A meta-analysis, published in the June 6, 2003 issue of the Lancet, showed that neoadjuvant cisplatin-based chemotherapy improves 5-year survival by approximately 5% in patients with advanced bladder cancer when compared to surgery, radiation therapy, or the combination of radiation therapy and surgery. Recent studies have suggested that the combination of Gemzar® and Platinol® represents the optimal current combination for treatment of advanced or metastatic bladder cancer. Studies have also suggested that the concurrent use of radiation and chemotherapy is superior to sequential use. In many of the current studies, an attempt is made to retain the bladder in those patients who respond to neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy.Some studies use carboplatin, which has largely replaced cisplatin in various cancer types as a less toxic equivalent. This substitution is supported by many studies and by accumulated clinical experience.

I was able to find two retrospective reviews on the use of Xeloda with radiation but no phase II studies.

Chauvet B, Lagrange JL, Geoffrois L, et al. Quality-of-Life (QOL) Assessment After Concurrent Chemoradiation for Invasive Bladder Cancer. Preliminary Results of a French Multicenter Prospective Study. Proceedings of the 45th Annual Meeting of the American Society For Therapeutic Radiology and Oncology. International Journal of Radiation Oncology Biology Physics 2003;57, Number 2, Supplement, Abstract Number 88:S177.

Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant Chemotherapy in Invasive Bladder Cancer:Review and Meta-analysis. Lancet 2003;361:1927-34
Chemoradiation in bladder cancer Bull Cancer. 2005 Dec 1;92(12): 1073-7.

NCCN.ORG, Bladder cancer

Patel B, Forman J, Fontana J et al. A single institution experience with concurrent capecitabine and radiation therapy in weak and/or elderly patients with urothelial cancer. International Journal of Radiation, Oncology, Physics. 2005;62:1332-1338. L. N. Minea, R. M. Anghel, L. R. Oprea, V. Primejdie, X. Bacinschi Definitive radiochemotherapy with capecitabine for elderly patients with bladder cancer Abstract No: 322, ASCO 2008.

David M. Reese MD, Eric J. Small MD, Therapy of Advanced Prostate Cancer Part II: Response End Points and the Use of Chemotherapy, The Prostate Journal 2000 2:4 173

R Collins et al, A systematic review of the effectiveness of docetaxel and mitoxantrone for the treatment of metastatic hormone-refractory prostate cancer British Journal of Cancer (2006) 95, 457-462.

nccn.org, prostate cancer 2015, PROS-5

Kent EC, Hussain MH.
The rationale for adjuvant chemotherapy for high-risk prostate cancer. Curr Opin Urol. 2003 Mar;13(2):123-31.

Vaishampayan U, Hussain M.The evolving role of systemic therapy in high risk prostate cancer: strategies for cure in the 21st century. Crit Rev Oncol Hematol. 2002 May;42(2):179-88.

Maria Schubert et al,The Role of Adjuvant Hormonal Treatment after Surgery for Localized High-Risk Prostate Cancer: Results of a Matched Multi-institutional Analysis, Advances in Urology Volume 2012 (2012), Article ID 612707, 6 pages NCCN, Prostate Cancer 2017

Since 2004, the standard first-line chemotherapy for patients with metastatic prostate cancer that progresses despite androgen deprivation has been docetaxel. Docetaxel is the first (and, to date, only) treatment for metastatic castration resistant prostate cancer to be approved specifically on the basis of survival, as shown in a randomized study comparing docetaxel and prednisone with mitoxantrone and prednisone. The practical clinical problem is that there is no proven, effective salvage therapy once Taxotere fails, usually within 6-8 months. Mitzantrone alone at that point has a response rate of 8%.

In a 2006 study, docetaxel plus carboplatin demonstrated encouraging activity in patients who progressed after docetaxel-based therapy. PSA declines >50% were seen in 19%; measurable responses in 20%. There are several other studies as well, which I referenced. A study of this combination with estrmustine has also been published.

