Pilot study examining tumor expression of RAD51 and clinical outcomes in human head cancers

Radiation therapy and chemotherapy are commonly used treatments for head and neck cancer. RAD51 is a highly conserved DNA repair protein that serves a central function in the homologous recombination pathway. High levels of RAD51 protein expression have been reported in number of human cancer cell lines, and studies suggest that RAD51 overexpression can increase cellular resistance to radiation and some chemotherapeutic drugs. In this study, RAD51 protein levels were quantified by immunohistochemistry in tumor samples from twelve head and neck cancer patients who received identical treatment with induction chemotherapy (paclitaxel and carboplatinum) followed by radiation therapy given concurrently with additional chemotherapy (paclitaxel, fluorouracil, hydroxyurea). Patients with high RAD51 protein levels in their pre-treatment tumor biopsies demonstrated poorer cancer-specific survival rates than patients with lower RAD51 levels (33.3% vs. 88.9% at 2 years; p=0.025). In addition, within a subgroup of patients with normal tumor cell p53 expression, there was a non-significant trend toward better induction chemotherapy response rates observed in the tumors with lower RAD51 protein levels. These results suggest that tumor cell RAD51 expression levels may influence the outcome of patients with head and neck cancer treated with chemotherapy and radiotherapy.     

Induction paclitaxel and carboplatin for patients with head and neck carcinoma. Analysis of 62 patients treated between 1994 an 1999

BACKGROUND: After standard therapy for advanced head and neck carcinoma, 5-year survival rate is less than 50%. Our purpose was to develop a new treatment for advanced head and neck carcinoma by using preoperative chemotherapy. Long term efficacy and toxicity of induction paclitaxel and carboplatin is reported here. METHODS: Between 1994 and 1999, 62 consecutive patients with newly diagnosed head and neck carcinoma were treated with paclitaxel and carboplatin induction chemotherapy. Chemotherapy was administered every 21 days with 3 courses of paclitaxel (150-265 mg/m(2)) and carboplatin at a dose calculated using the Calvert formula area under the curve of 7.5. Patients who achieved complete or partial response at the primary received definitive radiation to the primary tumor and those with lymph node disease received neck dissection followed by radiation to the regional lymph nodes. Nonresponders received standard resection of primary tumor and draining lymph node basin followed by radiation. RESULTS: Sixty-two consecutive patients were treated. Seventy-four percent had Stage IV (according to the 5th edition of American Joint Committee on Cancer Staging manual) disease. The median duration of follow-up from initiation of chemotherapy was 64 weeks (range, 1-272 weeks). Overall complete plus partial response rate was 41 of 62 (66%). Responses were observed at all anatomic sites: oropharynx 20 of 33 (61%); hypopharynx 8 of 12 (67%); and larynx 13 of 17 (76%). Kaplan-Meier estimates of overall survival (OS), at 230 weeks, were significantly better in Stage IV oropharynx/hypopharynx responders than nonresponders (55% vs. 27%; P = 0.04). Of the variables evaluated in multivariate models, response at the primary tumor and lymph nodes were associated with improved disease free survival and OS. Organ preservation was achieved in 28 of 62 (45%) of patients at all anatomic sites: oropharynx 39%, hypopharynx 42%, larynx 59%. Seventeen of 28 (61%) patients had their primary organ site preserved for a mean duration of 78 weeks (range, 13-238 weeks). CONCLUSIONS: Induction paclitaxel and carboplatin was well tolerated. The response rate was encouraging considering most patients were Stage IV. Chemotherapy response identified a group with improved prognosis. Organ preservation was possible at all anatomic sites.     

