Favorable Pathologic Response Research Articles

Generalized or personalized treatment for stage IIIA-N2 non-small-cell lung cancer?

The optimal approach to and the role of surgery in stage IIIA – N2 (ipsilateral lymph node metastases) non-small-cell lung cancer (NSCLC) remains a challenge for many clinical oncologists. Much of the question relates to the choice between a generalized or personalized approach. We should realize that a generalized approach – ‘chemoradiotherapy fits all’ – as advocated by some based on Phase III trials – is not optimal for these patients, just as ‘any platinum doublet fits all’ is no longer the best choice in stage IV NSCLC. While chemoradiotherapy may be the choice for patients with bulky or multilevel N2-disease, for others surgery will be an important part of the multimodality treatment. To make this distinction, ‘personalization factors’ should be considered: complete resectability, downstaging of mediastinal nodes and favorable clinical and pathological response of the primary tumor. A personalized approach making the appropriate choice based on multidisciplinary assessment of stage, resectability and cardiopulmonary fitness is in the interest of each of our individual stage IIIA – N2 patients.

Neoadjuvant therapy of gastric cancer with cetuximab added to both irinotecan and cisplatin, followed by surgical resection and adjuvant chemoradiation

e15552 Background: We previously demonstrated the efficacy of irinotecan (CPT) and cisplatin (Cis) combination therapy as neoadjuvant therapy for locally advanced gastric cancer [Newman E et al. J Gastrointest Surg. 2002.]. This trial was designed to add cetuximab (C) to both induction treatment and adjuvant chemoradiation (CRT) with bolus 5-FU/LV. Methods: Pts with untreated locally advanced (T3, T4 or N+) gastric/GE cancers were eligible. Neoadjuvant therapy consisted of Cis 25mg/m2 + CPT 75mg/m2 on d1,8 q21d x 4, C 400mg/m2 on d1, then 250mg/m2 qwk. Curative (R0) resection was performed 4–6 wks later. Adjuvant CRT with 5-FU/LV (425/20/m2 qd x 5 on wks 1,14,19; 400/20/m2 qd x 4 on wk 5, x 3 on wk 9) was given with C 250mg/m2 qwk. Results: Since 11/05, 21 pts [median age 59 (32–82); 9 Caucasian, 11 Asian, 1 Hispanic; 15 male, 20 PS 0–1] received neoadjuvant therapy. The most common toxicities were gr 3 neutropenia (38%), gr 2 rash (33%), gr 2 fatigue (29%); gr 4 included 1 pt each of diarrhea, neutropenia, & hypomagnesemia. 3 did not complete neoadjuvant therapy, due to gr 3 rash, diarrhea and GI bleeding (2 had gastrectomy; 1 lost to f/u). All 18 pts who completed neoadjuvant therapy were surgically explored. 4 had occult metastases, and went off study. 14 underwent R0 gastrectomy (see table); 8 were downstaged, 2 had stable disease, 4 were upstaged compared to the preoperative EUS. There was no postoperative mortality. Of 14 resected pts, 2 did not receive adjuvant therapy (prolonged postoperative recovery), 1 too early to assess, and 11 remaining receiving CRT. The most common toxicities for CRT were gr 3 nausea, gr 3 emesis, gr 2 and 3 fatigue, 3 pts each and 1 each of gr 4 neutropenia and thrombocytopenia. Among the 18 pts who completed neoadjuvant therapy, 5 died of disease, 1 is alive with disease, 12 remain NED with median f/u of 11.6mos (4.1–27.7mos). Conclusions: The addition of C to CPT/Cis as neoadjuvant therapy and to postoperative adjuvant CRT is well tolerated. The regimen induces a favorable pathologic response on the primary tumor. Ongoing evaluation includes K-ras mutation status on outcome and survival benefit. [Supported in part by a grant from BMS.] [Table: see text]

Diffuse optical spectroscopic imaging measures tumor functional response to bevacizumab: initial studies.

