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October 21, 2002

Traditional Chinese Medicine in the Treatment of Breast Cancer - Part Three
Isaac Cohen, LAc, OMD, Mary Tagliaferri, MD, LAc & Debu Tripathy, MD

Abstract
TCM and chemotherapy
Modifications to all formulas
Acupuncture for chemotherapy-induced nausea and vomiting

Formularies
Acupuncture for nausea and vomiting
Herbs for chemotherapy-induced nausea and vomiting
Acupuncture effects on haematologic, immunologic and hormonal function
Traditional Chinese herbal therapy aimed at enhancing immune function

Traditional Chinese herbs for hematopoeisis during chemotherapy
Peripheral neuropathy in TCM
Addendum: The use of docetaxel (Taxotere) in early stage breast cancer
Conclusion
Traditional Chinese Medicine in the Treatment of Breast Cancer - Part One
Traditional Chinese Medicine in the Treatment of Breast Cancer - Part Two


Tables and Studies - Traditional Chinese Medicine in the Treatment of Breast Cancer
(Part 3) References

Abstract
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Traditional Chinese medicine (TCM) is becoming increasingly popular in many medical contexts, particularly among patients with cancer. TCM encompasses a range of modalities including herbal medicine, acupuncture, medical qigong, dietary recommendations and meditation (daoyin). In contrast to standard chemotherapeutic and hormonal regimens used for the adjuvant treatment of early stage breast cancer, very little data from controlled clinical trials has been generated using TCM modalities in relationship to the outcomes of recurrence or survival, or even overall quality of life and safety. As we previously reported1, the objectives of TCM modalities are manifold - the reduction of therapeutic toxicity, improvement in cancer-related symptoms, improvements in the immune system, and even a direct anti-cancer effect. The primary basis of TCM rests upon empirical evidence and case studies, as well as its theoretical principles. In some cases, laboratory or clinical data lend support to these modalities. Although TCM practices are based on ancient medical tenets founded on centuries of experience, and documented through oral and written texts, its direct relationship to breast cancer treatment in an integrative setting is very young. There is still a paucity of evidence in the clinical setting, which limits firm conclusions about the effectiveness or safety of most TCM approaches to breast cancer. This review will summarise the application of certain TCM modalities in the context of chemotherapy, enhancing immune function, and treating hematopoesis and peripheral neuropathy.

TCM and chemotherapy
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We previously reported the clinical benefits of adjuvant chemotherapy in the treatment of early breast cancer.1-2 Although chemotherapy can be useful in the prevention of breast cancer recurrence and in reducing breast tumour size, its toxicity causes many adverse and unpleasant side effects which affect quality of life. The most common regimens that are in use in early breast cancer adjuvant chemotherapy are Doxorubicin (Adriamycin) with Cyclophosphomide (Cytoxan) [usually abbreviated to AC chemotherapy], Cytoxan, Methotraxate and 5- flourauracil (5-FU) [usually abbreviated to CMF] and Paclitaxel (Taxol) or Docetaxel (Taxotere).

In recent years there has been a trend to integrate TCM treatment with standard western medicine in an attempt to further optimise the treatment outcomes, minimise the side effects of surgery, radiation and chemotherapy, increase immune function and improve survival. This form of treatment is known as Fu Zheng Therapy(FZ) or Support the Normal Qi FZ therapy is a comprehensive system of utilising traditional medical principles to affect the following goals:

i. Tumour load reduction or antineoplastic effect. TCM treatment principles of antineoplastic action include: attacking, dissolving, moving, detoxifying, resolving pathogenic factors, warming, and cooling down the tumours.

ii. Prevent the formation and development of cancer. TCM principles of treatment with anticarcinogenic and antimutagenic action include harmonising and strengthening nutritive and defensive qi and clearing pathogenic factors.

iii. Modulate the immune system and prevent immune suppression by tonifying qi, blood, yin and yang, harmonising flow and distribution, and promoting production and metabolism of body fluids.

iv. Enhance the regulating function of the endocrine system. Regulate the flow of qi, invigorate the flow of blood and tonify yang.

v. Enhance and protect the structure and function of the organs. Tonify yin and yang of the viscera and bowels.

vi. Strengthen the digestion and absorption of nutrients and improve metabolism. Invigorate, tonify and strengthen the Stomach and Spleen.

vii. Protect bone marrow and haematopoietic function. Nourish and tonify essence.

viii. Increase effectiveness of surgery, radiation, chemotherapy and hormonal therapy with herbs that lower drug resistance and increase peripheral blood flow. Harmonise the flow of qi, move and invigorate the flow of blood

ix. Prevent, ameliorate and control adverse side effects (such as nausea and vomiting, fatigue, insomnia and pain) and diseases caused by cancer therapy (such as cardiac toxicity and hepatic toxicity). Protect the viscera, regulate qi, redirect the flow of qi and assist branch symptoms. 3-11

Many herbal decoctions have been designed to achieve the above-stated goals. The herbs are chosen according to both their traditional use and to some modern pharmacological and clinical research about them individually and in groupings.

The therapeutic goal is to tailor the formula to the specific cancer, the chemotherapy agents and chemotherapy dose, whilst conforming with the individual's TCM diagnosis. As an example, during AC chemotherapy regimen, usually given in twenty-one day intervals for 4 cycles, the symptoms vary with individuals and with the progression of the therapy. Some women experience more symptoms at the initiation of the treatment while others more towards the end. Doses are monitored by weight, height and desired therapeutic purpose:

i. From days 1-6 of chemotherapy, most of the AC agents are metabolised in the body and assume most of their cytotoxic activity. Erosion of epithelial mucous and serous membranes is the most noticeable effect, creating dry mouth, bleeding gums, ulceration and sores in the mouth, vomiting, nausea, loss of appetite, diarrhoea, constipation, abdominal pain and distention, cystitis, skin rashes and palpitations. More severe reactions are stomatitis, oesophagitis, pancreatitis, pericarditis, haemorrhagic cystitis and bleeding ulcers.

