Paclitaxel,Carboplatin, and Concomitant Radiotherapy for Resected Patients with High Risk Head and Neck Cancer

Abstract

Many resected patients with locally advanced head and neck cancer are found on pathological assessment to have high-risk features for recurrence. We thus performed a feasibility trial of post-operative radiotherapy with paclitaxel and carboplatin in high-risk carcinoma of the head and neck. All patients were planned for 6 cycles of weekly paclitaxel (40 mg/m²) and carboplatin (AUC=1) and concomitant radiotherapy, 60 Gy in 6 weeks. The most common side effect was grade 3 and 4 mucositis in 5/6 patients and g-tube placement in 4/6 patients. Five out of 6 patients remain alive without evidence of disease at a mean time of 19 months since completion of therapy. Our pilot study treated 6 postoperative patients. Since 4 of 6 enrolled patients were unable to complete the treatment as prescribed, we conclude that this regimen is not feasible. With an 83% grade 3 or 4 mucositis rate and 67% of patients enrolled requiring feeding tube placement, this regimen is not tolerable.     

Role of Concomitant Chemoradiation in Locally Advanced Head and Neck Cancers

Standard therapy for advanced head and neck cancer consists of a combination of surgery and radiation.However, survival of this patient population has not improved during the past 20 years. Many differentmultimodality treatment schedules have been proposed, and chemotherapy is often used with the intent of organpreservation. The present study was intended to establish the efficacy of concomitant chemoradiation with asingle agent carboplatin in advanced head and neck cancers.The objectives were to investigate the feasibility ofconcomitant administration of carboplatin, monitor acute toxicity during radiotherapy, and determine subacuteside effects, such as wound healing following surgery after chemoradiotherapy. A prospective study was conductedwherein a total of 40 patients with stage III and IV squamous cell carcinomas of oral cavity, oropharynx,hypopharynx and larynx were enrolled. All patients were treated with external beam radiotherapy and weeklycarboplatin area under curve (AUC of 5). Radiotherapy was given in single daily fractions of 1.8-2 grays (Gy)to a total dose of 66-72 Gy. Salvage surgery was performed for any residual or recurrent locoregional disease.Neck dissection was recommended for all patients with neck disease showing less than a complete responseafter chemoradiation. A total of 40 patients were enrolled of whom 32 were males and 8 were females. Highestincidence of cancer was seen in the 5th-6th decades of life with a median age of 47.7 years. Oropharyngeal tumoursconstituted a maximum of 21 patients followed by hypopharynx in 10, larynx in 7 and oral cavity in 2. 80% ofthe patients had a neck node on presentation of which 40% had N2-N3 nodal status. TNM staging revealed that58% of patients were in stage III and 43% in stage IV. Evaluation of acute toxicity revealed that 50% had gradeII mucositis, 25% grade III mucositis, 2.5% grade IV mucositis. 50% of patients had grade I skin reactions,65% of patients had grade I thrombocytopenia, and 24% of patients had grade I anaemia. After completion oftreatment 65% of patients had complete response at the primary and regional sites, and 35% of patients hada partial response of whom 23% underwent neck dissection and 5% of them underwent salvage surgery at theprimary site. At the end of one year there were six deaths and four recurrences and 70% were free of disease.Concurrent chemoradiation with carboplatin provided good locoregional control for locally advanced head andneck cancers. This regimen, although toxic, is tolerable with appropriate supportive intervention. Primary siteconservation is possible in many patients. Chemoradiotherapy appears to have an emerging role in the primarymanagement of head and neck cancers.     

