Correction to: Standard (8 weeks) vs long (12 weeks) timing to minimally-invasive surgery after NeoAdjuvant Chemoradiotherapy for rectal cancer: a multicenter randomized controlled parallel group trial (TiMiSNAR).

Following publication of the original article [1], the authors reported that the family name of the author, Ludovica Baldari, was misspelled.

Standard (8 weeks) vs long (12 weeks) timing to minimally-invasive surgery after NeoAdjuvant Chemoradiotherapy for rectal cancer: a multicenter randomized controlled parallel group trial (TiMiSNAR).

BACKGROUND: The optimal timing of surgery in relation to chemoradiation is still controversial. Retrospective analysis has demonstrated in the recent decades that the regression of adenocarcinoma can be slow and not complete until after several months. More recently, increasing pathologic Complete Response rates have been demonstrated to be correlated with longer time interval. The purpose of the trial is to demonstrate if delayed timing of surgery after neoadjuvant chemoradiotherapy actually affects pathologic Complete Response and reflects on disease-free survival and overall survival rather than standard timing. METHODS: The trial is a multicenter, prospective, randomized controlled, unblinded, parallel-group trial comparing standard and delayed surgery after neoadjuvant chemoradiotherapy for the curative treatment of rectal cancer. Three-hundred and forty patients will be randomized on an equal basis to either robotic-assisted/standard laparoscopic rectal cancer surgery after 8 weeks or robotic-assisted/standard laparoscopic rectal cancer surgery after 12 weeks. DISCUSSION: To date, it is well-know that pathologic Complete Response is associated with excellent prognosis and an overall survival of 90%. In the Lyon trial the rate of pCR or near pathologic Complete Response increased from 10.3 to 26% and in retrospective studies the increase rate was about 23-30%. These results may be explained on the relationship between radiation therapy and tumor regression: DNA damage occurs during irradiation, but cellular lysis occurs within the next weeks. Study results, whether confirmed that performing surgery after 12 weeks from neoadjuvant treatment is advantageous from a technical and oncological point of view, may change the current pathway of the treatment in those patient suffering from rectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT3465982.

ESMO expert consensus statements on the screening and management of financial toxicity in patients with cancer.

BACKGROUND: Financial toxicity, defined as both the objective financial burden and subjective financial distress from a cancer diagnosis and its treatment, is a topic of interest in the assessment of the quality of life of patients with cancer and their families. Current evidence implicates financial toxicity in psychosocial, economic and other harms, leading to suboptimal cancer outcomes along the entire trajectory of diagnosis, treatment, supportive care, survivorship and palliation. This paper presents the results of a virtual consensus, based on the evidence base to date, on the screening and management of financial toxicity in patients with and beyond cancer organized by the European Society for Medical Oncology (ESMO) in 2022. METHODS: A Delphi panel of 19 experts from 11 countries was convened taking into account multidisciplinarity, diversity in health system contexts and research relevance. The international panel of experts was divided into four working groups (WGs) to address questions relating to distinct thematic areas: patients with cancer at risk of financial toxicity; management of financial toxicity during the initial phase of treatment at the hospital/ambulatory settings; financial toxicity during the continuing phase and at end of life; and financial risk protection for survivors of cancer, and in cancer recurrence. After comprehensively reviewing the literature, statements were developed by the WGs and then presented to the entire panel for further discussion and amendment, and voting. RESULTS AND DISCUSSION: A total of 25 evidence-informed consensus statements were developed, which answer 13 questions on financial toxicity. They cover evidence summaries, practice recommendations/guiding statements and policy recommendations relevant across health systems. These consensus statements aim to provide a more comprehensive understanding of financial toxicity and guide clinicians globally in mitigating its impact, emphasizing the importance of further research, best practices and guidelines.

The role of neck dissection after radical chemoradiation for locally advanced head and neck cancer: should we move back?.