The function of the herbal formula at this stage is to increase blood and lymphatic circulation to promote the distribution of the chemotherapy agents and to promote elimination of cell debris, nourish the yin to protect the mucous membranes, control nausea and vomiting, promote urination, direct the flow of qi downward, and promote appetite.

ii. From days 7-12, most of AC's cytotoxic activity is accomplished, and the damage to the bone marrow and organs is at its peak. This stage is marked by fatigue, malaise, dizziness, insomnia, fever, arthralgia, cognitive vagueness (what women call chemo-head) poor circulation, alternating hot and cold sensations, unproductive cough, palpitations, tachycardia, bradycardia, anaemia, leukopenia and thrombocytopenia, and in rare severe incidents, cardiac toxicity, hepatic toxicity or renal toxicity. The role of the herbal formula in this stage is to tonify qi, blood, yin and yang, nourish essence, protect and restore the vital functions of the organs and the bone marrow, promote circulation, promote urination, enhance metabolism, harmonise defensive and nutritive energy in order to increase immunity, and prevent infections.

iii. Days 12-21. At this stage the body is regenerating, eliminating and recovering its functions and structure. The symptoms and signs at this stage are improvement and recovery from all previous symptoms although fatigue, malaise, insomnia, joint pain, and cognitive vagueness may still occur. New symptoms may also appear, such as alopecia, hyper pigmentation of nail beds, and increased psychological and emotional reactions. The role of the herbal formula at this stage is to tonify qi, blood, yin and yang to promote the recovery and regeneration of the cells, bone marrow and organs, promote circulation and urination, and calm the spirit12 (see formulas).

Modifications to all formulas13-16
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Constipation: Gua Lou (Fructus Trichosanthis), Da Huang (Rhizoma Rhei), Rou Cong Rong (Herba Cistanches). Diarrhoea: Huang Lian (Rhizoma Coptidis), Qin Pi (Cortex Fraxini), Hou Po (Cortex Magnoliae Officinalis).

Insomnia: Suan Zao Ren (Semen Ziziphi Spinosae), Wu Wei Zi (Fructus Schisandrae Chinensis), Bai Zi Ren (Semen Biotae Orientalis), Mu Li (Concha Ostreae), Ye Jiao Teng (Caulis Polygoni Multiflori).

Herbs to avoid in cases of insomnia: Ma Huang (Herba Ephedrae), Fu Zi (Radix Aconiti Carmichaeli Praeparatae), Ren Shen (Radix Ginseng) at night, Zhi Shi (Fructus Citri seu Ponciri Immaturus), Jin Yin Hua (Flos Lonicerae Japonicae).

Mouth sores and loss of sense of taste (used as a mouth rinse): Hu Lu Ba (Semen Trigonellae Foeni-graeci), Wu Zhu Yu (Fructus Evodiae Rutaecarpae).

Acupuncture for chemotherapy-induced nausea and vomiting
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There is a substantial amount of scientific literature that supports the efficacy of both acupressure and acupuncture to treat chemotherapy-induced nausea and vomiting. In 1997, the strength of the scientific evidence for this application led the 12-member US National Institutes of Health (NIH) consensus panel on acupuncture to conclude that needle acupuncture treatment is effective for postoperative and chemotherapy nausea and vomiting17. This led to a special request for applications (RFA) by the NIH for research projects in the area of acupuncture for indications including pain due to cancer and nausea associated with chemotherapy.

Chemotherapy-induced nausea and vomiting continues to be one of the most frequent, severe and distressing side effects endured by cancer patients. In chemotherapy regimens used for early stage breast cancer, 30-40% of patients still experience nausea and vomiting within 1 week of chemotherapy administration, even with the use of newer seratonin receptor antagonists.18-19 In some cases, these side effects make a difference in the choices patients and physicians make and can also lead to early discontinuation or dose reductions of chemotherapy. Modalities such as relaxation, visualisation and acupuncture have historically been used as an adjunctive to nausea in many settings. Much of the scientific literature regarding acupuncture for nausea and vomiting, including the setting of chemotherapy administration, has been published by J.W. Dundee and his colleagues at the Queen's University of Belfast20-26. In his studies, Dundee evaluates the role of the most widely used acupuncture point for nausea and vomiting, Neiguan P-6. Dundee's initial comparative studies examined the antiemetic effect of Neiguan P-6 in 105 patients who had a history of nausea and vomiting in a previous round of chemotherapy. This study reported a 63% anti-emetic benefit from the acupuncture. Findings from a smaller, single blind, crossover study provide evidence that the beneficial effects were limited to the specific acupuncture point Neiguan P-6 when compared to a dummy or sham acupuncture point25. Subsequent well-controlled studies have similarly shown that acupressure or acupuncture applied to Neiguan P-6 provides a treatment benefit in 60-70% of patients compared to a 30% treatment benefit with sham acupressure or sham acupuncture, implying that point location is an important determinant27.

In Chinese medicine nausea and vomiting are divided into subcategories according to traditional differential diagnosis: cold vomiting (han ou), heat vomiting (ren ou), phlegm vomiting (tan ou), food accumulation vomiting (shi ji ou tu), qi vomiting (qi ou), vomiting of clear water (tu qing shui), bitter vomiting (ou ku), acid vomiting (tu suan), water counterflow (shui ni), vomiting of phlegm-drool (ou tu tan xian). It is further divided into the following categories: stomach reflux (fan wei), malign obstruction (e zu), ejection of foamy drool (tu xian mo) and nausea (e xin).

Acupuncture treatment for nausea and vomiting
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Basic treatment: Neiguan P-6, Zusanli ST-36, Gongsun SP-4, Zhongwan REN-12.

