The issue of chemosensitivity testing is complex and controversial. 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 , a variety of testing for resistance to very high chemo concentrations rather than testing for sensitivity, should be paid for. This became a cause celebre with a vigorous debate in the literature and variant opinions offered by professional bodies. The American Society of Clinical 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 with Dr. Wiesenthal dissented from this recommendation, see http://weisenthal.org/medicareletter.pdf.

In conclusion, the proposed assay is not supported by the near-total consensus of expert opinion or professional bodies. There are important dissenters, including some physicians and Medicare.

Rationale:

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.

The impact of maintenance treatment with rituximab on overall survival is one of the most important open questions for patients with indolent non-Hodgkin lymphoma. Recent randomized trials performed by the German Low Grade Lymphoma Study Group (GLSG) and by the EORTC demonstrated the superiority of rituximab maintenance after immunochemotherapy and after chemotherapy compared with observation alone.

Clinical trials have demonstrated prolongation of progression-free survival and, in some cases, increased survival when “maintenance” rituximab is given following rituximab induction, chemotherapy induction, or rituximab/chemotherapy (relapsed setting).

A recent guideline says this about maintenance rituximab for low grade lymphoma: “For previously treated patients with follicular or other indolent B-cell-histology lymphoma (such as mantle cell lymphoma, marginal zone lymphoma, and lymphoplasmacytoid lymphoma), excluding small lymphocytic lymphoma (SLL):
However, a Canadian guideline does recommend this approach and it is becoming the predominant approach in clinical practice.NCCN also lists it as category 1 recommendation on p. FOLL-B. First line extended therapy – If initially treated with single-agent Rituxan, consolidation with Rituximab 375mg/m2 one dose q 12 weeks is supported. FDA approved Rituxan as a maintenance therapy for patients with advanced follicular lymphoma in January of 2011. Farthermore, NCCN marginal lymphoma guideliens take one to the follicular lymphoma pages, where maintenance is recommended

On June 13, 2011, at the 16th Congress of the European Hematology Association in London, there was presented a study of maintenance rituximab after responding to initial therapy. It was restricted to elderly patients and showed that maintenance doubled the duration of remission doubled. Overall survival at 4 years also improved with rituximab maintenance, and experts suggest it should become the new standard of care. At 4 years, 57% of the patients treated with rituximab were still in in remission, compared with 26% of those treated with interferon (P = .0117). ” This study has not yet been published. The schedule is not NCCN prescribed and various schedules have been reported. NCCN recommends up to 2 years of maintenance therapy on FOll-B, 1

For large cell lymphoma, NCCN does NOT recommend maintenance Rituxan. Rituxan after CHOP, but not after R-CHOP, significantly prolongs TTF, but fails to prolong OS, possibly due to a delayed pattern of relapse and/or the efficacy of rituximab in the salvage setting(An Intergroup E4494/C9793 update). NCCN on p. BCEL specifically states that and does not recommend it.

For mantle cell lymphoma, NCCN also does not recommend maintenance. On June 13, 2011, at the 16th Congress of the European Hematology Association in London, there was presented a study of maintenance rituximab after responding to initial therapy. It was restricted to elderly patients and showed that maintenance doubled the duration of remission doubled. Overall survival at 4 years also improved with rituximab maintenance, and experts suggest it should become the new standard of care. At 4 years, 57% of the patients treated with rituximab were still in in remission, compared with 26% of those treated with interferon (P = .0117). ” This study has not yet been published.