Concomitant Chemoradiotherapy for Advanced Head and Neck Cancer

Head and neck cancer is mostly curable in the early stages byeither surgery or radiotherapy alone, but the control rate foradvanced stages is low, even with combined surgery and postoperativeradiotherapy. From September, 1990, to January, 1992, 35 patientswith locoregionally advanced head and neck cancers were enteredin a prospective study of concomitant chemoradiotherapy. Thirty-threecompleted the treatment. There were 29 males and four femaleswith a median age of 53 years. All except one patient were instage IV. Radiotherapy was delivered using a telecobalt unitand by conventional fractionation (1.8 Gy/fraction, 5 fractions/wk).Chemotherapy with cisplatin (10 mg/m²/day, daily, days 1-5)and 5-FU (500 mg/m²/day continuously infused for five days)was given concurrently during the first and fifth weeks of radiation.Twenty-four among 31 eligible patients achieved complete response(77.4%) and the other seven (22.6%) partial response, resultingin a 100% response rate. The toxicities experienced were increasedcompared with those caused by radiotherapy alone. The most commonside effects were gastrointestinal and hematologic toxicitiesbut the whole treatment was well tolerated. The two-year actuarialsurvival rate is 45%. We found the primary origin and overalltreatment time to affect survival significantly. The survivalrate for tumors arising from the nasopharynx or paranasal sinusis better than for those arising from other regions of the headand neck. The shorter treatment times (within eight weeks) hada better survival rate. Our preliminary experience suggeststhat concomitant chemoradiotherapy is both feasible and effectivefor head and neck cancer. The optimal scheduling and dosageof concomitant chemoradiotherapy should be further researched.     

Hypofractionated Accelerated Radiotherapy with Concurrent Carboplatin for Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Aims

Hypofractionated accelerated radiotherapy with concurrent carboplatin utilises both advantages of altered fractionation and synchronous chemotherapy to maximise local control in locally advanced head and neck cancer. Such fractionation schedules are increasingly used in the intensity-modulated radiotherapy era and the aim of this study was to determine the outcome of hypofractionated accelerated radiotherapy with carboplatin.

Materials and methods

One hundred and fifty consecutive patients with squamous cell carcinoma of the larynx, oropharynx, oral cavity and hypopharynx (International Union Against Cancer [IUAC] stage II-IV) treated with 55 Gy in 20 fractions over 25 days with concurrent carboplatin were analysed. Outcome measures were 2 year overall survival, local control and disease-free survival.

Results

The median follow-up in surviving patients was 25 months. IUAC stages: II n = 15; III n = 42; IV n = 93. Two year overall survival for all patients was 74.9% (95% confidence interval 66.0-81.7%). Two year local control was 78.3% (95% confidence interval 69.6-84.8%). Two year disease-free survival was 67.2% (95% confidence interval 58.3-74.7%). There were 135 patients with stage III and IV disease. For these patients, the 2 year overall survival, local control and disease-free survival were 74.3% (95% confidence interval 64.7-81.6%), 79.1% (95% confidence interval 69.8-85.9%) and 67.6% (95% confidence interval 58.0-75.4%), respectively. Prolonged grade 3 and 4 mucositis seen at ≥4 weeks were present in 9 and 0.7%, respectively. Late feeding dysfunction (determined by dependence on a feeding tube at 1 year) was seen in 13% of the surviving patients at 1 year.

Conclusion

Hypofractionated accelerated radiotherapy with concurrent carboplatin achieves a high local control. This regimen should be considered for a radiotherapy dose-escalation study using intensity-modulated radiotherapy.     

Definitive Chemoradiation and Durvalumab Consolidation for Locally Advanced,Unresectable KRAS-mutated Non-Small Cell Lung Cancer