All nausea and vomiting is the clinical sign of Stomach qi ascending counterflow, which can arise from a variety of Stomach disorders. Each of those conditions requires a different variation of acupuncture point prescription. TCM holds that when the analysis of the condition is more accurate, the practitioner has more choices to render a safer and more effective treatment. Understanding the root cause of a condition and differentiation of branch symptoms can add both to the practitioner's arsenal of treatment tools and to insight into the prognosis of the condition

  • Spleen-Stomach vacuity cold (pi wei xu han)
    Signs include reduced food intake, vomiting of un-transformed food or of clear water without acid taste that gives a sense of relief, cold limbs, fatigue, dizziness, distention and fullness after eating. Tongue: pale, soft enlarged tongue, with thin tongue coating. Pulse: forceless (mai huo da wu li), moderate (huan), fine (xi). Add to basic treatment: Dadu SP-2 or Sanyinjiao SP-6.
  • Dual vacuity of Stomach qi and yin (wei qi yin xu)
    Signs include dry lips and mouth, desire for fluids, inability to drink sufficient amount of fluids, reduced food intake, dry bound stool, short voiding of scant urine, sometimes hiccup and dry retching, heart palpitations, spontaneous sweating, hot flushes. Tongue: red without coating or peeling tongue coating. Pulse: Rapid (shu), vacuous (xu), fine (xi). Add to basic treatment: Zhaohai KID-6 and or Tianshu ST-25.
  • Liver- Stomach disharmony due to qi congestion (gan wei bu he)
    Signs include pain in both ribs sides, belching, oppression and fullness in the upper abdomen, stomach pain, swallowing of up-flowing acid, bloating, indigestion, poor appetite, vomiting of acid fluid or food. Tongue: normal pink or slightly purple, with moderate coating. Pulse: moderate (huan), slippery (hua). Add to basic treatment: Taichong LIV-3 and Hegu L.I.-4 or Tianshu ST-25.
  • Phlegm-heat accumulation (tan re ji)
    Signs include gurgling sounds in the stomach, heart palpitations, dizzy head, flowery vision, vomiting of phlegm with or without bitter taste, oppression and fullness in the chest. Tongue: red or purple tongue, yellow slimy tongue coating. Pulse: rapid (shu), string-like (xian). Add to basic treatment: Yanglingquan GB-34.
  • Debilitation of the life gate fire (ming men huo shuai)
    Signs include bright white complexion, aversion to cold, lack of warmth in the extremities, dizziness, tinnitus, weak lower back and knees, profuse urination at night or inhibited urination, vomiting of untransformed food, weakness, lassitude of spirit, oedema. Tongue: pale enlarged tongue Pulse: fine (xi), sunken (chen). Add to basic treatment: Taixi KID-3 or Sanyinjiao SP-6.

Differentiation according to clinical symptoms and signs

  • Vomiting and nausea with dryness in the throat and mouth: signs include dryness in the mouth and throat, mouth sores, dry retching, thirst. Tongue: red, no coating or peeling tongue coating, cracked tongue. Pulse: rapid (shu), vacuous (xu), fine (xi). Add to basic treatment: Zhaohai KID-6.
  • Vomiting and nausea with bitter taste: signs include bitter taste in the mouth or bitter vomiting, irritability, gurgling sounds in the stomach. Tongue: red or purple tongue, yellow slimy tongue coating, or no tongue coating. Add to basic treatment: Yanglingquan GB-34.
  • Nausea and vomiting of untransformed food: signs include vomiting of untransformed food, sense of relief after vomiting, lack of desire to eat or drink, fatigue, fullness after eating. Tongue: pale, soft enlarged tongue, with thin tongue coating. Pulse: forceless (mai huo da wu li), moderate (huan), fine (xi). Add to basic treatment: Dadu SP-2 or Sanyinjiao SP-6.
  • Nausea and vomiting with acid taste: signs include belching, acid foul taste in the mouth, bloating, reduced desire to eat. Add to basic treatment: Taichong LIV-3 and Hegu L.I.-4 and/or Tianshu ST-25.
  • Vomiting of clear fluid without acid taste: signs include cold extremities, vomiting on exposure to cold or long after eating, blue-green complexion. Tongue: pale, sometimes enlarged, moist. Pulse: sunken (chen), fine (xi) pulse or sometimes string-like (xian), slow (chi). Add to basic treatment: Dadu SP-2 and or Taixi KID-3 and or Sanyinjiao SP-6.
  • Nausea and vomiting with pain in the throat
    Any of the above types of nausea and vomiting with pain in the throat and neck. Add to basic treatment: Hegu L.I.-4 and Binao L.I.-14.

Herbs for chemotherapy-induced nausea and vomiting
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Scientifically proven antiemetic herbs13-14
Ban Xia (Rhizoma Pinelliae Ternatae), Di Yu (Radix Sanguisorbae Officinalis), Lian Qiao (Fructus Forsythiae Suspensae), Sheng Jiang (Rhizoma Zingiberis Officinalis Recens), Wu Zhu Yu (Fructus Evodiae Rutaecarpae).

Additional herbs commonly used as antiemetics
Huang Lian (Rhizoma Coptidis), Shi Di (Calyx Kaki Diospyri), Zhu Ru (Caulis Bambusae in Taeniis), Ding Xiang (Flos Caryophylli), Xuan Fu Hua (Flos Inulae), Chen Xiang (Lignum Aquilaria), Zhu Ling (Sclerotium Polypori Umbellati), Dao Dou Zi (Semen Canavaliae), Gao Liang Jiang (Rhizoma Alpiniae Officinari), Rou Dou Kou (Semen Myristicae Fragranticis), Sha Ren (Fructus seu Semen Amomi), Hong Dou Kou (Fructus Galangal).

