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1.  Results of the GYNECO 02 Study, an FNCLCC Phase III Trial Comparing Hysterectomy with No Hysterectomy in Patients with a (Clinical and Radiological) Complete Response After Chemoradiation Therapy for Stage IB2 or II Cervical Cancer 
The Oncologist  2012;17(1):64-71.
The therapeutic impact of completion surgery (hysterectomy) after chemoradiotherapy was investigated in patients with stage IB or II cervical cancer. Hysterectomy had no therapeutic impact in patients with a clinical and radiological complete response after chemoradiotherapy, but this conclusion is limited by the lack of power.
Learning Objectives
After completing this course, the reader will be able to: Evaluate the therapeutic impact of hysterectomy after chemoradiation therapy in locally advanced cervical cancer.Evaluate the rate of histologic residual disease in patients with complete clinical and radiologic response after chemoradiation therapy.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Concomitant chemoradiation (CRT) (including brachytherapy) is considered the standard management for stage IB2 or II cervical cancer in many countries. Nevertheless, some of them discuss completion surgery (hysterectomy [HT]) after CRT. The aim of this study was to investigate the therapeutic impact of such surgery.
Methods.
A randomized trial was opened in France in 2003 to evaluate the interest in HT after CRT. Inclusion criteria were: (a) stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging; (b) pelvic external radiation therapy (45 Gy with or without parametrial or nodal boost) with concomitant cisplatin chemotherapy (40 mg/m2 per week) followed by uterovaginal brachytherapy (15 Gy to the intermediate risk clinical target volume); and (c) complete clinical and radiological response 6–8 weeks after brachytherapy. Patients were randomized between HT (arm A) and no HT (arm B). Unfortunately this trial was closed because of poor accrual: 61 patients were enrolled (in 2003–2006) and are reported on here.
Results.
Thirty one and 30 patients were enrolled, respectively, in arm A and arm B. Twelve patients recurred (five of them died): respectively, eight and four in arm A and arm B. The 3-year event-free survival rates were 72% (standard error [SE], 9%) and 89% (SE, 6%) (not significant [NS]) in arm A and arm B, respectively. The 3-year overall survival rates were 86% (SE, 6%) and 97% (SE, 3%) (NS) in arm A and arm B, respectively.
Conclusions.
Results of the current trial seem to suggest that completion HT had no therapeutic impact in patients with clinical and radiological complete response after CRT (but this conclusion is limited by the lack of power).
doi:10.1634/theoncologist.2011-0276
PMCID: PMC3267825  PMID: 22234626
Chemoradiation therapy; Surgery; Locally advanced cervical cancer; Nodal involvement; Prognostic factors; Residual disease; Survival
2.  Treatment for Advanced and Recurrent Endometrial Carcinoma: Combined Modalities 
The Oncologist  2010;15(8):852-861.
The treatment options available to treat recurrent and locally advanced endometrial cancer are reviewed.
Learning Objectives
After completing this course, the reader will be able to: Discuss the role of radiation therapy for advanced stage endometrial cancer in order to differentiate between patients who should receive only radiation therapy and patients requiring surgery and/or chemotherapy in addition to radiation.Evaluate the role of surgery for stage IV and recurrent endometrial cancer in order to select patients most likely to benefit from cytoreductive surgery.Evaluate the role of chemotherapy, particularly in conjunction with radiotherapy, in advanced stage endometrial carcinoma and select appropriate candidates for multimodality therapy.
This article is available for continuing medical education credit at CME.TheOncologist.com
Women with recurrent or advanced endometrial cancer constitute a heterogeneous group of patients. Depending on previous treatment, women with recurrent endometrial cancer may be appropriate candidates for surgery, radiation therapy, hormonal therapy, or chemotherapy. Women with advanced stage disease at presentation may also be appropriate candidates for systemic and local therapies. We review the treatment options available to treat recurrent and locally advanced endometrial cancer.
Treatment choice depends largely on the localization of disease, the patient’s performance status and previous treatment history, as well the tumor’s hormonal receptor status. Radiation therapy is appropriate for isolated vaginal recurrences in patients with no previous history of radiation therapy. Patients with recurrent low-grade tumors overexpressing estrogen and progesterone receptors may be treated with progestin therapy. Systemic therapy is appropriate for patients with disseminate recurrences or advanced stage disease at presentation, or for those with receptor-negative tumors. We review all these different treatment strategies available to patients with advanced or recurrent endometrial cancer.
doi:10.1634/theoncologist.2010-0091
PMCID: PMC3228028  PMID: 20660059
Endometrial cancer; Radiation; Chemotherapy; Hormonal therapy
3.  Is Renal Thrombotic Angiopathy an Emerging Problem in the Treatment of Ovarian Cancer Recurrences? 
The Oncologist  2012;17(12):1534-1540.
A retrospective review at two institutions was conducted to document the frequency and contributing factors to the emergence of chronic kidney disease among patients receiving long-term treatment for recurrent ovarian cancer.
Learning Objectives
After completing this course, the reader will be able to: Describe the need for additional vigilance regarding renal dysfunction when platinums, pegylated liposomal doxorubicin, bevacizumab, and gemcitabine are used for prolonged treatment of recurrent ovarian cancer in combination or sequentially following pre-existing renal damage.Describe and quantify the risk of chronic kidney disease in patients treated for ovarian cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background and Objective.
Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions.
Patients and Methods.
Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997–2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002–2010. Patients were diagnosed with CKD if they had an estimated GFR <60 mL/minute per 1.73 m2 for >3 months and were staged according to the National Kidney Foundation guidelines.
Results.
Thirteen patients (23%) developed stage ≥3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy.
Conclusions.
CKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.
doi:10.1634/theoncologist.2011-0422
PMCID: PMC3528385  PMID: 22622146
Chronic kidney disease; Ovarian cancer; Pegylated liposomal doxorubicin; Renal thrombotic microangiopathy
4.  The Prognostic Impact of Duration of Anemia During Chemotherapy in Advanced Epithelial Ovarian Cancer 
The Oncologist  2011;16(8):1154-1161.
A binary variable is introduced based on the duration of anemia, that is, a hemoglobin level <10 g/dL, during chemotherapy in advanced epithelial ovarian cancer patients for use as a potential prognostic factor for progression-free and overall survival.
Learning Objectives
After completing this course, the reader will be able to: Compare the prognostic factors for hemoglobin level in ovarian cancer patients.Explain the prognostic relationship between the duration of anemia during chemotherapy and survival in patients with advanced epithelial ovarian cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com
Objective.
