95% CI, 1.03‐1.25; P = .013). A significant increase in the probability of achieving a response was evident in KRAS wild‐type patients (relative risk, 1.17; 95% CI, 1.04‐1.33; P = .011). In this population, the interaction in response rate according to adopted chemotherapy favored irinotecan‐containing regimens (P = .01), and at meta‐regression analysis the relative increase in response rate was significantly related to PFS (P = .00001) and OS (P = .00193) benefit.

CONCLUSIONS:

The addition of an anti‐EGFR MoAb to first‐line chemotherapy produces a clear benefit in response rate. This advantage is restricted to KRAS wild‐type patients and translates into a small benefit in PFS. At present, irinotecan‐based backbone chemotherapy could be a preferable option. The correlation between activity and survival parameters corroborates the hypothesis that anti‐EGFR MoAbs might be more suitable for patients needing tumoral shrinkage. Cancer 2011;. © 2011 American Cancer Society.     

Comparison of gefitinib versus erlotinib in patients with nonsmall cell lung cancer who failed previous chemotherapy

BACKGROUND:

Gefitinib and erlotinib are commonly used for salvage therapy in patients with nonsmall cell lung cancer (NSCLC) who have progressed on prior therapies. Although both agents have similar structure and have demonstrated efficacy in NSCLC, gefitinib and erlotinib have not been directly compared in terms of efficacy and other clinical outcomes in patients with NSCLC who have failed prior chemotherapy. This prompted us to analyze the clinical outcomes between gefitinib‐treated and erlotinib‐treated patients with metastatic or recurrent NSCLC.

METHODS:

A total of 467 patients with metastatic or recurrent NSCLC who had progressed on prior therapies and received gefitinib or erlotinib therapy between January 2006 and December 2008 were retrospectively reviewed. By using a matched‐pair case‐control study design, 171 pairs of gefitinib‐treated and erlotinib‐treated patients were matched according to sex, Eastern Cooperative Oncology Group (ECOG) performance status, histologic type, and smoking history.

RESULTS:

The median age of all patients was 58 years (range, 20‐85 years), and the median ECOG performance status was 1 (range, 0‐3). Of 342 patients, 294 (86%) received an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor as second‐line or third‐line therapy, whereas the remaining 14% had received >2 prior chemotherapy regimens before starting EGFR TK inhibitor therapy. The confirmed overall response rate was 35.1%, and the disease control rate was 64%. With 13.2 months of follow‐up, the median overall survival (OS) for the total 342 patients was 12.4 months (95% confidence interval [95% CI], 10.66‐14.14 months), and the median progression‐free survival (PFS) was 3.2 months (95% CI, 2.65‐3.75 months). The overall response rates and disease control rates in the gefitinib‐treated and erlotinib‐treated groups were 38% versus 32.2% (P = .273) and 63.2% versus 64.9%, respectively (P = .677). There was no statistically significant difference noted with regard to OS (median, 12.6 vs 12.1 months; P = 0.99) and PFS (median, 4.6 vs 2.7 months; P = .06) between the gefitinib‐treated and erlotinib‐treated groups.

CONCLUSIONS:

This retrospective analysis shows that gefitinib and erlotinib appear to have similar antitumor activity in terms of response rate and OS in pretreated patients with metastatic or recurrent NSCLC. Further prospective studies are warranted to elucidate any potential differences in toxicity and in dose intensity between gefitinib‐ and erlotinib‐treated patients. Cancer 2010. © 2010 American Cancer Society.     

A comparison of the outcomes of neoadjuvant and adjuvant chemotherapy for clinical T2-T4aN0-N2M0 bladder cancer

BACKGROUND:

Despite evidence supporting perioperative chemotherapy, few randomized studies compare neoadjuvant and adjuvant chemotherapy for bladder cancer. Consequently, the standard of care regarding the timing of chemotherapy for locally advanced bladder cancer remains controversial. We compared patient outcomes following neoadjuvant or adjuvant systemic chemotherapy for cT2‐T4aN0‐N2M0 bladder cancer.