Antiemetic formulas used in chemotherapy
Jia Wei Ban Xia Xing Tang
Ban Xia (Rhizoma Pinelliae Ternatae) 4 9, Zhu Ru (Caulis Bambusae in Taeniis) 4 9, Chen Pi (Pericarpium Citri Reticulatae) 4 9, Fu Ling (Sclerotium Poriae Cocos) 4 9, Sheng Jiang (Rhizoma Zingiberis Officinalis Recens) 4, Dang Shen (Radix Codonopsis Pilosulae) 12, Bei Sha Shen (Radix Glehniae Littoralis) 4 9, Bai Zhu (Rhizoma Atractylodis Macrocephalae) 4 9, Gan Cao (Radix Glycyrrhizae Uralensis). 3
Wen Wei Zhi Ou Tang
Ban Xia (Rhizoma Pinelliae Ternatae) 4 9, Huo Xiang (Herba Agastaches seu Pogostemi) 4 9, Ding Xiang (Flos Caryophylli) 4 6, Shi Di (Calyx Kaki Diospyri) 4 6, Chen Pi (Pericarpium Citri Reticulatae) 4 9, Sheng Jiang (Rhizoma Zingiberis Officinalis Recens) 4, Gan Cao (Radix Glycyrrhizae Uralensis) 3, Da Zao (Fructus Zizyphi Jujubae) 4 6, Dang Shen (Radix Codonopsis Pilosulae) 10.
Liu Wei Tong Guan Tang
Xuan Fu Hua (Flos Inulae) 4 9, Dai Zhe Shi (Haematitum) 12, Fu Ling (Sclerotium Poriae Cocos) 12, Dang Shen (Radix Codonopsis Pilosulae) 15, Bai Zhu (Rhizoma Atractylodis Macrocephalae) 10, Gan Cao (Radix Glycyrrhizae Uralensis) 3, Ban Xia (Rhizoma Pinelliae Ternatae) 4 9, Chen Pi (Pericarpium Citri Reticulatae) 4 9, San Qi (Radix Pseudoginseng) (ground and taken separately) 1.5, Bei Sha Shen (Radix Glehniae Littoralis) 4 9, Ma Bin Lang (Semen Capparis) 4 6, Bai Hua She She Cao (Herba Oldenlandiae Diffusae) 24, Shu Yang Quan (Herba Solani Lyrati) 24, Wu Zhu Yu (Fructus Evodiae Rutaecarpae). 4 8

Acupuncture effects on haematologic, immunologic and hormonal function
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Decreased white blood cell (WBC) count due to chemotherapy induced myelosuppression is commonly seen in cancer patients. Studies have suggested an effect of acupuncture in the maintenance and restoration of WBC counts28-30. In a study of 48 patients with chronic leukopenia, acupuncture stimulation to Zusanli ST-36 led to an increased WBC count in over 90% of patients28. Markers of immune function, including IgG, IgA, IgM, C3 complement levels and lymphocyte reactivity to phytohemaglutinin (PHA) were alsoelevated when compared to pretreatment levels. The influence of acupuncture on specific immune function has been examined in a number of studies. A second study of 121 patients with leukopenia who were undergoing chemotherapy showed a significant increase in WBC counts following 5 days of daily acupuncture and moxibustion treatment30.

In a review article, Wu et.al. summarise the immune modulatory effects of acupuncture among patients undergoing chemotherapy and radiation. These include an increase in peripheral blood counts of CD3 +, CD4 + and NK cells as well as an increase in the CD4 +/ CD8 + ratio and a decrease in secreted IL-2 receptor. In addition, macrophage activity can be elevated by both acupuncture and moxibustion31. The immune and hormonal levels of premenopausal women with benign mammary hyperplasia were compared to normal women. After acupuncture, levels of CD8 + cells rose significantly, CD4 +/ CD8 + ratio was reduced to match that of normal patients, Serum E2 and Prolactin levels were lowered and levels of FSH were increased. Over 50% of the patients had complete resolution of their nodules, while the other patients had very significant reduction. All patients responded to the acupuncture treatment and had a measurable change in immune function and endocrine effect32.

Climacteric symptoms are prevalent among female cancer patients as a result of early menopause due to chemotherapy, stopping hormone replacement therapy or treatment with hormonal agents like tamoxifen. Symptoms and conditions like hot flushes, night sweats, insomnia, dry skin and vaginal dryness as well as an increase in bone mineral density loss and coronary artery disease risk, are thought to be related to waning oestrogen levels. Acupuncture has been shown in several studies to help control climacteric symptoms in over 90% of subjects.33-35 The effectiveness of acupuncture appears to be lower if the duration of symptoms has been longer.

Traditional Chinese herbal therapy aimed at enhancing immune function
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Patients with cancer often demonstrate depression of immune function that usually worsens as the disease progresses. This is manifested as impaired humoral and cell-mediated responsiveness as well as decreased nonspecific defense mechanisms (e.g. natural killer, or NK cells).36 In advanced stages of breast cancer, defects in skin test responses, NK cell activity, T-cell proliferative responses to mitogens or antigens and monocyte function, along with decreases in IgG production, T-cell counts and CD4/CD8 ratios, have been noted. These immunological defects become more pronounced with progression of disease and are compounded by chemotherapy and radiotherapy. Adjuvant chemotherapy for early stage breast cancer leads to a transient drop in phytohemaglutinin (PHA) response in peripheral blood lymphocytes (PBL) at 6 months with recovery by 12 months, and in one study, a correlation between lower immune function and subsequent risk of recurrence was seen.37 However, the effect of modulating the immune system in early stage breast cancer remains unclear. An overview of trials of nonspecific immune stimulation with agents such as Bacillus Calmette-Guerin (BCG) for early stage breast cancer did not show evidence of improved outcome.38 Whether or not newer techniques of tumour specific immunostimulation such as using tumour specific antigens as immunogens, manipulating cytokines and modulating co-stimulatory pathways can be effective in advanced or early stage breast cancer is being tested in preclinical and early clinical studies. One of the intended outcomes of Chinese herbal therapy is modulation of the immune system. In one study, patients with stage III and IV stomach cancer receiving FAP (5-fluorouracil, epirubicin and cisplatin) or FMP (5-fluorouracil, mitomycin C, and cisplatin) were randomly assigned to intravenous Ren Shen (Radix Ginseng) and Mai Men Dong (Tuber Ophiopogonis Japonici) herb extract or placebo, and a significant increase in the CD4/ CD8 ratio and level of Th1 cells was seen in the treatment group along with an increase in the overall T-cell count, compared to a drop in all these indices in the control group. 39 Several herbs have been shown to have different effects on immune effector cells and cytokine levels in laboratory, animal and human studies as shown in the table, below. However, information on the influence of these therapies on recurrence and mortality in early stage breast cancer remains scant.