Until a few decades ago neck dissection (ND) was the standard surgical approach for node-positive tumours. Nowadays patients with locally advanced head and neck cancer can be treated with definitive chemoradiation (CRT), which includes the treatment of the neck; however, results on residual viable tumour after conservative treatment are heterogeneous and depend on initial node stage and primary treatment. Many authors accept adjuvant surgery in patients with N2-3 disease. Regardless of the results of upfront CRT, even if there is no evidence of lymph node metastases, when the risk for persistent positive neck nodes exceeds 15-20%, elective ND might be indicated. However, despite the diffusion of innovative technologies and therapies, there are controversies about both response evaluation and surgical management of initially involved neck nodes after definitive CRT and organ preservation treatment. In this paper we will analyse state of art of neck evaluation after CRT and discuss the role of ND.

Cisplatin-based chemoradiation plus cetuximab in locally advanced head and neck cancer: a phase II clinical study.

BACKGROUND: Intensification of chemoradiation for advanced head and neck squamous cell carcinoma (HNSCC) is unlikely due to toxicity. Cetuximab combined either with radiotherapy or with chemotherapy showed favourable toxic profile with positive results in both combinations. Therefore, cetuximab could intensify chemoradiation without worsening toxicity. We conducted a phase II study of chemoradiation and cetuximab. PATIENTS AND METHODS: Eligible patients had stage III-IV M0 HNSCC. Treatment consisted of three cycles of cisplatin (20 mg/m(2)/day × 5 days) and fluorouracil (200 mg/m(2)/day × 5 days) rapidly alternated to three split courses of radiotherapy up to 70 Gy and concurrent weekly cetuximab. The primary end point of the study was complete response (CR) rate. Secondary end points were toxicity, progression-free survival (PFS) and overall survival (OS). RESULTS: Fourty-five patients were enrolled: median age was 56 years, 38 had stage IV disease and 40 nodal involvement. CR occurred in 32 patients (71%). PFS and OS was 21+ months and 32.6+, respectively. Acute grade 3-4 toxic effects were in the expected range, but grade 3 radiodermatitis occurred in 33 patients. CONCLUSIONS: The combination of cetuximab, cisplatin, fluorouracil and radiotherapy leads to a very high proportion of CR and it is feasible with toxic effects similar to those expected by radiochemotherapy. The only unexpected toxicity was skin toxicity: grade 3 radiodermatitis occurred in 73% of the patients.

Transformation of Cancer Care during and after the COVID Pandemic, a point of no return. The Experience of Italy.

Policymakers everywhere struggle to introduce therapeutic innovation while controlling costs, a particular challenge for the universal Italian National Healthcare System (SSN), which spends only 8.8% of GDP to care for one of the world's oldest populations. Oncology provides a telling example, where innovation has dramatically improved care and survival, transforming cancer into a chronic condition. However, innovation has also increased therapy duration, adverse event management, and service demand. The SSN risks collapse unless centralized cancer planning changes gear, particularly with Covid-19 causing treatment delays, worsening patient prognosis and straining capacity. In view of the 750 billion Euro "Next Generation EU", released by the European Union to relieve Member States hit by the pandemic, the SSN tapped a multidisciplinary research team to identify key strategies for equitable uptake of innovations in treatment and delivery, with emphasis on data-driven technological and managerial advancements - and lessons from Covid-19.

The process of truth disclosure: an assessment of the results of information during the diagnostic phase in patients with cancer.

BACKGROUND: Surveys carried out in Mediterranean countries demonstrated very low rates of awareness of both diagnosis and prognosis among cancer patients. In our institution, a long-term training program aimed at improving communication skills among all physicians interacting with cancer patients was conducted. We report here the results of an extensive assessment of patients' awareness conducted after the first training period. PATIENTS AND METHODS: In a 2-year period, after every first visit of patients with a histological diagnosis of cancer, oncologists elicited perception of the patients and completed a structured questionnaire focusing on the understanding of the diagnosis and prognosis. Our data are thus a photograph of the results of the informative process conducted during the diagnostic phase. RESULTS: Among the enrolled 649 patients, 79.3% were aware of their diagnosis; factors significantly associated with higher levels of awareness were age younger than 70 and referral from surgery (versus internal medicine). Knowledge about the palliative or curative aims of future treatments (a surrogate sign of prognostic consciousness) was evident in 55.2%. CONCLUSIONS: Compared with historical data, our results show a high level of comprehension of the diagnosis of malignancy, probably due to the extensive training effort together with the method chosen for assessment.

Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck.

BACKGROUND: In 1992, we reported the first analysis of a randomized trial comparing alternating radiotherapy and chemotherapy with radiotherapy alone in the treatment of squamous cell carcinoma of the head and neck. The results of that 3-year analysis indicated that the combined treatment had superior efficacy. PURPOSE: After an additional 2 years of follow-up, we again compared the efficacy of the two treatment regimens, with attention paid to differences in overall survival, progression-free survival, and locoregional relapse-free survival. METHODS: One hundred fifty-seven patients with untreated, unresectable squamous cell carcinoma of the head and neck were randomly assigned to receive either chemotherapy (four courses of cisplatin [20 mg/m2] and fluorouracil [200 mg/m2], given daily for 5 consecutive days during weeks 1, 4, 7, and 10) plus radiotherapy (three courses of 20 Gy each, given in fractions of 2 Gy per day during weeks 2-3, 5-6, and 8-9) or radiotherapy alone (70 Gy total dose, given in fractions of 2 Gy per day, 5 days per week). Eighty patients received the combined therapy, and 77 were treated with radiotherapy alone. Responses, failures, and toxic effects associated with the two treatment regimens were compared. Overall survival, progression-free survival, and locoregional relapse-free survival were calculated according to the Kaplan-Meier method; the logrank test was used to compare survival parameters between the two patient groups. Reported P values are two-sided. RESULTS: As reported previously, toxic effects associated with the combined therapy included both chemotherapy- and radiotherapy-related effects; however, the incidence and severity of mucositis were nearly identical among patients in the two treatment arms. The combined treatment was associated with a statistically significant increase in the frequency of complete response (i.e., the disappearance of clinically detectable disease for at least 4 weeks) (43% for the combined-treatment group compared with 22% for the radiotherapy-only group; P = .037, chi-squared test). Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24% (95% confidence interval [CI] = 14%-40%) and 10% (95% CI = 4%-24%), respectively (P = .01, logrank test). The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21% (95% CI = 11%-37%) and 9% (95% CI = 3%-22%), respectively (P = .008, logrank test). Finally, the 5-year estimates of locoregional relapse-free survival were 64% (95% CI = 36%-84%) in the combined-treatment group and 32% (95% CI = 10%-65%) in the radiotherapy-only group (P = .038, logrank test). CONCLUSIONS AND IMPLICATIONS: The superiority of alternating chemotherapy and radiotherapy over radiotherapy alone in treating unresectable squamous cell carcinoma of the head and neck seen at 3 years was confirmed at 5 years. However, additional trials must be conducted before considering the combined approach as standard therapy.

Non-surgical organ preservation strategies for locally advanced laryngeal tumors: what is the Italian attitude? Results of a national survey on behalf of AIRO and AIOM.

Chemoradiotherapy is the treatment mostly used as organ preservation (OP) strategy worldwide in advanced laryngo-hypopharyngeal cancer. Due to the not homogeneous results of the literature data regarding the pre-treatment assessment and treatment schedule in this setting of patients, the Italian societies of radiation oncology and medical oncology surveyed (by an online survey) their memberships regarding the Italian attitude on larynx preservation in clinical practice. The survey outline addressed different items such as: demographics (11 items), pre-treatment evaluation (12 items), treatment schedules (10 items) and outcomes (3 items). The survey was filled in by 116 clinical oncologists (64 % radiation and 36 % medical oncologists). Results highlighted that pretreatment evaluation was not homogeneous among the respondents. The treatment of choice for the OP program resulted the concurrent chemoradiotherapy (66 %). Induction chemotherapy was proposed mostly in case of aggressive tumors such as advanced stage (T4 or N3) and/or unfavorable primary sites (hypopharynx). Moreover, after induction chemotherapy, for responders patients most participants (46 %) proposed concurrent chemoradiotherapy, while 18 and 19 % proposed radiotherapy alone or radiotherapy and cetuximab, respectively. For patients with stable disease after induction chemotherapy, the respondents declared to suggest surgery, radiotherapy and cetuximab or radiotherapy alone in 38, 32 and 15 % of cases, respectively. Results of the present survey highlighted the variability of therapeutic approaches offered in clinical practice for patients candidate to a larynx OP program. Analysis of abovementioned results may give the chance to modify some clinical attitudes and create the background for future clinical investigation in this field.

