Advanced Unresectable Squamous Cell Carcinoma Research Articles

Concurrent chemoradiation with low-dose and long-duration weekly infusion of gemcitabine in unresectable squamous cell carcinoma of head and neck (SCCHN).

Concurrent chemoradiotherapy now represents the standard of care in locally advanced unresectable squamous cell carcinoma of the head and neck, and the administration of cisplatin in triweekly or weekly schedules is the most commonly used chemotherapeutic agent. However, the chemotherapeutic agent and its scheduling with radiation is still an area of investigation with safer toxicity profile and better response rates. Gemcitabine is a potent radiosensitizer, and non-cytotoxic concentration results in decreased systemic toxicity while maintaining radiosensitization properties. Furthermore, data are emerging for low-dose and long-duration infusion where this strategy is found to be effective and a safe alternative to standard brief infusion. Based on these two strategies, that is, non-cytotoxic concentration with long duration, we have explored the unique possibility of further lowering the toxicity profile without compromising the efficacy. Eligible patients of locally advanced unresectable squamous cell carcinoma of the head and neck underwent radiation treatment with concurrent gemcitabine. A total dose of 70 Gy in 35 fractions over a period of seven weeks with conventional fractionation schedule was delivered with cord off after 44 Gy. Concurrent gemcitabine was administered intravenously for over two hours once a week, 1-2 h before radiation and for seven consecutive weeks at 50 mg/m2. Fifty-two patients was enrolled in this study, out of which 41 completed the treatment. Fifty-nine percent completed treatment within seven weeks. Sixty-four percent were found to have received more than five cycles. Mean follow-up of patients was found to be 4.9 months. Sixty-eight percent had complete response. Stage III patients achieved more complete response compared to stage IV. There was no site-wise difference in achieving complete response. Patients who have received less than five chemo cycles or completed the treatment in more than seven weeks had less complete response. Sixty-one percent had severe mucositis while 39% developed mild/moderate mucositis. Considering skin toxicity, 80% were found to have mild/moderate skin toxicity, while only 20% suffered from severe grades of skin toxicity. Gemcitabine in low-dose and long-duration infusion is a potent radiosensitizer with safer hematological toxicity and manageable local toxicities.

Prospective randomized comparative study between EBRT alone and EBRT with ILRT boost in locally advanced unresectable esophageal cancer - Tertiary rural Indian cancer center experience

Background: Local recurrence within the gross tumor volume following a conventional radiation dose of 50 Gy is a major hurdle in achieving a better prognosis for esophageal carcinoma. Consequently, there remains a lack of consensus globally regarding the optimal dose for definitive concurrent chemoradiotherapy. Certain studies propose that radiation dose escalation could enhance clinical outcomes. Aims and Objectives: The current study aimed to compare the safety and effectiveness of external beam radiotherapy (EBRT) alone versus EBRT with intraluminal radiotherapy (ILRT) boost. Materials and Methods: A total of 60 patients with locally advanced unresectable squamous cell carcinoma of the esophagus were prospectively enrolled in this study. A comparison was conducted between 50 Gy EBRT alone and 50 Gy EBRT with 8 Gy ILRT boost, alongside weekly concurrent chemotherapy, to assess the response and toxicities. Results: On initial assessment, a complete response (CR) was achieved in 76.66% of patients in the ILRT boost arm and 70% in the EBRT alone arm (P=0.559). At the 6th-month follow-up, 60% of patients in the ILRT boost arm and 50% in the EBRT alone arm still had a CR. No statistically significant differences were observed between the two arms in terms of leukopenia (P=0.576), nephrotoxicity (P=1.0), radiation dermatitis (P=0.615), vomiting (P=0.921), and diarrhea (P=1.0). Five patients in the ILRT boost arm and three in the EBRT alone arm experienced stricture, while no cases of fistula formation were reported. Conclusion: Dose escalation with ILRT can result in an enhanced CR accompanied by manageable toxicity, ultimately leading to improved locoregional control.

Nimotuzumab combined with radiotherapy for the treatment of hypopharyngeal cancer – A case report from a tertiary cancer center

Nimotuzumab is a monoclonal antibody against epidermal growth factor receptor which can be combined with chemotherapy and radiotherapy for the treatment of locally advanced unresectable squamous cell carcinoma of head-and-neck region and its role has already been established in India. The aim of this case report is to show the role of nimotuzumab in carcinoma hypopharynx. We report a patient with Stage III carcinoma of hypopharynx, who received radiotherapy along with weekly nimotuzumab due to his comorbidities. The patient had tolerated the treatment very well without any major side effects. The patient is on regular follow-up with a complete response (CR) of the disease and with the disease-free interval (DFI) of 7 months. Nimotuzumab along with radiotherapy can be safely given in the patients with carcinoma hypopharynx, who are ineligible for chemotherapy. Nimotuzumab can be added with radiotherapy to the patients with head-and-neck malignancies who are ineligible for chemotherapy to improve the clinical outcome with minimal toxicity.

