Cancer Treatment

TPF induction chemotherapy or head and neck cancer

A growing body of data from randomized clinical trials has demonstrated that induction chemotherapy -- in combination with chemoradiotherapy -- may play an important role in the treatment localized head and neck cancers.

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.

Two large, randomized trials -- the Veterans Affairs Laryngeal Cancer Study Group trialand 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 more advanced unresectable tumors, 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[12] of neoadjuvant chemotherapy in patients with oropharyngeal 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).

 A number of randomized trial have demonstrated improved organ preservation or survival with TPF compared with PF. The phase 3 TAX 323 trial, a direct comparison of PF and TPF induction chemotherapy conducted by the EORTC, included patients with locally advanced and unresectable squamous cell head and neck cancer who were randomized to receive induction therapy with either PF or TPF every 3 weeks for 4 cycles, followed by radiotherapy or surgery.
The international TAX 324 trial assessed PF induction chemotherapy, with or without docetaxel, followed by chemoradiotherapy and surgical resection in patients with locally advanced head and neck cancer. Finally, a randomized phase 3 trial comparing PF induction chemotherapy with and without docetaxel in patients with laryngeal cancer demonstrated an improvement in organ preservation with the addition of the taxane to the PF regimen.

Although the question sistill being studied in the DeCIDE trial -- Docetaxel Based emotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer -- a phase 3 trial sponsored by the University of Chicago, NCCN already lists induction chemotherapy as an option.Two European randomized trials comparing a sequential treatment approach including TPF induction chemotherapy and chemoradiotherapy vs standard chemoradiotherapy alone for the treatment of head and neck cancer are in progress, and data are anticipated within 2 years.

Posner MR, Haddad RI, Wirth L, et al. Induction chemotherapy in locally advanced squamous cell cancer of the head and neck: evolution of the sequential treatment approach. Semin Oncol. 2004;31:778-785.
Remenar E, Van Herpen C, Germa Lluch J, et al. A randomized phase III multicenter trial of neoadjuvant docetaxel plus cisplatin and 5-fluorouracil (TPF) versus neoadjuvant PF in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN). Final analysis of EORTC 24971. Proc Am Soc Clin Oncol. 2006;24:284s. Abstract 5516.
The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991;325:1685-1690.
Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst. 1996;88:890-899.
Paccagnella A, Orlando A, Marchiori C, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst. 1994;86:265-272. Abstract
Zorat PL, Paccagnella A, Cavaniglia G, et al. Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up. J Natl Cancer Inst. 2004;96:1714-1717.
Domenge C, Hill C, Lefebvre JL, et al. Randomized trial of neoadjuvant chemotherapy in oropharyngeal cancer. French Groupe d'Etude des Tumeurs de la Tete et du Cou. Br J Cancer. 2000;83:1594-1598.
Vermorken JB, Remenar E, Van Herpen C, et al. Standard cisplatin/infusional 5-fluorouracil (PF) vs docetaxel (T) plus PF (TPF) as neoadjuvant chemotherapy for nonresectable locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN): a phase III trial of the EORTC Head and Neck Cancer Group (EORTC #24971). Proc Am Soc Clin Oncol. 2004;22:14s.
Posner MR, Haddad RI, Wirth LJ. The evolution of induction chemotherapy and sequential therapy for locally advanced squamous cell cancer of the head and neck. American Society of Clinical Oncology Educational Book, 2006; pp 346-352.
Calais G, Pointreau Y, Alfonsi M, et al. Randomized phase III trial comparing induction chemotherapy using cisplatin (P) fluorouracil (F) with or without docetaxel (T) for organ preservation in hypopharynx and larynx cancer. Preliminary results of GORTEC 2000-01. Proc Am Soc Clin Oncol. 2006;24:281s.