To propose a measure of anemia to be used as a prognostic factor for progression-free survival and overall survival in advanced epithelial ovarian cancer patients.
Patients and Methods.
Seventy-six patients with International Federation of Gynecology and Obstetrics stage III and stage IV epithelial ovarian cancer who had received at least six courses of platinum- and taxane-based systemic chemotherapy and achieved clinical or pathologic complete response were included. A novel prognostic factor based on the duration of anemia was proposed and the impact of anemia on progression-free and overall survival times was analyzed by a log-rank test and a Cox proportional hazards model.
Results.
We introduce a binary variable, Hb1020, that takes a value of 1 if the duration of a hemoglobin (Hb) level <10 g/dL is ≥20% of the total duration of chemotherapy. We propose Hb1020 as a potential prognostic factor for epithelial ovarian cancer. The 5-year progression-free survival rates were 48.4% in the Hb1020 = 0 group (duration of Hb <10 g/dL <20% of total duration) and 17.7% in the Hb1020 = 1 group (p = .026). The 5-year overall survival rates were 64.6% and 45.0%, respectively (p = .015).
Conclusions.
Hb1020, based on the duration of anemia, is a potential prognostic factor for epithelial ovarian cancer. Using Hb1020, we will be able to administer highly optimized treatment for anemia to improve patient survival. Further independent studies are needed to confirm its prognostic role.
doi:10.1634/theoncologist.2010-0236
PMCID: PMC3228149  PMID: 21705663
Ovarian cancer; Anemia; Prognostic factor; Survival; Chemotherapy
5.  Current Status of Adjuvant Therapy for Pancreatic Cancer 
The Oncologist  2010;15(11):1205-1213.
The rationale for and outcomes associated with the use of adjuvant and neoadjuvant therapy for resectable and borderline resectable cancer of the pancreatic head and uncinate process are reviewed.
Learning Objectives
After completing this course, the reader will be able to: Explain the rationale for the use of adjuvant and neoadjuvant chemoradiation and/or chemotherapy in the treatment of patients with potentially resectable pancreatic cancer.Describe the limitations of prior prospective, randomized trials of adjuvant therapy strategies and the clinical implications of these limitations.Compare modern strategies for the multidisciplinary management of potentially resectable and borderline resectable pancreatic cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com.
In this article, we review the rationale for and outcomes associated with the use of adjuvant and neoadjuvant therapy for resectable and borderline resectable cancer of the pancreatic head and uncinate process. Localized pancreatic cancer is a systemic disease that requires nonoperative therapies to minimize the local and systemic recurrences that almost invariably occur in the absence of such therapy, even following complete surgical resection. A well-defined role exists for the systemic administration of gemcitabine or 5-fluorouracil in the postoperative setting. Although the survival benefit associated with adjuvant chemoradiation has not been as rigorously defined, its use is supported by extensive historic experience; chemoradiation should be considered particularly for patients at high risk for local recurrence. Delivery of chemotherapy and/or chemoradiation prior to surgery has multiple potential advantages, although the superiority of neoadjuvant therapy over standard postoperative therapy has yet to be demonstrated. Neoadjuvant therapy may be particularly beneficial among patients with borderline resectable cancers. Although the existing literature is confusing, and indeed controversial, available evidence suggests that systemic chemotherapy and/or chemoradiation should be offered to all patients with pancreatic cancer who undergo potentially curative resection. Well-designed prospective trials are needed to define the optimal adjuvant or neoadjuvant therapy strategy for these patients.
doi:10.1634/theoncologist.2010-0121
PMCID: PMC3227902  PMID: 21045189
Pancreatic cancer; Adjuvant therapy; Neoadjuvant therapy; Chemoradiation; Chemotherapy; Pancreaticoduodenectomy
6.  Prognosis and Prognostic Factors of the Micropapillary Pattern in Patients Treated for Stage II and III Serous Borderline Tumors of the Ovary 
The Oncologist  2011;16(2):189-196.
In this study on 168 patients with stage II and stage III serous borderline tumor of the ovary, micropapillary pattern did not appear to signify a poor prognosis. The only prognostic factor for recurrence in these patients was the use of conservative surgery.
Learning Objectives
After completing this course, the reader will be able to: Discuss the prognostic impact of a micropapillary pattern in patients with stage II and III serous borderline ovarian tumors (SBOT).Consider when conservative surgery is an appropriate intervention in patients with SBOT-MP.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
To determine the prognosis of a micropapillary (MP) pattern in patients with stage II and stage III serous borderline tumor of the ovary (SBOT).
Methods.
Review of patients with stage II and stage III SBOT treated or referred to our institution with characterization of an MP pattern and its clinical impact.
Results.
In 1969–2006, 168 patients were reviewed. Fifty-six patients had SBOT-MP. The rate of conservative surgery was lower in the SBOT-MP group than in the typical SBOT group, but the rate of patients with more than three peritoneal sites with implants was higher in the SBOT-MP group. The rate of invasive implants was not statistically different between the two groups. Eighteen recurrences were observed (six of them in the form of invasive disease) in the SBOT-MP group. Only one death was observed. The overall survival times and recurrence-free intervals were similar in both groups. The only prognostic factor for recurrence in the SBOT-MP group was the use of conservative surgery.
Conclusions.
In the present series, an MP pattern doesn't appear to signify a poor prognosis. The only prognostic factor for recurrence in SBOT-MP was the use of conservative surgery. Further studies on the MP pattern are needed to evaluate prognosis and the results of conservative surgery.
doi:10.1634/theoncologist.2009-0139
PMCID: PMC3228092  PMID: 21273510
Borderline tumor; Conservative surgery; Micropapillary pattern; Ovary; Peritoneal implants; Recurrence
7.  Analysis of Morbidity and Clinical Implications of Laparoscopic Para-Aortic Lymphadenectomy in a Continuous Series of 98 Patients with Advanced-Stage Cervical Cancer and Negative PET–CT Imaging in the Para-Aortic Area 
The Oncologist  2011;16(7):1021-1027.
A series of patients with locally advanced cervical cancer, with no positive para-aortic nodes on positron emission tomography–computed tomography who had undergone a primary laparoscopic para-aortic lymphadenectomy was retrospectively reviewed. Morbidity was limited and the completion of treatment was not delayed when complications occurred.
Background.
Laparoscopic para-aortic lymphadenectomy (PAL) is being used increasingly to stage patients with locally advanced cervical cancer (LACC) and to define radiation field limits before chemoradiation therapy (CRT). This study aimed to define clinical implications, review complications, and determine whether surgical complications delayed the start of CRT.
