Sachin Dhumal

A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck.

BACKGROUND Cetuximab based treatment is the recommended chemotherapy for head and neck squamous cell cancers in the palliative setting. However, due to financial constraints, intravenous (IV) chemotherapy without cetuximab is commonly used in lesser developed countries. We believe that oral metronomic chemotherapy may be safer and more effective in this setting. METHODS We conducted an open label, superiority, parallel design, randomized phase II trial comparing oral MCT [daily celecoxib (200mg twice daily) and weekly methotrexate (15mg/m(2))] to intravenous single agent cisplatin (IP) (75mg/m(2)) given 3 weekly. Eligible patients had head and neck cancers requiring palliative chemotherapy with ECOG PS 0-2 and adequate organ functions who could not afford cetuximab. The primary end point was progression-free survival. RESULTS 110 Patients were recruited between July 2011 to May 2013, 57 randomized to the MCT arm and 53 to the IP arm. Patients in the MCT arm had significantly longer PFS (median 101 days, 95% CI: 58.2-143.7 days) compared to the IP arm (median 66 days, 95% CI; 55.8-76.1 days) (p=0.014). The overall survival (OS) was also increased significantly in the MCT arm (median 249 days, 95% CI: 222.5-275.5 days) compared to the IP arm (median 152 days, 95% CI: 104.2-199.8 days) (p=0.02). There were fewer grade 3/4 adverse effects with MCT, which was not significant. (18.9% vs. 31.4%, P=0.14). CONCLUSION Oral metronomic chemotherapy has significantly better PFS and OS than single agent platinum in the palliative setting.

Neoadjuvant chemotherapy followed by surgery in very locally advanced technically unresectable oral cavity cancers

BACKGROUND The median survival of technically unresectable oral-cavity cancers (T4a and T4b) with non surgical therapy is 2-12 months. We hypothesized that neoadjuvant chemotherapy (NACT) could reduce the tumour size and result in successful resection and ultimately improved outcomes. We present a retrospective analysis of consecutive patients who received NACT at our centre between January 2008 and August 2012. PATIENTS AND METHODS All patients with technically unresectable oral cancers were assessed in a multidisciplinary clinic and received 2 cycles of NACT. After 2 cycles, patients were reassessed and planned for either surgery with subsequent CTRT or nonsurgical therapy including CT-RT, RT or palliation. SPSS version 16 was used for analysis of locoregional control and overall survival (OS). Univariate and multivariate analysis was done for factors affecting the OS. RESULTS 721 patients with stage IV oral-cavity cancer received NACT. 310 patients (43%) had sufficient reduction in tumour size and underwent surgical resection. Of the remaining patients, 167 received chemoradiation, 3 radical radiation and 241 palliative treatment alone The locoregional control rate at 24 months was 20.6% for the overall cohort, 32% in patients undergoing surgery and 15% in patients undergoing non surgical treatment (p=0.0001). The median estimated OS in patients undergoing surgery was 19.6 months (95% CI, 9.59-25.21 months) and 8.16 months (95%, CI 7.57-8.76) in patients treated with non surgical treatment (p=0.0001). CONCLUSION In our analysis, NACT led to successful resection and improved overall survival in a significant proportion of technically unresectable oral-cancer patients.

Neoadjuvant Chemotherapy in Locally Advanced and Borderline Resectable Nonsquamous Sinonasal Tumors (Esthesioneuroblastoma and Sinonasal Tumor with Neuroendocrine Differentiation)

Introduction. Sinonasal tumors are chemotherapy responsive which frequently present in advanced stages making NACT a promising option for improving resection and local control in borderline resectable and locally advanced tumours. Here we reviewed the results of 25 such cases treated with NACT. Materials and Methods. Sinonasal tumor patients treated with NACT were selected for this analysis. These patients received NACT with platinum and etoposide for 2 cycles. Patients who responded and were amenable for gross total resection underwent surgical resection and adjuvant CTRT. Those who responded but were not amenable for resection received radical CTRT. Patients who progressed on NACT received either radical CTRT or palliative radiotherapy. Results. The median age of the cohort was 42 years (IQR 37–47 years). Grades 3-4 toxicity with NACT were seen in 19 patients (76%). The response rate to NACT was 80%. Post-NACT surgery was done in 12 (48%) patients and radical chemoradiation in 9 (36%) patients. The 2-year progression free survival and overall survival were 75% and 78.5%, respectively. Conclusion. NACT in sinonasal tumours has a response rate of 80%. The protocol of NACT followed by local treatment is associated with improvement in outcomes as compared to our historical cohort.

Metronomic chemotherapy in platinum-insensitive failures and/or early failures postmultimodality management in oral cancers.