Hyperfractionated radiotherapy in head and neck cancer

Hyperfrationated radiotherapy has been extensively studied, both in the treatment of head and neck cancer and in other cancer types. Hyperfractionated radiotherapy (multiple fractions per day) yields higher rates of acute toxicity compared with conventional radiotherapy (one fraction per day, five days per week). Data on the incidence and severity of late complications associated with hyperfractionation are incomplete. It is premature to conclude that hyperfractionation with dose escalation does not increase late tissue complications.
Although the improvements in loco-regional control and survival are promising, longer follow-up and more complete information on late complications will be needed to meaningfully compare these results to those achieved with concomitant chemoradiation in locally advanced squamous cell carcinoma of the head and neck.
A recent guideline concluded that conclusions regarding loco-regional control are limited by the quality of the published data. To date, only three of seven randomized controlled trials have provided convincing evidence of improved loco-regional control with hyperfractionation compared with conventional radiotherapy. In one of these three studies, improved loco-regional control was accompanied by an increase in overall survival. Two other randomized controlled trials have documented improved overall survival with hyperfractionation, but both studies have been criticized for failing to report complete data. Another emtaanalysis, hosever, concluded that altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma and that comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit. The issue requires more study and the propsoed treatment should be considered experimental.

Head and Neck Cancer Disease Site Group. Mackenzie RG, Hodson DI, Browman GP, Zuraw L. Hyperfractionated radiotherapy for locally advanced squamous cell carcinoma of the head and neck [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2003 Jan [online update]. 13 p. (Practice guideline report; no. 5-6b). [22 references]

Lancet. 2006 Sep 2;368(9538):843-54. Links

Overgaard J, Audry H, Ang KK, Saunders M, Bernier J, Horiot JC, Le Maître A, Pajak TF, Poulsen MG, O'Sullivan B, Dobrowsky W, Hliniak A, Skladowski K, Hay JH, Pinto LH, Fallai C, Fu KK, Sylvester R, Pignon JP;Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis.Bourhis J,  Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH) Collaborative Group.Comment in:
Lancet. 2006 Nov 25;368(9550):1867-8; author reply 1868.
Lancet. 2006 Nov 25;368(9550):1867; author reply 1868.
Lancet. 2006 Sep 2;368(9538):819-21.
Republished in:
Clin Otolaryngol. 2007 Apr;32(2):119.

nccn.org, head and neck cancer

Chemotherapy and Navelbine for salivary gland neoplasms

Lay Summary: Navelbine has a role in treating salivary gland neoplasms.

Parotid glands tumors are relatively uncommon but they diverse and range from less to highly aggressive.  Surgery is the primary treatment of choice for most neoplasm of salivary glands.Chemotherapy should be considered in special circumstances, when radiation or surgery are refused or when tumors are recurrent or nonresponsive. Numerous studies with small sample sizes have assessed the activity of different cytotoxic agents. Both single agent and combination chemotherapy have been used for the treatment of this disease. For these agents, the response rates are generally modest with objective response rates ranging from 15-50%. Duration of response is typically cited in the range of 6-9 months.

A radomized Phase II study of Navelbine alone versus with cisplatin found that there was no significant difference with regard to other side-effects between the two treatment arms

Xeloda for palliation for head and neck cancer

Lay Summary: Xeloda is a reasonable palliative option in metastatic head and neck cancer.

Xeloda for pallaitve use in head and neck cancer is supported by phase II studies. To my knowledge there is only one phase II study as a single agent but CXeldoa is certianly active in heand adn neck cancer as it its close relative 5FU and there are a number of studies of Xeloda in combination with platin drugs that confirm its effectiveness. It is not FDA approved for this indication and would be consdiered off-label.

Arnedos M, Carbonell X, et al. Phase I Study of Capecitabine in Combination With Platinol in Patients (pts) With Advanced and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN). Annals of Oncology. 2002. 13(Suppl. 5): p. A#567.

J. Martínez-Trufero, D. Isla, J. C. Adansa, R. Hitt, J. J. Cruz, Phase II study of capecitabine (X) as palliative treatment for patients (p) with squamous head and neck cancer (HNC) with locoregional and/or metastatic relapse after previous platinum-based treatment (PBT): An interim analysis. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 6074

Combining platin and Erbitux with radiation for head and neck cancer

Lay Summary: Erbitux or platin with radiation or induction chemotehrapy followed by one of these two options with radiation is the standard of care. One study described the combination of the two.