Methods.
We retrospectively reviewed a continuous series of patients with LACC, with no positive para-aortic (PA) nodes on positron emission tomography–computed tomography (PET–CT) and who had undergone a primary laparoscopic PAL.
Results.
From November 2007 to June 2010, 98 patients with LACC underwent pretherapeutic PAL. Two patients did not undergo PAL: extensive carcinomatosis was discovered in one case and a technical problem arose in the other. No perioperative complications occurred. Seven patients had a lymphocyst requiring an imaging-guided (or laparoscopic) puncture. Eight patients (8.4%, which corresponds to the false-negative PET–CT rate) had metastatic disease within PA lymph nodes. In cases of suspicious pelvic nodes on PET–CT, the risk for PA nodal disease was greater (24.0% versus 2.9%). When patients with and without surgical morbidity were compared, the median delay to the start of treatment was not significantly different (15 days; range, 3–49 days versus 18 days; range, 3–42 days).
Conclusions.
The morbidity of laparoscopic PAL was limited and the completion of treatment was not delayed when complications occurred. Nevertheless, if PET–CT of the pelvic area is negative, the interest in staging PAL could be discussed because the risk for PA nodal disease is very low.
doi:10.1634/theoncologist.2011-0007
PMCID: PMC3228132  PMID: 21659610
Cervical cancer; Para-aortic lymphadenectomy; Laparoscopy; Staging; Morbidity; Lymphocyst
8.  Pathological correlation with diffusion restriction on diffusion-weighted imaging in patients with pathological complete response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: preliminary results 
The British Journal of Radiology  2012;85(1017):e566-e572.
Objective
The objective of this study was to assess causative pathological factors associated with diffusion restriction on diffusion-weighted imaging (DWI) in patients who achieved pathological complete response (pCR) after treatment with neoadjuvant chemoradiation therapy (CRT) for locally advanced rectal cancer.
Methods
In total, 43 patients with locally advanced rectal cancer (≥T3 or lymph node positive) who underwent neoadjuvant CRT, subsequent surgery and ultimately achieved pCR were enrolled. All patients underwent pre- and post-CRT 3.0 T rectal MRI with DWI. Two radiologists blinded to pathological staging reviewed pre- and post-CRT 3.0 T rectal MRI for the presence of diffusion restriction in the corresponding tumour areas on post-CRT DWI, with a third radiologist arbitrating any disagreement. The consensus of these findings was then correlated with pathological data such as intramural mucin and the degree of proctitis and mural fibrosis seen on surgical specimen. Additionally, the pre-CRT tumour volume was measured to define the effect of this variable on the degree of radiation proctitis and fibrosis, as well as the presence of intramural mucin.
Results
Diffusion restriction occurred in 18 subjects (41.9%), while 25 subjects remained diffusion restriction-free (58.1%). The diffusion restriction group tended to have more severe proctitis and mural fibrosis when compared with non-diffusion restriction group (p<0.001). Intramural mucin was also more common in the diffusion restriction group (p=0.052). Higher pre-CRT tumour volumes were significantly predictive of the degree of proctitis (p=0.0247) and fibrosis (p=0.0445), but not the presence of intramural mucin (p=0.0944). Proctitis and mural fibrosis severity were also identified as independent pathological risk factors for diffusion restriction on multivariate analysis (p=0.0073 and 0.0011, respectively).
Conclusion
Both radiation-induced proctitis and fibrosis were significant and independent predictors of diffusion restriction in patients achieving pCR after treatment with neoadjuvant CRT for locally advanced rectal cancer, and pre-CRT tumour volume significantly affects both variables.
doi:10.1259/bjr/24557556
PMCID: PMC3487069  PMID: 22422387
9.  Curative Strategies for Liver Metastases from Colorectal Cancer: A Review 
The Oncologist  2012;17(2):201-211.
The optimal selection of patients and timing of surgery and selection of chemotherapy for colorectal cancer patients with potentially resectable liver metastases are discussed by addressing a series of questions. Regional therapies are also discussed.
After completing this course, the reader will be able to: Among patients with liver metastases from colorectal cancer, determine which would benefit from liver resection, the timing for surgery, and an appropriate perioperative chemotherapy regimen.Determine which patients are candidates for perioperative chemotherapy and the appropriate timing of chemotherapy, and describe the relevant toxicities and their impact on morbidity and mortality.
This article is available for continuing medical education credit at CME.TheOncologist.com
Colorectal cancer is a very common malignancy and frequently manifests with liver metastases, often without other systemic disease. Margin-negative (R0) resection of limited metastatic disease, in conjunction with systemic antineoplastic agents, is the primary treatment strategy, leading to long survival times for appropriately selected patients. There is debate over whether the primary tumor and secondaries should be removed at the same time or in a staged manner. Chemotherapy is effective in converting some unresectable liver metastases into resectable disease, with a correspondingly better survival outcome. However, the ideal chemotherapy with or without biological agents and when it should be administered in the course of treatment are uncertain. The role of neoadjuvant chemotherapy in initially resectable liver metastases is controversial. Local delivery of chemotherapy, with and without surgery, can lead to longer disease-free survival times, but it is not routinely used with curative intent. This review focuses on methods to maximize the disease-free survival interval using chemotherapy, surgery, and local methods.
doi:10.1634/theoncologist.2011-0300
PMCID: PMC3286169  PMID: 22234631
Colorectal neoplasms; Liver neoplasms; Metastasis; Chemotherapy; Surgery
10.  Role of Postoperative Radiotherapy in Resected Non-Small Cell Lung Cancer: A Reassessment Based on New Data 
The Oncologist  2011;16(5):672-681.
Randomized trials and a meta-analysis of postoperative radiation therapy in non-small cell lung cancer patients are discussed along with studies evaluating adjuvant chemoradiation in this patient population.
Learning Objectives
After completing this course, the reader will be able to: Identify patients with non-small cell lung cancer who may benefit from postoperative radiotherapy based upon current evidence.Summarize the results of analyses of both older and more recent data regarding postoperative radiotherapy in NSCLC patients.