Intensity-modulated radiotherapy with concurrent chemotherapy for previously irradiated, recurrent head and neck cancer

PURPOSE: Primary treatment fails in >70% of locally advanced head and neck cancer patients. Salvage therapy has a 30-40% response rate, but few long-term survivors. Intensity-modulated radiotherapy (IMRT) has recently emerged as a new modality for salvage therapy. This retrospective study evaluated our experience using every-other-week IMRT with concurrent chemotherapy. METHODS AND MATERIALS: Between 2001 and 2006, 41 patients underwent IMRT as repeat RT with concurrent chemotherapy. All but 6 patients received 60 Gy at 2 Gy/fraction. RT was delivered on an alternating week schedule. RESULTS: With a median follow-up time of 14 months, the overall response rate was 75.6%, with a complete response and partial response rate of 58.5% and 17.1%, respectively. The Kaplan-Meier estimate of overall survival, disease-free survival, and progression-free survival at 24 months was 48.7%, 48.1%, and 38%, respectively. Patients who underwent surgery as a part of their salvage therapy had a mean estimated survival of 30.9 months compared with 22.8 months for patients who received only chemoradiotherapy (p = 0.126). Grade 3 or 4 acute toxicities occurred in 31.7% of patients, but all had resolved within 2 months of therapy completion. No deaths occurred during treatment, except for 1 patient, who died shortly after discontinuing treatment early because of previously undiagnosed metastatic disease; 6 patients had long-term complications. CONCLUSIONS: Concurrent chemotherapy with repeat radiotherapy with IMRT given every other week appears to be both well tolerated and feasible in patients treated with previous radiotherapy for recurrent head and neck cancer. IMRT represents a reasonable modality for reducing treatment-related toxicities in a repeat RT setting.     

Second-line chemotherapy in gastric cancer following S-1 with CPT-11 chemotherapy performed as clinical trial

We previously conducted a phase I/II study of irinotecan (CPT-11) combined with S-1 as first-line chemotherapy for metastatic advanced gastric cancer. In the present study,second-line chemotherapy was given to 32 of 44 patients whose disease became refractory to this first-line treatment. Overall survival time of the patients given second-line chemotherapy was significantly longer than that of patients not given such therapy (444 days vs. 230 days, p = 0.013). The response rate to second-line chemotherapy was 13% (4/32). Survival time of patients who responded to second-line chemotherapy was significantly longer than that of non-responders. Second-line chemotherapy may produce a better clinical response in patients who have progressive disease during first-line chemotherapy. Overall survival time and time to progression after second-line chemotherapy did not significantly differ between patients who received second-line chemotherapy regimens including S-1 and those who received regimens not including S-1.     

Combination chemotherapy, radiotherapy, and BCG immunotherapy in limited small-cell carcinoma of the lung: a Southwest Oncology Group Study

From November 1976 to March 1979 the Southwest Oncology Group treated 298 patients with limited (disease confined to the chest and encompassed by one radiotherapy port) small-cell carcinoma of the lung with combination chemotherapy and radiotherapy with or without BCG immunotherapy. Two induction chemotherapy programs were utilized: (1) cyclophosphamide, vincristine, methotrexate, fluorouracil; or (2) cyclophosphamide, doxorubicin, and vincristine. Patients received 4500 rads of radiation therapy to the bulk primary tumor and 3000 rads to whole brain followed by maintenance chemotherapy. One-half of all the patients were randomized to receive one vial (5 x 10(8)) of high viability Pasteur BCG by scarification technique given on days 8 and 15 of each 21--28 day treatment cycle. Increased granulocytopenia accompanied the addition of BCG immunotherapy. Patients receiving BCG achieved a response rate of 49% vs. those patients not receiving BCG of 44% (P = 0.579). Median response duration was 40 weeks for the BCG arms and 38 weeks for the arms without BCG; survival was no different, 42 weeks for the BCG arms vs. 50 weeks for the arms without BCG. In patients who responded to therapy and survived longer than one year, those who continued to receive BCG therapy demonstrated a slight, yet significant, survival benefit over those patients not receiving BCG (93 weeks vs. 81 weeks, P = 0.03). It appears that BCG immunotherapy has no beneficial effect on response rate, duration of response, or survival in programs using chemotherapy and radiotherapy for control of limited small-cell carcinoma of the lung except in this small group of long-term survivors.     

Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer

PURPOSE: Neck dissection has traditionally played an important role in the treatment of patients with squamous cell carcinoma of the head and neck who present with regionally advanced neck disease (N2-N3). Radiotherapy and concurrent chemotherapy improves overall survival in advanced head-and-neck cancer compared with radiotherapy alone. The necessity for postchemoradiation neck dissection is controversial. The intent of this report was to define the value of neck dissection in this patient population better. METHODS AND MATERIALS: Patients with locally advanced squamous carcinoma of the head and neck who also presented with nodal disease and underwent hyperfractionated radiotherapy and concurrent cisplatin/5-fluorouracil chemotherapy constituted the study population. Adjuvant modified neck dissection (MND) was planned 6 to 8 weeks after completion of chemoradiation in those patients who had a biopsy-proven pathologically complete response at the primary tumor site, irrespective of the clinical/radiographic neck response. A cohort of patients underwent electrode assessment of tumor oxygenation. Pathologic findings from the MND were used to compute the negative and positive predictive values and overall accuracy of the clinical/radiographic response (cCR). Regional control, failure-free survival, and survival were compared according to whether patients actually underwent MND. RESULTS: A total of 154 patients received concurrent chemoradiation. Of these, 108 presented with nodal disease: N1, n = 30; and N2-N3, n = 78. MND was performed in 65 (60%) of 108 patients, including 13 (43%) of 30 with Stage N1 and 52 (66%) of 78 with Stage N2-N3. For N1 patients, the negative predictive value of a cCR, positive predictive value of less than a cCR, and the overall accuracy for clinical response was 92%, 100%, and 92%, respectively. For N2-N3 patients, the corresponding values were 74%, 44%, and 60%. Patients with poorly oxygenated tumors were more likely to have residual disease at MND. The median follow-up was 4 years. The 4-year disease-free survival rate was 70% for N1 patients, irrespective of the clinical response or whether MND was performed. The 4-year disease-free survival rate was 75% for N2-N3 patients who had a cCR and underwent MND vs. 53% for patients who had a cCR but did not undergo MND (p = 0.08). The 4-year overall survival rate was 77% vs. 50% for these two groups of patients (p = 0.04). CONCLUSION: The clinical and pathologic responses in the neck correlated poorly with one another for patients with N2-N3 neck disease undergoing concurrent chemoradiation for advanced head-and-neck cancer. MND still appears to confer a disease-free survival and overall survival advantage with acceptably low morbidity. Tumor oxygenation assessment may be useful in selecting patients who are especially prone to have residual disease. Better tools need to be developed to determine prospectively whether this procedure is required for individual patients.     

The dynamics of plasma transforming growth factor beta 1 (TGF-beta1) level during radiotherapy with or without simultaneous chemotherapy in advanced head and neck cancer

To assess the plasma TGF-beta1 level during radio(chemo)therapy and to test the predictive power of TGF-beta1 for treatment response in patients with advanced head and neck cancer. Twenty nine patients with advanced head and neck cancer were treated with curative radio(chemo)therapy. Plasma TGF-beta1 level was established at the beginning, in the middle and at the end of the therapy. The dynamics of the TGF-beta1 level was assessed separately for patients with and without chemotherapy. Treatment response was correlated to the TGF-beta1 level. Eighteen patients achieved complete remission, eight partial remission and three patients progressed. Patients treated with radiotherapy had significantly higher initial plasma TGF-beta1 level compared to radiochemotherapy patients (p=0.044). During the treatment, there was a significant decrease in patients treated with radiochemotherapy (p=0.008) but not in radiotherapy patients (p=0.34). Tumor burden did not correlate with plasma TGF-beta1 level (p=0.07). TGF-beta1 has no predictive value for treatment response (CR vs. PR and PD, p=0.12). The combination of radiotherapy and chemotherapy significantly decreases plasma TGF-beta1 level in patients with advanced head and neck cancer. Treatment response cannot be predicted using TGF-beta1.     