The best quality data in head and neck cancer for locally advanced disease are available for cetuximab since the 2006 publication of a randomized clinical trial comparing radiation treatment plus cetuximab versus radiation treatment alone. This study found that concurrent cetuximab and radiotherapy improves survival and locoregional disease control compared to radiotherapy alone, without a substantial increase in side effects, as would be expected with the concurrent chemoradiotherapy, which is the current gold standard treatment for advanced head and neck cancer. Whilst this study is of pivotal significance, interpretation is difficult since cetuximab-radiotherapy was not directly compared to chemoradiotherapy. The results of ongoing studies to clarify the role of cetuximab in this disease are awaited with interest. Among strategies being evaluated in a phase II trial is combining a platin drug and Erbitux.

A recent Phase II study of Erbitux and cisplatin concluded: "This regimen is not currently recommended outside of the clinical trial setting. Further investigation of its safety profile is needed. However, preliminary efficacy is encouraging, and further development of this targeted combined-modality paradigm is warranted.

Bonner J, Harari P, Giralt J, Azarnia N, Shin D, Cohen R, Jones C, Sur R, Raben D, Jassem J, Ove R, Kies M, Baselga J, Youssoufian H, Amellal N, Rowinsky E, Ang K (2006). "Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck". N Engl J Med 354 (6): 567-78. 2006

Pfister DG, Su YB, Kraus DH, Wolden SL, Lis E, Aliff TB, Zahalsky AJ, Lake S, Needle MN, Shaha AR, Shah JP, Zelefsky MJ.Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm.J Clin Oncol. 2006 Mar 1;24(7):1072-8.

nccn.org, Head and Neck"

Taxo, carboplatin, Erbitux for stage IV head and neck cancer

For the treatment of recurrent and/or metastatic head and neck cancer, therapeutic options include re-irradiation and salvage surgery and chemotherapy, with best supportive care for patients unable or unwilling to undergo treatment. Palliative chemotherapy has demonstrated survival advantages over best supportive care, and the most commonly used agents are cisplatin and carboplatin, generally in combination regimens with infusional fluorouracyl or a taxane. The question therefore relates to the addtion of Erbitux to an otherwise standard of care regimen.

Following the observation that the combination of cisplatin plus cetuximab was safe, different clinical trials were performed to test this approach. In a phase III study in metastatic or recurrent SCCHN, 117 patients were randomised to receive cisplatin plus cetuximab, or cisplatin plus placebo. Median PFS was 2.7 months for the control arm and 4.2 months for the experimental arm. Median overall survival was 8.0 months and 9.2 months, respectively. Objective response rates were 10% and 26%. The toxicity was similar in both groups, except for the cutaneous rash associated with cetuximab. Recently, a retrospective evaluation of these clinical trials has been reported. In the study, a total of 330 platinum-refractory patients with recurrent or metastasic SCCHN treated with cetuximab alone or in combination with platinum-based chemotherapy were considered and compared with a historical series of 151 patients. The observed toxicity was mainly cutaneous (69% with the monotherapy treatment and 72% with the combination). The median survival time of around 6 months achieved with cetuximab in platinum-refractory SCCHN is similar to that seen with first-line therapy and represents an increase in survival of 2.5 months compared with platinum-refractory historical controls.

Taking all these data into consideration, the administration of cetuximab in combination with a platinum compound in recurrent or metastatic platinum-resistant SCCHN could be an appropriate therapeutic approach that increases response rate and possibly time to treatment progression, without increased toxicity

In regard to Taxol/platin + cetuximab: A phase II trial evaluating this induction chemotherapy plus cetuximab (Erbitux) resulted in a 100% overall response rate among patients with head and neck cancer. These results were presented at the 42nd annual meeting of the American Society of Clinical Oncology (ASCO).The trial known as Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME), involved 442 patients. About a third had cancer in the oral cavity or hypopharynx, nearly half had metastases, and most patients had already received treatment with radiotherapy (77% – 80%) and chemotherapy (36% – 41%). In this trial, all patients were treated with a chemotherapy regimen containing either carboplatin (in about a third of patients) or cisplatin plus 5-fluorouracil, and 1 group of patients also received cetuximab (400 mg/m² as an initial dose, followed by 250 mg/m² weekly).