METHODS:

In a retrospective review of a single institutional database from 1988 through 2009, we identified patients receiving neoadjuvant or adjuvant multiagent platinum‐based systemic chemotherapy for locally advanced bladder cancer. Survival analysis was performed comparing disease‐specific survival (DSS) and overall survival (OS).

RESULTS:

A total of 146 patients received systemic perioperative chemotherapy (73 neoadjuvant, 73 adjuvant). Of these, 84% (122/146) received cisplatin‐based chemotherapy compared with carboplatin‐based chemotherapy (24/146, 16.4%). Most patients receiving cisplatin‐based chemotherapy were treated with methotrexate/vinblastine/adriamycin/cisplatin (79/122, 64.8%), whereas the remaining patients received gemcitabine/cisplatin (GC) (43/122, 35.2%). In multivariable analysis, there was no significant difference in DSS (P = .46) or OS (P = .76) between neoadjuvant or adjuvant chemotherapy groups. There was statistically significant improvement in DSS when patients received neoadjuvant GC rather than adjuvant GC (P = .049, hazard ratio, 10.6; 95% confidence interval, 1.01‐112.2).

CONCLUSION:

In this study, there was no statistically significant difference in OS and DSS between patients receiving neoadjuvant versus adjuvant systemic platinum‐based chemotherapy for locally advanced bladder cancer. In addition, there was no significant difference between neoadjuvant and adjuvant cisplatin‐ or carboplatin‐based chemotherapy. Chemotherapy sequence relative to surgery appeared less important than whether or not a patient actually received perioperative chemotherapy. Cancer 2011;. © 2011 American Cancer Society.     

Comparison of adverse events during 5-fluorouracil versus 5-fluorouracil/oxaliplatin adjuvant chemotherapy for stage III colon cancer: a population-based analysis

BACKGROUND:

In clinical trials, combined 5‐fluorouracil (5FU) plus oxaliplatin improves the survival of patients who have resected, stage III colon cancer with manageable toxicity. However, the tolerability of this in the general population of patients with colon cancer is uncertain.

METHODS:

Adverse outcomes were compared in patients with stage III colon cancer who received either 5FU or 5FU/oxaliplatin within 120 days of undergoing resection versus a control group of patients with stage II colon cancer who did not receive chemotherapy in the Surveillance, Epidemiology, and End Results (SEER)‐Medicare database and in data from the New York State Cancer Registry linked to Medicare and Medicaid. Hospitalizations, emergency room (ER) visits, and outpatient adverse events (AEs) were measured in claims from 30 days to 9 months after patients underwent resection. Multiple logistic regression was used to calculate adjusted odds ratios of events by treatment. Propensity score matching was used to minimize selection bias.

RESULTS:

Adverse outcomes were more frequent for chemotherapy recipients. AE rates were higher in patients who received 5FU/oxaliplatin (81%) compared with patients who received 5FU alone (72%), in the SEER‐Medicare data. The effect of oxaliplatin on AEs was greater in older patients: The odds ratio was 2.10 (95% confidence interval, 1.53‐2.87) for patients aged ≥75 years versus 1.75 (95% confidence interval, 1.39‐2.21) for patients aged <75 years. ER use was high in Medicaid patients (83% of those who received chemotherapy), but neither ER use nor hospitalization was increased by oxaliplatin. The 60‐day mortality rate was 1% to 3% for patients who received 5FU alone and 1% to 2% for patients who received combined 5FU/oxaliplatin.

CONCLUSIONS:

The incremental harms of adjuvant chemotherapy with 5FU/oxaliplatin versus 5FU alone were modest in patients with stage III colon cancer who were insured by Medicare and Medicaid. The additional harms in patients aged ≥75 years largely were restricted to outpatient events and did not extend to an increased rate of hospitalization or early death. Cancer 2012. © 2012 American Cancer Society     

Gefitinib versus pemetrexed as second‐line treatment in patients with nonsmall cell lung cancer previously treated with platinum‐based chemotherapy (KCSG‐LU08‐01)

BACKGROUND:

Gefitinib was compared with pemetrexed as second‐line therapy in a clinically selected population previously treated with platinum‐based chemotherapy.