This article is available for continuing medical education credit at CME.TheOncologist.com
In completely resected non-small cell lung cancer (NSCLC) patients with pathologically involved mediastinal lymph nodes (N2), administration of adjuvant platinum-based chemotherapy is now considered the standard of care, based on level 1 evidence. The role of postoperative radiation therapy (PORT) in this group of patients remains controversial. The PORT meta-analysis published in 1998 concluded that adjuvant radiotherapy was detrimental to patients with early-stage completely resected NSCLC, but that the role of PORT in the treatment of tumors with N2 involvement was unclear, and that further research was warranted. Recent retrospective and nonrandomized studies, as well as subgroup analyses of recent randomized trials evaluating adjuvant chemotherapy, provide evidence of the possible benefit of PORT in patients with mediastinal nodal involvement. The role of PORT is also a valid question in patients with proven N2 disease who have undergone only induction chemotherapy followed by surgery, because the local recurrence rate for such patients varies in the range of 20%–60%. Based on the currently available data, PORT should be discussed for fit patients with completely resected NSCLC with N2 nodal involvement, preferably after completion of adjuvant chemotherapy. There is a need for new randomized evidence to evaluate PORT using the modern three-dimensional conformal radiation technique, with attention paid to reducing the risk for, particularly, pulmonary and cardiac toxicity. A new large multi-institutional randomized trial evaluating PORT in this patient population is needed and now under way.
doi:10.1634/theoncologist.2010-0150
PMCID: PMC3228187  PMID: 21378080
Non-small cell lung cancer; Post-operative radiotherapy; Adjuvant treatment; Mediastinal involvement
11.  The Evolution of the Locoregional Therapy of Breast Cancer 
The Oncologist  2011;16(10):1367-1379.
The evolution of the local therapy of breast cancer is reviewed with an emphasis on current areas of controversy.
Learning Objectives
After completing this course, the reader will be able to: Describe the influence of tumor biology when selecting options for local treatment of breast cancer.Identify key areas of controversy relating to localized treatment of breast cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com
Breast-conserving therapy (BCT) and mastectomy have equal survival outcomes. Rates of local recurrence after BCT have declined steadily, largely as a result of the widespread use of systemic therapy. Sentinel node biopsy has replaced axillary dissection for staging the axilla, and in women undergoing BCT with whole-breast irradiation (WBI), axillary dissection is not needed for local control or survival in those with fewer than three involved sentinel nodes. Alternatives to 6 weeks of WBI have been shown to be safe and effective for subsets of breast cancer patients, and the use of preoperative chemotherapy allows BCT in some women who require mastectomy if surgery is the initial step in treatment. The combination of the smaller cancers detected with screening and the routine use of multimodality therapy has resulted in a decrease in the morbidity of local therapy and improved cancer treatment outcomes.
doi:10.1634/theoncologist.2011-0223
PMCID: PMC3228069  PMID: 21964004
Breast surgery; Lumpectomy; Sentinel node; Partial breast irradiation
12.  Simplified Prognostic Model in Patients with Oxaliplatin-Based or Irinotecan-Based First-Line Chemotherapy for Metastatic Colorectal Cancer: A GERCOR Study 
The Oncologist  2011;16(9):1228-1238.
The present study was done to establish a prognostic model for patients and trials using an oxaliplatin-based or irinotecan-based first-line chemotherapy in metastatic colorectal cancer. Serum lactate dehydrogenase level was the main prognostic factor in predicting survival, followed by World Health Organization performance status. Three risk groups for death depending on these two baseline parameters were identified.
Learning Objectives
After completing this course, the reader will be able to: Describe prognostic factors in metastatic colorectal cancer.Estimate prognostic score with a simple model using only PS and LDH as parameters.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
The present study was done to establish a prognostic model for patients and trials using an oxaliplatin-based or irinotecan-based first-line chemotherapy in metastatic colorectal cancer.
Patients and Methods.
Eight hundred three patients treated with FOLFOX or FOLFIRI in three prospective trials were randomly separated into learning (n = 535) and validation (n = 268) samples. Eleven baseline variables were evaluated in univariate and multivariate analysis as prognostic factors for overall survival, and a prognostic score was developed.
Results.
Independent prognostic factors identified in multivariate analysis for overall survival were performance status (PS) (p < .001), serum lactate dehydrogenase (LDH) (p < .001), and number of metastatic sites (p = .005). A prognostic score based on these three variables was found efficient (Harrell's C index 0.61). This new model was improved by selecting only PS and LDH (Harrell's C index 0.64). Three risk groups for death could be identified: a low-risk group (n = 184; median overall survival [OS] 29.8 months), an intermediate-risk group (n = 223; median OS 19.5 months), and a high-risk group (n = 128; median OS 13.9 months). Median survival for the low-, intermediate-, and high-risk groups were 26.8, 21.1, and 16.5 months, respectively, in the validation sample (Harrell's C index 0.63).
Conclusions.
Serum LDH level was the main prognostic factor in predicting survival, followed by WHO PS. We identified three risk groups for death depending on these two baseline parameters. This simple prognostic model can be useful for clinician's use and patient stratification in future clinical trials.
doi:10.1634/theoncologist.2011-0039
PMCID: PMC3228179  PMID: 21859820
Colorectal cancer; Prognostic model; Chemotherapy
13.  Prognostic significance of pathological response after neoadjuvant chemotherapy or chemoradiation for locally advanced cervical carcinoma 
Background
Cisplatin-based chemoradiation is the standard of care for locally advanced cervical cancer patients; however, neoadjuvant modalities are currently being tested. Neoadjuvant studies in several tumor types have underscored the prognostic significance of pathological response for survival; however there is a paucity of studies in cervical cancer investigating this issue.
Methods
Four cohorts of patients with locally advanced cervical carcinoma (stages IB2-IIIB); included prospectively in phase II protocols of either neoadjuvant chemotherapy with 1) cisplatin-gemcitabine, 2) oxaliplatin-gemcitabine, 3) carboplatin-paclitaxel or 4) chemoradiation with cisplatin or cisplatin-gemcitabine followed by radical hysterectomy were analyzed for pathological response and survival.
Results
One-hundred and fifty three (86%) of the 178 patients treated within these trials, underwent radical hysterectomy and were analyzed. Overall, the mean age was 44.7 and almost two-thirds were FIGO stage IIB. Pathological response rates were as follows: Complete (pCR) in 60 cases (39.2%), Near-complete (p-Near-CR) in 24 (15.6 %) and partial (pPR) in 69 cases (45.1%). A higher proportion rate of pCR was observed in patients treated with chemoradiotherapy (with cisplatin [19/40, 47.5%]; or with cisplatin-gemcitabine [24/41, 58.5%] compared with patients receiving only chemotherapy, 6/23 (26%), 3/8 (37.5%) and 8/41 (19.5%) for cisplatin-gemcitabine, oxaliplatin-gemcitabine and carboplatin-paclitaxel respectively [p = 0.0001]). A total of 29 relapses (18.9%) were documented. The pathological response was the only factor influencing on relapse, since only 4/60 (6.6%) patients with pCR relapsed, compared with 25/93 (26.8%) patients with viable tumor, either pNear-CR or pPR (p = 0.001). Overall survival was 98.3% in patients with pCR versus 83% for patients with either pNear-CR or pPR (p = 0.009).