NCCN recommends it for marginal zone lymphoma

NCCN, MZA-A, 2 2017

NCCN.ORG, NHLm follicular 2017

NCCN, MANT-4 2017

Revised 2/4/2012

Imrie K, Stevens A, Meyer R, Hematology Disease Site Group. Rituximab in lymphoma and chronic lymphocytic leukemia: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Dec 22. 46 p. (Evidence-based series; no. 6-8). [65 references]

S. J. Horning
Optimizing Rituximab in B-Cell Lymphoma
J. Clin. Oncol., February 20, 2005; 23(6): 1056 – 1058.

John D. Hainsworth, Sharlene Litchy, Don W. Shaffer, Van L. Lackey, Manuel Grimaldi, F. Anthony Greco, Maximizing Therapeutic Benefit of Rituximab: Maintenance Therapy Versus Re-Treatment at Progression in Patients With Indolent Non-Hodgkin’s Lymphoma—A Randomized Phase II Trial of the Minnie Pearl Cancer Research Network
Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1088-1095

Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006;24:3121–3127.

In order to provide a framework for erythropoietin therapy, several evidence-based guidelines have been developed, differing in scope and methodological rigor. Evaluation of iron stores is essential to proper application of these guidelines. In iron deficiency, erythropoietic factors are presumed not to be effective and the guidelines aim to avoid adminsitration of Aranesp or Procrit without prior or concommitant iron therapy in such cases. The most authoritative guideline to date was developed by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH), as well as NCCN. Guidance on the use of darbepoetin alfa was given in the more-recently published guidelines of the European Organization for Research and Treatment of Cancer (EORTC), the National Comprehensive Cancer Network and Cancer Care Ontario. To summarize, erythropoietin or darbepoietin may be used routinely outside of clinical trials to increase Hb levels and to reduce the need for transfusion in patients with Hb levels of less than 10 g/dl and in patients with falling Hb levels approaching 10 g/dl and kept between 1o and 112, but not above 11.

There are required parameters to exclude coexisting iron deficiency which center on iron saturation above 20%. Ferritin alone can be misleading in cancer patients since it is an acute phase reactant. Iron saturation tends to rise rather than a decrease in cancer patients.

Procrit, Prescribing Information 2018

Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR.
American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer.
Blood. 2010 Oct 25.

J. Seidenfeld, M. Piper, C. Flamm, V. Hasselblad, J. O. Armitage, C. L. Bennett, M. S. Gordon, A. E. Lichtin, J. L. Wade III, S. Woolf, and N. Aronson Epoetin Treatment of Anemia Associated With Cancer Therapy: a Systematic Review and Meta-analysis of Controlled Clinical Trials J Natl Cancer Inst, August 15, 2001; 93(16): 1204 – 1214

Rizzo JD et al. (2002) Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20: 4083-4107

Bokemeyer C et al. (2004) EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 40: 2201-2216

http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf, 2012

Steinbrook R. Medicare and erythropoietin. N Engl J Med. 2007; 356:4-6.

Ellervik C, Tybjaerg-Hansen A, Nordestgaard BG. Risk of cancer by transferrin saturation levels and haemochromatosis genotype: population-based study and meta-analysis. J Intern Med. 2012 Jan;271(1):51-63.

Jones D, Kamel-Reid S, Bahler D, Dong H, Elenitoba-Johnson K, Press R, Quigley N, Rothberg P, Sabath D, Viswanatha D, Weck K, Zehnder J.
J Mol Diagn. 2009 Jan;11(1):4-11. doi: 10.2353/jmoldx.2009.080095. Epub 2008 Dec 18.

Gluckman, J. Reiffers, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood, January 1, 2007; 109(1): 58 – 60.

J. V. Melo, T. P. Hughes, and J. F. Apperley. Chronic Myeloid Leukemia. Hematology, January 1, 2003; 2003(1): 132 – 152.

Hematology Disease Site Group. Walker I, Makarski J, Stevens A, Meyer RM. Treatment of chronic myeloid leukemia with imatinib. Toronto (ON): Cancer Care Ontario (CCO); 2004 Jul 16. 27 p. (Practice guideline report; no. 6-15). [39 references]

http://www.cdhb.govt.nz/chlabs/miscdocuments/CML_Monitoring_Guidelines_Jul%202007.pdf

Palliative chemotherapy for metastatic lung cancer is now standard. Platinum-based combinations were the first regimens to convincingly have an impact on survival and have been the standard of care in NSCLC. A European study showed that gemcitabine/cisplatin was essentiall equivalent to paclitaxel and a platin and the former became standard in Europe whereas the latter is most often used in the USA. Docetaxel has been shown to be equivalent to paclitaxel in phase III studies.A randomized comparative study showed that paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non–small-cell lung cancer (NSCLC)are equivalent and equally tolerated.

