Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study.

PURPOSE: The regimens approved for the treatment of advanced head and neck squamous cell carcinoma are accessible to only 1%-3% of patients in low- and middle-income countries because of their cost. In our previous study, metronomic chemotherapy improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low-dose nivolumab to triple metronomic chemotherapy (TMC) improved overall survival (OS). METHODS: This was a randomized phase III superiority study. Adult patients with recurrent or newly diagnosed advanced head and neck squamous cell carcinoma being treated with palliative intent with an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Patients were randomly assigned 1:1 to TMC consisting of oral methotrexate 9 mg/m2 once a week, celecoxib 200 mg twice daily, and erlotinib 150 mg once daily, or TMC with intravenous nivolumab (TMC-I) 20 mg flat dose once every 3 weeks. The primary end point was 1-year OS. RESULTS: One hundred fifty-one patients were randomly assigned, 75 in TMC and 76 in the TMC-I arm. The addition of low-dose nivolumab led to an improvement in the 1-year OS from 16.3% (95% CI, 8.0 to 27.4) to 43.4% (95% CI, 30.8 to 55.3; hazard ratio, 0.545; 95% CI, 0.362 to 0.820; P = .0036). The median OS in TMC and TMC-I arms was 6.7 months (95% CI, 5.8 to 8.1) and 10.1 months (95% CI, 7.4 to 12.6), respectively (P = .0052). The rate of grade 3 and above adverse events was 50% and 46.1% in TMC and TMC-I arms, respectively (P = .744). CONCLUSION: To our knowledge, this is the first-ever randomized study to demonstrate that the addition of low-dose nivolumab to metronomic chemotherapy improved OS and is an alternative standard of care for those who cannot access full-dose checkpoint inhibitors.

Weight loss and its impact on outcome in head and cancer patients during chemo-radiation.

BACKGROUND: Weight loss during chemotherapy and its impact on the cancer outcomes have been invariably reported in the literature. We also did a post-hoc analysis of a randomized phase III trial to see the same. MATERIALS AND METHODS: The database of a recently published randomized study comparing cisplatin-radiation with nimotuzumab cisplatin-radiation was used for this analysis. Week-wise weight loss during the course of treatment was noted. The impact of severe weight loss (grade 2-3) on progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) was studied using the Kaplan Meier method. Binary logistic regression analysis was used to see the effect of various factors. RESULTS: Out of a total of 536 patients, weight loss was captured in 524. Out of these 524 patients, any degree of weight loss was seen in 293 (55.91%) patients. Grade 1 weight loss was noted in 192 (36.6%) patients, grade 2 in 96 (18.3%) and grade 3 in 5 (1%) patients. The 2-year PFS was 53% and 57.1% in severe and non-severe weight loss groups respectively (p-value = 0.36). The 2-year LRC was 60% in patients with severe weight loss, while it was 63.5% in those with non-severe weight loss (p-value = 0.47). The 2-year OS was 59.3% versus 62.2% in severe and non-severe weight loss cohorts respectively (p-value = 0.21). None of the factors was found to be associated with severe weight loss. CONCLUSION: Severe weight loss was uncommon in our patients. Weight loss during treatment was not associated with poor survival outcomes.

Post hoc analysis of a randomized controlled trial comparing concurrent chemoradiation with cisplatin versus nimotuzumab-cisplatin, focusing on acute oral mucositis.

BACKGROUND: Acute oral mucositis has been infrequently studied in the patients with head and neck squamous cell carcinoma (HNSCC) receiving once-weekly cisplatin-based chemoradiotherapy (CRT). Hence, this analysis was conducted to explore the various aspects of the same. RESULTS: The overall incidence of mucositis was 96.9% (n = 508) and of grade 3-5 mucositis was 61.3% (n = 321). The overall incidence of oral mucositis was similar in both the arms (CCRT and NCRT) (p value = 0.58) while grade 3-5 mucositis was more common in the NCRT arm (p value = 0.01). Out of all factors listed, the presence of nimotuzumab was the only significant risk factor for the development of grade 3 or more oral mucositis (p value = 0.01); (OR = 1.64, 95%CI 1.15-2.32). Delays in the treatment delivery were similar in both the arms. CONCLUSION: Acute oral mucositis is a common occurrence in locally advanced-HNSCC patients receiving chemoradiotherapy. Nimotuzumab is a significant factor for development of grade 3 and above oral mucositis.