Herbal agent Immune modulatory effects reported*
Huang Qi (Radix Astragali) Increased CD4/CD8 ratio and phagocytic activity in patients with gastric cancer undergoing chemotherapy. Stimulation of lymphocyte IL-2, IL-3, IL-6, TNFa and IFN-g
Dan Shen (Radix Salviae Miltiorrhizae) Increased T lymphocyte production and function
Bai Zhu (Rhizoma Atractylodis Macrocephalae) Increased phagocytosis, lymphocyte transformation, rosette formation, and serum IgG post chemotherapy
Fu Ling (Sclerotium Poriae Cocos) Increased monocyte GM-CSF production Enhanced recovery of myelosuppression in mice after radiation. Increased spontaneous rosette formation, lymphocyte transformation, and serum IgG
Gou Qi Zi (Fructus Lycii Chinensis) Enhanced hematopoiesis, ameliorates lowering of number and function of Tlymphocytes, CTL, and NK cells in mice after cyclosphosphamide
Tian Men Dong (Tuber Asparagi Cochinchinensis) Enhanced humoral and cellular immunity Wu Zhu Yu (Fructus Evodiae Rutaecarpae) Increased production of IL-1b, IL- 6, TNFa and GM-CSF in mononuclear cells in vitro
Xi Yang Shen (Radix Panacis Quinquefolii) Increased TNF production, reversal of suppression of cytokine production in mice after cyclophosphamide. Increased IL-2 and IFN-g by murine splenic lymphocytes both in vitro and in vivo and IL-2 and IFN-g production in mice after cyclophosphamide
Shu Di Huang (Radix Rehmanniae Glutinosae Conquitae) Increased DNA and protein synthesis in lymphocytes, IL-2 production, T- lymphocyte proliferation, and NK and CTL activity in murine splenocytes. Reduced immunosupression effect in mice caused by cyclosphosphamide and steroids
Nu Zhen Zi (Fructus Ligustri Lucidi) Lessened leukopenia due to chemotherapy or radiation
Liu Zhi (Radix Salix) Improved regenerative capacity of bone marrow after chemotherapy
* In some cases, other herbs included in combination therapy25-26

Traditional Chinese herbs for hematopoeisis during chemotherapy
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Traditional Chinese medicine practitioners apply Fu Zheng, or supportive therapy, to benefit patients during chemotherapy. As we stated above, one aim is to restore hematopoeitic function to improve peripheral blood counts. A herbal formula used to improve leukopenia is Shi Quan Da Bu Tang (All-Inclusive Great Tonifying Decoction) which is an ancient formula first introduced during the latter Han Dynasty (25-220 C.E.). Shen et al. studied the effects of this formula on improving white blood counts in 134 patients with cancer who had previously undergone chemotherapy and radiation therapy that resulted in leukopenia. Following treatment, 113 of the 134 patients had an increase in WBC levels to normal40. In a study of 58 patients with osteogenic sarcoma undergoing chemotherapy with either cisplatin and dexamethasone (CD) or high dose methotraxate and vincristine (MV), patients receiving standard palliative care were randomly assigned to a herbal regimen or observation. In the herbal therapy arm, improvements in WBC and platelet counts were seen in the MV group and there was less transaminase enzyme elevation in the MV group. Patients in the herbal therapy arm in both chemotherapy groups also showed improvement in post therapy cardiac function (as measured by ECG reading), less nausea and vomiting and fewer skin rashes41.

Herbs from the berberidaceae family can increase white blood cells. E Zhu (Rhizoma Curcumae Zedoariae) and Rou Gui (Cortex Cinnamomi Cassiae) have been shown in humans and in animals to offset the bone marrow suppressive effect of chemotherapy.

Several herbs have been shown to have bone marrow stimulatory (hematopoietic) effects, including Gou Qi Zi (Fructus Lycii Chinensis), Nu Zhen Zi (Fructus Ligustri Lucidi) and Ren Shen (Radix Ginseng). The herbs Ji Xue Teng (Radix et Caulis Jixueteng) and Dang Gui (Radix Angelicae Sinensis) can also treat anaemia by increasing red blood cells13-14.

Peripheral neuropathy in TCM
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The induction of peripheral neuropathy is a common factor in limiting therapy with chemotherapeutic drugs. Little is known about the mechanisms responsible for the development of neuropathy. Depending on the substance used, a pure sensory and painful neuropathy (with cisplatin, oxaliplatin, carboplatin) or a mixed sensorimotor neuropathy with or without involvement of the autonomic nervous system (with vincristine, taxol, suramin) can ensue. Neurotoxicity depends on the total cumulative dose and the type of drug used. In individual cases neuropathy can evolve even after a single drug application. A general predisposition for developing a chemotherapy-induced neuropathy has been observed in nerves previously damaged by diabetes mellitus, alcohol or inherited neuropathy. The recovery from symptoms is often incomplete and a long period of regeneration is required to restore function. Up to now, no drug is available to reliably prevent or cure chemotherapy-induced neuropathy42.

In traditional Chinese medicine peripheral neuropathy was usually classified as wilting-impediment syndrome (wei bi). As in modern medicine, it implies a vast array of disorders of the nerves and muscles. The manifestations are many and it is difficult to diagnose and treat accurately. In Chinese medicine nerves were not described in the literature until Chinese medicine was exposed to Western medicine influences. Wilting-impediment syndrome was mainly associated with the affect of various aetiologies on the channels (meridians). It was classified and described from as early as the first major medical classic, the Yellow Emperors Classic of Medicine (Neijing).

Studies have reported that acupuncture can be safe and effective in improving pain and the clinical course of herpes zoster, a side effect encountered by patients undergoing chemotherapy. 43 Acupuncture has also shown a positive effect on the regeneration of nerve tissue as evidenced by improved nerve conduction in patients suffering from peripheral neuropathy44-46, 47-48. The potential to improve upon peripheral neuropathy symptoms encountered by the use of adjuvant paclitaxel (Taxol) remains unstudied. The herbs Tian Ma (Rhizoma Gastrodiae Elatae) and Du Zhong (Cortex Eucommiae Ulmoidis) show a nerve-regenerating effect in animal models . 49

The following is a traditional classification and treatment of wilting-impediment syndrome that correspond to peripheral neuropathy induced by various chemotherapeutic agents:

Bone wilting (gu wei)
Symptoms: limp aching lumbar spine preventing normal movement, weak atrophying lower limbs preventing the patient from getting out of bed, weak teeth and a somber dark facial complexion.

