Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial

Background Our previous phase-3 study (TTCC 2503) failed to show overall survival advantage of 2 induction chemotherapy (IC) regimens followed by standard concurrent chemoradiotherapy (CRT) over CRT alone in patients with unresectable locally advanced head and neck squamous-cell carcinoma (LAHNSCC). This study described the long-term survival of those patients. Materials and methods Long-term follow-up study of patients with untreated LAHNSCC assigned to IC (three cycles), with either docetaxel, cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CRT, or CRT alone, included in the previous TTCC 2503 trial. Results In the intention-to-treat population (n = 439), the median OS times were 25.4 (95% CI, 16.8–34.4), 26.2 (95% CI, 18.2–36.6) and 25.4 months (95% CI, 17.4–36.0) in the TPF-CRT, PF-CRT and CRT arms, respectively (log-rank p = 0.51). In the per-protocol population (n = 355), patients with larynx–hypopharynx primary tumors treated with IC (TPF or PF) followed by CRT had a longer median PFS than those who received CRT alone. Moreover, patients with ECOG 0 treated with IC (TPF or PF) followed by CRT had a better TTF than those with CRT alone. There were no statistically significant differences in terms of OS, PFS or TTF, according to the tumor load or affected nodes. Conclusion After a long follow-up, the TTCC 2503 trial failed to show the benefit of IC-CRT in unresectable LAHNSCC regarding the primary end point. However, fit patients with ECOG 0 and primary larynx–hypopharyngeal tumors may benefit from the use of IC if administered by an experienced team (AU)

Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial.

BACKGROUND: Our previous phase-3 study (TTCC 2503) failed to show overall survival advantage of 2 induction chemotherapy (IC) regimens followed by standard concurrent chemoradiotherapy (CRT) over CRT alone in patients with unresectable locally advanced head and neck squamous-cell carcinoma (LAHNSCC). This study described the long-term survival of those patients. MATERIALS AND METHODS: Long-term follow-up study of patients with untreated LAHNSCC assigned to IC (three cycles), with either docetaxel, cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CRT, or CRT alone, included in the previous TTCC 2503 trial. RESULTS: In the intention-to-treat population (n = 439), the median OS times were 25.4 (95% CI, 16.8-34.4), 26.2 (95% CI, 18.2-36.6) and 25.4 months (95% CI, 17.4-36.0) in the TPF-CRT, PF-CRT and CRT arms, respectively (log-rank p = 0.51). In the per-protocol population (n = 355), patients with larynx-hypopharynx primary tumors treated with IC (TPF or PF) followed by CRT had a longer median PFS than those who received CRT alone. Moreover, patients with ECOG 0 treated with IC (TPF or PF) followed by CRT had a better TTF than those with CRT alone. There were no statistically significant differences in terms of OS, PFS or TTF, according to the tumor load or affected nodes. CONCLUSION: After a long follow-up, the TTCC 2503 trial failed to show the benefit of IC-CRT in unresectable LAHNSCC regarding the primary end point. However, fit patients with ECOG 0 and primary larynx-hypopharyngeal tumors may benefit from the use of IC if administered by an experienced team. ClinicalTrials.gov identifier NCT00261703.

Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer.

BACKGROUND: In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1. PATIENTS AND METHODS: Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes. RESULTS: Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35). CONCLUSIONS: Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings. CLINICAL TRIAL REGISTRATION: NCT01345682.

Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial.

BACKGROUND: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years. PATIENTS AND METHODS: Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed. RESULTS: Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups. CONCLUSIONS: Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients. CLINICAL TRIAL REGISTRATION: NCT01345682 (ClinicalTrials.gov).