More recently Avastin has been shown to add to the survival benefit. Bevacizumab (Avastin®) is a humanized recombinant antibody to vascular endothelial growth factor-A (VEGF-A). VEGF-A bound to bevacizumab cannot bind to or activate VEGF receptors (VEGF-R) on vascular endothelial and other cells. Biological consequences include inhibition of angiogenesis (growth of new blood vessels) in tumors. Bevacizumab combined with intravenous fluorouracil-based chemotherapy is indicated as first- or second-line therapy for advanced or metastatic colon or rectal cancers.

An Eastern Cooperative Oncology Group (ECOG) multicenter RCT (E2100) on paclitaxel with (n=341) versus without (n=339) bevacizumab as first-line therapy for inoperable metastatic disease found that it was of value. The first interim analysis reported statistically significant improvement in overall response rate (ORR), PFS, and OS. The second interim analysis also found statistically significant improvement in ORR (30% versus 14%, p<0.0001) and PFS (11.4 versus 6.1 months; p<0.0001), but effects on OS were no longer statistically significant (28.4 versus 25.2 months; p=0.12). Avastin has subsequently gained approval for breast cancer in the US and EU, and for first-line NSCLC in the US.

A second large multicenter study, AVAIL, has shown that adding bevacizumab (Avastin, Genentech) to chemotherapy improves survival in patients with advanced non–small-cell lung cancer (NSCLC). This latest study was conducted in Europe and used a different chemotherapy regimen, gemcitabine and cisplatin, the European standard, from that used in the first trial, which was carried out in the United States. But the results from both trials were similar — adding bevacizumab significantly improved progression-free survival (PFS).

In breast cancer where Avastin was FDA approved, the role of Avastin is beng re-evaluated following reports of a new study showing no benefit in first line. One can question the true benefit of bevacizumab for lung canner as well, pointing out that the improvement in median PFS over control was only 2 weeks. On the other hand, the drug increases the risk for adverse events and costs thousands of dollars. However, the same is true of the now accepted in the USA paclitaxel and carboplatin + Avastin. In the USA paclitaxel and carboplatin is now standard and Avastin was approved by the FDA in a “a first-line treatment of patients with locally advanced, metastatic or recurrent non-small cell lung cancer in combination with platinum-based chemotherapy”. NCCN now recommends bevacizumab with “chemotherapy” without defining is solely as being platin based.

NCCN has first and second line therapy recommendations, both single agents and in combination.  For third line therapy NCCN recommends  Docetaxel, Pemetrexed, Erlotinib or Docetaxel, Pemetrexed, Erlotinib, Gemcitabine. Therefore, there are standard options and a clinical study is not standard of care.

American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small Cell Lung Cancer, Focused Update of Recommendation A6 published in Journal of Clinical Oncology, Vol 29, No 28 (October 1), 2011:3825-3831

nccn.org, NSCL Cancer, NSCL-F 2017

R. Milroy New American College of Chest Physicians Lung Cancer Guidelines*: An Important Addition to the Lung Cancer Guidelines Armamentarium
Chest, September 1, 2007; 132(3): 744 – 746.

Lung Cancer Disease Site Group. Chemotherapy in stage IV (metastatic) non-small cell lung cancer. Toronto (ON): Cancer Care Ontario (CCO); 2005 Jan. 22 p. (Practice guideline report; no. 7-2). [28 references]

Volk V et al, Weekly carboplatin in combination with weekly paclitaxel in the treatment of metastatic non-small cell lung cancer: a single center 10-year experience.Spport Care Cancer. 2016 May;24(5):2119-2128. 