Hu Qian Wan (Hidden Tiger Pill) Shu Di Huang (Radix Rehmanniae Glutinosae Conquitae), Gui Ban (Plastrum Testudinis), Huang Bai (Cortex Phellodendri), Zhi Mu (Radix Anemarrhenae Asphodeloidis), Long Gu (Os Draconis), Suo Yang (Herba Cynomorii Songarici), Huai Niu Xi (Radix Achyranthis Bidentatae), Dang Gui (Radix Angelicae Sinensis), Bai Shao (Radix Paeoniae Lactiflorae), Chen Pi (Pericarpium Citri Reticulatae), Gan Jiang (Rhizoma Zingiberis Officinalis), Yang Rou (Lamb Meat).

Jin Gang Wan (Metal Strength Pill) Sha Yuan Ji Li (Semen Astragali Complanati), Qian Shi (Semen Euryales Ferox), Lian Xu (Stamen Nelumbinis Nucifera), Su Zhi Long Gu (Crispy Fried Os Draconis), Duan Mu Li (Calcined Concha Ostreae), Lian Zi Rou (Semen Nelumbinis Nuciferae), Nu Zhen Zi (Fructus Ligustri Lucidi), Gui Ban (Plastrum Testudinis)

.
Flesh wilting (rou wei)
Symptoms: numbness of the muscles, in severe cases inability to move the limbs.

Zhi Lian Er Chen Tang (Gardenia and Coptis Two-Cured Decoction)Ban Xia (Rhizoma Pinelliae Ternatae), Chen Pi (Pericarpium Citri Reticulatae), Fu Ling (Sclerotium Poriae Cocos), Gan Cao (Radix Glycyrrhizae Uralensis), Zhi Zi (Fructus Gardeniae Jasminoidis), Huang Lian (Rhizoma Coptidis), Wu Mei (Fructus Pruni Mume).

Vessel wilting (mai wei)
Symptoms: the joints in the four limbs are as if they are broken, inability to lift the limbs, and weakness in the lower leg preventing the patient from standing.

Si Wu Tang (Four-Substance Decoction) Shu Di Huang (Radix Rehmanniae Glutinosae Conquitae), Dang Gui (Radix Angelicae Sinensis), Bai Shao (Radix Paeoniae Lactiflorae), Chuan Xiong (Radix Ligustici Wallichii).

Damp-heat wilting (shi re wei)
Symptoms: atrophy of the muscles of the limbs, slight swelling, and numbness of the lower limbs, generalised sense of heaviness, oppression in the chest, difficult dark urination.

Jia Wei Er Miao San (Supplemented Two-Marvel Powder) Huang Bai (Cortex Phellodendri), Cang Zhu (Rhizoma Atractylodis), Huai Niu Xi (Radix Achyranthis Bidentatae), Yi Yi Ren (Semen Coicis Lachryma-jobi), Huang Qin (Radix Scutellariae Baicalensis).

Damp phlegm wilting (shi tan wei)
Symptoms: Atrophy and weakness of the limbs, lower legs and knees, fatigue.

Er Cheng Tang Jia Jian (Modified Two-Cured Decoction) In addition to Er Cheng Tang: Cang Zhu (Rhizoma Atractylodis), Bai Zhu (Rhizoma Atractylodis Macrocephalae), Huang Qin (Radix Scutellariae Baicalensis), Huang Bai (Cortex Phellodendri), Zhu Li (Succus Bambusae), Jiang Zhi (Ginger juice).

Dryness-heat wilting (zao re wei)
Symptoms: limpness of the extremities, movement is difficult and stiff, dry skin and hair, dry mouth and parched lips.

Qing Zao Jiu Fei Tang (Eliminate Dryness and Rescue the Lungs Decoction) Sang Ye (Folium Mori Albae), Shi Gao (Gypsum), Mai Men Dong (Tuber Ophiopogonis Japonici), E Jiao (Gelatinum Asini), Hei Zhi Ma (Semen Sesami Indici), Ku Xing Ren (Semen Pruni Armeniacae), Mi Zhi Pi Pa Ye (Honey-fried Folium Eriobotryae Japonicae), Ren Shen (Radix Ginseng), Gan Cao (Radix Glycyrrhizae Uralensis).

Blood stasis wilting (xue yu wei)
Symptoms: atrophy, limpness, and pain in the limbs, difficult movement

Tao Hong Si Wu Tang (Four-Substance Decoction with Safflower and Peach Pit) Dang Gui (Radix Angelicae Sinensis), Shu Di Huang (Radix Rehmanniae Glutinosae Conquitae), Chuan Xiong (Radix Ligustici Wallichii), Bai Shao (Radix Paeoniae Lactiflorae), Hong Hua (Flos Carthami Tinctorii), Tao Ren (Semen Persicae)

.
Blood impediment (xue bi)
Symptoms: numbness and pain in the limbs.

Dang Gui Tang (Tangkuei Decoction) Dang Gui (Radix Angelicae Sinensis), Hou Po (Cortex Magnoliae Officinalis), Gan Cao (Radix Glycyrrhizae Uralensis), Ban Xia (Rhizoma Pinelliae Ternatae), Ren Shen (Radix Ginseng), Shan Jiao (Zanthoxyli Piperati). or Huang Qi Gui Zhi Wu Wu Tang (Astragalus and Cinnamon Twig Five-Substance Decoction) Huang Qi (Radix Astragali), Gui Zhi (Ramulus Cinnamomi Cassiae), Sheng Jiang (Rhizoma Zingiberis Officinalis Recens), Bai Shao (Radix Paeoniae Lactiflorae), Da Zao.

Blood vacuity impediment (xue xu bi)
Symptoms: numbness of the skin and inabillity to lift the limbs.

Dang Gui Jian Zhong Tang (Tangkuei Decoction to Construct the Middle) Dang Gui (Radix Angelicae Sinensis), Yi Tang (Saccharum Granorum), Gui Zhi (Ramulus Cinnamomi Cassiae), Bai Shao (Radix Paeoniae Lactiflorae), Zhi Gan Cao (Radix Glycyrrhizae Praeparatae), Sheng Jiang (Rhizoma Zingiberis Officinalis Recens), Da Zao (Fructus Zizyphi Jujubae).