A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with unresectable, nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN). This randomized, open-label, phase III clinical trial compared the efficacy between standard CCRT and two different induction chemotherapy (ICT) regimens followed by CCRT. PATIENTS AND METHODS: Patients with untreated LASCCHN were randomly assigned to ICT (three cycles), with either docetaxel (Taxotere), cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CCRT [7 weeks of radiotherapy (RT) with cisplatin 100 mg/m(2) on days 1, 22 and 43]; or 7 weeks of CCRT alone. The primary end points were progression-free survival (PFS) and time-to-treatment failure (TTF). RESULTS: In the intention-to-treat (ITT) population (n = 439), the median PFS times were 14.6 (95% CI, 11.6-20.4), 14.3 (95% CI, 11.8-19.3) and 13.8 months (95% CI, 11.0-17.5) at TPF-CCRT, PF-CCRT and CCRT arms, respectively (log-rank P = 0.56). The median TTF were 7.9 (95% CI, 5.9-11.8), 7.9 (95% CI, 6.5-11.8) and 8.2 months (95% CI, 6.7-12.6) for TPF-CCRT, PF-CCRT and CCRT alone, respectively (log-rank P = 0.90). There were no statistically significant differences for overall survival (OS). Toxic effects from ICT-CCRT were manageable. CONCLUSION: Overall, this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN.

SEOM clinical guidelines for the treatment of head and neck cancer (HNC) 2013

Head and neck cancer represents 5 % of oncologic cases in adults. Early stage treatments are local with surgery and/or radiotherapy. For locally advanced stages, treatment requires radiotherapy combined with platinum-based drugs or cetuximab. Induction chemotherapy should be considered for selected cases. In the case of metastatic disease, adjuvant or palliative treatment is based on platinum agents and cetuximab (AU)

SEOM clinical guidelines for the treatment of nasopharyngeal carcinoma 2013

Nasopharyngeal carcinoma cases are not frequently encountered in our environment. Local stages are treated with radiotherapy. For advanced local stages, the association of chemotherapy with radiotherapy improves the rates of survival. In the case of metastatic disease stages, treatment requires platinum-based chemotherapy and patients may achieve a long survival time (AU)

SEOM clinical guidelines for the treatment of nasopharyngeal carcinoma 2013.

Nasopharyngeal carcinoma cases are not frequently encountered in our environment. Local stages are treated with radiotherapy. For advanced local stages, the association of chemotherapy with radiotherapy improves the rates of survival. In the case of metastatic disease stages, treatment requires platinum-based chemotherapy and patients may achieve a long survival time.

SEOM clinical guidelines for the treatment of head and neck cancer (HNC) 2013.

Head and neck cancer represents 5 % of oncologic cases in adults. Early stage treatments are local with surgery and/or radiotherapy. For locally advanced stages, treatment requires radiotherapy combined with platinum-based drugs or cetuximab. Induction chemotherapy should be considered for selected cases. In the case of metastatic disease, adjuvant or palliative treatment is based on platinum agents and cetuximab.

Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck.

BACKGROUND: The efficacy and safety of a novel combination of weekly paclitaxel and the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab for the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck were investigated. PATIENTS AND METHODS: Patients received paclitaxel (80 mg/m(2)) and cetuximab (400/250 mg/m(2)), weekly, until disease progression or unacceptable toxicity. The primary end point was response rate. RESULTS: Among 46 patients enrolled, the overall response rate was 54% [95% confidence interval (CI) 39% to 69%], with 10 (22%) complete responses and a disease control rate of 80%. Median progression-free and overall survival times were 4.2 (95% CI 2.9-5.5 months) and 8.1 months (95% CI 6.6-9.6 months), respectively. Common grade 3/4 adverse events were acne-like rash (24%), asthenia (17%) and neutropenia (13%). Prior chemotherapy and the development of acne-like rash were associated with tumor response but not survival. No association between tumor EGFR expression or EGFR gene copy number and response or survival was found. CONCLUSION: The combination of cetuximab and weekly paclitaxel was active and well tolerated by these poor prognosis patients and may be an option for the treatment of medically unfit patients, particularly those for whom platinum is contraindicated.

Prognostic significance of surgical margins in transoral CO2 laser microsurgery for T1-T4 pharyngo-laryngeal cancers.