BackgroundConsolidation durvalumab immunotherapy following definitive chemoradiation (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. As therapeutic options for patients with KRAS-driven disease evolve, more understanding regarding genomic determinants of response and patterns of progression for durvalumab consolidation is needed to optimize outcomes.MethodsWe conducted a single-institutional retrospective analysis of real-world patients with locally advanced, unresectable NSCLC who completed CRT and received durvalumab consolidation. Kaplan-Meier analyses compared progression-free survival (PFS) and overall survival (OS) from start of durvalumab consolidation between patients with KRAS-mutated and non-mutated tumors. Fisher's exact test was used to compare rates of intrathoracic or extrathoracic progression.ResultsOf 74 response-evaluable patients, 39 had clinical genomic profiling performed. 18 patients had tumors with KRAS mutations, 7 patients had tumors with non-KRAS actionable alterations (EGFR, ALK, ERBB2, BRAF, MET, RET, or ROS1), and 14 patients had tumors without actionable alterations. Median PFS for the overall cohort was 16.1 months. PFS for patients with KRAS-mutated NSCLC was 12.6 months versus 12.7 months for patients with non-actionable tumors (P= 0.77, log-rank). Fisher's exact test revealed a statistically significantly higher rate of extrathoracic progression versus intrathoracic-only progression for patients with KRAS-driven disease compared to patients with non-actionable tumors (P= 0.015).ConclusionPatients with KRAS-mutated NSCLC derived similar benefit from durvalumab as patients with non-actionable tumors. A higher rate of extrathoracic progression was also observed among the patients with KRAS-mutated NSCLC compared to patients with non-actionable tumors. This highlights the potential unmet needs for novel systemic therapies and surveillance methods for KRAS-mutated stage III NSCLC.     

Impact of Adaptive Radiotherapy on Locally Advanced Head and Neck Cancer - A Dosimetric and Volumetric Study

Objective of the study is to evaluate volumetric and dosimetric alterations taking place during radiotherapy for locally advanced head and neck cancer (LAHNC) and to assess benefit of replanning in them. Materials and Methods: Thirty patients with LAHNC fulfilling the inclusion and exclusion criteria were enrolled in a prospective study. Planning scans were acquired both pre-treatment and after 20 fractions (mid-course) of radiotherapy. Single plan (OPLAN) based on initial CT scan was generated and executed for entire treatment course. Beam configuration of OPLAN was applied to anatomy of interim scan and a hybrid plan (HPLAN30) was generated. Adaptive replanning (RPLAN30) for remaining fractions was done and dose distribution with and without replanning compared for remaining fractions. Results: Substantial shrinkage of target volume (TV) and parotids after 4 weeks of radiotherapy was reported (p<0.05). No significant difference between planned and delivered doses was seen for remaining fractions. Hybrid plans showed increase in delivered dose to spinal cord and parotids for remaining fractions. Interim replanning improved homogeneity of treatment plan and significantly reduced doses to cord (Dmax, D2% and D1%) and ipsilateral parotid (D33%, D50% and D66%) (p<0.05). Conclusions: Use of one or two mid-treatment CT scans and replanning provides greater normal tissue sparing alongwith improved TV coverage     

Induction Chemotherapy in Advanced Head and Neck Cancer Preliminary results of a randomized study

From March 1983 to June 1986, 100 patients with locally advanced squamous cell carcinoma of the head and neck were randomized to receive either two courses of chemotherapy prior to local therapy (group A), or local therapy alone (group B). Local treatment consisted of primary radiotherapy in all patients. When a poor response was observed after 55 Gy, surgery was performed. The chemotherapy regimen was a combination of cisplatinum, bleomycin, vindesine, and mitomycin C. The response rate to induction chemotherapy (group A) was 50% for the primary tumor (CR: 10% and PR: 40%). At the end of radiotherapy, the overall tumor response rates in the two groups A and B, were 77% and 79% respectively. Complete disappearance of the primary tumor occurred more often than that of the lymph node metastases. The response rate to induction chemotherapy for lymph node metastases was 27.1 % (CR: 9% and PR: 18.1 %). An initial major response to chemotherapy predicted subsequent efficacy of irradiation on 90% of the cases, while a failure of chemotherapy had no predictive value in this respect. The survival rates in groups A and B were 66.5% vs. 65.1% at 1 year and 35% vs. 46.2% at 2 years. Local disease-free and disease-free intervals were similar in both groups. A Cox's multi-step regression analysis revealed two significant independant prognostic factors: size of primary tumor and nodal status. After adjustment for these factors, the chemotherapy did not seem to improve the effectiveness of the local treatment in terms of loco-regional control and survival.     