Combination chemotherapy with high-dose methotrexate, bleomycin, and cisplatin in management of head and neck squamous cell carcinoma

Fifty-nine patients with stage IV head and neck squamous cell cancer were treated with an intensive induction chemotherapy consisting of high-dose methotrexate-leucovorin, bleomycin, and cisplatin. Forty-five patients had recurrent disease following surgery and/or radiation therapy. The response rate in this group was 22%, with a median response duration of 10 weeks and a median survival of 19 weeks. The median survival in responders was 20 weeks and in nonresponders 18 weeks. Fourteen previously untreated patients (13 T4 and one T2) received identical chemotherapy followed by radiation and/or surgery. The response to chemotherapy in previously untreated patients was impressively higher (93%). These patients had a median survival of 48 weeks, and 30% survived 2 years. The initial chemotherapy did not compromise the succeeding radiation therapy or surgery. Toxicities were frequent, but generally well tolerated. It is concluded that prior surgery and/or radiation therapy compromises the efficacy of subsequent chemotherapy in head and neck cancer. Responses to intensive chemotherapy prior to surgery and/or radiation therapy are excellent in patients with T4 tumors and provides a basis for further intensive treatment in attempts to augment cure rates.     

Salvage re-irradiation for recurrent head and neck cancer

PURPOSE: To present a retrospective review of treatment outcomes for recurrent head and neck (HN) cancer patients treated with re-irradiation (re-RT) at a single medical center. METHODS AND MATERIALS: From July 1996-September 2005, 105 patients with recurrent HN cancer underwent re-RT at our institution. Sites included were: the neck (n = 21), nasopharynx (n = 21), paranasal sinus (n = 18), oropharynx (n = 16), oral cavity (n = 9), larynx (n = 10), parotid (n = 6), and hypopharynx (n = 4). The median prior RT dose was 62 Gy. Seventy-five patients received chemotherapy with their re-RT (platinum-based in the majority of cases). The median re-RT dose was 59.4 Gy. In 74 (70%), re-RT utilized intensity-modulated radiation therapy (IMRT). RESULTS: With a median follow-up of 35 months, 18 patients were alive with no evidence of disease. The 2-year loco-regional progression-free survival (LRPFS) and overall survival rates were 42% and 37%, respectively. Patients who underwent IMRT, compared to those who did not, had a better 2-year LRPF (52% vs. 20%, p < 0.001). On multivariate analysis, non-nasopharynx and non-IMRT were associated with an increased risk of loco-regional (LR) failure. Patients with LR progression-free disease had better 2-year overall survival vs. those with LR failure (56% vs. 21%, p < 0.001). Acute and late Grade 3-4 toxicities were reported in 23% and 15% of patients. Severe Grade 3-4 late complications were observed in 12 patients, with a median time to development of 6 months after re-RT. CONCLUSIONS: Based on our data, achieving LR control is crucial for improved overall survival in this patient population. The use of IMRT predicted better LR tumor control. Future aggressive efforts in maximizing tumor control in the recurrent setting, including dose escalation with IMRT and improved chemotherapy, are warranted.     

Induction chemotherapy with a new regimen alternating cisplatin, fluorouracil with mitomycin, hydroxyurea and bleomycin in carcinomas of nasopharynx or other sites of the head and neck region.

Sixty-six patients with locally advanced (Stages III and IV) carcinoma of the head and neck were treated with three cycles of induction chemotherapy, consisting of cisplatin, fluorouracil (FU) infusion, bleomycin, mitomycin, and hydroxyurea, followed by radiotherapy and/or surgery. There were 48 men and 18 women with a median age of 55 years (range, 18 to 75 years) and Karnofsky performance status of 80 (range, 40 to 90). Primary site was nasopharynx (28 patients), followed by larynx (12) and others (26). Forty-one (62%) patients were presented with Stage IV disease. The response rate to induction chemotherapy was 27% complete response, 50% partial response, 20% stable disease, and 3% progressive disease. There was no significant difference in response rate between patients with cancer of nasopharynx or other sites (P greater than 0.1). Survival was 61% at 24 months. Patients with cancer of nasopharynx had a better survival than those with other primaries (P = 0.033). Toxicities from chemotherapy included alopecia (73%), nausea/vomiting (66%), leukopenia (54%), stomatitis (36%), anemia (32%), thrombocytopenia (16%), and diarrhea (9%). Grade IV toxicity was not observed. Induction chemotherapy with this new regimen resulted in a high response rate but may not be superior to cisplatin and FU alone. It can be safely combined with radiotherapy as a potentially curative therapy in squamous cell carcinoma of the head and neck. Chemotherapy followed by radiation therapy may yield survival similar to radical surgery in laryngeal and other head and neck cancers.     