 I did not find any currently ongoing trials of this combination (except with radiation in stage III) but the conensus of experts is that these results must be confirmed before accepted as standard of care. Per most plan definitions, this renders this combination experimental.

L. Licitra, P. Bossi, L. D. Locati, and C. Bergamini
Is Restoring Platinum Sensitivity the Best Goal for Cetuximab in Recurrent/Metastatic Nasopharyngeal Cancer?
J. Clin. Oncol., October 20, 2005; 23(30): 7757 - 7758.

JJ Cruz, A Ocaña, E Del Barco and A Pandiella Targeting receptor tyrosine kinases and their signal transduction routes in head and neck cancer
Annals of Oncology 2007 18(3):421-430;

nccn.org, head and neck

Vermorken J, Bourhis J, Trigo M, et al. (2005) Cetuximab (Erbitux®) in recurrent/metastatic (R&M) squamous cell carcinoma of the head and neck (SCCHN) refractory to first-line platinum-based therapies. Proc Am Assoc Clin Oncol 501s: (Abstr 5505).

Kies M, Garden A, Holsinger C, et al. Induction Chemotherapy (CT) with Weekly Paclitaxel, Carboplatin, and Cetuximab for Squamous Cell Carcinoma of the Head and Neck (HN). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 5520.

Taxotere Avastin for salivary gland

Salivary galnd tumors are not common in stage IV and not much is known about how to optimally treat metastatic salivary galnd cancer.  Their cancer may be responsive to aggressive combinations of chemotherapy and radiation. Patients with any metastatic lesions could be considered for clinical trials. Chemotherapy using doxorubicin, cisplatin, cyclophosphamide, and fluorouracil as single agents or in various combinations is associated with modest responses. NCCN recommends trials, supportive care, chemotherapy (without specifying regimen) or radiotherapy with chemotherapy.

Bevacizumab is an anti-VEGF monoclonal antibody that is FDA-approved for use in other malignancies. Savvides and colleagues from Case Comprehensive Cancer Center in Cleveland reported the preliminary results of a phase 2 study examining the efficacy of bevacizumab in combination with docetaxel and radiation in locally advanced HNC. Eight patients with stage IV disease completed therapy and 5 of 8 had a posttreatment neck dissection that demonstrated a pathologic complete response. These patients are now receiving adjuvant bevacizumab. The addition of this agent to curative CRT appears to be feasible. No episodes of severe bleeding were noted, which has been a concern with this agent. Khuntia and colleagues from the University of Wisconsin presented the design of an ongoing phase 1 trial of neoadjuvant bevacizumab followed by concurrent radiation, cisplatin, and bevacizumab for locally advanced HNC. Results of this study were not yet available.Seiwert and colleagues reported the results of a phase 1 study of bevacizumab plus 5-FU and hydroxyurea with concomitant radiotherapy for poor-prognosis HNC. Thirty-four patients completed treatment and, although there were toxicities, the addition of bevacizumab did not appear to be associated with a major synergistic toxic effect.

Speight PM, Barrett AW: Salivary gland tumours. Oral Dis 8 (5): 229-40, 2002.

Seiwert TY, Haraf DJ, Cohen EE, et al. A phase I study of bevacizumab with fluorouracil and hydroxyurea with concomitant radiotherapy for poor prognosis head and neck cancer. Proc Am Soc Clin Oncol. 2006;24:287s. Abstract 5530.

nccn.org, salvary gland

Savvides P, Greskovich J, Bokar J, et al. Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell cancer of the head and neck (SCCHN). Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 122.

Khuntia D, Jeraj R, Kruser TJ, et al. Phase I trial of neoadjuvant bevacizumab followed by concurrent radiation, cisplatin and bevacizumab for locoregionally advanced squamous cell carcinoma of the head and neck. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 63.