Pain management in head and neck cancer patients undergoing chemo-radiotherapy: Clinical practical recommendations.

Pain in head and neck cancer represents a major issue, before, during and after the oncological treatments. The most frequent cause of pain is chemo/radiation related oral mucositis, which involves 80% of the patients and worsens their quality of life inhibiting speaking, eating, drinking or swallowing and sometimes reducing the treatment compliance, the maximum dose intensity and thus the potential efficacy of treatment. Nevertheless pain is still often under estimated and undertreated. An Italian multidisciplinary group of head and neck cancer specialists met with the aim of reaching a consensus on pain management in this setting. The Delphi Appropriateness method was used for the consensus. External expert reviewers evaluated the final statements. The paper contains 30 consensus-reached statements about pain management in HNC patients and offers a review of recent literature in these topics.

Sequence effect of epirubicin and paclitaxel treatment on pharmacokinetics and toxicity.

PURPOSE: Sequence-dependent clinical and pharmacokinetic interactions between paclitaxel and doxorubicin have been reported. Some data have shown an influence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated whether reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics. PATIENTS AND METHODS: Patients receiving epirubicin 90 mg/m(2) by intravenous bolus followed by paclitaxel 175 mg/m(2) over 3-hour infusion or the opposite sequence every 3 weeks for four cycles were eligible. Toxicity was recorded at nadir. Pharmacokinetic data were evaluated at the first and the second cycle and were correlated with toxicity parameters. RESULTS: Thirty-nine consecutive stage II breast cancer patients were treated. Twenty-one patients received epirubicin followed by paclitaxel (ET group), and 18 received the opposite sequence (TE group). No significant difference in nonhematologic toxicity was seen. A lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery was observed in the TE group. Area under the concentration-time curve (AUC) of epirubicin was higher in the TE group (2,346 ng/mL. h v 1,717 ng/mL. h; P =.002). An inverse linear correlation between epirubicin AUC and neutrophil recovery was also observed (P =.012). No difference was detected in paclitaxel pharmacokinetics. CONCLUSION: Our results support a sequence-dependent effect of paclitaxel over epirubicin pharmacokinetics that is associated with increased myelotoxicity. Because schedule modifications of anthracyclines and paclitaxel can have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.

Weekly cisplatin paclitaxel and continuous infusion fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma: a phase II study.

BACKGROUND: Cisplatin, paclitaxel and 5-fluorouracil (5-FU) have demonstrated significant activity in patients with advanced squamous head and neck cancer (HNSCC) despite relevant toxicity. A weekly administration of cisplatin and paclitaxel with continuous infusion of 5-FU could offer a better toxicity profile without affecting dose intensity or treatment outcome. We evaluated the toxicity and the activity of weekly cisplatin/paclitaxel with continuous infusion 5-FU in patients with recurrent and/or metastatic HNSCC. METHODS: A total of 44 patients were studied. Treatment consisted of two 6-week cycles with weekly cisplatin 20 mg/m2 and paclitaxel 60 mg/m2 and daily continuous infusion 5-FU 200 mg/m2 from day 1 to 42. Patients were evaluated for toxicity and response. RESULTS: 40 out of 44 patients were evaluable for response. After two cycles we observed seven complete responses (16%) and 12 partial responses (27%), with a 43% (95% CI 28-58%) overall response rate. Stable disease was seen in 13 patients (29%) and progressive disease in 12 patients (27%). Toxicity was mild in treated patients: we observed less than 10% of grade 3/4 hematological and gastroenteric toxicity. CONCLUSIONS: A weekly schedule of cisplatin and paclitaxel associated with continuous infusion 5-FU showed low toxicity in the treatment of advanced HNSCC while significant activity was conserved.