Abstract CT170: KEYNOTE-629: Phase II study of pembrolizumab for recurrent/metastatic or locally advanced unresectable cutaneous squamous cell carcinoma

Abstract Background: Findings from Phase I and II clinical trials suggest that treatment with an anti-programmed death 1 (PD-1) antibody is well tolerated and provides durable antitumor activity in patients with local/regionally advanced or metastatic cutaneous squamous cell carcinoma (cSCC). Encouraging efficacy and safety findings have also been reported from an expansion cohort in the phase 1 KEYNOTE-012 trial with the PD-1 inhibitor pembrolizumab. KEYNOTE-012 demonstrated that pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful overall response rate with evidence of durable responses in patients with recurrent and/or metastatic head and neck cSCC. To test the clinical activity of pembrolizumab, the open-label, single-arm, phase 2 KEYNOTE-629 trial (NCT03284424) will be carried out in patients with locally advanced, unresectable, and recurrent or metastatic cSCC. Trial design: Patients will receive intravenous pembrolizumab 200 mg every 3 weeks for up to 35 infusions (≤24 months) or until protocol-specified treatment discontinuation. Treatment will not be stratified in this study. Eligibility criteria include age ≥18 years; locally advanced cSCC that is ineligible for surgical resection or radiotherapy (RT) or that previously underwent RT to the index site or systemic therapy for curative intent; presence of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; and Eastern Cooperative Oncology Group performance status 0 or 1. Treatment will be discontinued for progressive disease, unacceptable toxicity, intercurrent illness preventing study treatment administration, investigator’s decision, patient withdrawal of consent, pregnancy, or cessation for administrative reasons. Response will be assessed by computed tomography or magnetic resonance imaging 6 weeks after treatment initiation, every 6 weeks through year 1, then every 9 weeks thereafter or more frequently if clinically indicted. After a patient experiences disease progression or starts new anticancer therapy, the patient will be followed up and contacted every 12 weeks until death, consent withdrawal, or study end, whichever occurs first. Safety will be monitored throughout the study treatment and for 30 days after treatment end and for 90 days for serious adverse events after the end of treatment. The primary end point is objective response rate (RECIST v1.1). Secondary end points include duration of response, disease control rate, progression-free survival, overall survival, and safety. Recruitment is ongoing in 10 countries and will continue until approximately 50 additional patients with locally advanced unresectable cSCC are enrolled. Citation Format: Jean-Jacques Grob, Rene Gonzalez Mendoza, Nicole Basset-Seguin, Jacob Schachter, Olga Vornicova, Jessica Bauman, Florent Grange, Nicolas Meyer, Josep Piulats, Pingye (Eric) Zhang, Burak Gumuscu, Ramona Swaby, Brett GM Hughes. KEYNOTE-629: Phase II study of pembrolizumab for recurrent/metastatic or locally advanced unresectable cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT170.

Randomized phase II study with or without induction chemotherapy combined with accelerated high dose radiotherapy and cetuximab in locally advanced unresectable HPV positive squamous cell carcinoma of the head and neck.