Bevacizumab(Avastin) was until recently FDA approved for breast cancer. It is now an off-label treatment.

A previous Phase III study of bevacizumab in metastatic breast cancer found that the addition of bevacizumab to capecitabine produced a significant increase in response rates, but this did not translate into improved progression free survival or overall survival (Miller, et al., 2005). This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab in 462 patients with metastatic breast cancer previously treated with an anthracycline and a taxane. Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment-Breast were comparable in both treatment groups. The investigators reported that bevacizumab was well tolerated in this heavily pretreated patient population (Miller, et al., 2005). No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab.

Results from a large, randomized clinical trial for patients with previously untreated recurrent or metastatic breast cancer — cancer that has spread from the breast to other parts of the body — show that those patients who received bevacizumab (Avastin™) in combination with standard chemotherapy had a longer time period before their cancer progressed than patients who received the same chemotherapy without bevacizumab. Preliminary results suggest that patients in the study who received bevacizumab in combination with standard chemotherapy consisting of single-agent paclitaxel had a delay in worsening of their cancer by approximately five months, on average, compared to patients treated with paclitaxel chemotherapy alone. In the E2100 study, the addition of bevacizumab (Avastin) to paclitaxel resulted in an increase in progression-free survival of more than 4 months. In the trial, patients receiving just paclitaxel had about 6.11 months before the cancer progressed. Those who were treated with both the cytotoxic agent and the new targeted therapy had progression-free survival that averaged 10.97 months. The difference in progression-free survival was statistically significant at the P <.001 level. Accordingly, Avastin had been added to the NCCN guidelines. Genetech has filed for the FDA approval for the breast cancer indication in May 2006. However, on Dec. 17th or 2007, ODAC has recommended that Avastin not be FDA approved. This was based on the newer analysis that revealed excess mortality and no increase in survival in the Avastin arm, although there was a small progression free survival advantage. Subsequently FDA rejected this recommendation and approved Avastin on 2/27/08 for first line.

On December 17^{th 2010}, The Food and Drug Administration concluded that four studies indicate that Avastin does not benefit patients with metastatic breast cancer live longer or provide other benefits that outweigh its potentially life-threatening risks. The problem is that as several studies matures, the overall survival advantage did not materialize, Progression free survival advantage decreased and the toxicities became better appreciated. The Decision was appealed by Roche but in late June, 2011, In three unanimous votes, the six members of the FDA oncology drug panel voted that Avastin is ineffective, unsafe and should have its approval for breast cancer withdrawn. The FDA decision appears supported by recent report of teh BEATRICE trial in the 2012.  Invasive disease-free survival (DFS) and preliminary overall survival (OS) results showed no significant advantage to the addition of bevacizumab compared with adjuvant chemotherapy alone. The researchers did find that outcomes were somewhat better than the literature would suggest for the group of patients not responsive to estrogen-, progesterone-, or HER2-targeted agents, with 83% to 84% without invasive cancer recurrence at 3 years.

There was significant debate on the role of Avastin for first line disease and not all compendia have followed the FDA’s withdrawal of the indication. In December 2010 the NCCN published an update to its breast cancer guidelines and compendia listing and remarkably its panel of experts decided unanimously to maintain usage of Avastin in breast cancer as a listed indication (evidence level 2A, 15-0 vote in favor). The Expert Breast Cancer Panel of the National Comprehensive Cancer Network^® (NCCN^®) met July 10-12, 2011 in Philadelphia, PA. At the meeting, the multidisciplinary breast cancer experts voted (24 For, 0 Against, 1 Abstain) in favor of maintaining the current position and recommendation in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Breast Cancer on the use of bevacizumab (Avastin^®, Genentech/Roche) in metastatic breast cancer. The recommendation is was follows:

Bevacizumab in combination with paclitaxel is an appropriate therapeutic option for metastatic breast cancer with the evidence designation 2A.