Conclusion
Complete pathological response but no Near-complete and partial responses is associated with longer survival in cervical cancer patients treated with neoadjuvant chemotherapy or chemoradiotherapy.
doi:10.1186/1477-7800-3-3
PMCID: PMC1386679  PMID: 16457727
14.  The Value of Ultrasound in Detecting Extra-Axillary Regional Node Involvement in Patients With Advanced Breast Cancer 
The Oncologist  2012;17(11):1402-1408.
The role of regional ultrasound in providing clinically relevant information was evaluated in the assessment of regional lymphatics for accurate staging and treatment of breast cancer patients. Regional ultrasound was found to be beneficial in initial staging evaluations.
Learning Objectives
After completing this course, the reader will be able to: Describe the ways in which regional ultrasound has contributed to more accurate staging in a population of locally advanced breast cancer patients.Explain how regional nodal information leads to changes in radiation therapy portals and total doses.Discuss the role of regional ultrasound in reflecting a truer level of disease burden in locally advanced breast cancer patients before therapies, including neoadjuvant chemotherapy, may limit knowledge of disease extent and consequently affect radiation treatment planning.
This article is available for continuing medical education credit at CME.TheOncologist.com
Assessment of the regional lymphatics is important for accurate staging and treatment of breast cancer patients. We sought to determine the role of regional ultrasound in providing clinically relevant information. We retrospectively analyzed data from patients who were treated curatively in 1996–2006 at The University of Texas MD Anderson Cancer Center for clinical stage III breast cancer. We compared differences in regional lymph node staging based on ultrasound versus mammography and physical examination in the 865 of 1,200 patients who had external-beam radiation as part of their treatment and regional ultrasound studies as part of their initial evaluation. Ultrasound uniquely identified additional lymph node involvement beyond the level I or II axilla in 37% of the patients (325 of 865), leading to a change in clinical nodal stage. Ninety-one percent of these abnormalities that could be biopsied (266 or 293) were confirmed to contain disease. The sites of additional regional nodal disease were: infraclavicular disease, 32% (275 of 865); supraclavicular disease, 16% (140 of 865); and internal mammary disease, 11% (98 of 865). All patients with involvement in the extra-axillary regional nodal basins received a radiation boost to the involved areas ≥10 Gy. Thus, over one third of patients with advanced breast cancer had their radiation plan altered by the ultrasound findings. Regional ultrasound evaluation in patients with advanced breast cancer commonly revealed abnormalities within and beyond the axilla, which changed the clinical stage of disease and the radiation treatment strategy. Therefore, regional ultrasound is beneficial in the initial staging evaluation for such patients.
doi:10.1634/theoncologist.2012-0170
PMCID: PMC3500360  PMID: 22982581
Regional ultrasound; Breast cancer; Staging; Locally advanced
15.  Adaptive 3D Image-Guided Brachytherapy: A Strong Argument in the Debate on Systematic Radical Hysterectomy for Locally Advanced Cervical Cancer 
The Oncologist  2013;18(4):415-422.
The outcomes of patients with locally advanced cervical cancer treated with three-dimensional image-guided brachytherapy after concomitant chemoradiation were evaluated. An excellent locoregional control rate with low treatment-related morbidity was observed, justifying the elimination of hysterectomy in the absence of obvious residual disease.
Learning Objectives
Evaluate control rates of IGABT combined with CCRT for the treatment of locally advanced cervical cancer.Describe survival outcomes in patients treated with IGABT combined with CCRT for locally advanced cervical cancer.Describe toxicities in patients treated with IGABT combined with CCRT for locally advanced cervical cancer.
Purpose.
To evaluate the outcomes of patients with locally advanced cervical cancer treated with three-dimensional image-guided brachytherapy (IGABT) after concomitant chemoradiation (CCRT).
Materials and Methods.
Data from patients treated with CCRT followed by magnetic resonance imaging-guided or computed tomography-guided pulsed-dose-rate brachytherapy, performed according to the Groupe Européen de Curiethérapie–European Society for Radiotherapy and Oncology guidelines, were reviewed. At first, stage I or II patients systematically underwent radical hysterectomy or were offered a randomized study evaluating hysterectomy. Then, hysterectomy was limited to salvage treatment.
Results.
Of 163 patients identified, 27% had stage IB, 57% had stage II, 12% had stage III, and 3% had stage IVA disease. The mean dose delivered (in 2-Gy dose equivalents) to 90% of the high-risk clinical target volume was 78.1 ± 9.6 Gy, whereas the doses delivered to organs at risk were maintained under the usual thresholds. Sixty-one patients underwent a hysterectomy. Macroscopic residual disease was found in 13 cases. With a median follow-up of 36 months (range, 5–79 months), 45 patients had relapsed. The 3-year overall survival rate was 76%. Local and pelvic control rates were 92% and 86%, respectively. According to the Common Toxicity Criteria 3.0, 7.4% of patients experienced late grade 3 or 4 toxicity. Most of those had undergone postradiation radical surgery (2.9% vs. 14.8; p = .005).
Conclusion.
IGABT combined with CCRT provides excellent locoregional control rates with low treatment-related morbidity, justifying the elimination of hysterectomy in the absence of obvious residual disease. Distant metastasis remains an important first relapse and may warrant more aggressive systemic treatment.
doi:10.1634/theoncologist.2012-0367
PMCID: PMC3639528  PMID: 23568003
Cervical cancer; Image-guided adaptive brachytherapy; Chemoradiation; Optimization; Dose escalation
16.  Lymphocele and Ovarian Cancer: Risk Factors and Impact on Survival 
The Oncologist  2012;17(9):1198-1203.
This retrospective study describes the incidence, impact on survival, and the risk factors for symptomatic lymphoceles in patients with ovarian cancer.
Learning Objectives
After completing this course, the reader will be able to: Identify risk factors for lymphoceles after cytoreductive surgery in ovarian cancer.Describe the impact of lymphocleles on outcomes in women with ovarian cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com
Introduction.