Histological affected or close margin is an adverse factor in conventional surgery of larynx-hypopharynx cancer. Our objective was to analyze the relevance of the margins in transoral laser microsurgery (TLM). A retrospective study of 357 consecutive patients with cancer of the larynx and hypopharynx (T1-T4) treated with TLM. Three possible margins were considered: tumor free, affected, and uncertain. An affected margin showed marked tumor infiltration. An uncertain margin was defined when the sample was insufficient, when it showed carbonization impeding accurate evaluation, or when tumor cells were less than 2 mm. Margins were free in 254 (71.1%) patients, affected in 64 (17.9%) and uncertain in 39 (10.9%). One hundred and three patients (28.9%) presented tumor relapse. The margins were associated with tumor relapse (P < 0.001), but were not significantly related to the tumor site (P = 0.307), the pT classification (P = 0.183), or the difficulty of surgical exposure (P = 0.427). Distant metastases were found in 4.7% of the patients with free margins, in 7.7% of those with uncertain margins, and in 14.1% with affected margins. These differences were statistically significant (P = 0.028). Tumor involvement of the surgical margin was associated with higher rates of local relapse, distant metastasis and the necessity of salvage surgery, together with a lower specific actuarial survival rate.

Clinical outcome in patients with intramedullary spinal cord metastases from lung cancer.

Intramedullary spinal cord metastases (ISCM) are uncommon and present with rapidly progressing neurological deficits. The objective of this study was to determine the rate, duration of neurological response and survival after radiation therapy. We have retrospectively reviewed the clinical outcome of six cases with a diagnosis of ISCM from primary lung cancer, non-small cell (NSCLC) (n=3) and small cell (SCLC) (n=3). Total radiation dose ranged from 27 Gy/5 fr to 40 Gy/20 fr. Ambulation was preserved in 3 patients and partially recovered in one. Five out of the six patients (83%) showed improvement in neurological signs/symptoms with a mean duration of 17.2 days (max: 40 days; min: 6 days). Median survival time was 5 months (confidence interval (CI) 95%: 0-12) for NSCLC and 5 months (CI 95%: 4-6) for SCLC. Although radiation response rate is high, the interval free of neurological progression is very short. A therapeutic approach should be considered for each individual.

Clinical outcome in patients with intramedullary spinal cord metastases from lung cancer

Intramedullary spinal cord metastases (ISCM) are uncommon and present with rapidly progressing neurological deficits. The objective of this study was to determine the rate, duration of neurological response and survival after radiation therapy. We have retrospectively reviewed the clinical outcome of six cases with a diagnosis of ISCM from primary lung cancer, non-small cell (NSCLC) (n=3) and small cell (SCLC) (n=3). Total radiation dose ranged from 27 Gy/5 fr to 40 Gy/20 fr. Ambulation was preserved in 3 patients and partially recovered in one. Five out of the six patients (83%) showed improvement in neurological signs/symptoms with a mean duration of 17.2 days (max: 40 days; min: 6 days). Median survival time was 5 months (confidence interval (CI) 95%: 0-12) for NSCLC and 5 months (CI 95%: 4-6) for SCLC. Although radiation response rate is high, the interval free of neurological progression is very short. A therapeutic approach should be considered for each individual (AU)

Serum protein s-100 predicts clinical outcome in patients with melanoma treated with adjuvant interferon--comparison with tyrosinase rt-PCR.

OBJECTIVE: To study the clinical value of the determination of serum S-100 protein as a single tumor marker or in combination with tyrosinase RT-PCR in patients with melanoma receiving adjuvant interferon. PATIENTS AND METHODS: Patients were tested for serum S-100 protein luminoimmunometric assay and for blood tyrosinase mRNA (RT-PCR), before starting interferon and every 2-3 months thereafter. RESULTS: One hundred and six patients (stage IIA, 27; IIB, 19; III, 49; and IV, 11) were included in the study. Median follow-up was 51 months (range 2-76). In the univariate analysis, under treatment S-100 > or =0.15 microg/l and a positive RT-PCR correlated with a lower disease-free survival and overall survival (OS). In the multivariate analysis, clinical stage, under therapy positive RT-PCR and S-100 levels > or =0.15 mug/ml, were independent prognostic factors for OS. The hazard ratio for OS was 3.9 (95% CI, 1.67-9.15; p = 0.004) and 2.2 (95% CI, 1.05-4.6; p = 0.016) for S-100 > or =0.15 microg/l and positive RT-PCR, respectively. When both techniques where combined, a positive RT-PCR indicated a poorer clinical outcome only in patients with S-100 <0.15 microg/l. CONCLUSIONS: S-100 > or =0.15 microg/l and a positive RT-PCR during adjuvant interferon therapy indicate a high risk of death in resected melanoma patients. S-100 determination has a higher positive predictive value than RT-PCR, while tyrosinase RT-PCR adds prognostic information in patients with S-100 <0.15 microg/l.

p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer.