The following footnote accompaniesdthe recommendation:

“Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first or second line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.”

As of 2016, this recommendation has been removed an Avastin is not listed by NCCN for breast cancer.

The efficacy and safety of Avastin as a second and third line treatment of patients with metastatic breast cancer were studied in a single open-label randomized study (Study 8 or AVF2119).  Patients who had received prior anthracycline and taxane therapy in the adjuvant setting or for their metastatic breast cancer were randomized to receive either capecitabine alone or in combination with Avastin.  The study enrolled 462 patients.  The study failed to demonstrate a statistically significant effect on PFS or overall survival.   The product labeling specifies that Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

Burstein and colleagues have reported the result of a phase II trial of vinorelbine (Navelbine) in combination with bevacizumab in patients with up to two prior chemotherapy regimens for metastatic breast cancer.  In this study, 56 patients received vinorelbine weekly at 25 mg/m² with bevacizumab at 10 mg/kg every 2 weeks until disease progression.  The overall response rate was 31% and 42% in those using this regimen as first-line treatment. The toxicity profile of this combination was also acceptable. Thus, it appears that bevacizumab with chemotherapy is generally well tolerated and has encouraging activity.

In regard to maintenance, this is an experimental strategy. While there is some supporting data, it remains in active clinical investigation, for example: A Study of Avastin (Bevacizumab) + Xeloda (Capecitabine)as Maintenance Therapy in Patients With HER2-Negative Metastatic Breast Cancer, NCT00929240

This randomized study will compare maintenance therapy with Avastin (bevacizumab) + Xeloda (capecitabine)versus Avastin alone, in patients with HER2-negative metastatic breast cancer who have not progressed during first-line therapy with docetaxel + Avastin.Eligible patients will receive up to 6 x 3week cycles of treatment with Avastin (15mg/mg iv on day 1 of each cycle) + docetaxel (75-100mg/m2 iv on day 1 of each cycle).Those patients who do not progress will be randomized to 3 week cycles of either a) Avastin (15mg/kg iv on day 1 of each cycle)+ Xeloda (1000mg/m2 po bid on days 1-14 of each cycle) or b)Avastin alone.The anticipated time on study treatment is until disease progression, and the target sample size is 100-500 individuals.

With gemcitabine, a study is ongoing: Gemcitabine Plus Bevacizumab in Locally Recurrent or Metastatic Breast Cancer, NCT00623233

Miller KD. E2100: A phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Clin Breast Cancer. 2003;3(6):421-422.

Miller, Kathy D., Chap, Linnea I., Holmes, Frankie A., Cobleigh, Melody A., Marcom, P. Kelly, Fehrenbacher, Louis, Dickler, Maura, Overmoyer, Beth A., Reimann, James D., Sing, Amy P., Langmuir, Virginia, Rugo, Hope S.
Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast Cancer
J Clin Oncol 2005 23: 792-799

Ramaswamy B, Shapiro CL. Phase II trial of bevacizumab in combination with docetaxel in women with advanced breast cancer. Clin Breast Cancer. 2003;4(4):292-294.

Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol. 2003;30(5 Suppl 16):117-124.

S. E. Waintraub, V. Tuchman The role of maintenance bevacizumab in patients with metastatic breast cancer treated with chemotherapy and bevacizumab upon achieving complete response or maximal radiologic response with stable disease.J Clin Oncol 26: 2008 (May 20 suppl; abstr 12022)

Despite nearly identical eligibility criteria and the use of an anthracycline-based induction treatment in all studies, the results are quite different. The previous studies found a significant advantage to autologous stem cell transplantation (ASCT). The German Lymphoma Study Group (GLSG) reported that patients randomized to transplantation had a 64.7% progression-free survival (PFS) rate at 5 years versus 33% with conventional chemotherapy. The Groupe Ouest-Est d’Etude des Leucémies aigues et autres Maladies du Sang (GOELAMS) group reported 60% PFS for those randomized to autologous transplantation versus 48% with conventional chemotherapy. By contrast, the Groupe d’Etude des Lymphomes de l’Adulte ( GELA) study does not show a significant PFS advantage for autologous transplantation.