We describe the incidence, impact on survival, and the risk factors for symptomatic lymphoceles in patients with ovarian cancer.
Methods.
This retrospective study includes patients with ovarian cancer who had complete cytoreductive surgery and para-aortic and pelvic lymphadenectomy performed in our institute from 2005 to 2011. Patients were classified into two groups: patients with symptomatic lymphoceles and a control group.
Results.
During the study period, 194 patients with epithelial ovarian cancer underwent cytoreductive surgery and a lymphadenectomy without macroscopic residual disease. Fifty-four patients had symptomatic lymphoceles (28%). In the multivariate analysis, only supraradical surgery was significantly and independently associated with the risk of symptomatic lymphoceles occurring postoperatively. Median follow-up was 24.8 months (range, 1–74 months). Survival rates were not significantly different between the symptomatic lymphocele group and the control group. Two-year disease-free survival rates were 54% for the lymphocele group and 48% for the control group. Two-year overall survival rates were 90% for the lymphocele group and 88% for the control group.
Conclusions.
Symptomatic lymphoceles occur frequently after cytoreductive surgery in ovarian cancer. Supraradical surgery is an independent risk factor. The occurrence of symptomatic lymphoceles does not decrease survival. Nevertheless, further studies are needed to reduce the risk of lymphoceles in such patients.
doi:10.1634/theoncologist.2012-0088
PMCID: PMC3448413  PMID: 22707515
Lymphadenectomy; Ovarian cancer; Lymphocele; Cytoreductive surgery; Survival
17.  Approval Summary: Pemetrexed Maintenance Therapy of Advanced/Metastatic Nonsquamous, Non-Small Cell Lung Cancer (NSCLC) 
The Oncologist  2010;15(12):1352-1358.
The study that led to U.S. Food and Drug Administration approval of pemetrexed injection for maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based doublet induction chemotherapy is reviewed.
Learning Objectives
After completing this course, the reader will be able to: Consider tumor histology when making treatment decisions for patients with NSCLC.Identify patients with NSCLC who may be appropriate candidates for maintenance therapy with pemetrexed.
This article is available for continuing medical education credit at CME.TheOncologist.com.
On July 2, 2009, the U.S. Food and Drug Administration approved pemetrexed injection (Alimta® Injection; Eli Lilly and Company, Indianapolis, IN) for maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based doublet induction chemotherapy.
A double-blind study of pemetrexed plus best supportive care versus placebo plus best supportive care was conducted. Pemetrexed, 500 mg/m2 i.v., was administered every 21 days until disease progression. Folic acid, vitamin B12, and a corticosteroid were given to all study patients.
There were 663 randomized patients (pemetrexed, 441; placebo, 222). Treatments were well balanced with respect to baseline disease characteristics and stratification factors.
The median overall survival (OS) time for intent-to-treat (ITT) patients was 13.4 months for patients receiving pemetrexed and 10.6 months for those receiving placebo (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.65–0.95; p = .012). Median OS times were 15.5 months versus 10.3 months for patients with nonsquamous histologies receiving pemetrexed and placebo, respectively (HR, 0.70; 95% CI, 0.56–0.88). The median OS time in patients with squamous histology receiving pemetrexed was 9.9 months, versus 10.8 months for those receiving placebo (HR, 1.07; 95% CI, 0.77–1.50). A significantly longer progression-free survival interval for both the ITT and nonsquamous patient populations receiving pemetrexed maintenance therapy was also observed.
The most common (>5%) adverse reactions in patients receiving pemetrexed were hematologic toxicity, an increase in hepatic enzymes, fatigue, gastrointestinal toxicity, sensory neuropathy, and skin rash.
doi:10.1634/theoncologist.2010-0224
PMCID: PMC3227931  PMID: 21148615
Pemetrexed; Non-small cell lung cancer; Maintenance treatment
18.  The role of neoadjuvant and adjuvant treatment for adenocarcinoma of the upper gastrointestinal tract 
Both locally advanced adenocarcinoma of the stomach and gastro-esophageal junction are associated with poor prognosis due to the lack of effective treatment. Recently multimodal treatment consisting of neoadjuvant chemotherapy in combination with radiotherapy is reported to improve survival when compared to surgery alone. Neoadjuvant therapy in these locally advanced tumors allows for early tumor responses and the extent of tumor regression that can be achieved is considered a significant prognostic factor. This, in turn, increases the resectability of these tumors. Also due to the high frequency of lymph node metastasis, patients with locally advanced adenocarcinoma should undergo a D2 lymphadenectomy. Postoperative chemoradiation and perioperative chemotherapy have been studied in gastric adenocarcinomas and showed a survival benefit. However, the surgical techniques used in these trials are no longer considered to be standard by today's surgical practice. In addition, there are no standard recommendations for adjuvant chemotherapy or chemoradiation after R0 resection and adequate lymph node dissection.
doi:10.1186/2047-783X-16-6-265
PMCID: PMC3353402  PMID: 21810561
19.  Neoplastic Meningitis from Solid Tumors: New Diagnostic and Therapeutic Approaches 
The Oncologist  2011;16(8):1175-1188.
The most recent and interesting developments on diagnostic and therapeutic approaches in the treatment of neoplastic meningitis from solid tumors are reviewed.
Learning Objectives
After completing this course, the reader will be able to: Compare the use of i.t. therapy and systemic therapies for patients with neoplastic meningitis.Describe new drugs showing promise for neoplastic meningitis.
This article is available for continuing medical education credit at CME.TheOncologist.com
Neoplastic meningitis is a result of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. This event occurs in 4%–15% of all patients with solid tumors and represents an important prognostic factor for poor survival. Neoplastic meningitis should be diagnosed in the early stages of disease to prevent important neurological deficits and to provide the most appropriate treatment. Despite new diagnostic approaches developed in recent years, such as positron emission tomography–computed tomography and new biological markers, the combination of magnetic resonance imaging without and with gadolinium enhancement and cytology still has the greatest diagnostic sensitivity.
Recently, no new randomized studies comparing intrathecal (i.t.) with systemic treatment have been performed, yet there have been a few small phase II studies and case reports about new molecularly targeted substances whose successful i.t. or systemic application has been reported. Trastuzumab, gefitinib, and sorafenib are examples of possible future treatments for neoplastic meningitis, in order to better individualize therapy thus allowing better outcomes.