Chemoradiotherapy as an alternative to radiotherapy alone in fast proliferating head and neck squamous cell carcinomas.

The aim of this pilot study was to explore the prognostic relevance of cell kinetics parameters on the local control of patients affected by head and neck squamous cell carcinoma (HN-SCC), randomly assigned to receive either alternating chemoradiotherapy or partly accelerated radiotherapy. Between 1992 and 1995, 40 patients with HN-SCC at stages III and IV entered the study. Multiple primary tumor biopsies were obtained 6 h after in vivo infusion of bromodeoxyuridine, an analogue of thymidine that is incorporated in DNA-synthesizing cells. In vivo S-phase fraction labeling index (LI), duration of S-phase (TS), and potential doubling time (Tpot) were obtained by analysis of the flow cytometric content of bromodeoxyuridine and DNA. Twenty patients were treated by alternating chemotherapy and conventional radiotherapy (arm A), whereas 20 other matching patients received partly accelerated radiotherapy alone (arm B). Univariate local control analysis showed that LI, TS, and Tpot were not prognostically significant in either arm. However, local control probability at 2 years for fast growing tumors, characterized by a LI of 9%, was higher for patients treated with alternating chemoradiotherapy than it was for those treated with partly accelerated radiotherapy alone (68 versus 39%). Conversely, local control probabilities for slow proliferating tumors (LI, <9%) treated in the two arms were similar. These results suggest a potential role for alternating chemotherapy and radiotherapy in HN-SCC patients with fast growing tumors.

The activity of raltitrexed (Tomudex) in malignant pleural mesothelioma: an EORTC phase II study (08992).

We investigated the activity and toxicity of raltitrexed (Tomudex) as a single agent treatment in patients with Malignant Pleural Mesothelioma (MPM) in a multicentre phase II European Organization for Research and Treatment of Cancer (EORTC) study. This study enrolled chemonaíve patients with histologically-confirmed measurable MPM. Raltitrexed was administered at the dose of 3 mg/m(2) intravenous (i.v.) bolus on an outpatient basis every 3 weeks. A maximum of eight cycles was planned in cases with an absence of progression or unacceptable toxicity. 24 patients received a total of 104 courses. 5 patients (20.8%, 95% confidence interval (CI) 7.1-42.2%) had a partial response (PR), which was confirmed by an independent radiology committee. Toxicity was mild, with diarrhoea, nausea, vomiting, fatigue and neutropenia as the major side-effects, but not exceeding grade 3 toxicity. We conclude that raltitrexed has activity as a single agent in the treatment of MPM, and that further studies with this drug in MPM are warranted.

Chemotherapy for relapsed head and neck cancer: paclitaxel, cisplatin, and 5-fluorouracil in chemotherapy-naive patients. A dose-finding study.

The aim of this trial was to identify the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered via a 3-hour infusion day 1, together with cisplatin 20 mg/m2/d days 1 to 3 and 5-fluorouracil 200 mg/m2/d bolus days 1 to 3 every 21 days. The prophylactic administration of colony-stimulating factors was not allowed. Twenty-three patients with relapsed and/or metastatic squamous cell carcinoma of the head and neck previously treated with surgery and/or radiotherapy were accrued. None had received chemotherapy previously. No grade 3/4 hematologic toxicity at nadir or other limiting toxicities were recorded with paclitaxel at 100 to 135 mg/m2 (six patients, 26 courses). Seven patients (six evaluable, 22 courses) were treated with 160 mg/m2. Grade 4 neutropenia at nadir with fever lasting 3 days was observed in one patient. Nonhematologic toxicities, including temporary peripheral neuropathy, asthenia, myalgias, vomiting, and mucositis were generally mild. Three patients were treated with 180 mg/m2 (eight courses). Grade 4 neutropenia at nadir was recorded in all patients and was febrile in two. Seven patients (six evaluable, 23 courses) were treated with paclitaxel 160 mg/m2, cisplatin 25 mg/m2/d, and 5-fluorouracil 250 mg/m2/d. Grade 4 febrile neutropenia at nadir was recorded in one patient. One episode of grade 4 mucositis and two episodes of grade 3 diarrhea were also recorded. Overall, eight responses (38%) were observed. In conclusion, the combination of paclitaxel 160 mg/m2, cisplatin 25 mg/m2/d, and 5-fluorouracil 250 mg/m2/d for 3 consecutive days can be administered safely without growth factor support. This regimen merits further investigation in a phase II trial.

