V. R. Pai

Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM) : an open-label phase 3 randomised trial

BACKGROUND Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients. METHODS This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m(2) on day 1 of each cycle) and fluorouracil (1000 mg/m(2) on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265. FINDINGS Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8-12·2) in the panitumumab group and 9·0 months (8·1-11·2) in the control group (hazard ratio [HR] 0·873, 95% CI 0·729-1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6-6·6) in the panitumumab group and 4·6 months (4·1-5·4) in the control group (HR 0·780, 95% CI 0·659-0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months [95% CI 9·7-13·7] vs 8·6 months [6·9-11·1]; HR 0·73 [95% CI 0·58-0·93]; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months [7·3-12·9] vs 12·6 months [7·7-17·4]; 1·00 [0·62-1·61]; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 [95% CI 0·47-1·04]). INTERPRETATION Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings. FUNDING Amgen Inc.

Phase II Study of High-Dose Ifosfamide as a Single Agent and in Combination with Cisplatin in the Treatment of Advanced and/or Recurrent Squamous Cell Carcinoma of Head and Neck

152 patients with histologically proven squamous cell carcinoma of the head and neck (advanced and/or recurrent) were treated with a single drug therapy of ifosfamide 1.5 g/m2 by intravenous drip for half an hour in 125 ml of dextrose saline for 5 days and mesna 20% of the total ifosfamide dose in 3 doses for 5 days, or in combination with cisplatin 10 mg/m2 by intravenous infusion for 5 days following the ifosfamide drip. The courses of treatment were repeated at the interval of every 4 weeks, and a total of 3 cycles was given. Out of 152 patients 64 received ifosfamide alone, and 88 received ifosfamide with cisplatin. 6 complete and 25 partial remissions (total response 53%) were observed in 58 evaluable patients of the ifosfamide group, and 10 complete and 40 partial remissions (total response 65.7%) were observed in 76 evaluable patients of the combination group. Nausea, vomiting, alopecia and leucopenia were experienced by all patients.

Survival of childhood acute lymphoblastic leukemia: results of therapy at Tata Memorial Hospital, Bombay, India.

The purpose of this study was to analyze the outcome of patients who completed therapy for acute lymphoblastic leukemia (ALL) and to study the role of an aggressive induction regimen in preventing post therapy relapses. Four hundred and twenty-two patients with ALL who completed therapy during the period 1975-1991 were followed. Two hundred and sixty patients received the aggressive MCP 841 protocol and 162 patients received various other less aggressive treatment regimens. Patients were followed with periodic examination and complete blood counts. The incidence of post therapy relapse was 27% in the less aggressive protocols and 15% in the MCP 841 protocol (p = 0.001). An higher percentage of relapses was seen in males (p = 0.05) and 89% relapses occurred within two years of stopping therapy. The relapse rate after 5 years of cessation of therapy was 0.59%. In conclusion, aggressive induction therapy is the most crucial factor in predicting relapses following cessation of therapy in ALL patients. However, relapses are unlikely to occur five years post therapy.

Treatment results of Hodgkin's disease in Indian children

This is a retrospective study of Hodgkins disease in children less than 15 years of age who were registered at Tata Memorial Hospital in India from January 1985 through December 1990. Clinicopathologic characteristics and response were evaluated in 147 patients and survival was calculated in 187. There were 126 boys and 21 girls (6:1). All patients were treated with combination chemotherapy and involved field radiotherapy. The COPP schedule was given to 108 patients. COPP/ABVD to 33, and ABVD to 6. Ninety-three patients (63%) had stage I or II disease and 54 (37%) had stage III or IV disease. B symptoms were observed in 65 patients (56%) and bulky disease in 40 (27%). Histologically, the most common subtype was mixed cellularity, seen in 95 patients (65%). Complete response was observed in 136 (89%), partial response in 6 (4%), and there were 4 treatment-related deaths. Relapse has been observed in 11%. Seven-year actuarial survival was 73% and event-free survival was 64%. Median survival has not yet been reached, with a median follow-up of 36 months.

Primary non-Hodgkin's lymphoma of the bone: a single institution experience.