Larynx preservation using induction chemotherapy plus radiation therapy as an alternative to laryngectomy in advanced head and neck cancer. A long-term follow-up report.

Since 1977, we have used induction chemotherapy (CT) plus radiation therapy (RT) with curative intent in 35 advanced head and neck cancer (Ca) patients who otherwise would have required total laryngectomy. Fourteen patients had advanced Ca of the larynx or supraglottic larynx (SGL); 21 patients had Ca of the hypopharynx. In six patients the Ca was Stage III; in 26 patients it was Stage IV. Three patients had Stage II disease--2 with cancer of the pyriform sinus and one patient with Stage II SGL Ca who refused surgery. Chemotherapy consisted of platinum (P) + bleomycin in 18 patients until 1982, then P + fluorouracil in the next 17 patients. Total response rate was 77%--complete (CR) in 26% and partial (PR) in 51%. There were two toxic deaths. Surgery was limited to tracheostomy in 4 patients prior to CT and to radical neck dissection after CT in 4 others. Two patients required salvage laryngectomy at 11 and 31 months, respectively. One patient underwent partial laryngectomy with voice preservation. Thirty-two patients were evaluable for overall response after RT. Final disease-free status was achieved in 20/34. One long-term survivor was lost to follow-up (44 months) and 8 patients remained alive at 13+ to 109+ months. Median failure-free survival for all patients was no less than 24 months. Not counting 4 early deaths free of disease, 2-year local control using only chemotherapy plus radiation was 52% (16:31). Overall, 33 of 35 patients retained their voices. Sixteen patients (46%) have survived 2 years or longer. Survival of patients who achieved CR after induction chemotherapy was 48 months versus 14 months for those with less than a CR (p = 0.001). Patients with a hypopharyngeal primary had only a 33% 2-year local control rate with chemotherapy and radiation and a median survival of only 12 months versus 77% control and a minimum 39-month survival for those whose tumor arose in the larynx (p = 0.009). Induction chemotherapy plus radiation therapy is an effective strategy which can produce a high rate of larynx preservation, local control, and long-term survival in patients with advanced cancer of the larynx. Patients with hypopharyngeal primaries have a lesser rate of long-term survival and local control, despite similar overall response rates.     

Efficacy of First-line Chemotherapy Affects the Second-Line Setting Response in Patients with Advanced Non-Small Cell Lung Cancer

Background: Chemotherapy is the mainstay of treatment for the majority of patients with advanced nonsmall cell lung cancer (NSCLC) without driver mutations and many receive therapies beyond first-line. Secondline chemotherapy has been disappointing both in terms of response rate and survival and we know relatively little about the prognostic factors. Materials and Methods: One thousand and eight patients with advanced NSCLC who received second-line chemotherapy after progression were reviewed in Shanghai PulmonaryHospital, China, from September 2005 to July 2010. We analyzed the effects of potential prognostic factors on the outcomes of second-line chemotherapy (overall response rate, ORR; progression free survival, PFS; overall survival, OS). Results: The response and progression free survival of first-line chemotherapy affects the ORR, PFS and OS of second-line chemotherapy (ORR: CR/PR 15.4%, SD 10.1%, PD2.3%, p<0.001; PFS: CR/PR 3.80 months, SD 2.77 months, PD 2.03 months, p<0.001; OS: CR/PR 11.60 months, SD 10.33 months, PD 6.57 months, p=0.578, p<0.001, p<0.001, respectively). On multivariate analysis, better response to first-line therapy (CR/PR: HR=0.751, p=0.002; SD: HR=0.781, p=0.021) and progression within 3-6 months (HR=0.626, p<0.001), together with adenocarcinoma (HR=0.815, p=0.017), without liver metastasis (HR=0.541, p=0.001), never-smoker(HR=0.772, p=0.001), and ECOG PS 0-1 (HR=0.745, p=0.021) were predictors for good OS following secondline chemotherapy. Conclusions: Patients who responded to first-line chemotherapy had a better outcome after second-line therapy for advanced NSCLC, and the efficacy of first-line chemotherapy, period of progression, histology, liver metastasis, smoking status and ECOG PS were independent prognostic factors for OS.     