Oncotech chemosensitivity and chemoresistance assays

Lay Summary: Chemosensitivity assays are controversial but most experts believe that they do not reliably assist in selecting chemotherapy. There is more evidence for chemoresistance assays but this also remains disputed.

Oncotech ER is a form of chemosensitivity testing, or rather, a modification that tests resistance to chemo rather than sensitivity. The recent article by Schrag et al1 criticized the field of chemosensitivity and drug resistance, concluding that these types of in vitro assays are not yet ready for prime time. The panel of authors attempted to present evidence that in vitro drug response assays should not be used clinically. This issue was first addressed by an exhaustive Medicare Coverage Advisory Committee (MCAC) in 1999. A panel of physicians selected by the Department of Health and Human Services reviewed hundreds of articles from the literature and heard two days of testimony by experts in the field in an open hearing. The panel voted unanimously that although chemosensitivity assays should not be covered, drug resistance assays should be paid for. This became a casue celebre with a vigorous debate in the literature and variant opinions offered by professional bodies. The Amreican Society of Clnical Oncology vigorously objected and recommended: "
The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority."  I believe that the So. California branch of ASCO disssented from this recommendation, see http://weisenthal.org/medicareletter.pdf.

The Extreme Drug Resistance Assay (EDR) Assay is a laboratory test performed on a patient's tumor cells. This lab test is claimed to determine the probability of a tumor's resistance to a specific chemotherapy drug. If the tumor cells grow in the presence of very high concentrations of chemotherapy drug, then the cancer cells are considered resistant to that drug.

Drug sensitivity and resistance assays have been examined for their potential utility in ovarian cancer by a number of clinical investigators. Unfortunately, analysis of these studies has suffered greatly from the absence of an appropriate control population. The majority of these trials have compared the survival of individuals whose treatment was selected by a particular assay with a historical/retrospective patient group treated at the same institution. A report in the Gynecologic Cancer session described an important attempt by investigators in Europe to directly address the value of the adenosine triphosphate (ATP)-based tumor chemosensitivity assay, by randomizing patients with platinum-resistant ovarian cancer (n = 180) to either "assay-directed therapy" or the treatment of the "physician's choice". The objective response rate was 40.5% for the assay-directed group vs 31.5% for the physician's choice of treatment. Progression-free survival (intention-to-treat analysis) was 104 days in the assay-directed vs 93 days in the physician's choice groups. In addition, there was no difference in overall survival between the strategies. This study provides support for the conclusion that the ATP-based tumor chemosensitivity assay is not superior to physician's choice in the selection of chemotherapy in women with platinum-resistant ovarian cancer.Some experts claim that resistance assays are different from chemosensitivity assays and Medicare does cover them. However, this distinction has not been sufficiently demonstrated and most expersts vigorously dispute this.

In conclusion, the technologies and the questions that they raise are quite different. It Oncotech Sensitivy testing not yet been  recommended by professional societies and gudielines pending completion of a phase III trial. With Oncotech ER the situation is as described above.

Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22 : 3631 -3638, 2004

John P. Fruehauf In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3641-3643

P. Hwu, A. Y. Bedikian, and E. A. Grimm
Challenges of chemosensitivity testing.
Clin. Cancer Res., September 15, 2006; 12(18): 5258 - 5259.

M. Markman Chemosensitivity and Chemoresistance Testing
J. Clin. Oncol., October 10, 2005; 23(29): 7363 - 7364.

R. Nagourney Chemosensitivity and Resistance Assays: A Systematic Review?
J. Clin. Oncol., May 20, 2005; 23(15): 3640 - 3641.

J. P. Fruehauf and D. S. Alberts
In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins
J. Clin. Oncol., May 20, 2005; 23(15): 3641 - 3643.
 
H. S. Wieand
Chemotherapy Sensitivity and Response Assays: Are the ASCO Guidelines for Clinical Trial Design Too Restrictive?
J. Clin. Oncol., May 20, 2005; 23(15): 3643 - 3644.
 
M. Castro Resisting a Fundamentalist Policy
J. Clin. Oncol., May 20, 2005; 23(15): 3645 - 3646.