6077 Background: Concomitant chemoradiotherapy (CT/RT) is the standard treatment for locally advanced non- resectable squamous cell carcinoma of the head and neck. Acute side effects can be serious and late effects important. Patients with HPV+ tumors carry a better prognosis than other patients. De-escalation studies are explored with respect to RT, dose, fractionation, target volumes, adjuvant pharmacotherapy, with encouraging results. However, several patients still recur locoregionally, also in high dose RT volumes. Some patients have distant metastases, often with massive tumor burden and late during follow up (FU). Purpose of the study: 1.To evaluate the effect of induction chemotherapy (IC) on (a) progression free survival (b) distant metastases as first site of failure (c) locoregional failure (d) pattern of tumor response, spatial and timely, exploring the possibility to reduce RT dose and/or target volume(s) in future protocols. 2. to address the impact of high dose RT for bulky disease, T3/T4 given concurrent with cetuximab (E). Methods: Patients had previously untreated stage III/IV (>80 % st IV; TNM 7th), M0 disease, WHO 0-1, unresectable squamous cell carcinoma of the head and neck, HPV positive as evaluated with p16 and/or PCR. Pts were randomised between 2 arms. Pts in arm A were scheduled for 2 cycles of TPF : T (docetaxel) 75 mg/m2 day 1, P (cisplatin) 75 mg/m2 day 1 and F (fluorouracil) 1000 mg/m2 over 24 hours day 1-4. RT was delivered with IMRT to all pts : 68 Gy in 6 weeks for T1/T2 tumors, 76 Gy in 6.5 weeks for T3/T4 tumors with E given one week before and weekly during RT. Tumor response was evaluated according to RECIST with CT, MRI or PET/CT after IC, at 6-8 weeks, 1 and 2 years FU. Results: From january 2011 to february 2016, 152 consecutive pts were enrolled, 77 in arm A. All pts had oropharyngeal cancer. In arm A, 7 pts had CR after TPF, 19 had PR out of 36 evaluable pts. At 2 years FU 70/77 pts (91%) were alive in arm A, 69/75 (92%) in arm B. Distant metastases as first site of failure was 3 (3.9%) in arm A and 7 (9.3%) in arm B. Adverse events grade 3-4, ever registered, were seen in 71 pts in arm A and 63 in arm B, were transient, most often related to RT. Conclusions: Survival and locoregional control at 2 years was high and similar in both arms. Distant metastases as first site of failure was more than doubled in arm B, not having induction chemotherapy (IC). Clinical trial information: EudraCT number: 2009-013438-26.

KEYNOTE-629: Phase 2 study of pembrolizumab for recurrent/metastatic or locally advanced unresectable cutaneous squamous cell carcinoma (cSCC).

TPS9598 Background: Findings from phase 1 and 2 studies suggest that targeting programmed death 1 (PD-1)/PD-L1 pathway can provide durable antitumor activity in patients with local/regionally advanced or metastatic cSCC and may be a promising treatment option. The open-label, single-arm, phase 2 KEYNOTE-629 trial (NCT03284424) will be conducted to test the clinical activity of the PD-1 inhibitor pembrolizumab in locally advanced, unresectable, and recurrent or metastatic cSCC. Methods: Patients will receive intravenous pembrolizumab 200 mg every 3 weeks for up to 35 infusions (≤24 months) or until protocol-specified treatment discontinuation. Treatment will not be stratified in this study. Eligibility criteria include age ≥18 years; locally advanced cSCC for which the patient is ineligible for resection or radiotherapy (RT) or for which the patient previously underwent RT to the index site or systemic therapy for curative intent; presence of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; and Eastern Cooperative Oncology Group performance status 0 or 1. Treatment will be discontinued for progressive disease, unacceptable toxicity, intercurrent illness preventing administration, investigator’s decision, patient withdrawal of consent, pregnancy, or cessation for administrative reasons. Response will be assessed by imaging 6 weeks after treatment initiation, every 6 weeks through year 1, and every 9 weeks thereafter or more frequently if clinically indicated. After disease progression or the start of new anticancer therapy, the patient will be followed up every 12 weeks until death, consent withdrawal, or study end, whichever occurs first. Safety will be monitored throughout the study and for 30 days after treatment end or 90 days if the patient experiences serious adverse events. The primary end point is objective response rate (RECIST v1.1). Secondary end points include response duration, disease control rate, progression-free survival, overall survival, and safety. Recruitment is ongoing in 10 countries and will continue until approximately 50 additional patients with locally advanced, unresectable cSCC are enrolled. Clinical trial information: NCT03284424.

The role of induction chemotherapy followed by surgery in unresectable stage IVb laryngeal and hypopharyngeal cancers: a case series

BackgroundThe purpose of this study was to evaluate the benefit of induction chemotherapy followed by surgery in locally advanced unresectable stage IVb laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC).MethodsData of patients with stage IVb LHSCC who received induction chemotherapy for the purpose of tumor resection between January 2007 and January 2016 were retrospectively collected. Definitive surgery with postoperative adjuvant therapy was performed in patients whose tumors became resectable (resectable group). Chemoradiotherapy, radiotherapy, or supportive care was considered in patients whose tumors remained unresectable (unresectable group).ResultsThirty-two patients were identified; the tumor resectability rate after induction chemotherapy was approximately 56%. The median overall survival (OS) rates of the resectable and unresectable groups were 20.0 months (range, 16.0–35.5 months) and 9.5 months (range, 6.0–15.0 months), respectively (p = 0.008). The estimated 2-year OS rates of the resectable and unresectable groups were 59.5% (95% confidence interval [CI], 33.2–78.3%) and 10.7% (95% CI, 1.1–35.4%), respectively (p = 0.008). The estimated 2-year disease-free survival (DFS) rates of the resectable and unresectable groups were 53.5% (95% CI, 27.9–73.6%), and 14.3% (95% CI, 2.3–36.6%), respectively (p = 0.009). On multivariate analysis, factors positively impacting OS and DFS in all patients were surgical resection, a laryngeal primary site, and induction chemotherapy with docetaxel, cisplatin, and fluorouracil.ConclusionsIn advanced unresectable stage IVb LHSCC patients, surgical resection following induction chemotherapy appears to improve survival outcomes.