Extranodal nonorbital indolent lymphomas of the head and neck: relationship between tumor control and radiotherapy

PURPOSE: To review our experience managing extranodal nonorbital indolent lymphomas of the head and neck. PATIENTS AND METHODS: A retrospective review was made of 40 patients with indolent lymphomas of the head and neck evaluated at Stanford. The tumor head-and-neck location was Waldeyer's ring, 14; salivary glands, 16; thyroid, 4; and other sites, 6. Twenty-five were Stage I-IIE. Pathology was re-reviewed in 37. The most common histologies were marginal zone lymphoma and follicular grade 2. Patients received combinations of surgery, chemotherapy, and radiotherapy. Local therapy included surgery alone in 6 patients, radiotherapy alone in 7, and surgery plus radiotherapy in 12. Median follow-up was 70.5 months. RESULTS: Freedom from local progression was 86%, and freedom from progression was 61% at 5 years. Patients with radiotherapy had significantly better freedom from local progression (5-year, 100% vs. 72% for patients without radiotherapy, p = 0.006) and freedom from progression (5-year, 90% vs. 34% for patients without radiotherapy, p = 0.001). Improvement in freedom from progression with radiotherapy was statistically significant for Stage I-II patients (88% vs. 50%, p = 0.02) and of borderline significance in Stage III-IV patients (100% vs. 23%, p = 0.07). Overall survival at 10 years was 70%. Multivariate analysis revealed that significant prognostic factors for survival were tumor site (favoring salivary and thyroid, p = 0.02) and age (favoring younger, p = 0.04). CONCLUSION: Survival is excellent in patients with indolent lymphomas of the head and neck. Patients with salivary and thyroid primary tumors had better survival compared with others. Early use of radiotherapy resulted in significantly higher rates of freedom from progression and freedom from local progression in early-stage patients.     

Evaluation of TS and ENOSF1 Variants as a Biomarker in Response to Neoadjuvant Chemotherapy based on 5FU in Gastric Cancer Patients

Objective: Neoadjuvant chemotherapy with 5-fluorouracil (5FU) is one of the most effective treatment options for gastric cancer patients.  However, treatment response varies significantly between patients based on their genetic profile. The purpose of this study was to determine the association between thymidylate synthase (TS) and enolase superfamily member 1 (ENOSF1) polymorphisms, treatment response, and overall survival in patients with gastric cancer. Methods: The TS and ENOSF1 variants were analyzed in formalin-fixed paraffin-embedded (FFPE) tissue from 100 gastric cancer patients receiving neoadjuvant 5FU-based chemotherapy. Polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) were used to determine TS polymorphisms’ genotypes, and the Tetra Arms PCR method was used to identify ENOSF1 polymorphisms. Patients were followed for up to five years, and the association between variants, treatment response, and overall survival (OS) was examined. Results: There was a significant association between the TS 5’ UTR polymorphism and response to treatment in patients with gastric cancer who received neoadjuvant 5FU therapy (P=0.032). Patients with the 2R3R genotype responded better to treatment, whereas those with the 3R3R genotype did not respond to treatment. Patients with the 2R2R and 3R3R genotypes had the longest and shortest median survival times, respectively, and the observed differences were significant (p=0.003). There was a statistically significant relationship between rs2612091 and chemotherapy response (P=0.017). Patients with genotype AG did not respond to treatment. Conclusion: This study established that the TS 5’ UTR and ENOSF1 rs2612091 polymorphisms could be used to predict treatment response and overall survival in patients with gastric cancer who received neoadjuvant chemotherapy based on 5FU.     