Oh WK, George DJ, Tay MH, Response to docetaxel/carboplatin in patients with hormone-refractory prostate cancer not responding to taxane-based chemotherapy. Clin Prostate , Cancer. 2005 Jun;4(1):61-4.

Michael J Morris Paclitaxel and carboplatin versus mitoxantrone: lessons of an underpowered study, Nature Clinical Practice Oncology (2006) 3, 536-537

William K. Oh et al, A Phase I Study of Estramustine, Weekly Docetaxel, and Carboplatin Chemotherapy in Patients with Hormone-Refractory Prostate Cancer Clinical Cancer Research Vol. 11, 284-289, January 2005

Tay MH, George D, Gilligan T, et al. Docetaxel plus carboplatin (DC) may have significant activity in hormone refractory prostate cancer (HRPC) patients who have progressed after prior docetaxel-based chemotherapy abstract. Proc Am Soc Clin Oncol 2004;23:2479.F. Vignani, L. Russo, M. Tucci, M. Motta, G. Vellani, M. Tampellini, M. Papotti, L. Dogliotti, and A. Berruti
Why castration-resistant prostate cancer patients with neuroendocrine differentiation should be addressed to a cisplatin-based regimen
Ann. Onc., December 1, 2009; 20(12): 2019 – 2020.
M. M. Regan , E. K. O’Donnell , W. K. Kelly , S. Halabi , W. Berry , S. Urakami , N. Kikuno , and W. K. Oh Efficacy of carboplatin–taxane combinations in the management of castration-resistant prostate cancer: a pooled analysis of seven prospective clinical trials
Annals of Oncology Advance Access published on July 24, 2009, DOI 10.1093/annonc/mdp308.

Pure choriocarcinoma, an extremely rare variant comprising less than 1% of NSGCT, is not as sensitive to chemotherapy as mixed NSGCT. A search of major textbooks and the literature revealed no clear guidelines as to how to treat these patients. Most case reports describe patients presenting with advanced metastatic disease, with varying responses to chemotherapy. In general, standard chemotherapy for poor-risk NSGCT is the initial therapy used in practice. However, these patients may require salvage regimens and may benefit from referral to a major cancer center to be treated under protocols that can involve cyclical regimens or dose escalation with growth factor/stem cell support. Standard chemotherapy for good-to-poor–risk NSGCT – Bleomycin, etoposide, cisplatin (BEP) for 4 cycles and salvage uses – Vinblastine, ifosfamide. A review in the past month stated: “Potentially curative options in the salvage setting include ifosfamide plus cisplatin-containing standard dose therapy and high-dose carboplatin plus stem-cell rescue. ”

Mead GM: Chemotherapeutic Management of Metastatic Germ Cell Testis Cancer. Risk-Adapted Therapy/Poor Risk Patients. In: Vogelzang et al, eds. Comprehensive Textbook of Genitourinary Oncology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Williams; 2000: 1024-1031.

http://www.nccn.org/professionals/physician_gls/PDF/testicular.pdf

G. Sonpavde, T. E. Hutson, and B. J. Roth Management of Recurrent Testicular Germ Cell Tumors Oncologist, January 1, 2007; 12(1): 51 – 61.

NCCN BL-G says that there are no standard options for second line therapy and recommends clincal trials. It lists palliative options: amongst them, cisplatina, carboplatin, docetaxel, doxorubicin, 5FU, gemcitabine, ifosfamide, paclitaxel, premetrexed(Alimta), methotrexate and vinblastine.

NCCN.ORG, Bladder cancer

Matthew D. Galsky, Svetlana Mironov, Alexia Iasonos, Joseph Scattergood, Mary G. Boyle and Dean F. Bajorin Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma Investigational New Drugs Volume 25, Number 3,

Sweeney C, Roth BJ, Kaufman DS, et al. Phase II study of pemetrexed (PEM) for second-line treatment of transitional cell cancer (TCC) of the bladder. Proc Am Soc Clin Oncol 2003;22,411 Abstract 1653.