Chemotherapy alternated with radiotherapy in the treatment of advanced head and neck carcinoma: predictive factors of outcome.

PURPOSE: To investigate the impact of pretreatment and treatment-related factors on local-regional control and overall survival rates in advanced (III and IV stage) head and neck cancer patients treated with alternating chemoradiotherapy, a selected group of 115 patients who had PS < or = 1 and received a total dose of radiotherapy (RT) within +/- 5% of that planned, was analyzed. METHODS AND MATERIALS: Patients were planned to receive 4 cycles of chemotherapy (cisplatin and 5-fluorouracil) alternated with radiotherapy (60 Gy/30 fractions). However, mainly due to systemic toxicity, about 30% of the patients received less than 90% of the planned combined chemotherapy total dose (CCTD). Based on differences in treatment planning and delivery, patients were divided into two groups. For living patients, median follow-up is 34 months (range: 24-111 months). RESULTS: At multivariate analysis, RT technique (p = 0.008), N stage (p = 0.010) and CCTD (p = 0.027) were independent predictors of LRC. Compared to each favorable subset (RR = 1), the relative risks of LRC failure were 2.18 (95% CI: 1.21-3.91), 2.23 (95% CI: 1.11-4.50) and 2.23 (95% CI: 1.15-4.31) for patients without improved dose distribution and treatment delivery, with bilateral nodes or nodes greater than 6 cm, and with a CCTD lower than 90%, respectively. Regarding overall survival, only RT treatment was found to be an independent predictor (p = 0.037), with an RR of 1.61 (95% CI: 1.02-2.53) for patients without improved dose distribution and treatment delivery. CONCLUSION: Optimal delivery of RT dose is crucial in patients with advanced head and neck tumors, even if they receive chemotherapy as part of their treatment. This study also suggests that chemotherapy total dose may play a role in patient outcome, but this must be confirmed prospectively.

Best supportive care in non-small cell lung cancer: is there a role for radiotherapy and chemotherapy?

Best Supportive Care (BSC) is the treatment of choice when cure is not achievable with anticancer treatments and involves management of disease-related symptoms. In the palliative treatment of non-small cell lung cancer (NSCLC) radiation therapy has for a long time been the cornerstone of symptom management, although the best schedule is still to be defined. Chemotherapy, on the other hand, has been excluded from classical definitions of BSC and has been reserved only for selected patient populations in which a survival benefit was demonstrated using cisplatin-based regimens. We reviewed randomized trials on both palliative radiotherapy and chemotherapy in order to assess the impact of anticancer treatments on quality of life in advanced NSCLC patients. While no randomized trials compared radiation therapy with a control arm not including it, several randomized trials assessed the use of different schedules. Hypofractionated schedules seem to have comparable palliative activity when compared with the standard fractionated regimens, at least in metastatic, poor-prognosis patients. In locally advanced, inoperable NSCLC higher radiation doses administered with conventional fractionation achieve better results in terms of local control and survival. The rate of palliation of local symptoms is high, being 60-80% for chest pain and hemoptysis, while breathlessness and cough are controlled at a somewhat lower rate (50-70%). General symptoms (fatigue, anorexia, and depression) are affected in a minority of patients. Chemotherapy was compared with BSC in several randomized trials, in some of which an analysis of the quality of life was included. Results are consistent in favor of its palliative role and, when local symptom control is assessed, rates of palliation seem similar to those achieved by radiation. Benefits apply to metastatic NSCLC patients with good performance status, low body weight loss, age below 70-75. However, some studies support the use of chemotherapy also in patients with poor prognostic features. A comparison in terms of quality of life and symptom palliation between different chemotherapy regimens is the object of few trials. Both chemotherapy and radiation have an important role in the palliative treatment of advanced NSCLC patients and should be included in BSC programs. Future randomized trials should assess the best way of combining these two approaches.