Qi vacuity impediment (qi xu bi)
Symptoms: inhibited movement of the joints, cold body and numbness in the limbs.

Si Jun Zi Tang (Four-Gentlemen Decoction) plus Fu Zi (Radix Aconiti Carmichaeli Praeparatae) and Rou Gui (Cortex Cinnamomi Cassiae).

Flesh impediment (rou bi)
Symptoms: pain in the muscles that may be accompanied by sweating all over the body, limp atrophied muscles, numbness of the skin and clouded spirit.

Shen Xiao Huang Qi Tang (Wondrous Effect Astragalus Decoction) Huang Qi (Radix Astragali), Yi Tang (Saccharum Granorum), Gui Zhi (Ramulus Cinnamomi Cassiae), Bai Shao (Radix Paeoniae Lactiflorae), Zhi Gan Cao (Radix Glycyrrhizae Praeparatae), Sheng Jiang (Rhizoma Zingiberis Officinalis Recens), Da Zao (Fructus Zizyphi Jujubae), Jin Yin Hua (Flos Lonicerae Japonicae), Dang Gui (Radix Angelicae Sinensis).

Bone impediment (gu bi)
Symptoms: pain and swelling of the joints, heavy sensation of the bones, aching of the bones and bone marrow, difficulty in lifting the limbs.

Wu Bi Tang (Five Impediment Decoction) plus Long Gu (Os Draconis), Du Huo (Radix Angelicae Pubescentis) at least 30g, Rou Gui (Cortex Cinnamomi Cassiae), Niu Xi (Radix Achyranthis Bidentatae), Huang Qi (Radix Astragali) and Bei Xie (Rhizoma Dioscoreae): Qiang Huo (Rhizoma et Radix Notopterygii), Du Huo (Radix Angelicae Pubescentis), Gui Zhi (Ramulus Cinnamomi Cassiae), Qin Jiao (Radix Gentianae Macrophyllae), Hai Feng Teng (Caulis Piperis), Sang Zhi (Ramulus Mori Albae), Dang Gui (Radix Angelicae Sinensis), Chuan Xiong (Radix Ligustici Wallichii), Mu Xiang (Radix Saussureae seu Vladimirae), Ru Xiang (Gummi Olibanum), Gan Cao (Radix Glycyrrhizae Uralensis), Fang Feng (Radix Ledebouriellae Sesloidis), Wei Ling Xian (Radix Clemetidis Chinensis), Cang Zhu (Rhizoma Atractylodis).

Each of the above has a specific traditional aetiology, or underlying pattern, associated with it. Generally speaking the pattern is identified by determining whether it is internal or external in origin, yin or yang in nature, and whether it exhibits signs of repletion or vacuity and is characterised by wind, cold, damp or heat symptoms. The complexity of the pattern and the identification of the specific disorder create a variety of treatment principles. It is further complicated by the fact that each patient may report differences in their subjective symptoms and signs. That will create a mixture of the treatment principles that make the treatment quite individualised. In the case of iatrogenic peripheral neuropathy, caused by the use of paclitaxil (taxol) the definitions of external and internal are hard to clarify, and yin and yang can be mixed in their manifestations. Therefore, careful observation of the symptoms and signs is required.

Standard acupuncture point selection
Points from the standard point selection for peripheral neuropathy can be utilised at each treatment depending on the limbs and the side the neuropathy is experienced. Hegu L.I.-4, Waiguan SJ-5, Zusanli ST-36, Jiexi ST-41, Yanglingquan GB-34, Xuanzhong GB-39.
Indications for additional acupuncture point selection
Heat in the Lung: Chize LU-5
Damp heat: Pishu BL-20, Yinlingquan SP-9
Liver and Kidney essence vacuity: Ganshu BL-18, Shenshu BL-23
Vessel wilting impediment: Ganshu BL-18, Shenshu BL-23
Bone wilting impediment: Taixi KID-3
Flesh wilting impediment: Mingmen DU-4
Sinew wilting impediment: Taichong LIV-3
Shoulder and elbow involvement: Jianyu L.I.-15, Quchi L.I.-11
Hip involvement: Biguan ST-31, Huantiao GB-30

Addendum: The use of docetaxel (Taxotere) in early stage breast cancer
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Several clinical trials have explored the efficacy of docetaxel (Taxotere) as primary chemotherapy for breast cancer. Two large, randomised phase III trials have demonstrated significant improvements in clinical and pathologic response rates with the sequential addition of docetaxel to an anthracycline-containing preoperative regimen. A trial conducted in the United Kingdom demonstrated that docetaxel sequential to CVAP (cyclophosphamide [Cytoxan, Neosar], vincristine, doxorubicin [Adriamycin], prednisolone) produced a higher overall clinical response rate (94% vs 66%, P = .001) and pathologic complete response rate (34% vs 18%) compared to additional cycles of CVAP as primary chemotherapy. This translated into a survival advantage for docetaxel-treated patients, whose 3-year disease-free and overall survival were significantly improved (97% vs 84%; 90% vs 77%, P = .03). The results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-27 demonstrated that primary doxorubicin/cyclophosphamide followed by docetaxel significantly increased the clinical complete response (65% vs 40%, P < .001) and pathologic complete response rates (25.6% vs 13.7%, P < .001) and decreased the rate of positive axillary nodes (40.5% vs 48.5%, P = .01). Final analysis of NSABP B-27 may also potentially demonstrate improved disease-free and overall survivals. Additional phase II and phase III randomised trials have compared docetaxel/anthracycline combinations with standard anthracycline-based regimens. In the BCIRG 001 trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC 5- fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients, the interim analysis after 33 months of follow up TAC shows statistically significant improvements in disease free survival (DFS) (32% risk reduction) and overall survival (OS) in patients with 1-3 positive lymph nodes (54% risk reduction). Women on this trial suffered more febrile neutropenia (24% vs. 2%) and severe infections (2.8% vs. 1.3%) with TAC. Other significant side effects to TAC were severe asthenia (11%) and stomatitis (7%). Final analysis will be available in three years when 5 years of follow up will be concluded. Due to the fact that the interim analysis shows such promising benefit at this time many oncologists offer TAC to women with even earlier disease. Unfortunately jumping to such conclusions may prove ineffective especially in lieu of the excitement paclitaxel (taxol) created in its early adjuvant trials of the mid 1990's.50-52