A real-world data of Immune checkpoint inhibitors in solid tumors from India.

BACKGROUND: Checkpoint inhibitors (Nivolumab and Pembrolizumab) are approved for multiple indications in solid tumors. However access to these therapies is limited in low and middle income countries. Hence we performed an audit to identify accessibility, adverse event rates, compliance, progression free survival and overall survival in solid tumors. METHODS: This was a single center retrospective analysis of prospective data base of patients with non-melanoma solid tumors who were treated with immunotherapy from August 2015 to November 2018. Adverse events during immunotherapy were documented and graded using CTCAE (Common terminology criteria for adverse events), v. 4.02. The response rates to immunotherapy, toxicities and the time to onset and resolution of toxicities were also evaluated as secondary endpoints. RESULTS: Out of 9610 patients, only 155 patients (1.61%) could receive immunotherapy. The most common malignancies included metastatic non-small cell lung cancer, metastatic renal cell carcinoma, metastatic urothelial carcinoma and relapsed/recurrent head and neck squamous cell carcinoma. Median overall survival in patients who received immunotherapy in non-melanoma solid malignancies was 5.37 months (95% CI, 3.73-9.73). Poor performance status at baseline was the only adverse prognostic factor. The median progression free survival was 2.57 months (95% CI, 1.73-3.83). Immunotherapy was well tolerated with most common side effects being fatigue 14.8% and anorexia 5.8%. The cumulative incidence of immune related adverse events like hepatitis, pneumonitis, colitis and nephritis was less than 10%. CONCLUSION: Real-world data in Indian setting confirms the benefit of immunotherapy in patients with advanced non-melanoma solid tumors.

Lymphopenia during chemoradiation-foe or friend.

BACKGROUND: Severe lymphopenia during treatment is considered to be a poor prognostic factor. The current literature lacks information regarding its impact on various outcomes in locally advanced head-and-neck cancer patients in a prospective setting. METHODS: We recently published a randomised study comparing cisplatin-radiation with nimotuzumab cisplatin-radiation. The database of this study was used for the present analysis. The impact of severe lymphopenia (grade 4 lymphopenia) on progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) was studied using the Kaplan-Meier method and Cox regression analysis. The binary logistic regression analysis was used to see the effect of various factors on the development of severe lymphopenia. RESULTS: We had a total of 536 patients, of which 521 patients (97.7%) developed lymphopenia. Grade 1 lymphopenia was noted in 10 (1.9%) patients, grade 2 in 100 (18.8%), grade 3 in 338 (63.1%) and grade 4 in 73 (13.7%) patients. The median PFS was 20.53 and 60.33 months in severe and non-severe lymphopenia, respectively (hazard ratio, 0.797; p-value = 0.208). The median duration of LRC was 56.3 months in severe lymphopenia, whereas it was not reached in non-severe lymphopenia (hazard ratio, 0.81; p-value = 0.337). The median OS was 28.46 versus 47.13 months in severe and non-severe lymphopenia, respectively (hazard ratio, 0.76; p-value = 0.11). Of various risk factors, gender was significantly associated with severe lymphopenia. CONCLUSION: The occurrence of severe lymphopenia was not significantly associated with the outcomes. Gender is the only risk factor significantly linked to severe lymphopenia.

Excellent response to erlotinib in breast carcinoma with rare EGFR mutation-a case report.