A phase II trial of concurrent chemoradiotherapy with weekly docetaxel plus cisplatin treatment for unresectable locally advanced head and neck cancer

PurposeAlthough concurrent chemoradiotherapy (CCRT) is the standard of care for locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN), the optimal CCRT regimen is not yet defined. We conducted a phase II study of weekly docetaxel and cisplatin treatment with concurrent radiotherapy (RT) to investigate the efficacy and toxicity profiles. Material and methodsForty-one patients with locally advanced SCCHN were treated with 20mg/m2 docetaxel plus 20mg/m2 cisplatin weekly for 6 cycles, concurrent with RT, between April 2010 and March 2013. ResultsThe mean total doses of docetaxel and cisplatin were 109.3mg/m2 and 110.7mg/m2, respectively. The mean total delivered dose of radiation was 67.7Gy. Thirty-seven patients (90.3%) received 5 or more cycles of treatment. At the 1-month post-CCRT tumor response evaluation, 13 patients (39.9%) achieved a complete response (CR) [95% confidence interval (95% CI), 20.1–56.6]. Thirty-two patients (78.0%) ultimately achieved CR during the post-treatment follow-up period. With a median follow-up of 3.4years, the 2-year overall survival (OS), disease-free survival (DFS), and distant disease-free survival (DDFS) were 85.4% (95% CI, 74.6–96.2%), 72.8% (95% CI, 59.2–86.4%), and 82.4% (95% CI, 70.7–94.1%), respectively. Overall, grade 3 toxicities occurred in 21 patients (51.2%), most commonly mucositis (39.0%), neutropenia (9.8%), or dysphagia (4.9%). A grade 4 adverse event was observed in only one patient with neutropenia. ConclusionsCCRT with weekly docetaxel and cisplatin shows promising antitumor activity with manageable toxicity profiles for patients with locally advanced SCCHN.

A Randomized Prospective Study of Concurrent Chemo-Radiotherapy vs Accelerated Hyperfractionation in Advanced Cancer of Head and Neck.

Locally advanced unresectable squamous cell carcinoma of head and neck has poor locoregional control when treated with conventionally fractionated Radiation Therapy (RT) alone. However, Concurrent Chemo-Radiotherapy (CRT) and altered fractionated RT schedules like Accelerated Hyperfractionation (AHF) are two different treatment strategies that have shown to be associated with better efficacy as compared to conventional RT alone in such cases. Aim of the study was to compare these two treatment strategies i.e., CRT and AHF radiation treatment to know which is better in terms of clinical outcome and toxicity in patients of locally advanced unresectable squamous cell carcinoma of head and neck. A prospective randomized trial was done to compare the effect of CRT and of AHF radiation treatment in locally advanced unresectable head and neck cancer on 15 patients in each arm and followed up over three months period. At the end of three months after completion of treatment protocol, complete response was 62% in CRT arm and 53% in AHF arm. In CRT arm and AHF arm, Grade 3 skin reactions were observed in 100% and 87%, grade 3 mucosal reactions were in 62% and 67% of cases, respectively. Three patients died in CRT arm (two due to myelosuppression and associated infection; one during the treatment and another after two weeks of treatment completion. The third patient expired after one month of treatment completion at his native place due to unknown reason). One patient died in AHF arm (during treatment due to cardiac event). Efficacy of AHF was comparable to CRT with lesser toxicity. So the present study suggests that AHF should be preferred over CRT in locally advanced, unresectable, squamous cell head and neck cancer followed over three months non-treatment period.