The overall role of ASCT in follicular lymphoma continues to be debated. It is an excellent treatment option for the management of younger patients with recurrent disease. In advanced newly diagnosed lymphoma, a survival advantage has yet to be shown; with more prolonged follow-up it may still emerge in the GLSG study. An increased risk for therapy-related acute myeloid leukemia (t-AML) was observed in the GLSG and GOELAMS studies, but this risk may be minimized by modulation of induction and mobilization therapy preceding transplantation. Despite spectacular advances since the introduction of rituximab, many patients with advanced disease and a high Follicular Lymphoma International Prognostic Index (FLIPI) score have disease recurrences. For such patients, the continued study of autologous transplantation, possibly in combination with rituximab for in vivo purging, remains an important area of investigation.

The 2016 NCCN )FOLL-6) recommends autologous transplantation in “second-line” and says that allogeneic transplantation is appropriate in selected cases. ESMO, representing an European approach says: “•Myeloablative consolidation followed by autologous stem cell transplantation prolongs PFS and overall survival but its role has to be redefined in the rituximab era [I, B]. A potentially curative allogeneic stem cell transplantation (optionally with dose-reduced conditioning) may be discussed in relapsed disease.” In 2013, NCCN says(FOLL-B, 1) that for second line consolidation autologous stem cell transplantation can be done, or allogeneic for “highly selected patients”.

Koen van Besien Autologous transplantation for follicular lymphoma? Not too soon! Blood, 15 October 2006, Vol. 108, No. 8, pp. 2496-2497. M. Dreyling on behalf of the ESMO Guidelines Working Group Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for treatment and follow-upAnn Oncol (2010) 21 (suppl 5): v181-v183.

Issa F. Khouri Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab Blood June 15, 2008 vol. 111 no. 12 5530-5536

Ronjon Chakraverty et al, Allogeneic Transplantation for Lymphoma JCO 2011 29:1855-1863

NCCN, Follicular FOLL-6, 2016

TAC is clearly effective in node positive women. Adjuvant chemotherapy with docetaxel reduced the risk of death from node-positive early-stage breast cancer by 30% at 55 months of follow-up in a major phase III trial. The combination of docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphomide (Cytoxan) (TAC) also cut the risk of relapse by 28% compared with the standard three-drug regimen of 5-fluorouracil, doxorubicin, and cyclophosphomide (FAC).

The Breast Cancer International Research Group (BCIRG) conducted the trial known as BCIRG 001. The randomized study enrolled 1,491 women in 20 countries from June 1997 to June 1999. The new data are based on 55-month follow-up from 92% of participants. Disease-free survival reached 75% for the women receiving TAC vs. 68% for those receiving FAC. This translated into a hazard ratio of 0.72 (P = .0010). Overall survival at five years was 81% for the FAC cohort compared with 87% for the women receiving TAC (hazard ratio, 0.70; P = .0080). Subgroup analyses showed relapse rates decreased 27% in estrogen receptor–positive women and 34% in those who were estrogen receptor–negative. While women with one to three nodes fared better than those with four or more, both benefited; the hazard ratios were 0.61 (P = .0009) for the former and 0.82 (P = .1629) for the latter.
Patients with HER2-neu amplification also did better on TAC. The hazard ratio for HER2-positive patients receiving TAC was 0.61 (P = .0118) and for HER2-negative patients it was 0.76 (P = .0380). The only group that did not show significantly better outcomes on TAC compared to FAC was women with four or more positive lymph nodes. Among these participants, there was a trend toward superior results with TAC vs. FAC, but it did not reach statistical significance.