Triple negative breast carcinoma is a problematic subtype with poor outcomes. Many clinical trials are underway to find possible target to increase treatment options. Epidermal growth factor receptor (EGFR) has emerged as one such molecule which is over expressed in some of these patients and can be targeted by tyrosine kinase inhibitors. We describe a diagnostically challenging case of metastatic breast carcinoma, with extensive lung disease and poor Eastern Cooperative Oncology Group (ECOG) performance status, which expressed an uncommon EGFR mutation (Exon 21L861Q) and which benefitted from erlotinib following failure of all primary treatment modalities. The case uncovers the presence of these unusual mutations in breast carcinoma and highlights the importance of performing molecular analysis and the appropriate targeted therapy. This approach can be an important problem-solving tool, especially in cases where the patient is not fit for the other standard treatment options.

Coughing up: "Adenosquamous carcinoma lung with unusual initial presentation as an ulceroproliferative growth" - case report and review of literature.

Lung carcinoma is the most common carcinoma seen in males with the skin being a rare metastatic site. Adenosquamous carcinoma as a rare histologic subtype, showing cutaneous metastasis is an unusual event with no reports in the literature till date. Skin metastasis is an alarming sign, carries poor prognosis, and is associated with shortened survival. Herein, we report a case of 60-year-old male who presented with isolated cutaneous metastasis as a chronic nonhealing ulcer over the sternal region for 3 years (unusual) in the first place, without any other associated symptoms and clinical evidence of the primary. Wide local excision of the lesion was performed after proper workup which revealed metastatic adenosquamous carcinoma. The patient was advised systemic chemotherapy. A high index of suspicion along with clinico-radio-pathological correlation in these cases is of utmost importance and forms the basis of accurate diagnosis.

Phase III Non-inferiority Study Evaluating Efficacy and Safety of Low Dose Gemcitabine Compared to Standard Dose Gemcitabine With Platinum in Advanced Squamous Lung Cancer.

BACKGROUND: Prolonged infusion of low dose gemcitabine (PLDG) in combination with platinum has shown promising activity in terms of improved response rate and progression free survival (PFS); especially in squamous non-small cell lung cancer (NSCLC). Hence, we conducted a phase 3 randomized non-inferiority study with the primary objective of comparing the overall survival (OS) between PLDG and standard dose of gemcitabine with platinum. METHODOLOGY: Adult subjects (age ≥ 18 years), with stages IIIB-IV, NSCLC (squamous) and ECOG performance status of ≤ 2 were randomized 1:1 into either carboplatin with standard dose gemcitabine (1000 mg/m2 intravenous over 30 min, days 1 and 8) (STD-G arm) or carboplatin along with low dose gemcitabine (250 mg/m2 intravenous over 6 h, days 1 and 8) (LOW-G arm) for a maximum of 6 cycles. Tumor response was assessed by RECIST criteria version 1.1 every 2 cycles till 6th cycle and thereafter at 2 monthly intervals till progression. The primary endpoint was overall survival. 308 patients were randomized, 155 in STD-G arm and 153 in LOW-G arm, respectively. RESULTS: The median overall survival in STD-G arm was 6.8 months (95%CI 5.3-8.5) versus 8.4 months (95%CI 7-10.3) in the LOW-G arm (HR-0.890 (90%CI 0.725-1.092). The results with per protocol analysis were in line with these results. There was no statistical difference in progression free survival (HR-0.949; 90%CI 0.867-1.280) and adverse event rate between the 2 arms. CONCLUSION: This study suggests that PLDG is an alternative to the standard gemcitabine schedule in squamous NSCLC, and either of these can be selected subject to patient convenience.

Cytological diagnosis of a rare case of cutaneous metastasis from transitional cell carcinoma, renal pelvis.

Transitional cell carcinoma (TCC) arising from renal pelvis rarely gives rise to cutaneous metastasis. Due to the insufficient literature, the exact incidence is not known till date. Moreover, the diagnosis is confirmed on histopathological examination with the aid of immunohistochemistry wherever needed. We are presenting a case of a 70-year-old female with metastatic TCC from the renal pelvis to the abdominal skin, which was diagnosed on cytology alone along with the cell block preparation. We also highlight the important cytomorphological and immunohistochemical features noted, which need to be known to avoid any diagnostic delay.

Gliosarcoma in Young Adults: A Rare Variant of Glioblastoma.