Taxotere can cause severe bone marrow suppression in women with breast cancer (neutropenia 98.5%, leukopenia 98.6%, thrombocytopenia 9.2%, anemia 93.6% and febrile neutropenia 12.3%). It can also cause hypersensitivity reactions (any 17.6%, severe 2.6%) with flushing, localised skin irritations and acute fluid retention. Generally patients are premedicated with the corticosteroid dexamethazone (decadron) in order to prevent severe hypersensitivity events. Fluid retention occurs in 59.7% of women, neuropathy in 58.3%, skin irritations in 47%, stomatitis in 51.7%, hair loss in 74.2%, fatigue in 66.3% muscular pain in 21.1%, joint pain in 8.2%, nausea in 42%, vomiting in 23.4%, diarrhoea in 42.6%53. The caveat with diarrhea or abdominal pain with women undergoing taxotere chemotherapy is that they may develop severe colitis with possible bowel perforation. This symptom should be taken seriously if encountered.54

Various TCM treatments can help prevent and treat many of the above symptoms. The difficulty is addressing all the possible symptoms at once. From a TCM point of view taxotere seems to damage the jing and yin fluids, causing severe bone marrow suppression with deficient heat symptoms and possible acute separation of yin and yang causing hypersensitivity reaction, severe oedema, bowel perforation and septic death (1.4%).

The inclusion in the Formula during Taxotere chemotherapy of the heat clearing herbs Pu Gong Ying (Herba Taraxaci Mongolici cum Radice), Jin Yin Hua (Flos Lonicerae Japonicae) and Sheng Di Huang (Radix Rehmanniae Glutinosae), as well as the increased dose of He Shou Wu (Radix Polygoni Multiflori), is to address these possible dangers. In older women Bie Jia (Carapax Amydae Sinensis) and Bai Hua She She Cao (Herba Oldenlandiae Diffusae) can be considered as well. Bu Gu Zhi (Fructus Psoraleae Corylifoliae) is very significant in this formula since it can reduce hypersensitivity reactions as well as prevent neuropathy and myalgias.

Stomatitis
Symptom: heat, pain, increased flow of saliva, bad breath (rancid smell usually), restlessness, sometimes fever, loss of appetite.
Rinse mouth with Green tea (3 grams) + Jin Yin Hua (Flos Lonicerae Japonicae) (10 grams). Steep with boiling water for 3-5 minutes. An alternative to this rinse is Xuan Shen (Radix Scrophulariae Ningpoensis) (10 grams) prepared and administered in the same way.
Skin Rashes
Add to the main formula:
Sheng Di Huang (Radix Rehmanniae Glutinosae) increase to 30- 60 grams
Shan Zhu Yu (Fructus Corni Officinalis)
Mu Dan Pi (Cortex Moutan Radicis)
Rou Cong Rong (Herba Cistanches) Although messy an external wash can be prepared with:
Ku Shen (Radix Sophorae Flavescentis) 30 grams
Huang Bai (Cortex Phellodendri) 30
Bai Xian Pi (Cortex Dictamni Dasycarpi Radicis) 15
Boil with 4 cups of water for 60 minutes and apply to affected areas with a wet gauze for 60 minutes.

Conclusion
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From the limited scientific research and empirical evidence, TCM therapies hold the potential to play an important role in ameliorating the many toxic side effects of chemotherapy and radiation for early stage breast cancer as well as in improving long term outcome. Very sparse and conflicting data currently exists on the mechanisms and clinical benefits of these therapies. Moreover, the practice of TCM modalities is highly individualised rather than standardised. The current literature reflects the heterogeneity of the therapies studied, and conclusions are usually limited by inadequately described outcome measures and statistical methods. Nevertheless, these approaches enjoy tremendous interest and use worldwide given their historical and natural appeal. The lay press, media, and even many books and articles aimed at women with breast cancer provide extensive coverage of these modalities and even recommendations for their use, yet there has been very little dissemination of scientific critiques of these therapies. This may be due to a commonly held belief that TCM modalities are not amenable to the same types of analytical studies inthe laboratory and clinic that are reserved for biomedical innovations. Though the practice of TCM has been modified over time, some empirically derived observations may be clinically useful, even if the physiologic basis remains unclear. We hypothesise that certain traditional Chinese medical disease categories may in fact relate to modern molecular and cellular biology classifications. Just as necessary vitamins and cofactors are derived from plants, so possibly are substances that may be useful in certain disease states. Furthermore, it is plausible that in some cases, the biological effects of herbs in higher organisms require several components whose presence in the plant may have evolved over time. There are examples of biological activity of herbal extracts that cannot be replicated with any single pure compound isolated and purified from the extract. On the other hand, many modern drugs originated from single plant-derived molecules.

In order to validate the usefulness of TCM for women with breast cancer, there is a need for safety and feasibility studies followed by controlled studies with well defined and clinically relevant endpoints and with adequate statistical power. Given its purported activities in symptom control, immunological effects and anti-tumour activity, TCM is an attractive modality to study in the adjuvant setting. Several difficulties remain in conducting such trials, however. A method for prioritising agents for study needs further refinement given the discordance in the literature and the numerous herbs used. In some cases, it may be difficult to separately evaluate modalities that are commonly used together - for example, herbal agents and acupuncture. Assessing safety may be difficult in patients receiving chemotherapy or in those with other co-morbid problems. Innovations in trial design such as cross-over schemes or 2:1 randomisations may improve accrual. Interpreting data from pilot trials is difficult because of weaker conclusions from multiple datapoint and other exploratory analyses. The ultimate demonstration of benefit will require large randomised studies, and so far, few funding mechanisms exist for such large-scale trials.

About the Authors

Reprinted by permission from
Journal of Chinese Medicine Number 2002.
(Part Three) Traditional Chinese Medicine in the Treatment of Breast Cancer
www.jcm.co.uk


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