In this review, we analyze the most recent and interesting developments on diagnostic and therapeutic approaches.
doi:10.1634/theoncologist.2011-0101
PMCID: PMC3228160  PMID: 21795431
Neoplastic meningitis; Leptomeningeal disease; Leptomeningeal carcinomatosis; Solid tumors; Targeted therapy; Brain tumors
20.  Calcium and Vitamin D Supplementation During Androgen Deprivation Therapy for Prostate Cancer: A Critical Review 
The Oncologist  2012;17(9):1171-1179.
Guidelines and studies on calcium and vitamin D supplementation in men with prostate cancer undergoing androgen deprivation therapy were reviewed. The authors conclude that the doses tested are inadequate to prevent loss of bone mineral density and that intervention studies are needed to evaluate safety and efficacy of calcium and vitamin D supplements in these men.
Learning Objectives
After completing this course, the reader will be able to: Describe the prevalence of bone loss with androgen deprivation therapy for prostate cancer.Discuss the possible increased risk of cardiovascular disease and of advanced prostate cancer with high calcium intake.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Loss of bone mineral density is an unintended consequence of androgen deprivation therapy in men with prostate cancer. Supplementation with calcium and/or vitamin D in these men seems logical and is advocated by many lay and professional groups.
Methods.
We reviewed guidelines for calcium and vitamin D supplementation and the results of clinical trials of calcium and vitamin D supplementation on bone mineral density in men with prostate cancer undergoing androgen deprivation therapy.
Results.
Whether supplementation of men undergoing androgen deprivation therapy with calcium and/or vitamin D results in higher bone mineral density than no supplementation has not been tested. The results of 12 clinical trials show that, at the doses commonly recommended, 500–1,000 mg calcium and 200–500 IU vitamin D per day, men undergoing androgen deprivation lose bone mineral density.
Conclusion.
The doses of calcium and vitamin D that have been tested are inadequate to prevent loss of bone mineral density in men undergoing androgen deprivation therapy. In light of evidence that high levels of dietary calcium and calcium supplement use are associated with higher risks for cardiovascular disease and advanced prostate cancer, intervention studies should evaluate the safety as well as the efficacy of calcium and vitamin D supplementation in these men.
doi:10.1634/theoncologist.2012-0051
PMCID: PMC3448410  PMID: 22836449
Calcium; Vitamin D; Bone mineral density; Prostate cancer; Androgen deprivation therapy; Clinical trials
21.  Advances in First-Line Treatment for Patients with HER-2+ Metastatic Breast Cancer 
The Oncologist  2012;17(5):631-644.
The results of a literature review of well-established and recently published trials, reviews, and ongoing clinical trials examining first-line treatment for human epidermal growth factor receptor 2–positive metastatic breast cancer patients are presented.
Learning Objectives:
After completing this course, the reader will be able to: Discuss the optimal strategies to treat HER-2+ metastatic breast cancer patients in the first-line setting and after recurrence with adjuvant trastuzumab.Identify the current first-line therapeutic options for HER-2+ metastatic breast cancer, including HER-2/hormone receptor copositive tumors.Discuss the most important advances for HER-2+ metastatic breast cancer and the potential of novel anti-HER-2 therapies.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
The prognosis for breast cancer patients overexpressing human epidermal growth factor receptor (HER)-2 has changed with anti–HER-2–targeted therapy. Although anti–HER-2 therapy with trastuzumab and chemotherapy is the standard first-line treatment, the best therapeutic regimen has yet to be defined, and new strategies are evolving.
Methods.
A literature review of well-established and recently published trials, reviews, and ongoing clinical trials addressing first-line treatment for HER-2+ metastatic breast cancer patients was performed.
Results.
Taxanes are the agents most commonly used in combination with trastuzumab, but other chemotherapy drugs, such as anthracyclines, vinorelbine, and gemcitabine and triple-combination therapies including platinum compounds, capecitabine, and taxanes have been studied. The combination of aromatase inhibitors with anti–HER-2 therapies is a new therapeutic option for some patients who coexpress HER-2 and hormone receptors, although its activity observed in randomized clinical trials seems to be inferior to that of chemotherapy plus anti–HER-2 therapies. In addition, new anti–HER-2 therapies have shown activity in HER-2+ tumors, both alone and in combination with trastuzumab.
Conclusions.
Trastuzumab plus chemotherapy is the current standard of care for the upfront treatment of HER-2+ breast cancer patients, though other anti–HER-2–targeting agents may appear as new standards in the upcoming years.
doi:10.1634/theoncologist.2011-0187
PMCID: PMC3360903  PMID: 22523199
Metastatic breast cancer; HER-2+; Trastuzumab; First-line treatment
22.  Molecular Diagnosis of Response to Neoadjuvant Chemoradiation Therapy in Patients with Locally Advanced Rectal Cancer 
Background
Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) is an important prognostic factor in locally advanced rectal cancer. However, it is uncertain whether histopathological techniques accurately detect pCR. We tested a novel molecular approach for detecting pCR and compared it to current histopathological approaches.
Study design
Pre-treatment tumor biopsies and surgical specimens were collected from 96 patients with locally advanced rectal cancer treated with neoadjuvant CRT and surgery. Tumor response was categorized by tumor regression grade (TRG). Tumor DNA from pre-CRT tumor biopsies was screened for K-ras and p53 mutations. DNA from paired surgical specimens was then screened for the same mutations using highly sensitive polymerase chain reaction (PCR)-based techniques.
Results
Sixty-eight out of 96 (71%) pre-treatment biopsies harbored K-ras and/or p53 mutation; 36 (38%) had K-ras mutations, 52 (54%) had p53 mutations and 20 (21%) carried both mutations. Of 70 patients with TRG 1–3, 66 (94%) had a concordant K-ras and p53 mutation profile in pre- and post-treatment tissues. Of 26 patients with TRG 0 (pCR), 12 had K-ras or p53 mutations in pre-treatment biopsies. Of these, 2 (17%) patients had the same K-ras (n=1) or p53 (n=1) mutation detected in post-treatment tissue.
Conclusions
Sensitive molecular techniques detect K-ras and p53 mutations in post-CRT surgical specimens in some patients with a pCR. This suggests histopathological techniques may not be completely accurate, and that some patients diagnosed with a pCR to CRT may indeed have occult cancers cells in their surgical specimens with K-ras and p53 mutations serving as reliable surrogates for residual disease.
doi:10.1016/j.jamcollsurg.2011.02.024
PMCID: PMC3104075  PMID: 21458303
chemoradiation; surgery; rectal cancer; molecular analysis; K-ras; p53
23.  Prospective Phase II Study of Preoperative Chemoradiation with Capecitabine in Locally Advanced Rectal Cancer 
Purpose
Capecitabine is an attractive oral chemotherapeutic agent that has a radiosensitizing effect and tumor-selectivity. This study was performed to evaluate the efficacy and toxicity of preoperative chemoradiation therapy, when used with oral capecitabine, for locally advanced rectal cancer.