Comparative evaluation of gemcitabine concurrent with radiotherapy against cisplatin concurrent with radiotherapy in locally advanced squamous cell carcinoma of esophagus

Background: Several trials using sequential and concurrent chemoradiation have established the role of concurrent chemoradiation in treatment of locally advanced esophageal carcinoma with encouraging but unsatisfactory results. We investigated the efficacy and toxicity of gemcitabine concurrent with radiotherapy against cisplatin concurrent with radiotherapy in locally advanced unresectable squamous cell carcinoma of the esophagus. Materials and Methods: Eighty patients were randomly allocated to two arms during the study. Arm 1 received cisplatin 40 mg/m2 weekly concurrent with external beam radiotherapy to a total dose of 65 Gy while Arm 2 received gemcitabine 200 mg/m2 weekly concurrent with external beam radiotherapy up to a total dose of 65 Gy. Results: Median follow-up was 11 months and 14.5 months in Arm 1 and Arm 2, respectively. Complete response was achieved in 20% of patients in Arm 1 and 32.5% of patients in Arm 2, with manageable acute toxicities in both arms. The progression-free survival in Arm 1 was 5.7 ± 4.7 months and 12.4 ± 6.8 months in Arm 2. The 2-year overall survival was longer in Arm 2. Conclusion: This study demonstrated that both cisplatin and gemcitabine concurrent with radiotherapy in locally advanced squamous cell carcinoma of the esophagus is safe and feasible with better response and progression-free survival with gemcitabine.

Evaluation of the impact of tumor HPV status on outcome in patients with locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) receiving cisplatin, 5-Fluorouracil with or without docetaxel: retrospective analysis of EORTC24971 study.

6061 Background: EORTC 24971 was phase III trial demonstrating superiority of induction regimen TPF over PF, in terms of progression-free (PFS) and overall survival (OS) in locally advanced unresec...

Therapy of Advanced Squamous Cell Carcinoma of the Skin

Advanced unresectable squamous cell carcinoma of the skin (SCCS) is a rare condition, which is difficult to treat. Because of its rarity, few therapeutic trials are available. Moreover, SCCS often occur in elderly. Conventional treatment options for advanced SCCS are chemotherapy mainly with cisplatin-based regimens. Immunotherapy with interferon alpha and retinoids combination was also shown to be efficient. Toxicity of these treatments limits, however, their use in elderly patients and an initial work up for a global assessment is needed in order to adapt the choice. More recently, epithelial growth factor receptor (EGFR) targeted therapies have been developed and induced interesting response rates in small series of patients with unresectable SCCS. Their efficacy in SCCS must be confirmed by larger phase III trials and the identification of predictive biological factors of response is warranted. New therapeutic approaches combining EGFR inhibitors either with IGFR inhibitors, or immunomodulators or inhibitors of the PI3K/AKT/mTOR pathway are currently under evaluation in head and neck carcinomas and might represent valuable therapeutic approaches for unresectable SCCS. Moreover, there are several new molecular candidate treatment targets for unresectable SCCS including somatic NOTCH1 or NOTCH2 inactivating mutations, ALK1, which could be a good candidate for antiangiogenic therapy and matrix metallopeptidase 7, which enhances proliferation, migration, and invasion of cancer cells. Organ transplant recipients often develop SCCS and in some patients, SCCS are rapidly progressing. Management of SCCS in this subgroup of patients includes both carcinologic treatment and modification of immunosuppression. Specific treatment is generally the same as in immunocompetent patients. Switching from calcineurin inhibitors to sirolimus or reducing immunosuppression has to be considered.

Phase II randomized study comparing concurrent chemoradiation versus neoadjuvant chemotherapy followed by chemoradiation in locally advanced unresectable squamous cell carcinoma of esophagus.

e15138 Background: A significant number of patients diagnosed with esophageal cancer (EC) presents with locally advanced disease. Nonsurgical curative therapy for unresectable EC has limited outcome. Methods: Phase II randomized control trial to assess early locoregional response (LRR) to neoadjuvant chemotherapy (NACT) followed by concurrent chemoradiation (CRT) versus definitive CRT in surgically unresectable squamous cell carcinoma of esophagus (ESCC). A total of 30 patients were randomly assigned to two arms. Arm 1: 2 cycles NACT regimen of 5-fluorouracil (750mg/m2 D1-4) and cisplatin (80mg D1-2) followed by CRT, radiation of 56Gy/ 28 Fr concurrent with weekly paclitaxel 50mg/m2 and carboplatin AUC2. Arm2: CRT; consisting of radiation 56Gy/28Fr and weekly paclitaxel 50mg/m2 and carboplatin AUC2. All the patients were followed till 6 months post treatment. LRR assessment was done at 1, 3 and 6 months post treatment. Wilcoxon multivariate analysis was carried out and difference of the factors were assessed by chi square test (x2 p<0.05). Results: Mean age in two arms were 52 and 54 years respectively. The study had median follow up of 6.6 months. Conclusions: In unresectable EC, CRT showed higher LRR, treatment completion and lesser toxicity compared to NACT combined with CRT. In this pilot cohort of locally advanced unresectable EC paclitaxel and carboplatin combined with radiotherapy has good tolerance and compliance. [Table: see text]