Dose intensity and clinical response in head and neck carcinoma treated with cisplatin + 5-fluorouracil

Chemotherapy dose adjustment has been associated with cancer treatment failure in some types of cancer. The aim of this study was to evaluate the impact of dose intensity in the efficacy of neoadjuvant treatment of locally advanced squamous cell carcinoma of head and neck (SCCHN). We reviewed the records of seventy patients with locally advanced SCCHN (stage III or IV) treated with three cycles of CDDP (100 mg/m²) plus 5-day continuous infusion of 5-FU (1,000 mg/m²/day) before local therapy. Planned and received dose intensity were both calculated, and clinical response and survival were assessed. Median dose intensity received was 28.38 mg/m²/week for CDDP (range: 7.45–35) and 278.16 for 5-FU (range: 74.47–350). Overall response rate to the chemotherapy combination was 76%. Cisplatin was administered ≥75% of the planned dose in 80% of the patients, and 5-FU was administered ≥75% in 76% of cases. The response rate was significantly higher in the patients that received ≥75% of the planned dose of CDDP (82% vs 50%, p=0.004), and in patients receiving ≥75% of the planned dose of 5-FU (83% vs 53%, p=0.028). Overall survival also correlated with the dose intensity of chemotherapy. Median survival of patients receiving ≥75% of CDDP was significantly longer that patients receiving <75% of CDDP (32 vs 18 months, p=0.03). Similarly, median survival of patients receiving ≥75% of 5-FU was significantly longer that patients receiving <75% of 5-FU (33 vs 21 months, p=0.02). Maintaining a dose-intensity of CDDP and 5-FU above 75% in patients with locally advanced head and neck cancer results in an improved treatment benefit, both in terms of response rate and overall survival.     

Prognostic value of p53, glutathione S-transferase pi, and thymidylate synthase for neoadjuvant cisplatin-based chemotherapy in head and neck cancer.

Neoadjuvant cisplatin-based chemotherapy has been widely used in the last decade for organ preservation or unresectable disease in advanced stage head and neck cancer. We examined the expression of a series of tumor markers that have been associated with chemotherapy resistance in pretreatment biopsies from 68 patients who received cisplatin-based neoadjuvant chemotherapy at either of two institutions. Patients received either cisplatin/5-fluorouracil (n = 49) or cisplatin/paclitaxel (n = 19). Expression of p53, glutathione S-transferase pi (GSTpi), thymidylate synthase (TS), c-erbB2, and multidrug resistance-associated protein was examined by immunohistochemistry. Expression of glutathione synthetase mRNA was measured by in situ hybridization. The overall response rate for cisplatin-based neoadjuvant treatment was 79%. The expression of several of the tumor markers was associated with resistance to neoadjuvant treatment, but none reached statistical significance. Overall survival (OS) was strongly correlated with the absence of p53 expression. The OS at 3 years was 81% in the p53-negative group, whereas it was 30% in the p53-positive group for patients treated with neoadjuvant chemotherapy (P < 0.0001). Expression of GST pi and TS was also significantly correlated with decreased OS after neoadjuvant treatment. At 3 years, the OS rate was 82% in the low GSTpi score group, compared to 46% in the high GSTpi score group (P = 0.0018). In the TS-negative group, the 3-year OS rate was 71% compared with 40% in the TS-positive group (P = 0.0071). We conclude that p53, GSTpi, and TS may be clinically important predictors of survival in patients receiving neoadjuvant chemotherapy for head and neck cancer.     

Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck

Induction chemotherapy, followed by surgery and/or radiotherapy was utilized in patients with advanced squamous cell carcinoma of the head and neck. During these trials, the authors observed that response to chemotherapy predicts further response to subsequent radiotherapy. This study was comprised of 57 patients with 60 separate neoplasms who demonstrated less than complete response (partial or no response) to initial treatment with a combination chemotherapy containing cisplatin. Subsequently radiotherapy, either 5000 rad preoperatively or 6600 rad as definitive therapy, was employed. Forty-one of the 42 tumors with initial partial response to chemotherapy also responded to radiotherapy (97.6%). Only one of the 18 tumors that initially failed to respond to chemotherapy subsequently responded to radiotherapy (5.5%). This observation suggests that patients with head and neck cancer sensitive to initial chemotherapy share parameters that are also radiation sensitive.     

Matrix metalloproteinase 3 polymorphism: a predictive factor of response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma.