Primary non-Hodgkin’s lymphoma of the bone is an unusual entity. Twenty-five patients with diffuse large cell lymphoma of the bone were registered at the Tata Memorial Hospital (TMH) from August, 1991, to May, 2002. Pain at the local site and soft tissue swelling were the commonest symptoms. Involvement of the bones in the lower half of the body was more frequent than the bones in the upper half. Osteolytic lesions and an associated soft tissue mass were the common radiological findings. Nineteen patients received CHOP chemotherapy and five received COP chemotherapy. Twenty-three patients received involved field radiotherapy. The overall response to therapy was 96%. On follow-up, two patients had a nodal relapse. One patient died of progressive disease, and one patient died of cryptococcal meningitis. There were no deaths due to treatment-related toxicity. The mean progression free survival was 9.39 yr and the overall survival was 11.66 yr. The median overall survival has not been reached. At last follow-up, 21 patients were being following up at TMH and are free of disease.Conclusion: Primary bone lymphoma is a malignancy that is highly curable with a combination of chemotherapy and radiotherapy.

The Pattern of Malignant Lymphoma in India: A Study of 1371 Cases

A retrospective clinical and histopathological analysis was performed of 1371 patients with Non-Hodgkins lymphomas presenting between January 1981 and December 1985. Pathologic material was reviewed and classified according to the modified Rappaport classification. The most common histologic type encountered was diffuse histiocytic lymphoma (29.5%), followed by diffuse poorly differentiated lymphoma (28%). A very low incidence of nodular lymphomas (10.6%) was seen. Twenty three percent of the patients had clinically stage 1 disease; 24.6% stage 11; 25.9% stage 111 and 26.2% stage IV disease. Bone marrow involvement was seen in 22.6% of patients. B symptoms were seen in 23.9% of patients. Primary extranodal lymphoma was seen in 307 (22.4%) patients. The commonest site of extranodal involvement was head and neck (36.1%) followed by gastrointestinal tract (24.4%). Treatment results could be analysed in only 599 patients. The response rate was 89% and complete response was seen in 67.5% patients. The overall survival for treated patients was 37.5% after 36 months, which is comparable to that reported by other investigators. This series is compared with different series reported from Asian as well as Western countries in order to highlight some common features as well as other major differences.

Neoadjuvant chemotherapy with ifosfamide and cisplatin combination in advanced head and neck cancer: a retrospective analysis of 519 patients: a single institution experience.

Advanced head and neck cancer is a major therapeutic problem in India. Ifosfamide has shown significant activity as a single agent in head and neck squamous carcinoma. In this study, we present our experience with two cycles of ifosfamide and cisplatin in the neoadjuvant setting given to a total of 519 patients. The complete response rate was 20% and the overall response rate was 80%. The treatment was well tolerated, there was no need for dose reduction, and there were no life-threatening side effects. We feel that this high response rate is sufficient to warrant more studies using ifosfamide-based combinations in a neoadjuvant setting for squamous carcinoma of the head and neck.

Adult Acute Lymphoblastic Leukemia: Results of an Aggressive Regimen in India

A total of 42 adults with acute lymphoblastic leukemia were treated with an aggressive induction/consolidation chemotherapy (MCP-841) between June 1986 and December 1991. 32 patients (76.19%) achieved complete remission at the end of induction. There were 9 induction deaths, 6 of them due to infection. All patients received cranial irradiation in the dose of 20 Gy and intrathecal methotrexate for CNS prophylaxis. Twelve patients relapsed, 10 in the bone marrow, one case had isolated CNS relapse and the other relapsed in the bone marrow and CNS. The actuarial overall survival of all patients at the end of 5 years was 41.94%. Patient characteristics including age, sex, FAB morphology, phenotype, WBC count, platelet count and LDH did not influence survival significantly.

Lower Dose Dexamethasone/Thalidomide and Zoledronic Acid Every 3 Weeks in Previously Untreated Multiple Myeloma