Induction chemotherapy with docetaxel, cisplatin, and 5FU (TPF) in unresectable advanced head and neck squamous cell carcinoma: Retrospective analysis of 300 cases and proposal for a prognostic index.

e16055 Background: Phase III studies have demonstrated that induction chemotherapy with TPF followed by cisplatin-based chemoradiation (CRT) is a valid option for the treatment of advanced unresectable head and neck squamous cell carcinoma. These studies have been done in highly selected patients. The aim of our study is to confirm these data in unselected patients and to identify prognostic factors of tolerance and survival. Methods: Between October 2005 and June 2010, 300 patients from 5 institutions with locally advanced neck and head cancer received at least one induction cycle, followed by locoregional radiotherapy (R) associated or not with platinum (P) or cetuximab (C)-based chemotherapy. Results: Mean age was 56 years old (range 31-76). Performance status was 0 or 1 in 97% of patients and 50 % of them presented current alcohol intoxication. 69% (n=208) received 3 cycles of TPF, and 91% (n=268) underwent R associated or not with P (n=167) or C (n=51). 52% of patients (n=156) received the conform treatment (ie 3TPF + RP or RC). Grade 3-4 toxicities have been reported in 19% (n= 57), including 3% febrile neutropenia (n=9) and 7% kidney failure (n=22). Grade 3-4 toxicity, during TPF induction, led systematically to permanently discontinuation of the chemotherapy. Overall response rate after TPF induction was of 88% with 23% of complete response. After a median follow-up of 21 months, median progression-free survival and cause-specific survival (SS) were not reached. Median overall survival (OS) was 49 months (95% CI 31.2-66.8). SS and OS were significantly improved (p<0.0001) in patients who received the conform treatment. In multivariate analysis the probability of death related to cancer or to toxicities induced by treatment was increased for hemoglobin level ≤ 12.6g/dl or GGT level ≥ 77U/I [HR = 3.45 (95% CI: 1.50-7.93) p=0.0029]. Conclusions: We propose to use a biological index based on baseline hemoglobin and GGT levels to select patient for induction therapy in SCCHN. This simple index, predictive of treatment conformity and specific survival, needs further prospectives investigations.

Cetuximab plus radiotherapy in patients with unresectable locally advanced squamous cell carcinoma of head and neck region - A open labelled single arm phase II study

To evaluate feasibility, safety and outcome of cetuximab concurrent with radiotherapy in locally advanced head-neck cancer. Between March 2007 and January 2008 eligible cases of locally advanced unresectable (Stage IV) squamous cell carcinoma of head and neck were enrolled in this single arm, open labeled phase II Study. They were treated with cetuximab for a duration of 8 weeks and concomitant RT for 7 weeks (starting one week after initiating Cetuximab). A total of 19 eligible patients were enrolled. The median age of patients was 53 years, all patients happening to be male. The performance status of the patients was 0/1. The location of the primary tumor was oropharynx in 12 cases, oral cavity in 4, larynx in 2, and hypopharynx in one case. The overall response rate (ORR) was 68.42% and the overall survival at 2 year was 84 %. All 13 patients who completed two years follow-up after completion of study treatment continued to be alive with no evidence of disease progression. One patient also remained alive with progressive disease. Cetuximab concurrent with radiotherapy is a safe and effective option in advanced head-neck cancer patients.

A multicenter randomized phase II (rPII)/III study comparing concurrent chemoradiotherapy (CRT) with low-dose cisplatin plus continuous infusion of 5-fluorouracil (LDPF) and standard-dose PF (SDPF) for locally advanced unresectable squamous cell carcinoma of the thoracic esophagus (JCOG0303).