Purpose: Oral cancer patients with platinum-resistant disease and or early failures have limited treatment options. This analysis was planned to study the efficacy of metronomic chemotherapy in this group of patients. Materials and Methods: This was a retrospective analysis of oral cancer patients who had squamous cell carcinoma and had an early failure and/or platinum-insensitive failure. Early failure was defined as a failure either within 1-month of adjuvant radiotherapy or within 6 months of chemoradiation (CTRT). A sample size of 100 patients was selected for this study. If ≥39 of 100 patients would have survived at 6 months with metronomic chemotherapy, then additional studies would be warranted. Results: The ECOG PS was 0-1 in 92 patients and 2 in 8 patients. The subsite of primary was buccal mucosa in 38 patients (38%), anterior two-third tongue (oral tongue) in 51 patients (51%), and alveolus in 11 patients (11%). The median estimated overall survival was 110 days (95% confidence interval [CI]: 85-134 days). The proportion of patients surviving at 6 months was 26.4% (95% CI: 17.9-35.6). Conclusion: Metronomic combination of methotrexate and celecoxib failed to meet its prespecified efficacy limit and should not be used in these patients as routine.

Weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer for patients ineligible for 3 weekly maximum tolerable dose chemotherapy

OBJECTIVE To study the safety and efficacy of weekly chemotherapy as part of induction chemotherapy, in locally advanced head and neck cancer for patients, who are unfit for upfront radical treatment. MATERIALS AND METHODS It is a retrospective analysis of on-use weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer, who are technically unresectable are unfit for upfront radical treatment. Induction chemotherapy given was a 2 drug combination of paclitaxel (80 mg/m 2 ) and carboplatin AUC 2. The decision to give weekly induction chemotherapy was given on the basis of presence of 2 more following features: Poor performance status (ECOG PS 2-3), presence of uncontrolled co morbidities, BMI below 18.5 kg/m 2 and age more than 60 years. The Statistical Package for the Social Sciences software (SPSS version 16.0) was used for analysis. The response rates, toxicity (accordance with CTCAE vs. 4.02), completion rate (Cp) of radical intent treatment post neoadjuvant chemotherapy (NACT), progression-free survival (PFS) and overall survival (OS) are reported. RESULTS Fifteen patients were considered for such therapy. Fourteen out of fifteen patients completed NACT. The median numbers of planned weekly cycles were 6 (3-8). Response (CR + PR) was seen in 10 patients. Overall grade 3-4 toxicity was seen in 6 patients. No toxicity related mortality was noted. The calculated completion rate (Cp) of radical intent treatment post NACT was 46.7%. The median PFS and OS were 10.36 months (95% CI 6.73-14.00 months) and 16.53 months (95% CI 4.22-28.84). CONCLUSION Use of induction chemotherapy with weekly regimen is safe and effective selected cohort of patients with locally advanced disease who are unfit for upfront radical treatment.

Neoadjuvant chemotherapy in geriatric head and neck cancers: Neoadjuvant chemotherapy in geriatric head and neck cancers

The purpose of this study was to present our findings on the treatment completion rates and outcomes in geriatric patients with head and neck cancer treated with neoadjuvant chemotherapy followed by definitive therapy.

Efficacy of second-line erlotinib in patients postprogression of first-line chemotherapy in head and neck cancers

BACKGROUND Oral tyrosine kinase inhibitor (gefitinib and erlotinib) have been used in the palliative treatment of head and neck cancers with limited success. In this report, we aim to quantify the symptomatic benefit, progression-free survival (PFS) and overall survival (OS) when erlotinib is given as second-line treatment in Head and neck cancers. METHODS This was a post-hoc retrospective analysis of a randomized study comparing metronomic chemotherapy with cisplatin. A patient who progressed on chemotherapy and had a PS0-2 were offered second-line chemotherapy. Patients who had received erlotinib (150 mg PO OD) as second line treatment were selected for this analysis. Erlotinib was discontinued in case of either progression of disease or if the patient had intolerable side effects. Patient were monitored 1-week after the start of erlotinib and subsequently at monthly intervals. The toxicity was recorded in accordance with CTCAE version 4.02 (NCI,USA) and the response were graded in accordance with RECIST version 1.1. All of these patients were followed-up till death. RESULTS Twenty-three patients were identified. The median age of these patients at the start of the second line was 47 years (interquartile range 40.5-51.75 years). The primary site of distribution was oral cavity primary in 17 patients (77.3%) and nonoral cavity primary in 05 (22.7%) patients. The immediate last chemotherapy regimen received was cisplatin in 9 patients (40.9%) and metronomic chemotherapy in 13 patients (59.1%). Symptomatic benefits post second-line erlotinib was seen in 18 patients (81.8%). The most common adverse events (any grade) seen were anemia in 20 patients (90.9%), rash in 10 patients (45.5%) and diarrhea in 7 patients (31.8%).The best radiological response documented were a partial response in 04 patients (19.2%). The median estimated PFS and OS were 110 days (95% confidence interval [CI]: 61-175 days) and 156 days (95% CI: 126-185 days) respectively. CONCLUSION Erlotinib single agent has promising activity in the second line and needs to be explored in future studies.