PURPOSE: Treatment of head and neck cancer often associates different therapeutic modalities, including surgery, radiotherapy, and chemotherapy. In an attempt to optimize therapeutics, the identification of molecular markers linked to response to chemotherapy remains important. Recently, the involvement of metalloproteinases in resistance to chemotherapy was suggested through their interaction with the Fas/Fas ligand pathway. Indeed metalloproteinases enhance Fas ligand shedding modulating chemotherapy efficiency. On the basis of these findings, we tested the existence of a correlation between response to chemotherapy and four metalloproteinase polymorphisms in a prospective series of 148 head and neck cancer patients. EXPERIMENTAL DESIGN: Patients were genotyped using automated fragment analysis and 5'-nuclease allelic discrimination assay. Response to chemotherapy was clinically assessed without knowledge of the genotype status. RESULTS: A significant relation between the metalloproteinase type 3 (MMP3) -1612insA polymorphism and response to chemotherapy was identified. Indeed, patients with the 6A/6A genotype responded more frequently (86%) to treatment as compared with patients with the 5A/6A (65%) or 5A/5A (55%) genotypes (P = 0.04). A multivariate analysis, including tumor stage, gender, TP53 mutations, and MMP3 polymorphism, showed that the 6A/6A genotype was an independent factor of response to 5-fluorouracil-cisplatin chemotherapy in head and neck cancer patients with an odds ratio of 6.7 as compared with the 5A/5A genotype. CONCLUSIONS: This work showed that genotyping the MMP3 gene enhancer polymorphism -1612insA could help predict chemosensitivity in head and neck cancer patients.     

The superiority of combination chemotherapy over single agent chemotherapy in small cell lung carcinoma.

From June 1974 to October 1976, 288 patients with small cell undifferentiated lung carcinoma were entered into a randomized, controlled study comparing the two noncycle-active induction regimens of cyclophosphamide vs. the combination of cyclophosphamide, doxorubicin and imidazole carboximide (DTIC). Patients were stratified by extent of disease, previous radiotherapy and performance status. Responding patients and those who did not progress were then randomized to receive their initial regimen alone, or their initial regimen with added cycle-active therapy (vincristine, hydroxyurea and methotrexate). While only 4/34 (12%) evaluable patients treated with cyclophosphamide achieved a response (greater than 50% regression), a final total of 119/217 (57%) evaluable patients on the three drugs have responded (p = 0.005). The survival curve for all the combination-treated patients was significantly better than for those treated with cyclophosphamide alone (p = 0.012). There was no demonstrable statistical superiority in length of remission or survival for patients on the combination who received in addition cycle-active consolidation therapy. In the combination chemotherapy group, survival duration was longer for patients with limited disease than extensive disease (p = 0.035). There was a strong correlation between quality of remission produced by the combination and survival.     

Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer

BACKGROUND: The importance of establishing hormone receptor status of tumors for the treatment of women with hormone receptor-positive breast cancer has been emphasized, however, there is no general agreement as to how immunohistochemical assays should be evaluated. It is critical to evaluate hormone receptor status when considering response to endocrine therapy. METHODS: Estrogen receptor (ER) and progesterone receptor (PgR) expression was examined by immunohistochemistry using Allred's score for primary breast tumors from 75 metastatic breast cancer patients who received first-line treatment with endocrine therapy (56 patients received tamoxifen, 11 patients received aromatase inhibitors, and 8 patients received LH-RH agonist or other endocrine reagents) on relapse. Correlation between hormone receptor status and response to endocrine therapy as well as post-relapse survival was analyzed. RESULTS: The most significant correlation between positive ER expression and response to any endocrine therapy (p = 0.011) or tamoxifen only (p = 0.030) occurred when the cutoff score was set at 10%. When the evaluation was based on Allred's score (TS), a cutoff point of TS>or=4 showed a more significant association between positive ER expression and response to all kinds of endocrine therapy (p = 0.020) or tamoxifen only (p = 0.047). When evaluated at a cutoff point of 1% positive cells, there were fifteen patients with both ER- and PgR-negative tumors, and three patients (20.0%) responded to the therapy. Patients with 1% or more ER or PgR positive cells had better survival after relapse (p = 0.0005 and p = 0.0008, respectively). CONCLUSIONS: The proportion score alone might be enough to predict hormone responsiveness and post-relapse survival in metastatic breast cancer. The cutoff might be set low, for example 1%, especially for metastatic disease.