The role of chemotherapy and radiation for advanced head and neck cancer has evolved considerably over the last 20 years. Several studies, most prominently the Radiation Therapy Oncology Group (RTOG) study 91-11, which was undertaken in collaboration with the Head and Neck Intergroup and published in 2003, established the use of concurrent chemotherapy with radiation as the superior nonsurgical, larynx preservation strategy. The RTOG study demonstrated that patients with advanced laryngeal cancer receiving concurrent cisplatin and radiation had a better larynx preservation rate (84%) at a median follow-up of 3.8 years compared to that afforded either by radiation alone or by induction cisplatin/fluorouracil followed radiation (rates of 67% and 72%, respectively). This was confirmed by other studies.

Two large, randomized trials — the Veterans Affairs Laryngeal Cancer Study Group trial and a phase 3 trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) — have demonstrated the benefit of induction chemotherapy with PF (100 mg/m2 of cisplatin on day 1 and 1000 mg/m2 of 5-FU by continuous infusion on days 1-5) with respect to organ preservation. In these trials, overall survival rates were similar in patients receiving either induction PF chemotherapy and radiation or surgery and radiation therapy. In patients with larger tumors that could not resected, PF induction therapy has been shown to produce long-term survival benefits, with overall survival times in a subset of inoperable patients receiving chemotherapy of 21% at 5 years and 16% at 10 years compared with 8% and 6%, respectively, in patients not receiving chemotherapy. In a phase 3 trial of neoadjuvant chemotherapy in patients with moth and pharyngeal cancer conducted by the French Groupe d’Etude des Tumeurs de la Tete et du Cou (GETTEC), the median overall survival time for patients with both resectable and unresectable tumors was 5.1 years when PF induction chemotherapy was followed by locoregional therapy vs 3.3 years for those who did not receive PF induction chemotherapy (P = .03).

Nonetheless, there have been strong and persistent undercurrents of interest in farther improving the induction chemotherapy for patients with locoregionally advanced head and neck cancer.  The standard neoadjuvant chemotherapy regimen has consisted of a platinum agent and 5-fluorouracil (5-FU), a regimen known as PF. More recently, the addition of a taxane such as docetaxel (or, less commonly, paclitaxel) to the PF regimen (a triple combination known as TPF) is emerging as a more effective and less toxic standard for induction chemotherapy. The potential for induction chemotherapy before concurrent treatment to improve survival, through patient selection or better disease control such as by reducing distant metastases, as well as to enhance larynx preservation while decreasing the morbidity of treatment, is of great interest. However, more data are needed before such sequential approaches, or as appears in this case, chemotherapy alone, can be promulgated as new treatment standards. The VA guidelines state: “Treatment options for stage III and IV (laryngela) patients include surgery plus postoperative radiation and induction chemotherapy followed by radiation”.
NCCN recommends both options, with induction or without but only lists the TPF regimen for induction.

In regard to using Taxol and carboplatin instead of TPF, a number of phase II trials suggest that it is a well tolerated and effective approach but the phase III trial did not confirm them. The Cancer and Leukemia Group B (CALGB) initially evaluated the combination of induction carboplatin and paclitaxel for two cycles followed by low-dose weekly concurrent chemotherapy with RT. They found a median survival time of 15.1 months, and the trial demonstrated the feasibility of this regimen]. A phase III trial, CALGB 39801, was then completed, in which all patients received low-dose weekly carboplatin and paclitaxel with concurrent RT to 66 Gy and were randomized to two cycles of induction chemotherapy. Both arms of that trial showed disappointing results, with a median survival time of 11–13 months, demonstrating that this was not an efficacious regimen.