4053 Background: Cisplatin-based CRT is one of the standard treatments for locally advanced unresectable esophageal carcinomas. Although both cisplatin and 5-FU are known to enhance the efficacy of radiotherapy, the optimal chemotherapy regimen has not been established. Thus, we evaluated CRT with LDPF on effectiveness and adverse events for locally advanced unresectable esophageal carcinomas in a randomized study to determine if it is an acceptable alternative to SDPF. Methods: Eligibility criteria included histologically proven squamous cell, adenosquamous, or basaloid carcinoma; tumor located in thoracic esophagus; and definite T4 and/or unresectable regional lymph node metastasis. In arm A, two courses of standard chemotherapy of cisplatin (70 mg/m2, div day1, 29) plus 5-FU (700 mg/ m2, ci day1-4, 29-32) were given with external beam radiation (EBRT) in 30 daily fractions, 5 d/week to a total dose of 60 Gy. In arm B, low dose daily cisplatin (4 mg/ m2, div) plus 5-FU (200 mg/ m2, ci) was administered on the same days that EBRT was given. The primary endpoint was overall survival (OS). The rPII study was designed to evaluate the efficacy of LDPF to decide whether it warranted a phase III trial. Results: Between Apr. 2004 and Jun. 2009, 135 pts (Arm A/B; 67/68) from 40 institutions were randomized. Tumor depth (T1-3/T4) was 18/49 in arm A and 13/55 in arm B. The median follow-up time for all eligible pts was 9.9 mos. Toxicities were almost equivalent in both arms; however LDPF necessitated long hospitalization. Moreover, the OS of pts of LDPF group was slightly inferior to that of those treated with SDPF (hazard ratio, 1.048, 95%CI, 0.782-1.045; median OS (A/B), 13.0/13.6 mos.; 3-year OS (A/B), 30/26%). Because of the inferior efficacy of LDPF, the Data and Safety Monitoring Committee of the JCOG recommended the termination of the study at the end of rPII. Conclusions: CRT with LDPF is not recommended for pts with locally advanced unresectable esophageal cancer. No significant financial relationships to disclose.

Concomitant Chemoradiotherapy With Mitomycin C and Cisplatin in Advanced Unresectable Carcinoma of the Head and Neck: Phase I–II Clinical Study

To evaluate the toxicity and efficacy of concomitant chemoradiotherapy with mitomycin C and cisplatin in the treatment of advanced unresectable squamous cell carcinoma of the head and neck. Treatment consisted of conventional radiotherapy (70 Gy in 35 fractions), mitomycin C 15 mg/m(2) IV, applied after the delivery of 10 Gy, and cisplatin at an initial dose of 10 mg/m(2)/d IV, applied during the last 10 fractions of irradiation ("chemoboost"). The cisplatin dose was escalated with respect to the toxic side effects by 2 mg/m(2)/d up to the maximum tolerated dose (MTD) or at the most 14 mg/m(2)/d (Phase I study), which was tested in the subsequent Phase II study. All 36 patients had Stage T4 and/or N3 disease, and the majority had oropharyngeal (50%) or hypopharyngeal (39%) primary tumors. Six patients were treated at each of the three cisplatin dose levels tested (Phase I study). Dose-limiting toxicity was not reached even at 14 mg/m(2)/d of cisplatin, which was determined as the MTD and tested in an additional 18 patients (Phase II study). After a median follow-up time of 48 months, 4-year locoregional control, failure-free, and overall survival rates were 30%, 14%, and 20%, respectively. In 24 patients treated at the cisplatin dose level of 14 mg/m(2)/d, the corresponding rates were 40%, 20%, and 22%, respectively. Concomitant chemoradiotherapy with mitomycin C and cisplatin "chemoboost" at 14 mg/m(2)/d is feasible, with encouraging survival results if the extremely poor disease profile of the treated patients is considered.

Cost-effectiveness analysis of the EORTC 24971 (TAX 323) trial comparing docetaxel plus cisplatin and 5-fluorouracil versus standard treatment (cisplatin and 5-fluorouracil) as induction chemotherapy followed by radiation therapy in locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN)

6090 Background: The phase III EORTC 24971 clinical trial (TAX 323) showed that induction chemotherapy followed by radiation therapy increases time to progression and improves outcomes in unresectable SCCHN patients. [Remenar et al. ASCO 2006; Abs 5516] Induction chemotherapy with cisplatin/5-FU (PF) is a standard regimen for patients with locally advanced SCCHN. The economic impact of adding docetaxel to cisplatin/5-FU (TPF) in this setting was assessed using a Markov state-transition model. Methods: The Markov model includes four health states (based on WHO criteria for measuring objective response): stable, response, progression, and death. Efficacy data from the TAX 323 clinical trial were used to derive transition probabilities between the health states. Adverse event rates were also derived from TAX 323. Data for resource utilization and costs for the UK were derived from the literature and from an advisory board of clinicians. In order to calculate quality adjusted life years (QALYs), utilities were derived by mapping the global score on the Health Related Quality of Life Questionnaire Core-30 (QLQ-C30) to the EQ-5D. Results: Patients survived longer in the TPF arm versus PF (2.5 vs. 2.0 years). Total costs for TPF and PF were £31,203 and £26,944, respectively. The incremental discounted cost per QALY gained for TPF versus PF was £9,859/QALY, which is below the £20,000 cost-effectiveness threshold suggested by NICE as a guide to the acceptability of a technology. Conclusion: Docetaxel, when given as induction chemotherapy in combination with cisplatin/5-FU, is cost-effective compared with PF in locally advanced unresectable SCCHN patients. Treating SCCHN patients with TPF followed by radiation represents good value for money based on the results of the analysis. No significant financial relationships to disclose.