Sweeney CJ, Roth BJ, Kabbinavar FF, et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006;24(21):3451-3457. Marin M. Clinical experience with pemetrexed in breast cancer. Semin Oncol. 2006;33(1 Suppl 2):S15-S18. Pagliaro LC, Sharma P. Review of metastatic bladder cancer. Minerva Urol Nefrol. 2006;58(1):53-71. Bellmunt J, Albiol S. Chemotherapy for metastatic or unresectable bladder cancer. Semin Oncol. 2007;34(2):135-144.

Hussain M, Vaishampayan U, Du W, et al. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol. 2001;19:2527.

Hussein M, Smith D, Al-Sukhum S, et al. Preliminary results of Her-2/neu screening and treatment with trastuzumab, paclitaxel, carbplatin and gemcitabine in patients with advanced urothelial cancer. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 800.

A case of T2 muscle-invasive bladder cancer treated with neoadjuvant chemotherapy Nature Scott M Gilbert and Cheryl T LeeClinical Practice Urology (2006) 3, 675-679

J. A. Garcia and R. Dreicer
Systemic Chemotherapy for Advanced Bladder Cancer: Update and Controversies
J. Clin. Oncol., December 10, 2006; 24(35): 5545 – 5551.

Thalidomide has minimal activity. In a recent metastatic study(Margulis et al), single-agent thalidomide was inactive, and that the risk-benefit ratio clearly did not favor the use of thalidomide In small randomized, controlled 2009 trial (Jonasch et al), adjuvant thalidomide therapy after complete resection of high-risk RCC did not improve the 2- and 3-year RFS rates or cancer-specific death rates.

Lee CP, Patel PM, Selby PJ, Hancock BW, Mak I, Pyle L, James MG, Beirne DA, Steeds

Randomized phase II study comparing thalidomide with medroxyprogesterone acetate in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Feb 20;24(6):898-903.

Choueiri TK, Dreicer R, Rini BI, Elson P, Garcia JA, Thakkar SG, Baz RC, Mekhail TM, Jinks HA, Bukowski RM. Phase II study of lenalidomide in patients with metastatic renal cell carcinoma. Cancer. 2006 Dec 1; 107 (11): 2609-16.

Motzer, Robert J., Berg, William, Ginsberg, Michelle, Russo, Paul, Vuky, Jacqueline, Yu, Richard, Bacik, Jennifer, Mazumdar, Madhu Phase II Trial of Thalidomide for Patients With Advanced Renal Cell Carcinoma J Clin Oncol 2002 20: 302-306

Novik Y, Dutcher JP, Larkin M, Wiernik PH. Phase II Study of Thalidomide (T) in Advanced Refractory Metastatic Renal Cell Cancer (MRCC): a Single Institution Experience. Proc Am Soc Clin Oncol 2001; 20 (abstr 1057).

Margulis V, Matin SF, Tannir N, Tamboli P, Shen Y, Lozano M, Swanson DA, Jonasch E, Wood CG. Randomized trial of adjuvant thalidomide versus observation in patients with completely resected high-risk renal cell carcinoma. Urology. 2009 Feb;73(2):337-41

NCCN, renal cell carcinoma

Revised 8/24/2011

Patients with relapsed/refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse. Patients who do poorly despite ABMT have a mediastinal primary site, true cisplatin-refractory disease, disease progression before ABMT, and/or markedly elevated beta-HCG at ABMT. New treatment modalities are needed for the latter group. This observation is in accordance with the view of Flechon and associates (2001) that new strategies are needed to improve the survival rate of poor prognosis germ cell tumor patients. Tandem transplants is an attempt to improve respnse in these situations. However, NCCN does not list tandem transplants and they remain investigational at this time.

Patients with relapsed/refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse, as this patient does.  High-dose chemotherapy has been shown in phase II trials to be an effective salvage strategy in poor-risk patients with a suggestion of an improvement in survival as compared to standard dose salvage chemotherapy, albeit through matched-pair analysis rather than randomized trials. High-dose chemotherapy has also been shown to be a potentially curative option for patients with second or subsequent relapses. NCCN lists autologous transplantation for this group.