BACKGROUND Physicians in Asia have anecdotally reported that Asian patients with multiple myeloma (MM) are frequently intolerant of conventional doses of dexamethasone (Dex) and/or thalidomide (Thal). Since zoledronic acid (Zol) has an anti-MM effect in preclinical studies, we investigated whether the approved 3-times-weekly Zol combined with lower dose Dex/Thal could be an effective and better tolerated regimen in Asian patients. PATIENTS AND METHODS In this first Asian cooperative multicenter phase II study, previously untreated patients with MM (N = 44) received up to 6 cycles of 3-times-weekly low-dose Dex/Thal and 4 mg Zol (the dtZ regimen). Response was graded using Bladé criteria. RESULTS The average doses of Dex and Thal administered were 185.2 mg/month; and 87.5 mg/day, respectively. Thirty-nine (88.6%) patients demonstrated at least a partial response (PR), including 18.2% very good partial response (VGPR), 15.9% near complete response (nCR) and 18.2% complete response (CR). Achievement of CR/nCR was related to significant (P < .05), rapid, and sustained inhibition of osteoclasts (OCs) and OC precursors (pOCs) by Zol. Sepsis was the most frequently reported serious toxicity, contributing to 3 of 4 deaths. Importantly, there was no peripheral neuropathy, osteonecrosis of the jaw, or nephrotoxicity. CONCLUSION We conclude that the dtZ regimen is an effective and well-tolerated regimen for Asian patients with newly diagnosed MM. The high rate of VGPR/nCR/CR suggests that Zol could have a clinically relevant anti-MM effect. Since infections are the most frequent adverse event, it is probably wise to further lower the dose of Dex in future studies.

Plasma Cell Dyscrasia Presenting As Ascites and Omental Mass

A 50-year-old male presented to us with complaints of abdominal distention and pain, vomiting, and breathlessness of 1.5-month duration. On physical examination, the patient had a mass in left hypogastrium that was 10 15 cm in size, nontender, and partially mobile with moderate ascites. He also had bilateral pedal edema and bilateral decreased air entry at the bases of the lungs. The result of hematological tests showed normocytic normochromic anemia with hemoglobin level 8.0 g/dL. Biochemical investigations were suggestive of altered renal functions with serum creatinine of 4.1 mg/dL. The albumin/globulin ratio was 0.23. Chest x-ray confirmed bilateral moderate pleural effusions. Computer tomography of the abdomen showed diffuse thickening of stomach wall involving fundus, body, and antrum with luminal narrowing. The perigastric fat planes were well preserved. There were omental and peritoneal nodular soft tissue masses in the abdomen and pelvis. Nodular masses (probably enlarged lymph nodes) were also detected in the paracaval and the para-aortic region. Extensive ascites with mesenteric edema was noted, though good passage of oral contrast was seen (Fig 1). Moderate bilateral pleural effusions were seen with subsegmental atelectasis of the underlying parenchyma of lung. Upper and lower GI endoscopy was suggestive of extrinsic compression at level of stomach, duodenum, and colon. Ascitic and pleural fluid analysis showed clusters of isolated mature and immature forms of plasmacytoid cells along with reactive mesothelial cells, macrophages, few polymorphs, and lymphocytes. Figure 2A and 2B shows ascitic fluid smear with sheets of plasma cells (Giemsa stain: Fig 2A, 40; Fig 2B, 100). Serum and ascitic fluid electrophoresis showed dense M band in immunoglobulin (Ig) A region (3.5 gm %) with kappa light chain restriction. Urinary Bence Jones Proteins were also positive. Figure 3A and 3B shows transduodenal biopsy with diffuse proliferation of plasmacytoid cells (hematoxylin and eosin: Fig 3A, 10; Fig 3B, 40). Immunohistochemistry revealed positive staining for kappa (Fig 4A) and leucocyte common antigen (Fig 4B). Multiple myeloma work-up with skeletal survey and bone marrow aspiration and biopsy showed no evidence of systemic disease. In view of these findings, a diagnosis of omental plasmacytoma with malignant pleural and peritoneal effusions was made. Extramedullary plasmacytoma (EMP) constitutes 4% of plasma cell tumors. It is defined as a solitary tumor composed of monoclonal proliferation of cells with plasmacytic differentiation at an extramedullary site. It is classified as either primary EMP (when there is absence of coexisting multiple myeloma) or secondary EMP (when it is associated with multiple myeloma). The most common sites for EMP are upper respiratory tract, including the oropharynx, nasopharynx, nasal cavities, nasal sinuses, and larynx. GI involvement by EMPs is rare and is seen in less than 5% of all EMP cases. In a review of EMP, 12 of 161 cases were GI in origin, and only three cases were gastric plasmacytomas. On the other hand, few reports are available of duodenal involvement by plasmacytoma.All the segments of the GI tract may be involved by plasma cell infiltration. The small bowel is the most common site of involvement, followed by stomach, colon, and esophagus. Gastroduodenal plasmacytomas may present with nonspecific GI symptoms like anorexia, weight loss, abdominal pain,