Feasibility study of capecitabine (cap) and cisplatin (cis) with radiation therapy (RT) in the management of patients with locally advanced unresectable squamous cell carcinoma of the head and neck (HNSCC)

16520 Background: Concurrent chemoradiation has become the standard of care for locally advanced unresectable HNSCC. The most commonly used chemotherapy is cis and 5-fluorouracil (5-FU). We evaluated the feasibility of using cap and cis during RT in this population. Cap is an oral pro-drug of 5-FU that can be given daily with RT in order to enhance the activity of RT. Methods: Between Oct, 2003 and Sept, 2005, 12 male patients aged 46–83 were treated at the VA Medical Center. Patients received cis 100 mg/m2 on days 1 and 29 and cap 450 mg/m2 bid (2 hours prior to RT and 12 hours later) for 5 days of each week concurrent with RT to a total dose of 70 Gy in 35 fractions over 7 weeks. Primary endpoint of the study was toxicity. Results: All 12 patients were able to complete therapy. Treatment delays and/or dose modifications were needed in 7 patients. Treatment related toxicities included 6 patients with grade 3 mucositis and 5 patients with grade 3 dysphagia. Other grade 3 toxicities included 3 patients with dehydration and 1 patient each with leucopenia, constipation, nausea and vomiting, and odynophagia. Percutaneous gastrostomy (PEG) tubes were required in 5 patients. Complete response to chemoradiation was seen in 9 patients, 2 patients obtained partial response, and 1 patient progressed. Median progression free and overall survivals have not been reached with a median follow-up of 21 months. Conclusions: Cis and cap administered concurrently with RT has manageable toxicities and is active in patients with locally advanced unresectable HNSCC. No significant financial relationships to disclose.

Impact on quality of life (QoL) of the addition of docetaxel (T) to neoadjuvant cisplatin plus 5-fluorouracil treatment in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN): EORTC study 24971

5522 Background: The EORTC 24971 trial compared the efficacy and safety of two neoadjuvant regimens in the treatment of stage III or IV, M0 SCCHN. Eligible patients (pts) with primary tumor sites in the oral cavity, oropharynx, hypopharynx, and larynx and WHO performance status (PS) ≤1) were randomized to 2–4 cycles of cisplatin (P) 100 mg/m2 day 1, followed by a continuous infusion of 5-fluorouracil (F) 1000 mg/m2/day from days 1- 5 (PF), or T 75 mg/m2 + P 75 mg/m2 day 1 then F 750 mg/m2/day from days 1 - 5 (TPF), followed by locoregional radiation therapy (RT). The impact of the two regimens on QoL was a secondary endpoint. Methods: QoL was assessed at baseline, at cycles 2 and 4, and 6 and 9 months after RT using the EORTC QLQ-C30 questionnaire to obtain the Global Health Status/Quality of Life (GHS/QoL) score, and the Head and Neck Performance Status Scale (PSS-HN) to assesses the normality of diet, eating in public, and understandability of speech on a scale of 0 to 100. The EORTC QLQ-HN35 questionnaire was also administered at those time-points. Results: 358 pts were randomized to PF (181 pts) or TPF (177 pts). Baseline (BL) characteristics of the pts were well balanced between groups. TPF was superior to PF in terms of response rate, progression-free survival (primary endpoint), overall survival, and tolerability. Compliance with the QLQ-C30 questionnaire was good ranging from 96% at BL to 41% at 9 months post RT, and was similar between the treatment arms. GHS/QoL scores were comparable at BL between the two arms (p = 0.54) and improved in both arms on starting treatment. Over time this score remained stable with TPF, but decreased after RT with PF (treatment-time interaction: p = 0.009). Evolution of the PSS-H&N score was better on TPF (normality of diet p= 0.0064; eating in public p = 0.0004; understandability of speech p = 0.0003). Moreover, TPF was associated with a 30% reduction in the risk of WHO PS deterioration (p = 0.0158) Conclusions: The use of docetaxel in neoadjuvant treatment of SCCHN improves efficacy without deleterious effects on QoL and functional outcomes. [Table: see text]