This study was undertaken to determine the value of tumour microvessel density (MVD) and the expression of p53 and vascular endothelial growth factor (VEGF) as prognostic markers in patients with gastric cancer operated on for cure. In all, 156 patients with curatively resected gastric cancer constituted the basis of this blinded retrospective evaluation. Patients were treated with either surgery alone (n=53) or surgery plus adjuvant chemotherapy (n=103). Tumour MVD, p53 expression, and VEGF expression were assayed using immunohistochemical techniques. After a mean follow-up of 43 months, 64 (41%) patients had died and 55 (35%) patients developed tumour recurrence. Positive correlations between MVD and both p53 (P=0.005) and VEGF (P=0.005) expression were observed. Both MVD >/=100 (P=0.05) and positive VEGF expression (P<0.02) were associated with shorter disease-free survival, and positive VEGF expression (P=0.01) was also associated with shorter overall survival. Multivariate analysis confirmed that, in addition to the pathological tumour stage, lymph node ratio, the extent of lymphadenectomy and perineural invasion, p53 expression, and VEGF expression were independently associated with both disease-free survival (P<0.0005 and 0.02, respectively) and overall survival (P<0.02 and 0.01, respectively). Finally, patients whose tumours did not show p53 expression had a survival benefit compared to those expressing p53 when treated with adjuvant chemotherapy (P=0.01). This investigation demonstrates that p53 expression and VEGF expression are independent prognostic factors for both disease-free survival and overall survival in patients with curatively resected gastric cancer, and that p53 status may also influence response to chemotherapy.

Breast cancer in Rubens paintings.

Rubens was one of main baroque painters who practices realism, which means that he painted whatever his eyes capture. That fact has helped us with the visual aspect and the circumstances where such paintings were painted. This has allowed us to discover alterations in the breast of the models he painted, which suggest breast cancer. Such painting are 'The three Graces', 'Diana and her nymphs pursued by satyrs', 'Orpheus and Euridice'. In 'The three Graces' we can see that the model on the right has an open ulcer with reddening of the skin, nipple retraction, reduction of breast volume as well as axilar lymph nodes. This is a visual aspect of a locally advanced breast cancer. In Diana and her nymphs pursued by satyrs and in Orpheus and Euridice we can see a breast retraction in the same place as in 'The three Graces', which suggest breast cancer indirectly. The analysis of the tumor mass in the models of these pictures allow us to know more on the works, the social environment and the diseases happened in the years this painter lived.

Age: a critical factor in cancer management. A prospective comparative study of 400 patients.

BACKGROUND: older people are often excluded from cancer treatments solely on the grounds of age. AIMS: to compare cancer treatment in older and younger patients. PATIENTS AND METHODS: between June 1992 and September 1994, 400 cancer patients were included in this prospective comparative study. The factors compared between younger and older subjects were performance status, associated chronic diseases, delay in diagnosis, stage of disease and initial treatment. RESULTS: 54 patients (25.5%) under 70 years of age were asymptomatic at the time of diagnosis, in comparison with 25 (12.5%) of the 200 older patients (P < 0.001). Associated chronic pathologies were more frequent in the older patients (55% vs 18.5%, P < 0.001). There were no statistical differences between both groups in diagnostic delay. Localized disease was found in 127 (63%) of the younger patients and in 109 (54%) of the older patients, the difference not being significant. The percentage of patients who underwent oncological treatment was higher in the younger than the older group (87.5% vs 56%, P < 0.001). The main cause of therapeutic exclusion in both groups was poor performance status; however, in the older group other variables--such as the presence of chronic disease and patients' or relatives' wishes and doctors' opinions--influenced the decision not to give specific treatment. CONCLUSIONS: this study confirms that the clinical characteristics and treatment of aged people with cancer are different from those of younger patients. Nevertheless, there is considerable doubt about whether an arbitrary age limit should continue to be accepted as a discriminatory factor in some diagnostic and therapeutic procedures in cancer patients.