The absolute benefit in patients with node-negative disease may be much smaller and this may not outweigh the expected increase in toxicity. Martin et al. reported on the results of a randomized adjuvant trial comparing TAC with FAC for high-risk N0 breast cancer patients, the GEICAM 9805 trial. Comparisons are reported for toxicity and quality of life, not for efficacy, as follow-up time is still too short. After a protocol amendment, patients on the TAC arm received primary granulocyte colony-stimulating factor (G-CSF) prophylaxis, whereas before the amendment, only secondary G-CSF prophylaxis was allowed or even mandatory after an episode of febrile neutropenia. Unfortunately the report centered only on toxicity and we are still awaiting publication of this important study.

For node negative women, guidelines recommend: For premenopausal women at average to high risk, but whose tumors are hormonally responsive, ovarian ablation and tamoxifen, chemotherapy and tamoxifen, tamoxifen alone, or ovarian ablation alone can be considered standard therapy. Node-negative and premenopausal women with hormone-unresponsive cancer should be offered chemotherapy with AC, CMF, or cyclophosphamide-adriamycin-fluorouracil (CAF).

Other guidelines, however, NCCN, for example, are not as stringent on assigning specific regimens to either node+ or node negative group.

Ahluwalia M. S., Daw H. A., Noronha V., Martin M., Vogel C., the Breast Cancer International Research Group Adjuvant Docetaxel for Node-Positive Breast Cancer.

N Engl J Med 2005; 353:954-955, Sep 1, 2005

Breast Cancer Disease Site Group. Adjuvant systemic therapy for node-negative breast cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2003 May 1 [online update]. 22 p. (Practice guideline report; no. 1-8). [79 references]

nccn.org, breast cancer

Martin M, Lluch A, Segui M et al. Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen. Ann Oncol 2006; 17: 1205–1212.

Because both docetaxel (Taxotere; Rhône-Pouleuc Rorer, Collegeville, PA) and paclitaxel have substantial non-cross-resistance with anthracyclines and therefore activity in anthracycline-resistant breast cancer, defining their roles in the adjuvant therapy of breast cancer is an area of great interest and active clinical investigation. The results of the adjuvant trials using docetaxel assume a particular importance because of the two taxanes in clinical use at this time, docetaxel may be the more active agent in the treatment of metastatic breast cancer, as demonstrated in the results from phase II and III randomized trials.

There are two substitutions to this standard in this case: Epirubicin for Adrimaycin and Taxoter for Taxol.

Based on the above studies, as well as phase II trials, 82 the NSABP B-30 study was designed to directly compare the sequential regimen of AC followed by docetaxel to the combination of doxorubicin plus docetaxel and to the triple combination of doxorubicin plus docetaxel plus cyclophosphamide. This trial was initiated in 1999 and has accrued more than 4,500 of the 5,300 patients needed. Final results are pending but docetaxela appears so far to be equivalent but perhaps slighly more toxic.

The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel. Incorporating docetaxel into anthracycline-based therapy resulted in an improvement in DFS that was of borderline statistical significance. However, important differences may be related to doxorubicin and docetaxel scheduling, with sequential but not concurrent administration, appearing to produce better DFS than anthracycline-based chemotherapy.

Thus, Taxotere is acceptable to sustitue for Taxol. Herceptin is also now an standard of care part of the adjuvant regimen for node positive disease.

The remaining question is whether epirubicin can substitute for adriamycin, a similar but more cardiotoxic drug. and whether CE is as effective given after Taxotere rather as in most studies, in reverse sequence. It seems that such is the case based on substantial literature.

.

National Comprehensive Cancer Network (NCCN). Breast cancer. Clinical Practice Guidelines in Oncology — v2.2005. Jenkintown, PA: NCCN; 2005.