Mitomycin and Fluorouracil in Combination with Concomitant Radiotherapy: A Potentially Curable Approach for Locally Advanced Head and Neck Squamous Cell Carcinoma

The above article appeared in Japanese Journal of Clinical Oncology35(10): 572–579 (2005). The authors would like to reportthat there     

Prolonged Overall Treatment Time and Lack of Skin Rash Negatively Impact Overall Survival in Locally Advanced Head and Neck Cancer Patients Treated with Radiotherapy and Concomitant Cetuximab

Background

Cetuximab, a chimeric monoclonal antibody against EGFR sensitizes tumors to radiotherapy (RT), but is associated with skin and mucosal toxicity.

Objective

We report outcomes and tolerance of definitive RT in association with cetuximab in patients with locally advanced squamous cell carcinoma (LASCC) of the head and neck.

Patients and Methods

Between 2006 and 2011, 92 consecutive patients with LASCC of the head and neck were treated with RT and concomitant weekly cetuximab. Median age was 61.7 years. Most patients presented with oropharyngeal tumors (52.2%) and stage IV disease (77.2%).

Results

Sixty-nine patients received at least 7 cycles of cetuximab. Cetuximab was stopped at the first infusion following allergic reactions in four patients. During RT, 37% of patients developed grade ≥ 3 dermatitis; grade ≥ 2 cetuximab-induced rash occurred in 43 patients (46.7%). Severe mucositis (grade ≥ 3) affected 57.6% of patients. Ten percent of patients did not receive the full course of RT, and temporary discontinuation due to acute toxicity was frequent and affected 37 patients (53%). The median RT overall treatment time (OTT) in patients with interrupted RT was 56 days (47–75) compared to 51 days (47–65) in patients who did not require toxicity-related radiation interruptions (p < 0.05). After a median follow-up of 17.5 months (1.3–107.6) for all patients, median overall survival was 17.9 months (95% CI: 12.7–23.2), and loco-regional control (LRC) was 9.2 months (95% CI: 3.9–14.4). On multivariate analysis, hemoglobin concentration and occurrence of rash grade ≥ 2 were independent prognostic factors for LRC (p = 0.023 and p = 0.006, respectively). Lack of rash and extended OTT negatively impacted overall survival (p = 0.048 and 0.052, respectively).

Conclusions

Skin and mucosal toxicity remains an issue in patients with LASCC of the head and neck treated with concomitant cetuximab and RT. Severe toxicity leads to treatment interruptions and prolonged overall treatment time, with consequent decreased overall survival in these patients.

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A Randomized,Multicenter, Phase II Study of Cetuximab With Docetaxel and Cisplatin as Induction Chemotherapy in Unresectable,Locally Advanced Head and Neck Cancer

Lessons Learned

• Addition of cetuximab may affect tolerability and, in turn, affect eventual outcomes.
• The incidence of prior human papillomavirus infection has emerged as an important variable that can confound trials enrolling patients with oropharyngeal cancer.

Background.

We investigated the efficacy of cetuximab when added to induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced head and neck squamous cell carcinoma.

Methods.

Patients were randomized to receive three cycles of docetaxel and cisplatin (TP regimen) with or without cetuximab (TP plus cetuximab [CTP] vs. TP) as induction chemotherapy. Patients in the CTP arm received CCRT with cetuximab and cisplatin, whereas patients in the TP arm received cisplatin alone. The primary endpoint was the objective response rate (ORR) after induction chemotherapy.

Results.