Concomitant administration of two standard regimens of chemotherapy and radiotherapy in advanced squamous carcinoma of the head and neck: a feasibility study.

BACKGROUND: In advanced squamous cell carcinoma of the head and neck, the superiority of a chemo-radiotherapy combination over radiotherapy alone has been strongly suggested. However, the best modality to combine the two treatments has still to be determinated. A pilot study was designed, testing a combination of two standard chemo- and radiotherapy regimens concomitantly administered. MATERIALS AND METHODS: 26 patients, with unresectable squamous cell carcinoma of the head and neck, were treated with three cycles of chemotherapy (cisplatin 20 mg/m2/day and fluorouracil 200 mg/m2/day as an intravenous bolus, for 5 consecutive days, every 21) simultaneously delivered with radiation (66-70 Gy/33-35 fractions/7 weeks). In order to reduce the mucoseal toxicity. observed in the first 15 patients, 1 week of pause was inserted after the third week of treatment in the subsequent 11 patients. RESULTS: Grade III-IV mucositis was detected in 40% of patients treated without pause after the third week of treatment and in 9% of those treated with. Complete responses were obtained in 13/26 patients (50%) and partial responses in 8/26 (31%). 1 stable disease, 3 early deaths (1 because of toxicity) and 1 lost before being evaluated were considered as treatment failures (19%). CONCLUSIONS: This concomitant chemo-radiotherapy approach showed a good antitumour activity but mucoseal toxicity is too high if no pause is planned during the treatment.

Hydration regimen and hematological toxicity of a cisplatin-based chemotherapy regimen. Clinical observations and pharmacokinetic analysis.

The administration of 100 mg/m2 Cisplatin (CDDP) in five 20 mg/m2 daily infusions together with bolus 5-Fluorouracil (5FU) allows patients with advanced head and neck cancer (HNC) to be treated with a rapidly alternating chemoradiotherapy regimen in an out-patient setting. Due to the extremely low rate of acute renal failure, the induction of forced diuresis is not mandatory, although hydration is usually performed at every CDDP administration. In this retrospective analysis of 73 homogenously treated HNC patients, the influence of hydration on hematological toxicity was studied. A lower incidence of grade II to IV acute myelosuppression (57% vs 92%; p < 0.005), together with a lower rate of anemia lasting two weeks or more (13% vs 46%; p < 0.009), were seen in the group of patients treated with CDDP along with a forced hydration scheme (2000 ml normal saline and 20 mg furosemide before the CDDP infusion) when compared to patients on a non-forced diuresis regimen (no furosemide and 1500 ml normal saline). The lower hematological toxicity translated into a better compliance to treatment. No differences in terms of other toxicities or response rate were evident between the two groups. A pharmacokinetic study with a cross over design was performed on 7 patients, and suggests that the first day Pt kinetics are not affected by the hydration scheme used, although a significantly lower Pt urinary concentration was found in the forced diuresis group. A further kinetic analysis performed on one additional patient over the entire five-day period of two consecutive cycles showed a marked increase in the AUC of filterable Pt and in the unbound Pt fraction (fu) from the second to the fifth day in the forced hydration course, while this was not the case in the non-forced hydration course. Results from this kinetic study support the hypothesis of a lowering of Pt reactive species after repeated CDDP-furosemide treatments and an influence of furosemide-induced diuresis on Pt binding to plasma proteins.