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672.
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684.

Ahluwalia M. S., Daw H. A., Noronha V., Martin M., Vogel C., the Breast Cancer International Research Group Adjuvant Docetaxel for Node-Positive Breast Cancer.
N Engl J Med 2005; 353:954-955, Sep 1, 2005

Adjuvant Chemotherapy With Sequential or Concurrent Anthracycline and Docetaxel: Breast International Group 02–98 Randomized Trial
Prudence Francis, John Crown, Angelo Di Leo, Marc Buyse, Ana Balil, Michael Andersson, Bo Nordenskjöld, Istvan Lang, Raimund Jakesz, Daniel Vorobiof, Jorge Gutiérrez, Guy van Hazel, Stella Dolci, Sophie Jamin, Belguendouz Bendahmane, Richard D. Gelber, Aron Goldhirsch, Monica Castiglione-Gertsch, Martine Piccart-Gebhart
On behalf of the BIG 02-98 Collaborative Group Journal of the National Cancer Institute
JNCI Journal of the National Cancer Institute 2008 100(2):121-133;

S. Gluck Adjuvant Chemotherapy for Early Breast Cancer: Optimal Use of Epirubicin
Oncologist, November 1, 2005; 10(10): 780 – 791.

Immunosuppressive agents such as cyclophosphamide have long been used to treat autoimmune disease, but the dose is often limited by bone marrow suppression. More than ten years ago several groups considered adopting the oncological approach of myeloablative therapy followed by haematological ‘rescue’ using either autologous or allogeneic hematopoietic stem cells to treat severe, therapy-resistant autoimmune disease. The concept was supported by animal model data, suggesting tolerance induction in a rat arthritis model and cases of patients receiving an hematopoietic stem cell transplantation (HSCT) for conventional indications and in whom a coincidental autoimmune disease was improved or eradicated.

After several international meetings, consensus guidelines were developed and the first published case of a patient receiving an HSCT as treatment for an autoimmune disease alone was published in October 1996. Since then, over 1000 patients have been transplanted for autoimmune disease, the majority within the context of phase I/II trials and more recently within phase III prospective randomized studies.

The recent phase 3 Autologous Stem Cell Transplantation International Scleroderma (ASTIS) open-label, parallel-group trial included 29 clinical centers in 10 countries. During a median follow-up of 5.8 years, there were a total of 53 events: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, more events occurred in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, the HSCT group experienced 14 events (17.7%) vs 14 events (18.2%) in the control group. At 4 years, a total of 15 events (19%) had occurred in the HSCT group vs 20 events (26%) in the control group. At 4 years, time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% confidence interval, 0.16 – 0.74) and 0.34 (95% confidence interval, 0.16 – 0.74) at 2 years. Transplant was more effective than cyclophosphamide alone. It was reported in JAMA. 2014;311:2485-2487, with an supportive editorial on pp. 2490-2498 and there is a recently supportive NEJM article referenced below.

Autologous stem cell transplantation is well supported and has become standard in poorly responding scleroderma cases.

Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med 2018;378:35-47

Nash RA, McSweeney PA, Crofford LJ, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the U.S. multicenter pilot study. Blood 2007; 23 April

van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 2014;311:2490-2498.

van Laar JM, Tyndall A. Adult stem cells in the treatment of autoimmune diseases. Rheumatology (Oxford) 2006; 45:1187-1193.

Alan Tyndall; Daniel E. Furst Adult Stem Cell Treatment of Scleroderma Curr Opin Rheumatol. 2007;19(6):604-610

http://www.fhcrc.org/science/clinical/ltfu/physician/physician.pdf, 2011

Jacob M. van Laar Kamran Naraghi Alan Tyndall, Haematopoietic stem cell transplantation for poor-prognosis systemic sclerosis. Rheumatology (Oxford) (2015) 54 (12): 2126-2133.