Overall, 92 patients were enrolled. The ORRs for induction chemotherapy in the CTP and TP arms were not different (81% vs. 82%). Adding cetuximab lowered the completion rate of induction chemotherapy and CCRT and resulted in more frequent dose reductions of the induction chemotherapy, although this did not reach statistical significance. In the CTP and TP arms, respectively, the 3-year progression-free survival (PFS) rates were 70% and 56% (p = .359), and the overall survival (OS) rates were 88% and 74% (p = .313). When limited to patients who completed induction chemotherapy, 3-year PFS rates of 78% and 59% (p = .085) and OS rates of 94% and 73% (p = .045) were observed in the CTP and TP arms, respectively.

Conclusion.

Adding cetuximab to sequential treatment did not increase the treatment efficacy and resulted in greater toxicity. In the intent-to-treat population, neither PFS nor OS was improved by the addition of cetuximab to sequential treatment; however, a suggestion of improved survival outcomes was observed in patients completing cetuximab-containing induction chemotherapy.     

Induction Gemcitabine Plus Concurrent Gemcitabine and Radiotherapy for Locally Advanced Unresectable or Resected Pancreatic Cancer

AimsTo determine the efficacy of induction gemcitabine followed by biweekly gemcitabine concurrent with radiotherapy for locally advanced pancreatic cancer.Materials and methodsBetween March 2001 and August 2009, 90 patients with unresectable (78) or resected (12) pancreatic cancer were treated with a standard treatment policy of induction gemcitabine (seven doses of weekly gemcitabine at 1000 mg/m²) followed by concurrent radiotherapy (52.5 Gy) and biweekly gemcitabine (40 mg/m²).ResultsAfter induction gemcitabine, 17.8% of patients did not proceed to chemoradiotherapy, due to either disease progression, performance status deterioration or gemcitabine toxicity. Of the patients who received chemoradiotherapy, 68.9% completed the course of 52.5 Gy, whereas 79.7% received more than 45 Gy. Chemoradiotherapy was stopped early due to treatment toxicity in 22.9% of patients. On intention to treat analysis, the median overall survival was 12.7 months in the locally advanced group and 18.2 months in the resected group. On multivariate analysis for the unresectable patients, a larger gross tumour volume was a significant poor prognostic factor for overall survival and local progression-free survival.ConclusionThis large series confirms, in a standard practice setting, similar efficacy and tolerability of treatment as previously reported in our phase I–II study. The benefit to patients with a gross tumour volume >48 cm³ may be limited.     

Role of PET/CT in Treatment Planning for Head and Neck Cancer Patients Undergoing Definitive Radiotherapy

Background: In this study, we aimed to investigate the benefits of 18F-deoxyglucose positron emissiontomography/computed tomography (FGD-PET/CT) imaging for staging and radiotherapy planning in patientswith head and neck cancer undergoing definitive radiotherapy. Materials and Methods: Thirty-seven headand neck cancer patients who had undergone definitive radiotherapy and PET/CT at the Uludag UniversityMedical Faculty Department of Radiation Oncology were investigated in order to determine the role of PET/CTin staging and radiotherapy planning. Results: The median age of this patient group of 32 males and 5 femaleswas 57 years (13-84years). The stage remained the same in 18 cases, decreased in 5 cases and increased in 14cases with PET/CT imaging. Total gross tumor volume (GTV) determined by CT (GTVCT-Total) was increasedin 32 cases (86.5%) when compared to total GTV determined by PET/CT (GTVPET/CT-Total). The GTV of theprimary tumor determined by PET/CT (GTVPET/CT) was larger in 3 cases and smaller in 34 cases comparedto that determined by CT (GTVCT). The GTV of lymph nodes determined by PET/CT (GTVLNPET/CT) waslarger in 20 cases (54%) and smaller in 12 cases (32.5%) when compared to GTV values determined by CT(GTVLNCT). No pathological lymph nodes were observed in the remaining five cases with both CT and PET/CT. Conclusions: We can conclude that PET/CT can significantly affect both pretreatment staging and assessedtarget tumor volume in patients with head and neck cancer. We therefore recommend examining such cases withPEC/CT before treatment.