Abstract Abstract #6056 Background: Diffuse Optical Spectroscopic Imaging (DOSI) is a non-invasive, bedside functional imaging technique that quantifies the concentrations and molecular states of tissue hemoglobin, water, and lipids. Pilot studies have shown that DOSI may be a useful tool for quantifying neoadjuvant chemotherapy response, typically by comparing the degree of change in tumor water and deoxy-hemoglobin concentrations before and after therapy. DOSI may offer a point-of-care measurement of tumor responses to therapeutic intervention. The majority of these DOSI studies have measured responses to Anthracyclines. However, the optical response to Bevacizumab has not been demonstrated in vivo in human subjects.
 Materials and Methods: Twenty-one patients diagnosed with stage II/III cancers were followed with DOSI prior to and during their two-stage neoadjuvant chemotherapy regimen that featured (a) Anthracyclines (2-4 cycles) and (b) Trastuzumab/Bevacizumab (for HER2+/HER2- status, respectively). Changes between pre-treatment and pre-surgical DOSI-measured parameters were compared against final surgical pathology (complete, partial, or non-responder). A functional tissue optical index (TOI) was calculated that has been shown to discriminate between normal and malignant tissues.
 Results: Both short-term and long-term changes in tumor physiology were observed. For both therapy strategies (N=21), statistically significant changes were measured in TOI from baseline to pre-surgery between complete (95+/-15%), partial (79+/-11%) and non-responders (38+/-42%). TOI changes after the initial therapy stage were strongest in patients with more favorable pathological responses (78%, 56%, and 12% for complete, partial, and non-responders respectively). For patients receiving Bevacizumab (N=9), more detailed serial image analysis of tumor deoxy-hemoglobin revealed short-term changes (7-14 days) where initial decreases in hemoglobin were soon followed by slow increases back to pre-treatment levels. Two of the patients who received Bevacizumab demonstrated detectible residual disease by DOSI after completion of all neoadjuvant therapy, despite that contrast-enhanced MRI signals had disappeared.
 Discussion: We have provided evidence that DOSI may be well-suited to monitor the response of different cancer drugs, including anti-angiogenic compounds such as Bevacizumab, in breast cancer patients. While the usage of Bevacizumab in human subjects is still under investigation in breast cancer, we foresee that DOSI may be a useful tool in general for the development of drugs and dosing strategies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6056.

The alternation of estrogen receptor (ER) and progesterone receptor (PgR) expression in primary breast cancer patients treated with neoadjuvant chemotherapy (NAC)

21165 Background: Currently, neoadjuvant chemotherapy (NAC) for the operable primary breast cancer has become standard treatment strategy. Primary treatment could affect the status of Estrogen receptor (ER) and Progesterone receptor (PgR) expressions in the tumor, and might have impact on the choice of adjuvant hormone therapy. Methods: We evaluated consecutive 165 primary breast cancer cases those treated with 4 cycles of FEC (500–100–500 mg/m2, q3wks) followed by 4 cycles docetaxel (75 mg/m2, q3wks) as their neoadjuvant treatment in our institution from January 2000 to February 2006. Except for the bilateral breast cancer cases and patients achieved pCR, 107 pairs of core needle biopsy before treatment and tumor block after surgery were evaluated by immunohistochemistry (IHC) for receptor status and analyzed by Allred scoring. Score 4 or more was designated as positive. Results: Median age of patients was 51 (23–71) years old. Hormone receptor (HR) phenotypes before treatment were following; ER+/PgR+:62(57.9%), +/ -:23(21.5%), -/ +:2(1.9%), -/ -:20(18.7%). As the HR status, 94.4 % of patients did not show any alternation for their HR evaluation. Only 4.7% of patients experienced changes from HR+ to HR-, and HR- to HR+ were extremely rare (0.9%). Although ER positivity was not changed in most of cases (95.1%), conversion from PgR + to - were observed in 35.5% of ER+/PgR+ cases. Particularly, the rate of negative conversion of PgR were found more frequently in patients with age under 50 (51.7% in <50y.o. vs. 22.6% in =50 y.o., p=0.03). Whereas, in older patients, negative conversion of PgR correlated to favorable pathological response. Conclusions: In most of patients, neoadjuvant chemotherapy did not affect the evaluation of HR status. Alternation of PgR expression seems to reflect the chemotherapy induced amenorrhea in younger patients. In the older patients, negative conversion of PgR may have some impact on pathological response. No significant financial relationships to disclose.