Gliosarcoma is a rare central nervous system (CNS) malignancy. It is characterized by classical biphasic histological pattern with both glial and sarcomatous components, often seen in fifth and sixth decade of life. They are generally located in the supratentorial region. Due to its rarity, exact treatment recommendations are not available in literature. Since it is considered as a variant of glioblastoma multiforme (GBM), it is treated with surgery followed by adjuvant radiotherapy and temozolomide-based chemotherapy. We present a series of four cases of this rare malignancy that were treated at our institute.

Radiation-Induced Malignancies Making Radiotherapy a "Two-Edged Sword": A Review of Literature.

Radiotherapy is one of the modalities of treatment of malignancies. Radiation-induced malignancies (RIMs) are late complications of radiotherapy, seen among the survivors of both adult and pediatric cancers. Mutagenesis of normal tissues is the basis for RIMs. The aim of this review of literature was to discuss epidemiology, factors affecting and different settings in which RIM occur.

Lung metastasis in primary cutaneous adenoid cystic carcinoma - Clinicopathological evaluation of a rare case with review of literature.

Primary cutaneous adenoid cystic carcinoma (ACC) is an extremely rare and indolent cutaneous malignancy with very infrequent distant metastasis. We present a case of primary cutaneous ACC with bilateral lung metastases in a 57-year-old male along with literature review. To the best of our knowledge this is the tenth case of primary cutaneous ACC reported presenting with distant metastasis.

Spectrum of fungal infection in head and neck cancer patients on chemoradiotherapy.

BACKGROUND: Radiotherapy for head and neck cancers (HNC) causes alteration of oral mucosal barrier predisposing it to colonization and infection. Such infections often result in pain and burning sensation thus contributing to major morbidity. OBJECTIVE: MATERIALS AND METHODS: Study was done on 50 patients of HNC treated with concurrent chemoradiotherapy. Three samples (throat, urine, blood) were collected for fungal culture and sensitivity. These samples were collected before the start of radiotherapy, during radiotherapy (2nd and 6th week) and post radiotherapy (10th week). RESULTS: Only 49 patients were available for analysis. Fungal infection was found in 27/49 patients (55.10%) out of which Non-albicans Candida was isolated in 18/49 (36.73%) and Candida albicans in 9/49 (18.36%) cases. About 66.66% (18/27) isolates were sensitive to fluconazole. Maximum isolation of yeast was during 6th week of radiotherapy. All grade 4 and 71.42% of grade 3 oral mucositis were found in patients who were positive for fungal infection. CONCLUSION: The spectrum of fungal species in throat swab was: Non-albicans Candida and Candida albicans observed in 36.73% and 18.36% of patients respectively. Higher rate of fungal colonization and infection was found in patients with grade 3/4 oral mucositis. Prophylactic fluconazole in HNC patients on concurrent chemoradiotherapy has the potential to reduce emerging invasive fungal infection and its associated morbidity.

Multiple cutaneous metastases in a patient of carcinoma tonsil - Report of a rare case.

Carcinoma tonsil with visceral metastasis is a rare entity, and cutaneous metastasis is seen even more infrequently. We present a case of a 55-year-old male with carcinoma tonsil having received concurrent chemo radiotherapy, presenting with multiple cutaneous metastases to the scalp and thigh. To the best of our knowledge, till date only two similar cases of carcinoma tonsil with cutaneous metastasis have been reported in the English literature.

Radiation-Induced Malignancies: Our Experiences With Five Cases.

Radiotherapy is one of the modalities of treatment of malignancies. Radiation-induced malignancies (RIMs) are late complications of radiotherapy, seen among the survivors of both adult and pediatric cancers. Mutagenesis of normal tissues is the likely basis for RIMs. Till date, RIM cannot be differentiated from primary cancers. We present a series of five patients who were treated at our institute between 2002 and 2016 and were subsequently diagnosed with RIM. Out of five patients, there were two cases of sarcomas, two of carcinomas and one neuroendocrine carcinoma of tongue (rare entity). Separate treatment guidelines are not available for RIM, so the treatment given was same as primary malignancies.