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When the primary site is not identified and when it does not fall neatly into certain specific clinical patterns, empiric front line broad-spectrum chemotherapy is recommended by NCCN. The issue remains second line chemotherapy. Erbitux is approved for second line treatment of squamous cell cancer of head and neck and is an attractive candidate for squamous unknown primary cancers.  Unfortunately, these patients have a dismal prognosis despite management with a variety of chemotherapeutic combinations in small clinical studies. A recent meta-analysis showed no evidence of superior efficacy of any of the administered regimens incorporating platinum salts, taxanes or new generation cytotoxic compounds (gemcitabine, vinca alkaloids, irinotecan). Modest if any survival prolongation and symptom palliation with preservation of quality of life are the only realistic aims of therapy for these patients. Consequently, low-toxicity patient-convenient chemotherapy regimens should be administered to reasonably fit poor-risk patients. Currently neither ESMO nor NCCN recommend Erbitux even in first line. NCCN recommendations do not include Erbitux(OCC-B, 1) and neither guideline recommends second line chemotherapy.

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Another disadvantage of proton beam therapy (PBT)is that the equipment that can produce it is very expensive, ensuring that it is only available in a limited number of academic centers.

Australia and New Zealand Horizon Scanning Network (2006) stated that PBT “may be of particular benefit” in the treatment of patients with intermediate depth tumors such as those in the head, cancers that are located in difficult or dangerous-to-treat areas, and tumors in locations where “conventional radiotherapy would damage surrounding tissue to an unacceptable level” (e.g., central nervous system (CNS) and head). PBT “may be ideal for use in the treatment of pediatric patients where the need to avoid secondary tumors is important due to the potentially long life span after radiation treatment when they may develop radiation induced malignancies.

A report by the American Society of Therapeutic Radiology (ASTRO) Emerging Technologies Committee states that there is reason to be optimistic about the potential developments in proton beam therapy (PBT) and the prospective research that is ongoing at centers worldwide. Current data do not provide sufficient evidence to recommend PBT outside of clinical trials in lung cancer, head and neck cancer, gastro-intestinal malignancies (with the exception of hepatocellular(liver) cancer) and pediatric non-Central Nervous System malignancies. In hepatocellular carcinoma and prostate cancer, there is evidence of the efficacy of PBT but no suggestion that it is superior to photon based approaches. In pediatric CNS malignancies, there is a suggestion from the literature that PBT is superior to photon approaches, but there is currently insufficient data to support a firm recommendation for PBT. In the setting of craniospinal irradiation for pediatric patients, protons appear to offer a dose measuring benefit over photons but more clinical data are needed. In large ocular melanomas and chordomas, we believe that there is evidence for a benefit of PBT over photon approaches. In all fields, however, further clinical research is needed and should be encouraged (ASTRO, 2011).

American College of Radiology (ACR) appropriateness criteria state that the physical characteristics of the proton beam would seem to allow for greater sparing of normal tissues, although there are unique concerns about its use for lung tumors. The small amount of clinical data on its use consists of small single institution series. These data as a whole can be challenging to interpret, as various different techniques have been used by these institutions, making comparisons between studies difficult. Results from larger, prospective, controlled trials that are underway will clarify the role of proton beam and other particle therapies for lung cancer (ACR, 2010).

A Blue Cross Blue Shield technology assessment evaluated health outcomes following proton beam therapy compared to stereotactic body radiotherapy (SBRT) for the management of Proton Beam Radiation Therapy: Medical Policy 12 non-small-cell lung cancer. The report concluded that, overall, evidence is insufficient to permit conclusions about the results of PBT for any stage of non-small-cell lung cancer. All PBT studies are case series, and there are no studies directly comparing proton beam therapy (PBT) and stereotactic body radiotherapy (SBRT). In the absence of randomized, controlled trials, the comparative effectiveness of PBT and SBRT is uncertain (BCBS, 2011).

The only guideline that I found that offers a qualified support is NCCN. The National Comprehensive Cancer Network (NCCN) states that the use of more advanced radiation technologies, such as proton therapy, is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints (NCCN, 2012).

It is quite clear from limited studies that proton beam is not inferior to other radiotherapy techniques. What has not been proven is that it is superior and that its ability to spare the tissues translates to a better outcome. It makes sense that it should, but in science that would be called a hypothesis that needs to be proven. Because PBT is only available in limited centers and is much more complex and expensive than other tissue sparing radiation therapy techniques, it should still be considered investigational.

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