Materials and Methods
A prospective phase II trial of preoperative chemoradiation for locally advanced adenocarcinomas of the lower two-thirds of the rectum was conducted. A radiation dose of 50 Gy over five weeks and a daily dose of 1650 mg/m2 capecitabine in two potions was administered during the entire course of radiation therapy. Surgery was performed with standardized total mesorectal excision four to six weeks after completion of the chemoradiation.
Results
Between January 2002 and September 2003, 61 patients were enrolled onto this prospective phase II trial. The pretreatment clinical stages were T3 in 64% (n=39), T4 in 36% (n=22) and N1-2 in 82% (n=50) of these patients. Fifty-six (92%) patients completed the chemoradiation as initially planned and a complete resection performed in 58 (95%). Down-staging was observed in 45 patients (74%) and a pathologic complete response in 6 (10%). Among the 37 patients with tumors located within 5 cm from the anal verge on colonoscopy, 27 (73%) underwent a sphincter-preserving procedure. No grade 3 and 4 proctitis or hematological toxicities were observed.
Conclusion
Preoperative chemoradiation therapy with capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation, with a low toxicity profile. This combined modality can be regarded as a safe and effective treatment for locally advanced rectal cancer.
doi:10.4143/crt.2004.36.6.354
PMCID: PMC2843876  PMID: 20368828
Rectal cancer; Preoperative; Chemoradiotherapy; Capecitabine
24.  Approval Summary: Erlotinib Maintenance Therapy of Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC) 
The Oncologist  2010;15(12):1344-1351.
Results of the trial that led to the U.S. Food and Drug Administration's recent approval of erlotinib as first-line maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer whose disease has not progressed (including stable disease) on first-line treatment with platinum-based chemotherapy are presented.
Learning Objectives
After completing this course, the reader will be able to: Evaluate the relationship between EGFR mutation status and clinical outcomes reported in this study.Identify patients with NSCLC who may be appropriate candidates for first-line maintenance therapy with erlotinib.
This article is available for continuing medical education credit at CME.TheOncologist.com.
On April 16, 2010, the U. S. Food and Drug Administration (FDA) approved erlotinib tablets (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY) for maintenance treatment of patients with stage IIIB/IV non-small cell lung cancer (NSCLC) whose disease had not progressed after four cycles of platinum-based first-line chemotherapy.
In total, 889 patients received either erlotinib (150 mg) or placebo once daily. Progression-free survival (PFS), in all patients and in patients with epidermal growth factor receptor (EGFR)+ tumors by immunohistochemistry (IHC), was the primary efficacy endpoint. Overall survival (OS) was a secondary sponsor endpoint but was the primary regulatory endpoint.
Median PFS times were 2.8 months and 2.6 months in the erlotinib and placebo arms, respectively (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.62–0.82; p < .001). Median OS times were 12.0 months and 11.0 months, favoring erlotinib (HR, 0.81; 95% CI, 0.70–0.95). The PFS and OS HRs in patients with EGFR+ tumors by IHC were 0.69 (95% CI, 0.58–0.82) and 0.77 (95% CI, 0.64–0.93), respectively. The PFS and OS HRs in patients with EGFR− tumors by IHC were 0.77 (95% CI, 0.51–1.14) and 0.91 (95% CI, 0.59–1.38), respectively.
Following disease progression, 57% of placebo-treated patients received additional chemotherapy, compared with 47% of erlotinib-treated patients. Fourteen percent of placebo-treated patients received erlotinib or gefitinib, 31% received docetaxel, and 14% received pemetrexed. In total, 59% of placebo-treated patients who received treatment received FDA approved second-line NSCLC drugs.
The most common adverse reactions in patients receiving erlotinib were rash and diarrhea.
doi:10.1634/theoncologist.2010-0257
PMCID: PMC3227916  PMID: 21148614
Erlotinib; Non-small cell lung cancer; Maintenance treatment
25.  Targeted Therapy in the Management of Advanced Gastric Cancer: Are We Making Progress in the Era of Personalized Medicine? 
The Oncologist  2012;17(3):346-358.
The underlying molecular basis, current clinical evidence, and ongoing trials supporting the use of targeted agents in the treatment of patients with advanced gastric cancer are summarized. Future perspectives are explored, including predictive biomarkers and novel signaling pathways.
Learning Objectives
After completing this course, the reader will be able to: Identify the subset of advanced gastric cancer patients who might benefit from approved anti-HER2 therapy.Explain the cellular signaling pathways and the biological rationale of novel targeted agents in the management of advanced gastric cancer.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Gastric cancer is one of the leading causes of cancer death. With greater understanding of the molecular basis of carcinogenesis, targeted agents have led to a modest improvement in the outcome of advanced gastric cancer (AGC) patients.
Methods and Results.
We conducted an overview of the published evidence regarding the use of targeted therapy in AGC patients. Thus far, the human epidermal growth factor receptor (HER) pathway, angiogenic pathway, and phosphatidylinositol-3-kinase (PI3K)–Akt–mammalian target of rapamycin pathway have emerged as potential avenues for targeted therapy in AGC patients. The promising efficacy results of the Trastuzumab for Gastric Cancer trial led to the approved use of trastuzumab-based therapy as first-line treatment for patients with HER-2+ AGC. On the other hand, the Avastin® in Gastric Cancer trial evaluating bevacizumab in combination with chemotherapy did not meet its primary endpoint of a longer overall survival duration despite a significantly higher response rate and longer progression-free survival time in patients in the bevacizumab arm. Phase III data are awaited for other targeted agents, including cetuximab, panitumumab, lapatinib, and everolimus.
Conclusion.
Recent progress in targeted therapy development for AGC has been modest. Further improvement in the outcome of AGC patients will depend on the identification of biomarkers in different patient populations to facilitate the understanding of gastric carcinogenesis, combining different targeted agents with chemotherapy, and unraveling new molecular targets for therapeutic intervention.
doi:10.1634/theoncologist.2011-0311
PMCID: PMC3316920  PMID: 22334453
Advanced gastric cancer; Angiogenic pathway; Biomarker; Epidermal growth factor Pathway; Targeted therapy

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