METHODS:

A phase 3 trial of gefitinib (250 mg/day) versus pemetrexed (500 mg/m² on day 1, every 3 weeks) was conducted in patients who had never smoked and who had advanced pulmonary adenocarcinoma treated with 1 previous platinum‐based regimen. The primary endpoint was progression‐free survival (PFS).

RESULTS:

A total of 135 patients were analyzed. The gefitinib group had significantly longer PFS compared with the pemetrexed group, with a median PFS time of 9.0 versus 3.0 months (P = .0006). The objective response rates were 58.8% and 22.4% for gefitinib and pemetrexed, respectively (P < .001). However, there was no statistically significant difference in overall survival between the 2 groups (22.2 vs 18.9 months; P = .37). The difference of PFS was increased in a subgroup analysis of 33 patients with activating epidermal growth factor receptor mutation (15.7 vs 2.9 months; hazard ratio, 0.3; 95% confidence interval, 0.13‐0.72; P = .005), with numerical superiority of gefitinib in the 38 patients testing negative for epidermal growth factor receptor mutation (5.9 vs 2.7 months; P = .099). Both regimens were well tolerated. There were no significantly different changes in quality of life between the 2 groups, except that symptom scores for dyspnea and diarrhea favored the gefitinib and pemetrexed arms, respectively.

CONCLUSIONS:

Gefitinib showed superior efficacy to pemetrexed as second‐line therapy in Korean never‐smokers with pulmonary adenocarcinoma. Cancer 2012. © 2012 American Cancer Society.     

The role of technetium‐99m methoxyisobutyl isonitrile scintigraphy in predicting the therapeutic effect of chemotherapy against nasopharyngeal carcinoma

BACKGROUND:

The authors prospectively evaluated the correlation between technetium‐99m methoxyisobutyl isonitrile (^99mTc‐MIBI) accumulation in tumors and response to induction chemotherapy in patients with nasopharyngeal carcinoma (NPC).

METHODS:

Eighty‐six patients with locally advanced NPC underwent single‐photon emission computed tomography 15 minutes after an intravenous injection of 740 megabecquerels (20 mCi) ^99mTc‐MIBI before chemotherapy. The tumor uptake ratio (TUR) was calculated. Two weeks after the second cycle of combined chemotherapy with 5‐fluorouracil (5‐FU) and cisplatin (DDP), the tumor response rate was evaluated. The correlation between ^99mTc‐MIBI accumulation in tumors and response to chemotherapy with 5‐FU/DDP was examined.

RESULTS:

Positive accumulation of ^99mTc‐MIBI in tumors was observed in 76 patients (88.4%). The tumor response was a complete response (CR) in 8 patients, a partial response (PR) in 68 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. The response rate (CR and PR) to 5‐FU/DDP chemotherapy in patients who had positive ^99mTc‐MIBI accumulation (tumor uptake ratio [TUR] >1.1) was higher than that in patients who had negative ^99mTc‐MIBI accumulation (TUR ≤1.1; 98.7% vs 10%; P < .001).

CONCLUSIONS:

Patients with negative ^99mTc‐MIBI accumulation were resistant to 5‐FU/DDP chemotherapy. ^99mTc‐MIBI imaging in patients with NPC was capable of predicting tumor response to chemotherapy with 5‐FU/DDP and can help in the selection of patients for induction chemotherapy. Cancer 2011. © 2010 American Cancer Society.     

Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI‐1 study

The global, randomized NAPOLI‐1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal‐IRI) plus 5‐fluorouracil/leucovorin (nal‐IRI+5‐FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine‐based therapy. Median overall survival (OS) with nal‐IRI+5‐FU/LV was 6.1 vs 4.2 months with 5‐FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post‐hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression‐free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal‐IRI+5‐FU/LV (n = 34) had significantly longer median OS versus 5‐FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal‐IRI+5‐FU/LV versus 5‐FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal‐IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5‐FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal‐IRI+5‐FU/LV versus 5‐FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal‐IRI+5‐FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine‐based therapy, with a safety profile agreeing with previous findings. The nal‐IRI+5‐FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506)