A tertiary care experience with paclitaxel and cetuximab as palliative chemotherapy in platinum sensitive and nonsensitive in head and neck cancers

Background: The combination of paclitaxel and cetuximab (PaCe) has led to an encouraging response rate in Phase 2 setting with limited toxicity. The aim of our study was to assess the efficacy of this regimen in our setting in platinum sensitive and nonsensitive patients. Methods: This was a retrospective analysis of head and neck cancer patients treated with weekly PaCe as palliative chemotherapy between May 2010 and August 2014. The standard schedule of cetuximab along with 80 mg/m2 of weekly paclitaxel was administered till either disease progression or withdrawal of patients consent. The toxicity and response were noted in accordance with CTCAE version 4.02 and RECIST version 1.1 criteria, respectively. The response rates between platinum sensitive and nonsensitive patients were compared by Chi-square test. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan–Meier survival method and log-rank test was used for comparison. Cox proportional hazard model was used for identification of factors affecting PFS and OS. Results: One Hundred patients with a median age of 52 years (interquartile range: 46–56 years) were included. Forty-five patients (45%) were platinum insensitive, whereas 55 patients (55%) were platinum sensitive. In platinum insensitive patients and sensitive patients, the response rates were 38.5% and 22.2%, respectively (P = 0.104), whereas the symptomatic benefit in pain was seen in 89.5% and 71.7%, respectively (P = 0.044). The median PFS in platinum insensitive and sensitive patients were 150 and 152 days, respectively (P = 0.932), whereas the median OS was 256 days (95% confidence interval [95% CI]: 168.2–343.8 days) and 314 days (95% CI: 227.6–400.4 days), respectively (P = 0.23). Nineteen patients (19%) had grades 3–4 adverse events during chemotherapy. Conclusion: Weekly paclitaxel combined with cetuximab has promising efficacy and good tolerability in the palliative setting in advanced head and neck cancer in both platinum sensitive and insensitive patients.

Comparison of paclitaxel-cetuximab chemotherapy versus metronomic chemotherapy consisting of methotrexate and celecoxib as palliative chemotherapy in head and neck cancers

BACKGROUND The present match pair analysis was planned to compare the efficacy of cetuximab-paclitaxel-based chemotherapy versus metronomic therapy. MATERIALS AND METHODS Sixty patients with metastatic/recurrent head and neck squamous cell cancer treated with weekly paclitaxel (80 mg/m2) and cetuximab were matched with sixty patients treated with oral metronomic chemotherapy consisting of methotrexate and celecoxib. The progression-free survival (PFS) and overall survival (OS) between the cohorts were compared using log-rank test. Cox proportional regression model was used to identify independent factors affecting PFS and OS. RESULTS The median OS was 191 days (95% confidence interval [CI]: 122.2-259.8 days) in metronomic cohort and 256 days (95% CI 177.0-334.9 days) in cetuximab cohort (hazard ratio: 0.58, 95% CI: 0.35-0.95, P = 0.031). On Cox proportional hazard model, Eastern Cooperative Oncology Group Performance Status (0-1 vs. 2) and therapy (cetuximab versus metronomic) had a statistically significant impact on OS. CONCLUSION Cetuximab-based chemotherapy leads to a significant improvement in OS in the match pair analysis in comparison to metronomic chemotherapy.

Metronomic palliative chemotherapy in maxillary sinus tumor

Background: Metronomic chemotherapy consisting of methotrexate and celecoxib recently has shown promising results in multiple studies in head and neck cancers. However, these studies have not included patients with maxillary sinus primaries. Hence, the role of palliative metronomic chemotherapy in patients with maxillary sinus carcinoma that is not amenable to radical therapy is unknown. Methods: This was a retrospective analysis of carcinoma maxillary sinus patients who received palliative metronomic chemotherapy between August 2011 and August 2014. The demographic details, symptomatology, previous treatment details, indication for palliative chemotherapy, response to therapy, and overall survival (OS) details were extracted. SPSS version 16 was used for analysis. Descriptive statistics have been performed. Survival analysis was done by Kaplan-Meier method. Results: Five patients had received metronomic chemotherapy. The median age was 60 years (range 37-64 years). The proportion of patients surviving at 6 months, 12 months, and 18 months were 40%, 40%, and 20%, respectively. The estimated median OS was 126 days (95% confidence interval 0-299.9 days). The estimated median survival in patients with an event-free period after the last therapy of <6 months was 45 days, whereas it was 409 days in patients with an event-free period postlast therapy above 6 months (P = 0.063). Conclusion: Metronomic chemotherapy in carcinoma maxillary sinus holds promise. It has activity similar to that seen in head and neck cancers and needs to be evaluated further in a larger cohort of patients.