Adra N, Abonour R, Althouse SK, Albany C, Hanna NH, Einhorn LH. High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience. J Clin Oncol. 2016;35(10):1096-1102.

http://nccn.org/professionals/physician_gls/PDF/testicular.pdf

Lori Wood et al, Canadian consensus guidelines for the management of testicular germ cell cancer. Can Urol Assoc J. 2010 Apr; 4(2): e19–e38

The role of chemotherapy and radiation for advanced head and neck cancer has evolved considerably over the last 20 years. The landmark Veterans Affairs’ (VA) laryngeal cancer study,1 initially published in 1991, provided the best initial evidence to support cisplatin-based, induction chemotherapy as part of a larynx preserving treatment approach. The VA investigators randomized patients with stage III or IV laryngeal cancer to primary surgery and postoperative radiation versus three cycles of induction chemotherapy followed by radiation. Laryngectomy was reserved for patients with a less than major response after two cycles of chemotherapy, suspected disease persistence after radiation, or relapse. The chemotherapy/radiation arm yielded survival rates comparable to those achieved with primary surgical management. Two thirds of surviving patients retained their larynx. The similarly designed European Organisation for Research and Treatment of Cancer (EORTC) larynx preservation study, which focused on patients with advanced cancer of the hypopharynx, further supported the principles of the VA trial. Induction chemotherapy followed by radiation with surgery reserved for salvage came to be considered a new standard treatment for patients with locally advanced cancer of the larynx. The standard approach now involves combined chemotherapy and radiation.

Subsequent 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 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 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).

Nonetheless, there have been strong and persistent undercurrents of interest in 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”.

There are five large studies ongoing. The DeCIDE trial — Docetaxel Based Chemotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer — a phase 3 trial sponsored by the University of Chicago, is currently recruiting patients with an expected total enrollment of 400. The trial’s primary objective is to determine the effect on overall survival when induction chemotherapy is administered prior to chemoradiotherapy in patients with nodal stage N2 or N3 head and neck cancer. The Paradigm study, a randomized phase 3 trial, is under way internationally, led by the Dana-Farber Cancer Institute. The trial is comparing sequential therapy with TPF/chemoradiation vs cisplatin-based chemoradiotherapy with accelerated concomitant boost radiotherapy for locally advanced squamous cell cancer of the head and neck. 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. There is also UC 13362B that includes hydroxyurea.

Long-term follow-up data from the TAX 324 clinical trial released in 2011 showed that adding docetaxel to standard cisplatin plus fluorouracil induction chemotherapy (TPF) reduced the risk for death among patients with head and neck cancer by 26% during a 6-year period.

All of these trials likely will provide definitive information about the role of neoadjuvant chemotherapy in the treatment of head and neck cancer and may finally end the long-standing debate.

NCCN recommends both options, depending on the cancer location(Head and Neck, CHEM-A, 1-3). It recommends the TPF regimen for recurrent, unresectable or metastatic disease.

Postop chemoradiation is sometimes warranted because of extracapsular extension and other factors. Postoperative chemo-radiation with cisplatin in such situations is indicated as per the NCCN guidelines on p. 25.

Hoebers FJP, Heemsbergen W, Balm AJ, van Zanten M, Schornagel JH, Rasch CR: Concurrent chemoradiation with daily low dose cisplatin for advanced stage head and neck carcinoma.
Radiother Oncol 2007, 85(1):42-47

Browman GP et al. (2001) Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: A systematic review of the published literature with subgroup analysis. Head Neck 23: 579–589

Adelstein DJ et al. (2003) An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21: 92–98

nccn.org, head and neck cancer 2017

Michael Schlumpf et al, Results of concurrent radio-chemotherapy for the treatment of head and neck squamous cell carcinoma in everyday clinical practice with special reference to early mortality. BMC Cancer. 2013; 13: 610